He conveys the constitutively human trifecta of responsibility, impotence, and blindness.
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Paradoxically, even in its refusal to be replaced, the "we" depends rhetorically and constitutively upon both an opposition to "you" and an address to "you" in order to assert itself.
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Importantly, if the AR lacks an LBD, the receptor will be nuclear and constitutively-active. Constitutively active splice variants of the AR that lack the C-terminal LBD are correlated to CRPC and poor survival. EPI-001 is an inhibitor of constitutively active splice variant of ARs that lack the C-terminal LBD. Conventional antiandrogens do not inhibit constitutively-active variants of AR that have a truncated or deleted C-terminal LBD.
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SCIMP is constitutively associated with Lyn kinase via SH3 domain.
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It is constitutively expressed on mast cells and basophils and is inducible in eosinophils.
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These mutations allow the pathway to be constitutively activated, regardless of the presence of mitogens.
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In many early developmental experiments using zebrafish, scientists used caBMPR (constitutively active) and tBMP (truncated receptor) to determine the effect of BMP7 in embryogensis. They found that the constitutively active, which causes BMP to be expressed everywhere creates a ventralized phenotype, whereas truncated, dorsalized.
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However, they are constitutively expressed on some tumour cells and they can be upregulated by retinoic acid.
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Other names in common use include methylglyoxal synthetase, and glycerone-phosphate phospho-lyase. This enzyme participates in pyruvate metabolism and is constitutively expressed.
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Mutant forms of the Kit receptor, which fire constitutively in a ligand-independent fashion, are found in a diverse array of cancerous malignancies.
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Moreover, while PCK1 expression is regulated by hormones or nutrients involved in gluconeogenesis, PCK2 is constitutively expressed. These differences indicate that PCK2 may also perform non-gluconeogenic functions.
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This shows that a single type of ion can be transported by several enzymes, which need not be active all the time (constitutively), but may exist to meet specific, intermittent needs.
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Trehalase is a monomeric glycoprotein with 20% carbohydrate content. It is optimally active at 50 °C. It is produced constitutively in T. lanuginosus, but is strongly bound to the hyphal wall.
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Antagomirs are used as a method to constitutively inhibit the activity of specific miRNAs. For example, antagomirs against miR-21 have been successfully used to inhibit fibrosis of heart and lung.
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With no GAPs to curb the G protein's activity, this results in constitutively active G proteins, unregulated cell growth, and the cancerous state. In the case of the latter, a loss of the G protein's ability to respond to GAP, the G proteins have lost their ability to hydrolyze GTP. With a nonfunctional G protein enzyme, GAPs cannot activate the GTPase activity, and the G protein is constitutively on. This also results in unregulated cell growth and cancer.
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G proteins without hydrolytic activity cannot hydrolyze bound GTP. GAPs cannot activate a nonfunctional enzyme, and the G protein is constitutively active, resulting in unregulated cell division and the formation of tumors.
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At the same time, materially, the 'practice of statehood is now constitutively and materially more abstract than at the time when princes ruled as the embodiment of extended power'., pp. 318–19.
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VWF is a large multimeric glycoprotein present in blood plasma and produced constitutively as ultra-large VWF in endothelium (in the Weibel–Palade bodies), megakaryocytes (α-granules of platelets), and subendothelial connective tissue.
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Little is understood about the function of these "class IV" nif genes, though they occur in many methanogens. In M. jannaschii they are known to interact with each other and are constitutively expressed.
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In isolation, the VCA region is constitutively active. However, in full-length N-WASp the control region suppresses VCA domain activity. The control region is located at N-terminal end of N-WASp.
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Although in most cancer, mTOR pathway is constitutively activated and the expression of DEPTOR is low, one study has found that DEPTOR is overexpressed in multiple myeloma cells and is necessary for their survival.
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Constitutively spliced exons have many different SR protein binding sequences that act as constitutive splicing enhancers. The difference between alternative and constitutive splicing is that during alternative splicing the splice site choice is regulated.
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Macrophages that constitutively express MARCO are within the spleen marginal zone and medullary lymph nodes. Certain interactions between the macrophage and bacteria up-regulate its expression, as well as stimulating the expression of MARCO on tissue macrophages.
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The developed tyrosine kinase inhibitor, imatinib mesylate, has had a tremendous effect on stopping cancer progression in the majority of chronic myeloid leukemia patients. BCR-Abl is constitutively active due chromosome translocation; therefore it over-phosphorylates the tyrosine kinase.
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The Escherichia coli DcuA and DcuB proteins have very different expression patterns. DcuA is constitutively expressed; DcuB is strongly induced anaerobically by FNR and C4-dicarboxylates, while it is repressed by nitrate and subject to CRP-mediated catabolite repression.
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In yeast, the Lon protease PIM1 is located in the mitochondrial matrix. It is required for mitochondrial function, it is constitutively expressed but is increased after thermal stress, suggesting that PIM1 may play a role in the heat shock response.
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Since constitutively active B-Raf mutants commonly cause cancer (see Clinical Significance) by excessively signaling cells to grow, inhibitors of B-Raf have been developed for both the inactive and active conformations of the kinase domain as cancer therapeutic candidates.
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It is also innervated and vascular. Juvenile and adult swimbladders exhibit key differences. Juveniles tend to have thicker and "gelatinous" walls with more spherical cells. Adults on the other hand have a less gelatinous appearance and a constitutively open lumen.
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ET-2 is believed to act on the follicle by binding to and stimulating EDNRA, which is expressed constitutively on the external layer of theca cells (another type of steroid-producing stromal cell). This causes smooth muscle cells surrounding the ovary to contract. This smooth muscle layer encapsulates the ovary but is absent at the site where the oocyte is expelled, creating a region of low surface tension which weakens the follicle wall and promotes the release of an egg. ET-2 also binds to and activates EDNRB, which is constitutively expressed by granulosa cells and theca interna.
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IstR sRNA (inhibitor of SOS-induced toxicity by RNA) is a family of non-coding RNA first identified in Escherichia coli. There are two small RNAs encoded by the IstR locus: IstR-1 and IstR-2, of which IstR-1 works as antitoxins against the toxic protein TisB (toxicity-induced by SOS B) which is encoded by the neighbouring tisAB gene. IstR-1 is a 75 nucleotide transcript expressed constitutively throughout growth, whereas IstR-2 is a 140 nucleotide transcript induced by Mitomycin C (MMC). Both IstR-2 and tisAB are thought to be regulated by LexA while IstR-1 is constitutively transcribed.
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GPR6 is a member of the G protein- coupled receptor family of transmembrane receptors. It has been reported that GPR6 is both constitutively active but in addition is further activated by sphingosine-1-phosphate. GPR6 up-regulates cyclic AMP levels and promotes neurite outgrowth.
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Lefty acts by preventing the phosphorylation of R-SMADs. It does so through a constitutively active TGFβ type I receptor and through a process downstream of its activation. Drug-based antagonists have also been identified, such as SB431542, which selectively inhibits ALK4, ALK5, and ALK7.
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Constitutively synthesized transcription factors for EPO, known as hypoxia-inducible factors, are hydroxylated and proteosomally digested in the presence of oxygen and iron. During normoxia GATA2 inhibits the promoter region for EPO. GATA2 levels decrease during hypoxia and allow the promotion of EPO production.
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Crenolanib inhibits both wild type FLT3 and its constitutively active mutations. In vitro studies have shown that crenolanib has low Kd for the FLT3 enzyme with constitutively activating internal tandem duplication (ITD) mutations and tyrosine kinase domain (TKD) mutations, D835H and D835Y, as compared to wild type. Crenolanib tightly binds to FLT3-ITD, FLT3-D835H and FLT3-D835Y with Kd of 0.74 nM, 0.4 nM, and 0.18 nM, respectively. Crenolanib inhibits the phosphorylation of the FLT3-ITD receptor in transfected TF-1 cells and the FLT3-D835Y TKD mutation in transfected Ba/F3 cells at nanomolar IC50 concentrations of 1.3 nM and 8.8 nM, respectively.
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Conversely, SMO can become constitutively localized to the primary cilium and potentially activate pathway signaling constitutively as a result of a tryptophan to leucine mutation in the aforementioned domain. SMO has been shown to move during patched stimulation from the plasma membrane near the primary cilium to the ciliary membrane itself via a lateral transport pathway along the membrane, as opposed to via directed transport by vesicles. The cAMP-PKA pathway is known to promote the lateral movement of SMO and hedgehog signal transduction in general. In invertebrates like Drosophila, SMO does not organize at cilia and instead is generally translocated to the plasma membrane following hedgehog binding to patched.
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Absent protein in previous studies may be due to the high amplitude circadian rhythm of expression of this isoform in some tissues. The mRNA is expressed in various peripheral tissues, either in a circadian fashion (e.g., in the liver and kidney) or constitutively (e.g., in the muscle).
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Serum amyloid A (SAA) proteins are a family of apolipoproteins associated with high-density lipoprotein (HDL) in plasma. Different isoforms of SAA are expressed constitutively (constitutive SAAs) at different levels or in response to inflammatory stimuli (acute phase SAAs). These proteins are produced predominantly by the liver.
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A fourth SAA (SAA4) was identified in humans and is expressed constitutively in the liver and, thus, is defined as a constitutive SAA (C-SAA). A similar protein that is now also called SAA4 has since been identified in the mouse; it had originally been designated SAA5.
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Paralogs are often regulated differently, e.g. by having different tissue-specific expression patterns (see Hox genes). However, they can also be regulated differently on the protein level. For instance, Bacillus subtilis encodes two paralogues of glutamate dehydrogenase: GudB is constitutively transcribed whereas RocG is tightly regulated.
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Mice genetically engineered to express a constitutively (i.e. continuously) activated PDGFRα mutant receptor eventually develop fibrosis in the skin and multiple internal organs. The studies suggest that PDGFRA plays fundamental roles in the development and function of mesodermal tissues, e.g., blood cells, connective tissue, and mesangial cells.
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Originally, IL-18 production was recognized in Kupffer cells, liver-resident macrophages. However, IL-18 is constitutively expressed in non-hematopoietic cells, such as intestinal epithelial cells, keratinocytes, and endothelial cells. IL-18 can modulate both innate and adaptive immunity and its dysregulation can cause autoimmune or inflammatory diseases.
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Similarly, MTOR, a gene encoding a cell regulatory kinase, has shown to be constitutively active, thereby increasing S6 phosphorylation. This active phosphorylation may serve as a biomarker in clear-cell carcinoma. Mechanochemical heterogeneity is a hallmark of living eukaryotic cells. It has an impact on epigenetic gene regulation.
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Collagen XVII is constitutively shed from the keratinocyte surface within NC16A domain by TACE (TNF-Alpha Converting Enzyme), metalloproteinase of the ADAM family. The shedding is lipid raft dependent. Collagen XVII is extracellularly phosphorylated by ecto- casein kinase 2 within the NC16A domain, phosphorylation negatively regulates ectodomain shedding.
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Proceedings of the National Academy of Sciences of the United States of America. 104 (2007): 12353-12358. Regulation of G proteins is lost because the regulator is absent, resulting in cancer. Without GAP, G proteins are constitutively on because of their slow hydrolytic activity and GEFs constantly replacing GDP with GTP.
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GAP works to activate a nonfunctional hydrolytic enzyme. T24 bladder cancer cells, for example, were shown to have a missense mutation, G12V, resulting in constitutively active Ras protein.Premkumar Reddy, E. et al. "A Point Mutation is Responsible for the Acquisition of Transforming Properties by the T24 Human Bladder Carcinoma Oncogene". Nature.
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This yeast-specific process acts constitutively under nutrient-rich conditions and selectively transports hydrolases such as aminopeptidase I to the yeast vacuole. The Cvt pathway also requires Atg8 localised to the PAS for the formation of Cvt vesicles which then fuse with the vacuole to deliver hydrolases necessary for degradation.
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The product encoded by this gene belongs to the heat shock protein 70 family which contains both heat-inducible and constitutively expressed members. The latter are called heat-shock cognate proteins. This gene encodes a heat-shock cognate protein. This protein plays a role in the control of cell proliferation.
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HRPAP20 was found to be significantly elevated in patient breast tumors as compared to normal tissue. Further analysis using tumor cell lines with constitutively expressed HRPAP20 suggests that it increases the invasiveness, proliferation, and apoptotic suppression of breast cancer cells. This is often indicative of tumor metastasis and malignant progression.
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The CD86 expression on antigen-presenting cells is constitutive (expression is independent of environmental factors). CD28 is the only B7 receptor constitutively expressed on naive T cells. Association of the TCR of a naive T cell with MHC:antigen complex without CD28:B7 interaction results in a T cell that is anergic.
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It is spectators' enjoyment of sports and the associated rivalries that drive media sport consumption. Fans become constitutively invested in a team, commercial enterprises find ways to make money off them, the media covers analysis of the rivalry, and the teams become emotionally invested, leading to tensions between the teams.
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However, given Rac1's role in glucose transport, drugs that inhibits Rac1 could potentially be harmful to glucose homeostasis. Dominant negative or constitutively active germline RAC1 mutations cause diverse phenotypes that have been grouped together as Mental Retardation Type 48. Most mutations cause microcephaly while some specific changes appear to result in macrocephaly.
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The heat shock protein 70 (Hsp70) family contains both heat-inducible and constitutively expressed members. The latter are called heat-shock cognate (Hsc) proteins. The heat shock 70 kDa protein 8 also known as Hsc70 belongs to the heat-shock cognate subgroup. This protein binds to nascent polypeptides to facilitate correct protein folding.
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CCL1 is a small glycoprotein with a molecular weight of approximately 15-16 kDa. CCL1 is secreted by activated monocytes/macrophages, T lymphocytes and endothelial cells. CLL1 binds to the chemokine receptor CCR8 and induces Ca2+ influx, chemotaxis and regulate apoptosis. CCR8 is constitutively expressed in monocytes/macrophages, Th2, and regulatory T lymphocytes.
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Unlike typical chromosomes, they are composed of circular fragments of DNA, up to only a few million base pairs in size and contain no centromere or telomere. Further to this, they often lack key regulatory elements, allowing genes to be constitutively expressed. Recently, some research groups are re-branding double minutes as ecDNA.
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Among these differences is the absence of docking sites for calcineurin, which is necessary for NFATc nuclear import. Instead, NFAT5 is a constitutively nuclear protein whose activity and localization does not depend on calcineurin-mediated dephosphorylation. Increased NFAT5 transcription is correlated with p38 MAPK-mediated phosphorylation. Pathway of NFAT5-Mediated Osmotic Response Activation.
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The protein encoded by this gene is constitutively tyrosine phosphorylated in hematopoietic progenitors isolated from chronic myelogenous leukemia (CML) patients in the chronic phase. It may be a critical substrate for p210(bcr/abl), a chimeric protein whose presence is associated with CML. This encoded protein binds p120 (RasGAP) from CML cells.
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Mutations in this gene have been associated with primary pulmonary hypertension. In the chick embryo, it has been shown that BMPR1B is found in precartilaginous condensations. BMPR1B is the major transducer of signals in these condensations as demonstrated in experiments using constitutively active BMPR1B receptors. BMPR1B is a more effective transducer of GDF5 than BMPR1A.
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Fukazawa, H., et al., Mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) inhibitors restore anoikis sensitivity in human breast cancer cell lines with a constitutively activated extracellular-regulated kinase (ERK) pathway. Mol. Cancer Ther., 303-309, (2002) Loss of contact with substratum triggers apoptosis in many normal cell types, a phenomenon termed anoikis.
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In another example, a mutated constitutively (persistently) expressed version of the oncogene c-Myc is found in many cancers. Among many functions, c-Myc negatively regulates microRNAs miR-150 and miR-22. These microRNAs normally repress expression of two genes essential for MMEJ, Lig3 and Parp1, thereby inhibiting this inaccurate, mutagenic DNA repair pathway.
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The cytosolic HSR is mainly mediated by the transcription factor family HSF (heat shock family). HSF is constitutively bound by Hsp90. Upon a proteotoxic stimulus Hsp90 is recruited away from HSF which can then bind to heat response elements in the DNA and upregulate gene expression of proteins involved in the maintenance of proteostasis.
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Reciprocally, around 60-70% of human genes have a CpG island in their promoter region. The majority of CpG islands are constitutively unmethylated and enriched for permissive chromatin modification such as H3K4 methylation. In somatic tissues, only 10% of CpG islands are methylated, the majority of them being located in intergenic and intragenic regions.
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This form of TAZ always resides in the nucleus and therefore is constitutively active. It binds and turns on a very important member of the TEAD family of transcription factors and this causes cells to proliferate. It is this production of the TAZ-TEAD transcriptome that causes the affected endothelial cells to grow into tumors.
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The majority of PtdIns3P appears to be constitutively synthesised by the class III PI 3-kinase, PIK3C3 (Vps34), at endocytic membranes. Class II PI 3-kinases also appear to synthesise PtdIns3P, their activity however appears to be regulated by a range of stimuli, including growth factors. This suggests that specific pools of PtdIns3P may be synthesised upon cell stimulation.
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Activating transcription factor 3 (Atf3) is a known RAG with numerous promoters. Atf3 expression increases after nerve injury and overexpression of a constitutively active form of Atf3 increases the rate of peripheral nerve regeneration. Four Atf3 isoforms were identified in dorsal root ganglia (DRG) so far. These four isoforms differ in TSS, and one differs in the CDS.
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Thrombus formation on an intact endothelium is prevented by nitric oxide, prostacyclin, and CD39. Endothelial cells are attached to the subendothelial collagen by von Willebrand factor (VWF), which these cells produce. VWF is also stored in the Weibel-Palade bodies of the endothelial cells and secreted constitutively into the blood. Platelets store vWF in their alpha granules.
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Ibuprofen may also rarely cause irritable bowel syndrome symptoms. NSAIDs are also implicated in some cases of Stevens–Johnson syndrome. Most NSAIDs penetrate poorly into the central nervous system (CNS). However, the COX enzymes are expressed constitutively in some areas of the CNS, meaning that even limited penetration may cause adverse effects such as somnolence and dizziness.
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Histone H4 is one of the slowest evolving proteins, and there appear to be no known sequence variants of histone H4. However, there are H4 genes that are constitutively expressed throughout the cell cycle that encode for proteins that are identical in sequence to the major H4. The reason for a lack of sequence variants remains unclear.
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CpG motifs are considered pathogen-associated molecular patterns (PAMPs) due to their abundance in microbial genomes but their rarity in vertebrate genomes. The CpG PAMP is recognized by the pattern recognition receptor (PRR) Toll-Like Receptor 9 (TLR9), which is constitutively expressed only in B cells and plasmacytoid dendritic cells (pDCs) in humans and other higher primates.
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NEAT1 is constitutively expressed in a number of non-neuronal tissues and cell lines. NEAT1 localizes to specific nuclear structures called paraspeckles. NEAT1 RNA interacts with a paraspeckle protein known as P54nrb or NONO and it is essential for paraspeckle formation. Some studies demonstrate that NEAT1 RNA is essential for the formation and maintenance of paraspeckles.
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Most Gram-negative bacteria keep TCT within the cell wall by using a PGN-transporter protein known as AmpG. However, B. pertussis is not capable of recycling PGNs via AmpG and thus, TCT escapes into the surrounding environment. Also, TCT appears to be constitutively expressed by B. pertussis. The first murine-model studies using TCT involved treatment of hamster tracheal cells.
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Duncia, J.V., et al., MEK inhibitors: The chemistry and biological activity of U0126, its analogs, and cyclization products. Bioorg. Med. Chem. Lett. 8, 2839-2844, (1998) The effects of U0126 on the growth of eight human breast cancer cell lines shown that U0126 selectively repressed anchorage-independent growth of MDA-MB231 and HBC4 cells, two lines with constitutively activated ERK.
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The abbreviation for the genes encoding for voltage-gated sodium channel starts with three letters: SCN. In contrast to these sodium channels, ENaC is constitutively active and is not voltage-dependent. The second N in the abbreviation (SCNN1D) represents that these are NON-voltage-gated channels. In most vertebrates, sodium ions are the major determinant of the osmolarity of the extracellular fluid.
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The PKC family, like Akt, plays roles in cell survival and motility. Most PKC isoforms are anti- apoptotic, although PKCδ (a novel PKC isoform) is pro-apoptotic in some systems. Although PKC possesses the same phosphorylation sites as Akt, its regulation is quite different. PKC is constitutively phosphorylated, and its acute activity is regulated by binding of the enzyme to membranes.
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HIF is synthesized constitutively, and hydroxylation of at least one of two critical proline residues mediates their interaction with the von Hippel Lindau E3 ubiquitin ligase complex, which targets them for rapid degradation. This reaction is catalysed by prolyl 4-hydroxylases. Fumarate and succinate have been identified as potent inhibitors of prolyl hydroxylases, thus leading to the stabilisation of HIF.
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The presence of IFN-gamma, a T-helper 1 type response cytokine important for cell-mediated immunity, dampens the production of CCL18. Furthermore, CCL18 is induced by fibroblasts, specifically by induction of collagen produced by fibroblasts, which is important in tissue healing and repair. Finally, CCL18 is constitutively and highly expressed in the lungs, suggesting that CCL18 plays role in maintaining homeostasis.
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The LacI repressor protein represses lacZYA by binding to the operator sequence lacO. The lacZYA repressor is constitutively expressed. It is always bound to the operator region of the promoter, which interferes with the ability of RNA polymerase (RNAP) to begin transcription of the lacZYA operon. In the presence of the inducer allolactose, the repressor changes conformation and falls off the operator.
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P-selectin is located on chromosome 1q21-q24, spans > 50 kb and contains 17 exons in humans. P-selectin is constitutively expressed in megakaryocytes (the precursor of platelets) and endothelial cells. P-selectin expression is induced by two distinct mechanisms. First, P-selectin is synthesized by megakaryocytes and endothelial cells, where it is sorted into the membranes of secretory granules.
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This positive autoregulation by stimulating its own transcription may be a mechanism for prolonging the signals from extracellular stimuli. This mechanism can have biological significance for the activity of c-jun in cancer. Also, the c-jun activities can be regulated by the ERK pathway. Constitutively active ERK is found to increase c-jun transcription and stability through CREB and GSK3.
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The protein encoded by this gene is a subunit of the receptor for IL-23. This protein pairs with the receptor molecule IL-12Rβ1 (IL12RB1), together forming the IL-23 receptor complex, and both are required for IL-23 signaling. This protein associates constitutively with Janus kinase 2 (JAK2), and also binds to transcription activator STAT3 in a ligand-dependent manner.
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HslV and hslU genes have also been identified in some eukaryotes, although these also require the constitutively expressed proteasome for survival. These eukaryotic HslVU complexes assemble to apparently functional units, suggesting that these eukaryotes have both functional proteasomes and functional hslVU systems.Ruiz-Gonzalez MX, Marin I. (2006). Proteasome-related HslU and HslV genes typical of eubacteria are widespread in eukaryotes.
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It is constitutively expressed in all mammalian tissue. In protozoan parasites, the nucleotide salvage pathway provides the sole means for nucleotide synthesis. Since the consequences of APRTase deficiency in humans is comparatively mild and treatable, it may be possible to treat certain parasitic infections by targeting APRTase function. In plants, as in other organisms, ARPTase functions primarily for the synthesis of adenylate.
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GSK3s are constitutively active enzymes implicated in several important regulatory processes. There is one requirement, though: substrates of GSK3 need to be pre-phosphorylated four amino acids downstream (C-terminally) of the actual target site. Thus it also requires a "priming kinase" for its activities. In the case of beta-catenin, the most important priming kinase is Casein Kinase I (CKI).
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New lesions did not appear, and a number of the liver metastases completely reduced to non-existence. The single patient in the study remained healthy following treatment. There are no effective means of treatment for advanced gastrointestinal stromal tumors, but that STI571 represents an effective treatment in early stage cancer associated with constitutively active c-kit, by inhibiting unfavourable tyrosine kinase activity.
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In contrast, the 5-HT2CR-INI is constitutively internalized and accumulates in endosomes 78. Structure As mentioned editing results in several codon changes. The editing sites are found in the second intracellular domain of the protein which is also the receptors G protein coupling domain. Therefore, editing of these sites can affect the affinity of the receptor for G protein binding.
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Cyclin B1 is a regulatory protein involved in mitosis. The gene product complexes with p34 (Cdk1) to form the maturation- promoting factor (MPF). Two alternative transcripts have been found, a constitutively expressed transcript and a cell cycle-regulated transcript that is expressed predominantly during G2/M phase of the cell cycle. The different transcripts result from the use of alternate transcription initiation sites.
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The abbreviation for the genes encoding for voltage-gated sodium channel starts with three letters: SCN. In contrast to these sodium channels, ENaC is constitutively active and is not voltage-dependent. The second N in the abbreviation (SCNN1A) represents that these are NON-voltage-gated channels. In most vertebrates, sodium ions are the major determinant of the osmolarity of the extracellular fluid.
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The abbreviation for the genes encoding for voltage-gated sodium channel starts with three letters: SCN. In contrast to these sodium channels, ENaC is constitutively active and is not voltage-dependent. The second N in the abbreviation (SCNN1A) represents that these are NON-voltage-gated channels. In most vertebrates, sodium ions are the major determinant of the osmolarity of the extracellular fluid.
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The abbreviation for the genes encoding for voltage-gated sodium channel starts with three letters: SCN. In contrast to these sodium channels, ENaC is constitutively active and is not voltage-dependent. The second N in the abbreviation (SCNN1) represents that these are NON-voltage-gated channels. In most vertebrates, sodium ions are the major determinant of the osmolarity of the extracellular fluid.
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Granulysin is present in cytolytic granules of cytotoxic T lymphocytes (CTL) and natural killer (NK) cells. Granulysin is made as a 15 kD molecule, and a portion of it is cleaved at both the amino and carboxy termini into a 9 kD form. The 9 kD form is released by receptor-mediated granule exocytosis while the 15 kD form is constitutively secreted.
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In neutrophil chemotaxis Dock2 signals downstream of the C5a and CXCL8/IL-8 receptors. Additional receptors which signal through Dock2 include the T cell receptor/TCR and EDG1, a sphingosine-1-phosphate (S1P) receptor. The HIV-1 protein Nef is able to constitutively activate Dock2 in T lymphocytes which disrupts chemotaxis and immunological synapse formation thereby inhibiting the antiviral immune response.
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Interleukin-18-binding protein is a protein that in humans is encoded by the IL18BP gene. The protein encoded by this gene is an inhibitor of the proinflammatory cytokine IL18. This protein binds to IL18, prevents the binding of IL18 to its receptor, and thus inhibits IL18-induced IFN-gamma production. This protein is constitutively expressed and secreted in mononuclear cells.
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Cif belongs to the α/β hydrolase family of proteins. Its structure was determined by X-ray crystallography and consists of the canonical α/β hydrolase fold with a cap domain, which it uses to constitutively homo-dimerize in solution. The active site is buried in the interior of the protein at the interface between the α/β hydrolase core and the cap.
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Human Hsc70 has 85% identity with human Hsp70 (SDSC workbench, blosom26 default analysis). The scientific community has long assumed that Hsp70 and Hsc70 have similar cellular roles, but this assumption proved incomplete. While Hsc70 also performed chaperone functions under normal conditions, unlike canonical heat shock proteins, Hsc70 is constitutively expressed and performs functions related to normal cellular processes, such as protein ubiquitylation and degradation.
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Upon tissue disruption they get into contact with β-glucosidases from the chloroplasts, which enzymatically release the toxic aglucones. Whereas some benzoxazinoids are constitutively present, others are only synthesised following herbivore infestation, and thus, considered inducible plant defenses against herbivory. The terpenoids, sometimes referred to as isoprenoids, are organic chemicals similar to terpenes, derived from five-carbon isoprene units. There are over 10,000 known types of terpenoids.
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Subsequently, phosphatidylinositol-3 kinase (PI3K) is activated, resulting in Akt kinase activation. Study results have shown that blocking PI3K or Akt activity results in death of sympathetic neurons in culture, regardless of NGF presence. However, if either kinase is constitutively active, neurons survive even without NGF. A second pathway contributing to cell survival occurs through activation of the mitogen-activated protein kinase (MAPK) kinase.
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Chemokine (C-X-C motif) ligand 17 (CXCL17) is a small cytokine belonging to the CXC chemokine family that has been identified in humans and mice. CXCL17 attracts dendritic cells and monocytes and is regulated in tumors. It is also known as VEGF co-regulated chemokine 1 (VCC-1) and dendritic cell- and monocyte-attracting chemokine-like protein (DMC). This chemokine is constitutively expressed in the lung.
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Thus far, most of the structural information pertaining to the PIM kinase family has been limited to PIM1. As a result, most of inhibitor development efforts has also been towards PIM1. PIM2 shares 55% sequence identity with PIM1, and the structure of PIM2 is quite closely related to PIM1. Like PIM1, PIM2 shows a bi-lobal kinase architecture with a constitutively active closed conformation.
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GPR56 has been shown to be cleaved at the GPS site and then remain associated with the 7TM domain. In a study where the N-terminus was removed up to N342 (the start of the GPS), the receptor became constitutively active and an up regulation of Gα12/13 was seen. When receptors are active, they are ubiquitinated and GPR56 lacking an N-terminus was highly ubiquitinated.
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The AQP4 channels are highly concentrated in the blood-brain barrier (BBB), as well as in other cerebrospinal fluid barriers. In the kidneys, AQP4 is primarily found in the inner medulla, and shows little to no presence in the outer medulla and cortex. It is constitutively expressed in the basolateral cell membrane of principal collecting duct cells and provide a pathway for water to exit these cells.
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Despite sharing similar amino acid sequence, Hsp90A expression is regulated in a different manner than Hsp90B. Hsp90A is the stress inducible isoform while Hsp90B is expressed constitutively. Several heat shock elements (HSE) are located upstream of Hsp90A allowing for its inducible expression. RNA levels measured in cell lines collected from cancer patients as well as normal tissue can be found at The Human Protein Atlas.
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Ser2 of cTnT at the N terminus is constitutively phosphorylated by unknown mechanisms. cTnT has been found to be phosphorylated by PKC at Thr197, Ser201, Thr206, Ser208 and Thr287 in the C-terminal region. Phosphorylation of Thr206 alone was sufficient to reduce myofilament calcium sensitivity and force production. cTnT is also phosphorylated at Thr194 and Ser198 under stress conditions, leading to attenuated cardiomyocyte contractility.
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BCR-ABL is a constitutively activated tyrosine kinase that is associated with chronic myeloid leukemia. It is formed from a fusion gene when pieces of chromosomes 9 and 22 break off and trade places. The ABL gene from chromosome 9 joins to the BCR gene on chromosome 22, to form the BCR-ABL fusion gene. Tyrosine kinase activity is crucial for the transformation of BCR-ABL.
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Her research elucidated the mechanism of cytokine activation that led to a constitutively activated form of full-length TyrRS. Yang became an assistant professor at The Scripps Research Institute Department of Molecular Medicine in 2005. She was promoted to associate professor in 2008 and to tenured full professor in 2014. At Scripps, she has continued making scientific advances in this field while running her own research laboratory.
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Cellular retinoic acid-binding protein 1 is a protein that in humans is encoded by the CRABP1 gene. CRABP1 is assumed to play an important role in retinoic acid-mediated differentiation and proliferation processes. It is structurally similar to the cellular retinol-binding proteins, but binds only retinoic acid. CRABP1 is constitutively expressed and is believed to have different functions in the cell than the related CRABP2.
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Retinoids can bind mammalian receptors other than RAR and RXR such as, PPAR, RORb, or COUP-TFII. Furthermore, RXR is sensitive to a wide range of molecules including retinoids, fatty acids, and phospholipids. # Study of steroid receptor evolution revealed that the ancestral steroid receptor could bind a ligand, estradiol. Conversely, the estrogen receptor found in mollusks is constitutively active and did not bind estrogen-related hormones.
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PCP-2 protein expression in these cell lines is increased by PMA stimulation. PCP-2 and the c-Kit tyrosine kinase receptor interact constitutively in these cells, and PCP-2 was shown to be tyrosine phosphorylated upon stimulation with the c-Kit ligand, SCF. Antisense oligonucleotide treatment of megakaryocyte cells to reduce PCP-2 protein expression resulted in a significant reduction in megakaryocyte progenitor proliferation.
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HIF has also been linked to mTOR, a central controller of growth decisions. It has recently been shown that HIF activation can inactivate mTOR. HIF can help explain the organ specific nature of VHL syndrome. It has been theorized that constitutively activating HIF in any cell could lead to cancer, but that there are redundant regulators of HIF in organs not affected by VHL syndrome.
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Multiple alternatively spliced transcript variants encoding the same protein have been described for this gene but the full length nature of some transcripts is not yet known. Reg3A (UniProt Q0614 1) is a bactericidal C-type lectin that is constitutively produced in the intestine that has antibacterial properties against Gram-positive bacteria. Bacterial killing is mediated by binding to surface-exposed carbohydrate moieties of bacterial peptidoglycan.
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Histone H4 is one of the slowest evolving proteins with no functional variants in the majority of species. The reason for a lack of sequence variants remains unclear. Trypanosoma are known to have a variant of H4 named H4.V. In Drosophila there are H4 replacement genes that are constitutively expressed throughout the cell cycle that encode proteins that are identical in sequence to the major H4.
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Embryologic mesenchymal cells (MSC) condense into layers of vascularized primitive connective tissue. Certain mesenchymal cells group together, usually near or around blood vessels, and differentiate into osteogenic cells which deposit bone matrix constitutively. These aggregates of bony matrix are called bone spicules. Separate mesenchymal cells differentiate into osteoblasts, which line up along the surface of the spicule and secrete more osteoid, which increases the size of the spicule.
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SRCCs are dedifferentiated adenocarcinomas that lose the capability for cell–cell interaction. Highly differentiated adenocarcinomas form SRCCs via a loss of adherens and tight junctions that typically separate MUC4, a mucin protein, and ErbB2, an oncogenic receptor. When MUC4 and ErbB2 are able to interact, they trigger an activation loop. As a result, the ErbB2/ErbB3 signaling pathway becomes constitutively activated, cell–cell interactions are lost and signet carcinomas are formed.
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Another serious result of inefficient blood flow is that cells do not receive adequate amounts of glucose. An immediate effect of low intracellular glucose is reduced ATP production in the cell. This effectively inactivates the Na-K pump, leading to the uptake of calcium ions by the cell. Continued influx of calcium serves to constitutively activate downstream effectors, including lipases, proteases, and endonucleases, whose actions eventually destroy the cell skeleton.
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The end-result is a B cell that is able to mass-produce specific antibodies against an antigenic target. Early evidence for these effects were that in CD40 or CD154 deficient mice, there is little class switching or germinal centre formation, and immune responses are severely inhibited. The expression of CD40 is diverse. CD40 is constitutively expressed by antigen presenting cells, including dendritic cells, B cells and macrophages.
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SLC26 proteins function as anion exchangers and Cl− channels. Ousingsawat et al. (2012) examined the functional interaction between CF transmembrane conductance regulator (CFTR) and SLC26A9 in polarized airway epithelial cells and in non-polarized HEK293 cells expressing CFTR and SLC26A9 (2.A.56.2.10). They found that SLC26A9 provides a constitutively active basal Cl− conductance in polarized grown CFTR-expressing CFBE airway epithelial cells, but not in cells expressing F508del-CFTR.
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FRP is constitutively active, both in vivo and in vitro. It is able to prevent quenching of phycobilin fluorescence by OCP in vitro. Overexpression of FRP in Synechocystis PCC 6803 leads to an absence of fluorescence quenching. Deletion mutants of FRP show a slightly larger degree of fluorescence quenching induced by strong blue-green light, but was unable to restore fluorescence levels when transferred to low-light or darkness.
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Tetherin, also known as bone marrow stromal antigen 2, is a lipid raft associated protein that in humans is encoded by the BST2 gene. In addition, tetherin has been designated as CD317 (cluster of differentiation 317). This protein is constitutively expressed in mature B cells, plasma cells and plasmacytoid dendritic cells, and in many other cells, it is only expressed as a response to stimuli from IFN pathway.
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Trp repressor dimer bound to operator DNA The operon operates by a negative repressible feedback mechanism. The repressor for the trp operon is produced upstream by the trpR gene, which is constitutively expressed at a low level. Synthesized trpR monomers associate into dimers. When tryptophan is present, these tryptophan repressor dimers bind to tryptophan, causing a change in the repressor conformation, allowing the repressor to bind to the operator.
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CCL9 can activate osteoclasts through its receptor CCR1 (the most abundant chemokine receptor found on osteoclasts) suggesting an important role for CCL9 in bone resorption. CCL9 is constitutively expressed in macrophages and myeloid cells. The gene for CCL9 is located on chromosome 11 in mice. CCL9 is a chemokine involved in the process of signaling an antileukemic response and is a potential form of immunotherapy for chronic myelogenous leukemia (CML).
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Gamma-interferon-inducible lysosomal thiol reductase is an enzyme that, in humans, is encoded by the IFI30 gene. The protein encoded by this gene is a lysosomal thiol reductase that at low pH can reduce protein disulfide bonds. The enzyme is expressed constitutively in antigen-presenting cells and induced by gamma-interferon in other cell types. This enzyme has an important role in MHC class II-restricted antigen processing.
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EID-2 interacts constitutively with Smad proteins, and most strongly with Smad3. Stable expression of EID-2 in the TGF- beta1-responsive cell line inhibits endogenous Smad3-Smad4 complex formation and TGF-beta1-induced expression of p21 and p15. EID-2 displays developmentally regulated expression with high levels in adult heart and brain. Overexpression of EID-2 inhibits muscle-specific gene expression through inhibition of MyoD-dependent transcription.
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CCR9 supports the migration of leukocytes into the intestine, CCR10 to the skin and CXCR5 supports the migration of B-cell to follicles of lymph nodes. As well CXCL12 (SDF-1) constitutively produced in the bone marrow promotes proliferation of progenitor B cells in the bone marrow microenvironment. Inflammatory: inflammatory chemokines are produced in high concentrations during infection or injury and determine the migration of inflammatory leukocytes into the damaged area.
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Veterinarians also administer transfusions to other animals. Various species require different levels of testing to ensure a compatible match. For example, cats have 3 known blood types, cattle have 11, dogs have 13, pigs have 16, and horses have 34. However, in many species (especially horses and dogs), cross matching is not required before the first transfusion, as antibodies against non-self cell surface antigens are not expressed constitutively – i.e.
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Using constitutively active forms of BMPR1A, it has been shown that BMPR1A plays a role in cell differentiation. Signals transduced by the BMPR1A receptor are not essential for osteoblast formation or proliferation; however, BMPR1A is necessary for the extracellular matrix deposition by osteoblasts. In the chick embryo, BMPR1A receptors are found in low levels in limb bud mesenchyme, a differing location to BMPR1B, supporting the differing roles they play in osteogenesis.
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The cGAS/STING pathway also has a role in tumor surveillance. In response to cellular stress, such as DNA damage, cells will upregulate NKG2D ligands so that they may be recognized and destroyed by Natural Killer (NK) and T cells. In many tumor cells, the DNA damage response is constitutively active, leading to the accumulation of cytoplasmic DNA. This activates the cGAS/STING pathway leading to activation of IRF3.
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Docking protein 1 is constitutively tyrosine phosphorylated in hematopoietic progenitors isolated from chronic myelogenous leukemia (CML) patients in the chronic phase. It may be a critical substrate for p210(bcr/abl), a chimeric protein whose presence is associated with CML. Docking protein 1 contains a putative pleckstrin homology domain at the amino terminus and ten PXXP SH3 recognition motifs. Docking protein 2 binds p120 (RasGAP) from CML cells.
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Tyrosine kinases are particularly important today because of their implications in the treatment of cancer. A mutation that causes certain tyrosine kinases to be constitutively active has been associated with several cancers. Imatinib (brand names Gleevec and Glivec) is a drug able to bind the catalytic cleft of these tyrosine kinases, inhibiting its activity. Tyrosine kinase activity is also significantly involved in other events that are sometimes considered highly unfavorable.
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Cyclin B is a member of the cyclin family. Cyclin B is a mitotic cyclin. The amount of cyclin B (which binds to Cdk1) and the activity of the cyclin B-Cdk complex rise through the cell cycle until mitosis, where they fall abruptly due to degradation of cyclin B (Cdk1 is constitutively present). The complex of Cdk and cyclin B is called maturation promoting factor or mitosis promoting factor (MPF).
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Bempegaldesleukin is a recombinant form of human cytokine interleukin-2 conjugated to six releasable polyethylene glycol chains. PEGylation of IL-2 is utilized to alter its receptor binding. PEG chains are located at the region of IL-2 that binds to the IL2Rα subunit of the heterotrimeric IL2Rαβγ complex, reducing its ability to bind and activate the heterotrimer. The IL2Rαβγ complex is constitutively expressed on regulatory T cells (Tregs).
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This suggests that PTPmu may be catalytically active at high cell density. Substrates of PTPmu (proteins that are dephosphorylated by PTPmu), such as p120catenin, tend to be dephosphorylated at high cell density, supporting the hypothesis that PTPmu is catalytically active when bound homophilically. PTPmu is constitutively dimerized due to its extracellular domain. Crystal structure analysis of the D1 of PTPmu demonstrated that PTPmu dimers are in an open active conformation.
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Th17 cells from mice expressing CYP1A1 constitutively metabolized FICZ rapidly and responded with lower production of IL-22 when treated with 0.01nM FICZ compared to wildtype Th17 cells. Metabolic clearance of FICZ in mice that overexpress Cyp1a1 in the gut epithelium led to a pseudo-AHR-deficient state and when infected with Citrobacter rodentium, these animals exhibited markedly reduced numbers of group 3 ILCs and Th17 cells and succumbed rapidly.
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Myc is a family of regulator genes and proto-oncogenes that code for transcription factors. The Myc family consists of three related human genes: c-myc (MYC), l-myc (MYCL), and n-myc (MYCN). c-myc (also sometimes referred to as MYC) was the first gene to be discovered in this family, due to homology with the viral gene v-myc. In cancer, c-myc is often constitutively (persistently) expressed.
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PDPK1 stands for 3- _p_ hosphoinositide- _d_ ependent _p_ rotein _k_ inase _1_. PDPK1 functions downstream of PI3K through PDPK1's interaction with membrane phospholipids including phosphatidylinositols, phosphatidylinositol (3,4)-bisphosphate and phosphatidylinositol (3,4,5)-trisphosphate. PI3K indirectly regulates PDPK1 by phosphorylating phosphatidylinositols which in turn generates phosphatidylinositol (3,4)-bisphosphate and phosphatidylinositol (3,4,5)-trisphosphate. However, PDPK1 is believed to be constitutively active and does not always require phosphatidylinositols for its activities.
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To cause gall formation, the T-DNA encodes genes for the production of auxin or indole-3-acetic acid via the IAM pathway. This biosynthetic pathway is not used in many plants for the production of auxin, so it means the plant has no molecular means of regulating it and auxin will be produced constitutively. Genes for the production of cytokinins are also expressed. This stimulates cell proliferation and gall formation.
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Dermicidin is a secreted protein that is subsequently processed into mature peptides of distinct biological activities. The C-terminal peptide is constitutively expressed in sweat and has antibacterial and antifungal activities. The N-terminal peptide, also known as diffusible survival evasion peptide, promotes neural cell survival under conditions of severe oxidative stress. A glycosylated form of the N-terminal peptide may be associated with cachexia (muscle wasting) in cancer patients.
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Several pectinesterase isoforms differing in molecular weight, isoelectric point and biochemical activity have been identified in dicotyledonous plants. Pectinesterase isoforms are encoded by a family of genes, some of which are constitutively expressed throughout the plant, whereas others are differentially expressed in specific tissues and at different developmental stages. Isoforms of pectinesterase differ in various biochemical parameters such as relative molecular mass, isoelectric point, optimum pH, substrate affinity, ion-requirement and location.
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Not all NES substrates are constitutively exported from the nucleus, meaning that CRM1-mediated export is a regulated event. Several ways of regulating NES-dependent export have been reported. These include masking/unmasking of NESs, phosphorylation and even disulfide bond formation as a result of oxidation. The binding of NES to the export receptor of a protein gives the universal export function of NES an individually specified activation of export to each protein.
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The para gene is located on the X chromosome within the Drosophila genome. There are 26 para exons, 13 are constitutively expressed in the transcript, while 15 are alternatively spliced. Alternative splicing allows for the formation of 60 unique transcripts and 57 unique polypeptides. The independent splicing of 11 exons allows for the unique cytoplasmic loops, the alternative splicing also can effect the Na+ channel kinetics, such as the varying gating conductivities.
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UVB broadband and narrowband lamps can be used, but narrowband ultraviolet picked around 311 nm is the choice. It has been constitutively reported that a combination of UVB phototherapy with other topical treatments improves re-pigmentation. However, some people with vitiligo may not see any changes to skin or re-pigmentation occurring. A serious potential side effect involves the risk of developing skin cancer, the same risk as an overexposure to natural sunlight.
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Activation of angiotensin II receptor AT1 couples to Gq/11 to activate phospholipase C and to increase the intracellular Ca2+ concentration. An increase in Ca2+ concentration then elevates WNK4 activity through mechanisms described above (Fig. 3, left panel). The PHAII-causing mutations in the acidic motif and the R1185C mutation in the calmodulin-binding domain constitutively activate the WNK4 kinase domain allowing it to function despite the absence of angiotensin II (Fig.
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Interleukin-31 receptor A is a protein that in humans is encoded by the IL31RA gene. IL31RA is related to gp130 (IL6ST; MIM 600694), the common receptor subunit for IL6 (MIM 147620)-type cytokines. Oncostatin M receptor (OSMR; MIM 601743) and IL31RA form the heterodimeric receptor through which IL31 (MIM 609509) signals. Expression of IL31RA and OSMR mRNA is induced in activated monocytes, and both mRNAs are constitutively expressed in epithelial cells (Dillon et al.
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Moreover, active mTOR supports tumor growth also indirectly by inhibiting autophagy. Constitutively activated mTOR functions in supplying carcinoma cells with oxygen and nutrients by increasing the translation of HIF1A and supporting angiogenesis. mTOR also aids in another metabolic adaptation of cancerous cells to support their increased growth rate—activation of glycolytic metabolism. Akt2, a substrate of mTOR, specifically of mTORC2, upregulates expression of the glycolytic enzyme PKM2 thus contributing to the Warburg effect.
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Since then, Neurospora has become a model organism for studying circadian clocks and rhythms. WC-1 was first discovered from a wc-1 mutant that inhibited carotenoid biosynthesis in mycelia but not in conidia. Conidia produce carotenoid constitutively and don't require regulation by light, unlike mycelia which require light-induction. This mutant created a phenotype in which these strains of Neurospora developed conidia with pigmentation, but with no pigmentation in the mycelium.
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The synthetic organism, Syn 3, has a minimal genome of 473 essential genes and quasi-essential genes (necessary for fast growth), although 149 have unknown function. Essential genes include housekeeping genes (critical for basic cell functions) as well as genes that are expressed at different times in the organisms development or life cycle. Housekeeping genes are used as experimental controls when analysing gene expression, since they are constitutively expressed at a relatively constant level.
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In both autoimmune and inflammatory diseases, the condition arises through aberrant reactions of the human adaptive or innate immune systems. In autoimmunity, the patient's immune system is activated against the body's own proteins. In chronic inflammatory diseases, neutrophils and other leukocytes are constitutively recruited by cytokines and chemokines, resulting in tissue damage. Mitigation of inflammation by activation of anti-inflammatory genes and the suppression of inflammatory genes in immune cells is a promising therapeutic approach.
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Cancer cells can manipulate cell signalling by producing excess levels of ROS, thereby constitutively activating pathways to promote their cellular growth and proliferation. Implicated pathways include NF-κB, PI3K, HIFs and MAPKs. In humans, mitochondrial ROS is required alongside those released in the oxidative burst for mitogenic pathway stimulation in oncogenic KRAS cells. However, in oncogenic Kras mice fibroblasts, NADPH oxidase inhibitors have been shown to be sufficient to block these growth factor pathways.
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Presence of a constitutively active NF-κB pathway manifests in multiple myeloma and other cancer-related diseases. Removal of LT-β receptors has shown to inhibit tumor growth and decrease angiogenesis. Thus, lymphotoxin and its downstream signaling via the NF-κB pathway illustrate the cytokine's influence on tumor development and metastasis. A fully humanized anti-LT-α antibody (Pateclizumab or MLTA3698A) has been shown to react with both LT-α and LT-β.
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Anaplastic lymphoma kinase (ALK) was originally discovered in 1994 in anaplastic large-cell lymphoma (ALCL) cells. ALCL is caused by a (2;5)(p23:q35) chromosomal translocation that generates the fusion protein NPM-ALK, in which the kinase domain of ALK is fused to the amino-terminal part of the nucleophosmin (NPM) protein. Dimerization of NPM constitutively activates the ALK kinase domain. The full-length protein ALK was identified in 1997 by two groups.
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Because the GAPDH gene is often stably and constitutively expressed at high levels in most tissues and cells, it is considered a housekeeping gene. For this reason, GAPDH is commonly used by biological researchers as a loading control for western blot and as a control for qPCR. However, researchers have reported different regulation of GAPDH under specific conditions. For example, the transcription factor MZF-1 has been shown to regulate the GAPDH gene.
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HIF-1α is a ubiquitous, constitutively synthesized transcription factor responsible for upregulating the expression of genes involved in the cellular response to hypoxia. These gene products may include proteins such as glycolytic enzymes and angiogenic growth factors. In normoxia, HIF alpha subunits are marked for the ubiquitin-proteasome degradation pathway through hydroxylation of proline-564 and proline-402 by PHD2. Prolyl hydroxylation is critical for promoting pVHL binding to HIF, which targets HIF for polyubiquitylation.
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Inner centromere protein is a protein that in humans is encoded by the INCENP gene. In mammalian cells, two broad groups of centromere-interacting proteins have been described: constitutively binding centromere proteins and 'passenger' (or transiently interacting) proteins. The constitutive proteins include CENPA (centromere protein A), CENPB, CENPC1, and CENPD. The term 'passenger proteins' encompasses a broad collection of proteins that localize to the centromere during specific stages of the cell cycle.
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CHS is constitutively expressed in plants but can also be subject to induced expression through light/ UV light and well as in response to pathogens, elicitors and wounding. The CHS promoter contains a G-box motif with a sequence of CACGTG. This has been shown to play a role in response to light. Other light sensitive domains include Box I, Box II, Box III, Box IV or three copies of H-box (CCTACC).
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Along with mammals such as humans and mice, orthologs of the Arntl gene are also found in fish (AF144690.1), birds (Arntl), reptiles, amphibians (XI.2098), and Drosophila (Cycle, which encodes a protein lacking the homologous C-terminal domain, but still dimerizes with the CLOCK protein). Unlike mammalian Arntl, circadian regulated, the Drosophila Cycle (gene) is constitutively expressed. In humans, three transcript variants encoding two different isoforms have been found for this gene.
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Michael J. Monahana argues that the rhetoric of privilege "obscures as much as it illuminates" and that we "would be better served by beginning with a more sophisticated understanding of racist oppression as systemic, and of individual agents as constitutively implicated in that system."Suarez, Cyndi (March 26, 2019), "Putting 'Privilege' in Perspective", Non Profit Quarterly.Monahana, Michael J. (17 March 2014), "The concept of privilege: a critical appraisal", South African Journal of Philosophy.
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For the bacteria to use quorum sensing constitutively, they must possess three characteristics: to secrete a signaling molecule, an autoinducer, to detect the change in concentration of signaling molecules, and to regulate gene transcription as a response. This process is highly dependent on the diffusion mechanism of the signaling molecules. QS Signaling molecules are usually secreted at a low level by individual bacteria. At low cell density, the molecules may just diffuse away.
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While the identity of natural ligands for the RORs remains controversial, similar to the liver X receptors (LXRs), it appears that the RORs are activated by oxysterols. Furthermore, the RORs appear to be constitutively active (absence of ligand) and that activity may be due to continuously bound natural ligands. Side chain oxygenated sterols (e.g., 20α-hydroxycholesterol, 22R-hydroxycholesterol, and 25-hydroxycholesterol) are high affinity RORγ agonists while sterols oxygenated at the 7-position, (e.g.
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Barres BA, Hart IK, Coles HSR, Burne JF, Voyvodic JT, Richardson WD, Raff MC. (1992) Cell death and control of cell survival in the oligodendrocyte lineage. Cell 70: 31–46. Conformational changes in receptor proteins are thought to occur, leaving the cell constitutively proliferating.Aloisi F, Giampaola A, Russo G, Peschle C, Levi G. (1992) Developmentalappearance, antigenic profile and proliferation of glial cells of the human embryonic spinal cord: an immunocytochemicalstudy using dissociated cultured cells.
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The mOTUs2 profiler, which is based on essential housekeeping genes, is demonstrably well-suited for quantification of basal transcriptional activity of microbial community members. Depending on environmental conditions, the number of transcripts per cell varies for most genes. An exception to this are housekeeping genes that are expressed constitutively and with low variability under different conditions. Thus, the abundance of transcripts from such genes strongly correlate with the abundance of active cells in a community.
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The human HIF1A gene encodes for the alpha subunit, HIF1A of the transcription factor hypoxia-inducible factor (HIF1) . Its protein expression level can be measured by antibodies against HIF-1-alpha through various biological detection methods including western blot or immunostaining. HIF1A expression level is dependent on its GC-rich promoter activation. In most cells, HIF1A gene is constitutively expressed in low levels under normoxic conditions, however, under hypoxia, HIF1A transcription is often significantly upregulated.
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Secreted by regulatory T-cells (Tregs), regulatory B-cells (Bregs) or even CD8+ regulatory T cells, IL-35 suppresses inflammatory responses of immune cells. IL-35 is not constitutively expressed in tissues, but the gene encoding IL-35 is transcribed by vascular endothelial cells, smooth muscle cells and monocytes after activation with proinflammatory stimuli. IL-35 has selective activities on different T-cell subsets; it induces proliferation of Treg cell populations but reduces activity of Th17 cell populations.
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IL-33 is constitutively located in the nucleus of structural cells of humans and mice and has a helix-turn-helix domain presumably allowing it to bind to DNA. There is a paucity of research into the nuclear role of IL-33 but amino acids 40-58 in human IL-33 are sufficient for nuclear localisation and histone binding. IL-33 also interacts with the histone methyltransferase SUV39H1 and murine appears to IL-33 interact to NF- κB.
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Housekeeping genes and proteins, including β-Actin, GAPDH, HPRT1, and RPLP1, are often used as internal controls in western blots because they are thought to be expressed constitutively, at the same levels, across experiments. However, recent studies have shown that expression of housekeeping proteins (HKPs) can change across different cell types and biological conditions. Therefore, scientific publishers and funding agencies now require that normalization controls be previously validated for each experiment to ensure reproducibility and accuracy of the results.
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F-actin distribution in the cell cortex as shown by rhodamine phalloidin staining of HeLa cells that constitutively express Histone H2B-GFP to mark chromosomes. F-actin is thus red, while Histone H2B is displayed in green. The left hand cell is in mitosis, as demonstrated by chromosome condensation, while the right hand cell is in interphase(as determined by intact cell nucleus) in a suspended state. In both cases F-actin is enriched around the cell periphery.
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There is a 70% sequence homology between mouse and rat and a 45% homology between human and mouse. The N-terminal, however, is highly conserved between all three species and is thought to contain potential casein kinase 2 (CK2) phosphorylation sites. CK2 is a constitutively and widely expressed serine/threonine kinase that has many substrates related to signal transduction and cell growth regulation. Several casein genes have also been found nearby to the FDC-SP gene.
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In this case the mutant version will out compete for the wildtype proteins partners resulting in a mutant phenotype. Other mutant forms can result in a protein that is abnormally regulated and constitutively active ('on' all the time). This might be due to removing a regulatory domain or mutating a specific amino residue that is reversibly modified (by phosphorylation, methylation, or ubiquitination). Either change is critical for modulating protein function and often result in informative phenotypes.
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This protein may play a role in physiologic functions at mucosal sites. FGL2 is a protein that exhibits pleiotropic effects within the body and is an important immune regulator of both innate and adaptive responses. The protein exists as both a Type II transmembrane protein (with the carboxy terminus on the extracellular side of the plasma membrane) found on the surface of macrophages and endothelial cells and can be constitutively secreted by both CD4+ and CD8+ T cells.
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Retinoic acid, part of a family of molecules called retinoids, need to be repressed in order for Chondroblasts to form. A 2003 study using transgenic mice with a weak, constitutively active retinoic acid receptor found that retinoids maintain cells within condensations in a prechondrogenic, mesenchymal cell state which prevents cell differentiation. It has also been suggested that the inhibition of receptor mediated retinoid signaling induces Sox9 expression which is considered a “master switch” for the differentiation of chondroblasts.
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These molecules are constitutively expressed in professional, immune antigen- presenting cells, but may also be induced on other cells by interferon γ. They are expressed on the epithelial cells in the thymus and on APCs in the periphery. MHC class II expression is closely regulated in APCs by CIITA, which is the MHC class II transactivator. CIITA is solely expressed on professional APCs however, non-professional APCs can also regulate CIITA activity and MHC II expression.
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Indeed, a bromodomain – a protein domain that specifically binds acetyl-lysine – is found in many enzymes that help activate transcription, including the SWI/SNF complex. It may be that acetylation acts in this and the previous way to aid in transcriptional activation. The idea that modifications act as docking modules for related factors is borne out by histone methylation as well. Methylation of lysine 9 of histone H3 has long been associated with constitutively transcriptionally silent chromatin (constitutive heterochromatin).
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However, these silencers can carry out their activity prior to transcription. Most silencers are constitutively expressed in organisms, only allowing activation of a gene by either inhibiting the silencer or by activating an enhancer region. The best example of this is the Neuronal-Restrictive Silencer Factor (NRSF) that is produced by the REST gene. The REST gene produces NRSF in order to repress the transcription of neuronal genes that are essential for localization of neuronal tissue.
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Cells that are genetically perturbed to manifest constitutively active adhesion regulators are unable to properly remodel their focal adhesions and facilitate the generation of a uniform actomyosin cortex. Overall, the biochemical events governing the morphological and mechanical changes in mitotic cells are orchestrated by the mitotic master regulator Cdk1. Apart from actomyosin-related genes, several disease genes have recently been implicated in mitotic cell rounding. These include Parkinson’s disease associated DJ-1/Park7 and FAM134A/RETREG2.
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The gene, HSP90AA1, encodes the human stress- inducible 90-kDa heat shock protein alpha (Hsp90A). Complemented by the constitutively expressed paralog Hsp90B which shares over 85% amino acid sequence identity, Hsp90A expression is initiated when a cell experiences proteotoxic stress. Once expressed Hsp90A dimers operate as molecular chaperones that bind and fold other proteins into their functional 3-dimensional structures. This molecular chaperoning ability of Hsp90A is driven by a cycle of structural rearrangements fueled by ATP hydrolysis.
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LEDGF/p75 is a 60kDa, 530-amino-acid-long protein. The N-terminal portion of the protein consists of a PWWP domain, a nuclear localization sequence, and two copies of the AT-hook DNA binding motif. The C-terminal portion of LEDGF/p75 contains a structure termed the integrase-binding domain, which interacts with lentiviral integrase proteins as well as numerous cellular proteins. The N-terminal portion interacts strongly with chromatin, making LEDGF/p75 a constitutively nuclear protein.
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IL-33 is a dual function cytokine. Besides its chromatin-associated function, it is constitutively expressed in healthy endothelial cells, because it acts as DAMPs after its release to extracellular space of cells in the context of immunologic not-silent cell death (necrosis or pyroptosis), and drives cytokine production in natural helper cells, nuocytes, Th2 lymphocytes, mast cells, basophils, eosinophils, invariant natural killer and natural killer T cells. It is involved in allergic and parasite-induced inflammatory responses.
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This oncogenic v-Src is a product of the Rous sarcoma virus and as a result of an carboxy-terminal truncation, v-Src lacks the negative regulatory site Tyr-527 leading this enzyme to be constitutively active that in turn causes uncontrolled growth of infected cells. Moreover, substitution of this tyrosine with phenylalanine in c-Src results in activation. A second regulatory phosphorylation site in Src is Tyr-416. This is an autophosphorylation site in the activation loop.
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If a pair of achondroplasia alleles are present, the result is fatal. Achondroplasia is a mutation in the fibroblast growth factor receptor 3. In the context of achondroplasia, this mutation causes FGFR3 to become constitutively active, inhibiting bone growth. Research by urologist Harry Fisch of the Male Reproductive Center at Columbia Presbyterian Hospital indicates that in humans this defect may be exclusively inherited from the father and becomes increasingly probable with paternal age: specifically males reproducing after 35.
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On the basis of their size and pattern of disulfide bonding, mammalian defensins are classified into alpha, beta and theta categories. Alpha-defensins, which have been identified in humans, monkeys and several rodent species, are particularly abundant in neutrophils, certain macrophage populations and Paneth cells of the small intestine. Defensins are produced constitutively and/or in response to microbial products or proinflammatory cytokines. Some defensins are also called corticostatins (CS) because they inhibit corticotropin-stimulated corticosteroid production.
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Pexa-Vec is an engineered oncolytic virus that selectively destroys cancer cells and induces tumor immune response. Uncontrolled cell division, inactivation of the interferon pathway that is necessary to defend against viral infections, and constitutively active EGFR-Ras signaling pathway, are common features of cancer cells. These features enable rapid replication of the JX-594 virus and lysis of the host cancer cells. Deletion of thymidine kinase (TK) from the JX-594 genome prevents virus replication in normal cells.
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As the most aggressive cancer originated in the brain, mutations found in patients with glioblastoma are related to the deletion of a part of the extracellular domain of the epidermal growth factor receptor (EGFR). This deletion causes CBL E3 ligase unable to bind the receptor for its recycling and degradation via a ubiquitin-lysosomal pathway. Thus, EGFR is constitutively active in the cell membrane and activates its downstream effectors that are involved in cell proliferation and migration.
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The ID4 promoter region has been found to be hypermethylated and its mRNA suppressed in breast cancer cell lines including that of primary breast cancers. Patients with invasive carcinomas have shown ID4 expression in their breast cancer specimens. This has been identified as a significant risk factor in nodal metastasis. ID4 is constitutively expressed in normal human mammary epithelium but found to be suppressed in ER positive breast carcinomas and preneoplastic lesions. ER negative carcinomas also show ID4 expression.
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Additionally, Lippincott-Schwartz's laboratory demonstrated that Golgi enzymes constitutively recycle back to the endoplasmic reticulum and that such recycling plays a central role in the maintenance, biogenesis, and inheritance of the Golgi apparatus in mammalian cells. Within Lippincott-Schwartz lab, current projects include several cell biological areas. For example, protein transport and cytoskeleton interaction, organelle assembly and disassembly, and cell polarity generation. There are also projects analyzing the dynamics of proteins that have been fluorescently labeled.
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Along with other subfamily of Rac and Rho proteins, they exert an important regulatory role specifically in cell motility and cell growth. Rac1 has ubiquitous tissue expression, and drives cell motility by formation of lamellipodia. In order for cancer cells to grow and invade local and distant tissues, deregulation of cell motility is one of the hallmark events in cancer cell invasion and metastasis. Overexpression of a constitutively active Rac1 V12 in mice caused a tumor that's phenotypically indistinguishable from human Kaposi's sarcoma.
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The protein encoded by this gene belongs to the HLA class II beta chain paralogues. The class II molecule is a heterodimer consisting of an alpha (DRA) and a beta chain (DRB), both anchored in the membrane. It plays a central role in the immune system by presenting peptides derived from extracellular proteins to T helper cells. Class II molecules are constitutively expressed in professional antigen-presenting cells (APC: B lymphocytes, dendritic cells, macrophages), and could be induced in non- professional APCs.
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NRF3 is a membrane bound glycoprotein that can be targeted specifically to the endoplasmic reticulum (ER) and the nuclear membrane. Biochemical studies have identified three migrating endogenous forms of NRF3 proteinA, B, and Cwhich are constitutively degraded by several proteolytic mechanisms. It is known that the "A" form is glycosylated, whereas "B" is unglycosylated, and "C" is generated by cleavage of "B." In total, seven potential sites of N-linked glycosylation has been observed in the center portion of the NRF3 protein.
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ADH is constitutively expressed at low levels in the roots of young plants grown on agar. If the roots lack oxygen, the expression of ADH increases significantly. Its expression is also increased in response to dehydration, to low temperatures, and to abscisic acid, and it plays an important role in fruit ripening, seedlings development, and pollen development. Differences in the sequences of ADH in different species have been used to create phylogenies showing how closely related different species of plants are.
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In chronic myelogenous leukemia, the Philadelphia chromosome leads to a fusion protein of abl with bcr (breakpoint cluster region), termed bcr-abl. As this is now a constitutively active tyrosine kinase, imatinib is used to decrease bcr-abl activity. The active sites of tyrosine kinases each have a binding site for ATP. The enzymatic activity catalyzed by a tyrosine kinase is the transfer of the terminal phosphate from ATP to tyrosine residues on its substrates, a process known as protein tyrosine phosphorylation.
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The B2 receptor is a G protein-coupled receptor, coupled to Gq and Gi. Gq stimulates phospholipase C to increase intracellular free calcium and Gi inhibits adenylate cyclase. Furthermore, the receptor stimulates the mitogen-activated protein kinase pathways. It is ubiquitously and constitutively expressed in healthy tissues. The B2 receptor forms a complex with angiotensin converting enzyme (ACE), and this is thought to play a role in cross-talk between the renin-angiotensin system (RAS) and the kinin-kallikrein system (KKS).
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Laruelle claims that all forms of philosophy (from ancient philosophy to analytic philosophy to deconstruction and so on) are structured around a prior decision, but that all forms of philosophy remain constitutively blind to this decision. The 'decision' that Laruelle is concerned with here is the dialectical splitting of the world in order to grasp the world philosophically. Laruelle claims that the decisional structure of philosophy can only be grasped non-philosophically. In this sense, non- philosophy is a science of philosophy.
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It is localized in the cytoplasm and acts as a dominant negative isoform. Contrary, another isoform that misses exon VII is constitutively active. Many Ras responsive genes harbor combinatorial Ets/AP1 recognition motifs through which Ets1 and AP1 synergistically activate transcription when stimulated by Ras. In adult humans, Ets1 is expressed at high levels mainly in immune tissues such as thymus, spleen, and lymph node (B cells, T cells, NK cells, and NK T cells and non-lymphoid immune cells).
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The B2 receptor is a G protein- coupled receptor, probably coupled to Gq and Gi. Gq stimulates phospholipase C to increase intracellular free calcium and Gi inhibits adenylate cyclase. Furthermore, the receptor stimulates the mitogen-activated protein kinase pathways. It is ubiquitously and constitutively expressed in healthy tissues. The B2 receptor forms a complex with angiotensin converting enzyme (ACE), and this is thought to play a role in cross-talk between the renin-angiotensin system (RAS) and the kinin-kallikrein system (KKS).
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The protein encoded by this gene is a member of the intercellular adhesion molecule (ICAM) family. All ICAM proteins are type I transmembrane glycoproteins, contain 2-9 immunoglobulin-like C2-type domains, and bind to the leukocyte adhesion LFA-1 protein. This protein is constitutively and abundantly expressed by all leukocytes and may be the most important ligand for LFA-1 in the initiation of the immune response. It functions not only as an adhesion molecule, but also as a potent signalling molecule.
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In this mutation, the amino acid valine (V) at position 600 within the BRAF protein has become replaced by glutamic acid (E) making the mutant BRAF protein constitutively active. In May 2013, trametinib was approved as a single-agent by the Food and Drug Administration for the treatment of patients with V600E mutated metastatic melanoma. Clinical trial data demonstrated that resistance to single-agent trametinib often occurs within 6 to 7 months. To overcome this, trametinib was combined with the BRAF inhibitor dabrafenib.
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Phenylalanine, tyrosine, and tryptophan, the aromatic amino acids, arise from chorismate. The first step, condensation of 3-deoxy-D-arabino-heptulosonic acid 7-phosphate (DAHP) from PEP/E4P, uses three isoenzymes AroF, AroG, and AroH. Each one of these has its synthesis regulated from tyrosine, phenylalanine, and tryptophan, respectively. The rest of the enzymes in the common pathway (conversion of DAHP to chorismate) appear to be synthesized constitutively, except for shikimate kinase, which can be inhibited by shikimate through linear mixed-type inhibition.
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Sequences 3 and 4 are thus free to form the 3-4 structure which terminates transcription. The end result is that the operon will be transcribed only when tryptophan is unavailable for the ribosome, while the trpL transcript is constitutively expressed. To ensure that the ribosome binds and begins translation of the leader transcript immediately following its synthesis, a pause site exists in the trpL sequence. Upon reaching this site, RNA polymerase pauses transcription and apparently waits for translation to begin.
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The human interferon-gamma receptor complex consists the heterodimer of two chains: IFNGR1 and IFNGR2. In unstimulated cells, these subunits are not preassociated with each other but rather associate through their intracellular domains with inactive forms of specific Janus family kinases (Jak1 and Jak2). Jak1 and Jak2 constitutively associate with IFNGR1 and IFNGR2, respectively. Binding of IFN-γ to IFNGR1 induces the rapid dimerization of IFNGR1 chains, thereby forming a site that is recognized by the extracellular domain of IFNGR2.
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Phorbol derivatives work primarily by interacting with protein kinase C (PKC), although they can interact with other phospholipid membrane receptors. The esters bind to PKC in a similar way to its natural ligand, diacylglycerol, and activate the kinase. Diacylglycerol is degraded quickly by the body, allowing PKC to be reversibly activated. When phorbol esters bind to the receptor, they are not degraded as efficiently by the body, leading to constitutively active PK. PKC is involved in a number of important cell signaling pathways.
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No endogenous ligands of ERRα have been identified to date, hence ERRα is classified as an orphan receptor. In addition both biochemical and structural studies indicate that ERRα is constitutively active in the absence of ligand. ERRα does, however, interact with the metabolic-inducible coactivator PGC1-α in its AF2 region which is sometimes referred to as the "protein ligand" of ERRα. The isoflavone phytoestrogens genistein and daidzein are non-selective ERR agonists, while XCT790 has been identified as a potent and selective inverse agonist of ERRα.
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Methylation of CpG islands is shown to reduce gene expression by the formation of tightly condensed heterochromatin that is transcriptionally inactive. CpG sites in a gene are most commonly found in the promoter regions of a gene while also being present in non promoter regions. The CpG sites in non promoter regions tend to be constitutively methylated, causing transcription machinery to ignore them as possible promoters. The CpG site near promoter regions are mostly left unmethylated until a cell decides to methylate them and repress transcription.
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All of these receptors contain LIR consensus sequences that bind LC3/GABARAP which can lead to the degradation of the mitochondria. In hypoxic conditions BNIP3 is upregulated by HIF1α. BNIP3 is then phosphorylated at its serine residues near the LIR sequence which promotes LC3 binding. FUNDCI is also hypoxia sensitive, although it is constitutively present at the outer mitochondrial membrane during normal conditions In neurons, mitochondria are distributed unequally throughout the cell to areas where energy demand is high, like at synapses and Nodes of Ranvier.
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They used pathway modulators outside of core cascade, Ste50 promotes activation of Ste11 by Ste20; Msg5 (negative, red) is MAPK phosphatase that deactivates Fus3 (Fig.2A). What they built was circuit with enhanced ultrasensitive switch behavior by constitutively expressing a negative modulator, Msg5 which is one of MAPK phoaphatase and inducibly expressing a positive modulator, Ste50 which is pathway modulators outside of core cascade(Fig.2B). The success of this recruitment-based engineering strategy suggests that it may be possible to reprogram cellular responses with high precision.
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RANK is constitutively expressed in mammary epithelial tissues. Calcium transferred from mother to fetus and neonate is provided by the degradation of the female bone by increased osteoclastic activity, which is regulated by the RANK/RANKL axis. RANKL also works through RANK to provide proliferative and survival signals to promote the final stages of lactating mammary gland development. Dysfunctional RANK or RANKL causes the arrest of differentiation and expansion of the alveolar bunds into mature lobulo-alveolar mammary structures, disabling the production of milk.
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Large scale studies such as The Cancer Genome Atlas have characterized recurrent somatic alterations likely driving initiation and development of cutaneous melanoma. The most frequent mutation occurs in the 600th codon of BRAF (50% of cases). BRAF is normally involved in cell growth and this specific mutation renders the protein constitutively active and independent of normal physiological regulation, thus fostering tumor growth. RAS genes (NRAS, HRAS and KRAS) are also recurrently mutated (30% of TCGA cases) and mutations in the 61st or 12th codons trigger oncogenic activity.
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Melanization may come at some metabolic cost to the fungal cells. In the absence of radiation, some non- melanized fungi (that had been mutated in the melanin pathway) grew faster than their melanized counterparts. Limited uptake of nutrients due to the melanin molecules in the fungal cell wall or toxic intermediates formed in melanin biosynthesis have been suggested to contribute to this phenomenon. It is consistent with the observation that despite being capable of producing melanin, many fungi do not synthesize melanin constitutively (i.e.
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CENP-H localizes outside of centromeric heterochromatin, where CENP-B is localized, and inside the kinetochore corona, where CENP-E is localized during prometaphase. It is thought that this protein can bind to itself, as well as to CENP-A, CENP-B or CENP-C. Multimers of the protein localize constitutively to the inner kinetochore plate and play an important role in the organization and function of the active centromere-kinetochore complex. CENP-H contains a coiled-coil structure and a nuclear localisation signal.
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STAT5 has been found to be constitutively phosphorylated in cancer cells, implying that the protein is always present in its active form. This constant activation is brought about either by mutations or by aberrant expressions of cell signalling, resulting in poor regulation, or complete lack of control, of the activation of transcription for genes influenced by STAT5. This leads to constant and increased expression of these genes. For example, mutations may lead to increased expression of anti-apoptotic genes, the products of which actively prevent cell death.
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Since the ERK signaling pathway is involved in both physiological and pathological cell proliferation, it is natural that ERK1/2 inhibitors would represent a desirable class of antineoplastic agents. Indeed, many of the proto-oncogenic "driver" mutations are tied to ERK1/2 signaling, such as constitutively active (mutant) receptor tyrosine kinases, Ras or Raf proteins. Although no MKK1/2 or ERK1/2 inhibitors were developed for clinical use, kinase inhibitors that also inhibit Raf kinases (e.g. Sorafenib) are successful antineoplastic agents against various types of cancer.
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Histological analysis revealed that the meningeal lymphatics constitutively contain T cells, B cells, and MHC class II-expressing myeloid cells, demonstrating that meningeal lymphatic vessels are capable of carrying immune cells. Furthermore, tracing the outflow of compounds injected into the brain parenchyma have indicated that meningeal lymphatics function downstream of the glymphatic system. Genetically engineered mice which lack the meningeal lymphatic vessels demonstrated attenuated clearance of macromolecules from the brain. The uptake of tracers from the brain into deep cervical lymph nodes was completely abrogated.
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Each HSF monomer contains one C-terminal and three N-terminal leucine zipper repeats. Point mutations in these regions result in disruption of cellular localisation, rendering the protein constitutively nuclear in humans. Two sequences flanking the N-terminal zippers fit the consensus of a bi-partite nuclear localization signal (NLS). Interaction between the N- and C-terminal zippers may result in a structure that masks the NLS sequences: following activation of HSF, these may then be unmasked, resulting in relocalisation of the protein to the nucleus.
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Inappropriate activation of the gene has been shown to play a key role in improper signal transduction, proliferation and malignant transformation. Mutations in a number of different genes as well as RAS itself can have this effect. Oncogenes such as p210BCR-ABL or the growth receptor erbB are upstream of Ras, so if they are constitutively activated their signals will transduce through Ras. The tumour suppressor gene NF1 encodes a Ras-GAP - its mutation in neurofibromatosis will mean that Ras is less likely to be inactivated.
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He explains that "the concepts of the social sciences are not produced about an independently constituted subject-matter, which continues regardless of what these concepts are. The findings of the social sciences very often enter constitutively into the world they describe."Giddens, The Constitution of Society (Cambridge: Polity, 1984), p. 20. Philosopher Dimitri Ginev said that since the 1970s, discussions about double hermeneutics in postempiricist epistemology and in critical theory have led to "a tendency to oppose the methodological to the ontological reading of double hermeneutics".
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Interleukin 3 (IL3) is a cytokine that regulates hematopoiesis by controlling the production, differentiation and function of granulocytes and macrophages. The protein, which exists in vivo as a monomer, is produced in activated T cells and mast cells, and is activated by the cleavage of an N-terminal signal sequence. IL3 is produced by T lymphocytes and T-cell lymphomas only after stimulation with antigens, mitogens, or chemical activators such as phorbol esters. However, IL3 is constitutively expressed in the myelomonocytic leukaemia cell line WEHI-3B.
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Bacterial quorum sensing Bioluminescence in bacteria can be regulated through a phenomenon known as autoinduction or quorum sensing. Quorom sensing is a form of cell-to-cell communication that alters gene expression in response to cell density. Autoinducer is a diffusible pheromone produced constitutively by bioluminescent bacteria and serves as an extracellular signalling molecule. When the concentration of autoinducer secreted by bioluminescent cells in the environment reaches a threshold (above 107 cells per mL), it induces the expression of luciferase and other enzymes involved in bioluminescence.
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In myeloid cells, IRF8 regulates the expression of Bax and Fas to regulate apoptosis. In chronic myelogenous leukemia (CML), IRF8 regulates acid ceramidase to mediate CML apoptosis. IRF8 is highly expressed in myeloid cells and was originally identified in as a critical lineage-specific transcription factor for myeloid cell differentiation, recent studies, however, have shown that IRF8 is also constitutively expressed in non- hematopoietic cancer cells, albeit at a lower level. Furthermore, IRF8 can also be up-regulated by IFN-γ in non-hemotopoietic cells.
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Small molecule allosteric activators of PDPK1 were shown to selectively inhibit activation of substrates that require docking site interaction. These compounds do not bind to the active site and allow PDPK1 to activate other substrates that do not require docking site interaction. PDPK1 is constitutively active and at present, there is no known inhibitor proteins for PDPK1. The activation of PDPK1's main effector, AKT, is believed to require a proper orientation of the kinase and PH domains of PDPK1 and AKT at the membrane.
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The enzyme also influences activity of macrophages by cleaving their toll-like receptors (TLRs) and downregulating cytokine expression by inhibiting nuclear translocation of NF-κB. In Familial Mediterranean fever (FMF), a mutation in the pyrin (or marenostrin) gene, which is expressed mainly in neutrophil granulocytes, leads to a constitutively active acute-phase response and causes attacks of fever, arthralgia, peritonitis, and – eventually – amyloidosis. Decreases in neutrophil function have been linked to hyperglycemia. Dysfunction in the neutrophil biochemical pathway myeloperoxidase as well as reduced degranulation are associated with hyperglycemia.
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Unlike most other Bordetella toxins, tracheal cytotoxin is expressed constitutively, being a normal product of the breakdown of the bacterial cell wall. Other bacteria recycle this molecule back into the cytoplasm, but in Bordetella and Neisseria gonorrhoeae, it is released into the environment. Tracheal cytotoxin itself is able to reproduce paralysis of the ciliary escalator, inhibition of DNA synthesis in epithelial cells and ultimately killing of the same. One of the most important of the regulated toxins is adenylate cyclase toxin, which aids in the evasion of innate immunity.
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Upon UV-B irradiation, light is absorbed by one or more Trp residues which are situated adjacent to Arg residues which form salt bridges across the dimer interface. It is thought that this light absorption induces the disruption of the salt- bridges and thus leads to the molecule's monomerization. Following monomerization, UVR8 accumulates in the nucleus where it interacts with a protein called constitutively photomorphogenic 1 (COP1). COP1 is known to act as an E3 Ubiquitin ligase that targets key transcription factors for ubiquitination and proteasome-mediated degradation.
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Thus, the use of siRNAs has great potential to be a human therapeutic, as it can target and silence the expression of potentially any protein you want. A problem arises when siRNA expression in a cell cannot be controlled, allowing its constitutive expression to cause toxic side-effects. With regard to practical treatment of cancer, it is required to either deliver the siRNAs specifically into cancer cells or control the siRNA expression. Previous methods of siRNA therapy employ the use of siRNA sequences cloned into vectors under the control of constitutively active promoters.
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CTLA4 or CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), also known as CD152 (cluster of differentiation 152), is a protein receptor that functions as an immune checkpoint and downregulates immune responses. CTLA4 is constitutively expressed in regulatory T cells but only upregulated in conventional T cells after activation – a phenomenon which is particularly notable in cancers. It acts as an "off" switch when bound to CD80 or CD86 on the surface of antigen-presenting cells. The CTLA-4 protein is encoded by the Ctla4 gene in mice and the CTLA4 gene in humans.
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The protein encoded by this gene is a member of the MAP (mitogen-activated protein) kinase family. MAP kinases are also known as extracellular signal-regulated kinases (ERKs), and are involved in signaling cascades that regulate a number of cellular processes, including proliferation, differentiation, and transcriptional regulation. MAPK15 is often referred to as ERK7 or ERK8, and the latter two share 69% amino acid sequence similarity; at least one study has suggested that the two are, in fact, distinct proteins. In vertebrate models, ERK8 is not constitutively active, and exhibits relatively low basal kinase activity.
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Sialyl Lewis X is also one of the most important blood group antigens and is displayed on the terminus of glycolipids that are present on the cell surface. The sialyl Lewis X determinant, E-selectin ligand carbohydrate structure, is constitutively expressed on granulocytes and monocytes and mediates inflammatory extravasation of these cells. Resting T- and B-lymphocytes lack its expression and are induced to strongly express sialyl Lewis X upon activation. The sialyl Lewis X determinant is expressed preferentially on activated Th1 cells but not on Th2 cells.
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The cytoplasmic domain of RANK binds TRAFs 1, 2, 3, 5, and 6 which transmit signals to downstream targets such as NF-κB and JNK. RANK is constitutively expressed in skeletal muscle, thymus, liver, colon, small intestine, adrenal gland, osteoclast, mammary gland epithelial cells, prostate, vascular cell, and pancreas. Most commonly, activation of NF-κB is mediated by RANKL, but over-expression of RANK alone is sufficient to activate the NF-κB pathway. RANKL (receptor activator for nuclear factor κ B ligand) is found on the surface of stromal cells, osteoblasts, and T cells.
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Cholesterol binds to and affects the gating of a number of ion channels such as the nicotinic acetylcholine receptor, GABAA receptor, and the inward-rectifier potassium channel. Cholesterol also activates the estrogen- related receptor alpha (ERRα), and may be the endogenous ligand for the receptor. The constitutively active nature of the receptor may be explained by the fact that cholesterol is ubiquitous in the body. Inhibition of ERRα signaling by reduction of cholesterol production has been identified as a key mediator of the effects of statins and bisphosphonates on bone, muscle, and macrophages.
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In transgenic mice engineered to constitutively express FDC-SP, the number and size of GCs formed after immunization with a T-dependent antigen significantly decreased. The position of these GCs is normal, but they do not form centres of highly- proliferating B cells, which us thought be due to FDC-SP affecting the development of GCs. The mechanism by which FDC-SP exerts its effects upon GC development is not currently known. The formation of FDC networks appears to be normal in transgenic mice, as does T cell response.
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Extracellular enzyme production supplements the direct uptake of nutrients by microorganisms and is linked to nutrient availability and environmental conditions. The varied chemical structure of organic matter requires a suite of extracellular enzymes to access the carbon and nutrients embedded in detritus. Microorganisms differ in their ability to break down these different substrates and few organisms have the potential to degrade all the available plant cell wall materials. To detect the presence of complex polymers, some exoenzymes are produced constitutively at low levels, and expression is upregulated when the substrate is abundant.
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Preference for members of the Src family varies, with mouse and hamster polyomavirus MTags having different distributions. Once phosphorylated, MTag interacts with and activates downstream signaling pathways through Shc, 14-3-3 proteins, phosphoinositide 3-kinase, and phospholipase Cγ1. The signaling functions of the phosphorylated MTag have been described as behaving like a mimic of a constitutively active receptor tyrosine kinase. Studies of MTag have often concentrated on its role in cellular transformation more than its natural role in the life cycles of the polyomaviruses in which it occurs.
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The “grow slow and moult” model describes a potential mechanism of de novo gene birth, particular to protein-coding genes. In this scenario, existing protein-coding ORFs expand at their ends, especially their 3’ ends, leading to the creation of novel N- and C-terminal domains. Novel C-terminal domains may first evolve under weak selection via occasional expression through read-through translation, as in the preadaptation model, only later becoming constitutively expressed through a mutation that disrupts the stop codon. Genes experiencing high translational readthrough tend to have intrinsically disordered C-termini.
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SK channels are activated by the binding of intracellular Ca2+ to the protein calmodulin, which is constitutively associated to the channel. Transport of potassium ions out of the cell along their concentration gradient causes the membrane potential to become more negative. The SK channels are present in a wide range of excitable and non-excitable cells, including cells in the central nervous system, intestinal myocytes, endothelial cells, and hepatocytes. Binding of apamin to SK channels is mediated by amino acids in the pore region as well as extracellular amino acids of the SK channel.
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Phyllogens interact directly with class A and class E MTFs, inducing protein degradation in a ubiquitin/proteasome-dependent manner that, at least for SAP54, is dependent on interactions with the proteasome shuttle factor RAD23. Interestingly, RAD23 mutants do not show phyllody when infected with phytoplasma indicating that RAD23 proteins are susceptibility factors; i.e. phytoplasmas and SAP54 require these plant proteins to induce phyllody symptoms. The accumulation of mRNAs encoding class B MTFs, the transcription of which is positively regulated by class A and class E MTFs, is drastically decreased in Arabidopsis constitutively expressing PHYL1.
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These include an immunity gene, a colicin structural gene, and a bacteriocin release protein (BRP), or lysis, gene. The immunity gene is often produced constitutively, while the BRP is generally produced only as a read-through of the stop codon on the colicin structural gene. The colicin itself is repressed by the SOS response and may be regulated in other ways, as well. Retaining the colicin plasmid is very important for cells that live with their relatives, because if a cell loses the immunity gene, it quickly becomes subject to destruction by circulating colicin.
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Silmitasertib (INN), codenamed CX-4945, is a small-molecule inhibitor of protein kinase CK2 (casein kinase II), a constitutively active serine/threonine-specific protein kinase that is overexpressed in several types of tumors. Silmitasertib is in clinical trials for use as an adjunct to chemotherapy in the treatment of cholangiocarcinoma (bile duct cancer), and in preclinical development for other cancers, including hematological and lymphoid malignancies. In January 2017, it was granted orphan drug status by the U.S. Food and Drug Administration for advanced cholangiocarcinoma. It is being developed by Senhwa Biosciences of Taiwan.
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More over, the ribosome is proposed to only block about 10 nts downstream, thus ribosome stalling in either the upstream Gly or further downstream Thr do not seem to affect the formation of the termination hairpin. The end result is that the operon will be transcribed only when tryptophan is unavailable for the ribosome, while the trpL transcript is constitutively expressed. This attenuation mechanism is experimentally supported. First, the translation of the leader peptide and ribosomal stalling are directly evidenced to be necessary for inhibiting the transcription termination.
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While ARHI is constitutively expressed in normal ovarian and breast epithelial cells, it is absent in cancers found in these tissues where no expression of ARHI has been detected. In non-cancerous cells growth factor signals associate ARHI N- and C-terminally to the plasma membrane, where it can interact with C-RAF. This interaction inhibits the activation of MEK and ERK and even cell migration. In cancer tissues, where ARHI is not expressed, cells will thus migrate; this possibly is a cause for metastasis especially in breast cancer.
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MHC class II molecules are differentially expressed across multiple cell-types. For example, MHC II molecules are constitutively expressed in thymic epithelial cells and antigen- presenting cells (APC's), whereas they undergo interferon-γ-mediated expression in other cell types. Central to the regulation of the complex gene- expression profile exhibited by MHC class II molecules is a single master regulatory factor known as the class II transactivator (CIITA). CIITA is a non-DNA-binding co-activator whose expression is tightly controlled by a regulatory region containing three independent promoters (pI, pIII and pIV).
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Essential for the differentiation and survival of sympathetic neurons and chromaffin cells, the transcription factor PHOX2B is highly specific for the peripheral autonomic nervous system. Neuroblasts are derived from sympathoadrenal lineage neural crest cells and therefore require and constitutively express PHOX2B. PHOX2B immunohistochemical staining, as a marker of neural crest derivation, has been shown to be sensitive and specific for undifferentiated neuroblastoma, enabling identification where other markers fail to recognize neuroblastoma among various different small round blue cell tumors of childhood. The diagnostic utility of PHOX2B staining extends to later stages of differentiation.
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NF-κB is widely used by eukaryotic cells as a regulator of genes that control cell proliferation and cell survival. As such, many different types of human tumors have misregulated NF-κB: that is, NF-κB is constitutively active. Active NF-κB turns on the expression of genes that keep the cell proliferating and protect the cell from conditions that would otherwise cause it to die via apoptosis. In cancer, proteins that control NF- κB signaling are mutated or aberrantly expressed, leading to defective coordination between the malignant cell and the rest of the organism.
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Loss-of-function mutations in the STAT3 gene result in Hyperimmunoglobulin E syndrome, associated with recurrent infections as well as disordered bone and tooth development. Gain-of-function mutations in the STAT3 gene have been reported to cause multi-organ early onset auto- immune diseases; such as thyroid disease, diabetes, intestinal inflammation, and low blood counts, while constitutive STAT3 activation is associated with various human cancers and commonly suggests poor prognosis. It has anti- apoptotic as well as proliferative effects. STAT3 can promote oncogenesis by being constitutively active through various pathways as mentioned elsewhere.
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Tumor necrosis factor receptor superfamily, member 4 (TNFRSF4), also known as CD134 and OX40 receptor, is a member of the TNFR-superfamily of receptors which is not constitutively expressed on resting naïve T cells, unlike CD28. OX40 is a secondary co-stimulatory immune checkpoint molecule, expressed after 24 to 72 hours following activation; its ligand, OX40L, is also not expressed on resting antigen presenting cells, but is following their activation. Expression of OX40 is dependent on full activation of the T cell; without CD28, expression of OX40 is delayed and of fourfold lower levels.
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These are typically allosterically-controlled enzymes, tightly locked into an inactive state by multiple mechanisms. The first step en route to their activation consist of relieving their autoinhibition by a smaller ligand (such as Ras for c-Raf, GADD45 for MEKK4 or Cdc42 for MLK3). This commonly (but not always) happens at the cell membrane, where most of their activators are bound (note that small G-proteins are constitutively membrane-associated due to prenylation). That step is followed by side-to-side homo- and heterodimerisation of their now accessible kinase domains.
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The proteasome plays a straightforward but critical role in the function of the adaptive immune system. Peptide antigens are displayed by the major histocompatibility complex class I (MHC) proteins on the surface of antigen-presenting cells. These peptides are products of proteasomal degradation of proteins originated by the invading pathogen. Although constitutively expressed proteasomes can participate in this process, a specialized complex composed of proteins, whose expression is induced by interferon gamma, are the primary producers of peptides which are optimal in size and composition for MHC binding.
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The function of this protein has been found, in Drosophila to inhibit branching of the trachea by antagonizing the BNL-FGF pathway. Also in Drosophila it is an antagonist of EGFR-mediated signaling in the eye. Most notably, in humans, it suppresses the insulin receptor and EGFR-transduced MAPK signaling pathway, but does not inhibit MAPK activation by a constitutively active mutant Ras. Sprouty inhibits of the Ras/mitogen- activated protein kinase (MAPK) cascade, a pathway crucial for developmental processes initiated by activation of various receptor tyrosine kinases.
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CAR is a member of the nuclear receptor superfamily, and is a key regulator of xenobiotic and metabolism. Unlike most nuclear receptors, this transcriptional regulator is constitutively active in the absence of ligand and is regulated by both agonists and inverse agonists. Ligand binding results in translocation of CAR from the cytosol into the nucleus, where the protein can bind to specific DNA sites, called response elements. Binding occurs both as a monomer and together with the retinoid X receptor (RXR) resulting in activation or repression of target gene transcription.
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Cartilage is not able to fully develop into bone, causing the individual to be disproportionately shorter in height. In normal development FGFR3 has a negative regulatory effect on bone growth. In achondroplasia, the mutated form of the receptor is constitutively active and this leads to severely shortened bones. The effect is genetically dominant, with one mutant copy of the FGFR3 gene being sufficient to cause achondroplasia, while two copies of the mutant gene are invariably fatal (recessive lethal) before or shortly after birth (known as a lethal allele).
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Hartelius further suggests that Wikipedia's dialogic construction of expertise illustrates both the instrumental and the constitutive dimensions of rhetoric; instrumentally as it challenges traditional encyclopedias and constitutively as a function of its knowledge production. Going over the historical development of the encyclopedic project, Hartelius argues that changes in traditional encyclopedias have led to changes in traditional expertise. Wikipedia's use of hyperlinks to connect one topic to another depends on, and develops, electronic interactivity meaning that Wikipedia's way of knowing is dialogic. Dialogic expertise then, emerges from multiple interactions between utterances within the discourse community.
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It is a type I transmembrane protein present on activated T cells, activated B cells, some thymocytes, myeloid precursors, and oligodendrocytes. Though IL2RA has been used as a marker to identify CD4+FoxP3+ regulatory T cells in mice, it has been found that a large proportion of resting memory T cells constitutively express IL2RA in humans. IL2RA is expressed in most B-cell neoplasms, some acute nonlymphocytic leukemias, neuroblastomas, mastocytosis and tumor infiltrating lymphocytes. It functions as the receptor for HTLV-1 and is consequently expressed on neoplastic cells in adult T cell lymphoma/leukemia.
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The mechanism behind behavioral changes is partially attributed to increased dopamine metabolism, which can be neutralized by dopamine antagonist medications. T. gondii has two genes that code for a bifunctional phenylalanine and tyrosine hydroxylase, two important and rate-limiting steps of dopamine biosynthesis. One of the genes is constitutively expressed, while the other is only produced during cyst development. In addition to additional dopamine production, T. gondii infection also produces long-lasting epigenetic changes in animals that increase the expression of vasopressin, a probable cause of alternations that persist after the clearance of the infection.
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In addition to sarcomeres, PKCε also targets cardiac mitochondria. Proteomic analysis of PKCε signaling complexes in mice expressing a constitutively-active, overexpressed PKCε identified several interacting partners at mitochondria whose protein abundance and posttranslational modifications were altered in the transgenic mice. This study was the first to demonstrate PKCε at the inner mitochondrial membrane, and it was found that PKCε binds several mitochondrial proteins involved in glycolysis, TCA cycle, beta oxidation, and ion transport. However, it remained unclear how PKCε translocates from the outer to inner mitochondrial membrane until Budas et al.
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FOXO3 belongs to the O subclass of the forkhead family of transcription factors which are characterized by a distinct fork head DNA-binding domain. There are three other FoxO family members in humans, FOXO1, FOXO4 and FOXO6. These transcription factors share the ability to be inhibited and translocated out of the nucleus on phosphorylation by proteins such as Akt/PKB in the PI3K signaling pathway (aside from FOXO6, which may be constitutively nuclear). Other post-translational modifications including acetylation and methylation are seen and can result in increased or altered FOXO3a activity.
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Phylogenomic analysis indicates that enzymes with true CCR activity first evolved in the of land plants. Most if not all modern land plants and all vascular plants are believed to have at least one functional CCR, an absolute requirement for any plant species with lignified tissues. Most CCR homologs are highly expressed during development, especially in stem, root, and xylem cells which require the enhanced structural support provided by lignin. However, certain CCRs are not constitutively expressed throughout development and are only up-regulated during enhanced lignification in response to stressors such as pathogen attack.
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This mechanism of action was elucidated in 1970 by John Vane (1927–2004), who received a Nobel Prize for his work (see Mechanism of action of aspirin). COX-1 is a constitutively expressed enzyme with a "house-keeping" role in regulating many normal physiological processes. One of these is in the stomach lining, where prostaglandins serve a protective role, preventing the stomach mucosa from being eroded by its own acid. COX-2 is an enzyme facultatively expressed in inflammation, and it is inhibition of COX-2 that produces the desirable effects of NSAIDs.
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In general, HSPA1L is widely distributed across tissues at low abundances, but in particular, it is constitutively and abundantly expressed in the testis. Along with other heat shock proteins, this protein stabilizes existing proteins against aggregation and mediates the folding of newly translated proteins in the cytosol and in organelles. In order to properly fold non-native proteins, this protein interacts with the hydrophobic peptide segments of proteins in an ATP- controlled fashion. Though the exact mechanism still remains unclear, there are at least two alternative modes of action: kinetic partitioning and local unfolding.
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The co-expression of this and IL12Rβ1 proteins was shown to lead to the formation of high-affinity IL12 binding sites and reconstitution of IL12 dependent signaling. While the IL12Rβ1 subunit is constitutively expressed, the expression of the IL12RB2 gene is up- regulated by interferon gamma. In Th1 cells, IL-12 signaling through the IL12 receptor leads to the phosphorylation of STAT4 and continued Th1 differentiation. The IL12Rβ2 subunit plays an important role in Th1 cell differentiation, since its absence leads to an abortive Th1 differentiation that has dysfunctional production of Th1 effector molecules.
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Reporter genes can be used to assay for the expression of a gene of interest that is normally difficult to quantitatively assay. Reporter genes can produce a protein that has little obvious or immediate effect on the cell culture or organism. They are ideally not present in the native genome to be able to isolate reporter gene expression as a result of the gene of interest's expression. To activate reporter genes, they can be expressed constitutively, where they are directly attached to the gene of interest to create a gene fusion.
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According to Eduard Jordaan of Singapore Management University: > All middle powers display foreign policy behaviour that stabilises and > legitimises the global order, typically through multilateral and cooperative > initiatives. However, emerging and traditional middle powers can be > distinguished in terms of their mutually-influencing constitutive and > behavioural differences. Constitutively, traditional middle powers are > wealthy, stable, egalitarian, social democratic and not regionally > influential. Behaviourally, they exhibit a weak and ambivalent regional > orientation, constructing identities distinct from powerful states in their > regions and offer appeasing concessions to pressures for global reform.
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An inverse agonist can have effects similar to those of an antagonist, but causes a distinct set of downstream biological responses. Constitutively active receptors that exhibit intrinsic or basal activity can have inverse agonists, which not only block the effects of binding agonists like a classical antagonist but also inhibit the basal activity of the receptor. Many drugs previously classified as antagonists are now beginning to be reclassified as inverse agonists because of the discovery of constitutive active receptors. Antihistamines, originally classified as antagonists of histamine H1 receptors have been reclassified as inverse agonists.
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COX-1 is traditionally defined as a constitutively expressed "housekeeping" enzyme and plays a role in the protection of the gastrointestinal mucosa, kidney hemodynamics, and platelet thrombogenesis. COX-2, on the contrary, is extensively expressed in cells involved in inflammation and is upregulated by bacterial lipopolysaccharides, cytokines, growth factors, and tumor promoters. Celecoxib is approximately 10-20 times more selective for COX-2 inhibition over COX-1. It binds with its polar sulfonamide side chain to a hydrophilic side pocket region close to the active COX-2 binding site.
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Since many bHLH transcription factors are heterodimeric, their activity is often highly regulated by the dimerization of the subunits. One subunit's expression or availability is often controlled, whereas the other subunit is constitutively expressed. Many of the known regulatory proteins, such as the Drosophila extramacrochaetae protein, have the helix-loop-helix structure but lack the basic region, making them unable to bind to DNA on their own. They are, however, able to form heterodimers with proteins that have the bHLH structure, and inactivate their abilities as transcription factors.
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Phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) is one of the seven phosphoinositides found in eukaryotic cell membranes.Di Paolo G, De Camilli P. Phosphoinositides in cell regulation and membrane dynamics. Nature. 2006 Oct 12;443(7112):651-7. In quiescent cells, the PtdIns(3,5)P2 levels, typically quantified by HPLC, are the lowest amongst the constitutively present phosphoinositides. They are approximately 3 to 5-fold lower as compared to PtdIns3P and PtdIns5P (Phosphatidylinositol 5-phosphate) levels, and more than 100-fold lower than the abundant PtdIns4P (Phosphatidylinositol 4-phosphate) and PtdIns(4,5)P2.
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Two-pore channels were analyzed by using cell biological methods, endolysosomal patch clamp techniques, and a variety of other methods to study their functions. From these, it was suggested that TPCs have some power in controlling the luminal pH in endolysosomal vesicles. When TPC2 expression is decreased or knocked out, there is a resultant elevation in production of melanin and thus melanosomal pH, and when TPC2 expression is increased, there is less production of melanin. TPCs also are involved in nutrient detection as they become active constitutively on identifying the status of the nutrients.
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Model of the AMP drosomycin Drosomycin is an antifungal peptide from Drosophila melanogaster and was the first antifungal peptide isolated from insects. Drosomycin is induced by infection by the Toll signalling pathway, while expression in surface epithelia like the respiratory tract is instead controlled by the immune deficiency pathway (Imd). This means that drosomycin, alongside other antimicrobial peptides (AMPs) such as cecropins, diptericin, drosocin, metchnikowin and attacin, serves as a first line defence upon septic injury. However drosomycin is also expressed constitutively to a lesser extent in different tissues and throughout development.
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When exposed to tamoxifen, the dominant negative fragment changed the conformation of the fusion protein, became active, and could therefore interfere with CREB binding sites. One advantage of this inducible transgenic system is that the altered protein is constitutively present and can therefore be rapidly activated following the administration of tamoxifen. Use of the LBD system to knock down CREB protein function during training (using both contextual freezing and tone fear paradigms) produced a deficit in long-term, but not short-term, memory. Impairing CREB function did not impair retrieval of the consolidated memory.
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NSAID (non-specific inhibitor of PTGS2 (COX-2)) flurbiprofen (green) bound to PTGS2 (COX-2). Flurbiprofen is stabilized via hydrophobic interactions and polar interactions (Tyr-355 and Arg-120). PTGS2 (COX-2) is unexpressed under normal conditions in most cells, but elevated levels are found during inflammation. PTGS1 (COX-1) is constitutively expressed in many tissues and is the predominant form in gastric mucosa and in the kidneys. Inhibition of PTGS1 (COX-1) reduces the basal production of cytoprotective PGE2 and PGI2 in the stomach, which may contribute to gastric ulceration.
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Selectins are involved in projects to treat osteoporosis, a disease that occurs when bone-creating cells called osteoblasts become too scarce. Osteoblasts develop from stem cells, and scientists hope to eventually be able to treat osteoporosis by adding stem cells to a patient’s bone marrow. Researchers have developed a way to use selectins to direct stem cells introduced into the vascular system to the bone marrow.In the lab of Robert Sackstein Harvard University E-selectins are constitutively expressed in the bone marrow, and researchers have shown that tagging stem cells with a certain glycoprotein causes these cells to migrate to the bone marrow.
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Subsequent reports, however, have varied in results: studies focusing on the allergen and non-allergen reactions find that GPR17-bearing cells do not respond to LTC4, LTD4, and uracil nucleotides while studies focusing on nerve tissue find that certain types of GPR17-bearing oligodendrocytes do indeed respond to them. In 2013 and 2014 reports, the International Union of Basic and Clinical Pharmacology took no position on which of these are true ligands for GPR17. GPR17 is a constitutively active receptor, i.e. a receptor that has baseline activity which is independent of, although potentially increased by, its ligands.
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Heat shock protein beta-6 is a protein that in humans is encoded by the HSPB6 gene. HSPB6 also known as hsp20 is a 17-kDa member of the small heat shock family of proteins. HSPB6 was first identified in 1994 when it was isolated from rat and human skeletal muscle as a complex with HSPB1 (also known as HSP27) and HSPB5 (also known as αB-crystallin). HSPB6 is expressed in multiple tissues; however, HSPB6 is most highly and constitutively expressed in different types of muscle including vascular, airway, colonic, bladder, uterine smooth muscle, cardiac muscle and skeletal muscle.
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IL-15 was discovered in 1994 by two different laboratories, and characterized as T cell growth factor. Together with Interleukin-2 (IL-2), Interleukin-4 (IL-4), Interleukin-7 (IL-7), Interleukin-9 (IL-9), granulocyte colony-stimulating factor (G-CSF), and granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-15 belongs to the four α-helix bundle family of cytokines. IL-15 is constitutively expressed by a large number of cell types and tissues, including monocytes, macrophages, dendritic cells (DC), keratinocytes, fibroblasts, myocyte and nerve cells. As a pleiotropic cytokine, it plays an important role in innate and adaptive immunity.
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The human TUBB3 gene is located on chromosome 16q24.3, and consists of 4 exons that transcribe a protein of 450aa. A shorter isoform of 378aa derived from alternative splicing of exon 1 is devoid of part of the N-terminus and may be responsible for mitochondrial expression. Like other β-tubulin isotypes, βIII- tubulin has a GTPase domain which plays an essential role in regulating microtubule dynamics. Differences between Class I (the most commonly represented and constitutively expressed isotype) and class III β-tubulin are limited to only 13aa within region 1-429aa, while all amino acids in region 430-450aa are divergent.
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The Ras/RAF/MEK/ERK pathway is also implicated in overexpression of osteopontin (OPN), which is important for maintenance of the hematopoietic stem cell niche, which indirectly influences unchecked proliferation characteristic of leukemic cells. BCR-ABL fusion cells also exhibit constitutively high levels of activated Ras bound to GTP, activating a Ras-dependent signaling pathway which has been shown to inhibit apoptosis downstream of BCR-ABL (Cortez et al). Interactions with the IL-3 receptor also induce the Ras/RAF/MEK/ERK pathway to phosphorylate transcription factors which play a role in driving the G1/S transition of the cell cycle.
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Tyrosine kinase inhibitors (such as sunitinib, pazopanib, and dasatinib) have shown some effect against several cancer types, most notably Imatinib-mesylate in gastrointestinal stromal tumors (GISTs). Tyrosine kinase (a subclass of protein kinases) is an enzyme that transfers a phosphate group from an ATP molecule to a protein in a cell. It functions as an “on” or “off” switch for many cellular functions, including signaling within the cell, and cell division. Tyrosine kinases can contain mutations that cause them to become constitutively active, or stuck in the “on” position, resulting in unregulated cell division (a hallmark of cancer).
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As nocodazole affects the cytoskeleton, it is often used in cell biology experiments as a control: for example, some dominant negative Rho small GTPases cause a similar effect as nocodazole, and constitutively activated mutants often reverse or negate the effect. Nocodazole is frequently used in cell biology laboratories to synchronize the cell division cycle. Cells treated with nocodazole arrest with a G2- or M-phase DNA content when analyzed by flow cytometry. Microscopy of nocodazole-treated cells shows that they do enter mitosis but cannot form metaphase spindles because microtubules (of which the spindles are made) cannot polymerise.
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The FGFR2lllc isoform, created via alternative splicing of exon 3 of the FGFR2 gene, uses exon 9 and is used in mesenchymal stem cells to control ossification. However, the mutation constitutively activates the transmembrane protein via a disulfide bond formed incorrectly due to the loss of cysteine 342. FGFR3 is expressed more in the frontal bones during embryonic development, guiding cranial bone development. A point mutation causes constitutive activation of tyrosine in the activation loop, located in the cytosolic region of the protein, leading to accelerated differentiation of frontal osteoblasts, resulting in premature fusion of frontal cranial bones.
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The SCN is situated in the anterior part of the hypothalamus immediately dorsal, or superior (hence supra) to the optic chiasm (CHO) bilateral to (on either side of) the third ventricle. The nucleus can be divided into ventrolateral and dorsolateral portions, also known as the core and shell, respectively. These regions differ in their expression of the clock genes, the core expresses them in response to stimuli whereas the shell expresses them constitutively. In terms of projections, the core receives innervation via three main pathways, the retinohypothalamic tract, geniculohypothalamic tract, and projections from some Raphe nuclei.
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One study demonstrated that imatinib mesylate was effective in patients with systemic mastocytosis, including those who had the D816V mutation in c-KIT. However, since imatinib binds to tyrosine kinases when they are in the inactive configuration and the D816V mutant of c-KIT is constitutively active, imatinib does not inhibit the kinase activity of the D816V mutant of c-KIT. Experience has shown, however, that imatinib is much less effective in patients with this mutation, and patients with the mutation comprise nearly 90% of cases of mastocytosis. Imatinib was initially thought to have a potential role in the treatment of pulmonary hypertension.
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When beads were placed in the middle of the flank tissue, the anterior portion expressed Tbx5 and forelimb features, while the posterior portion of the limb expressed Tbx4 and hindlimb features. #When chick embryos were engineered to constitutively express Tbx4 (via viral- transfection) throughout their flank tissue, every limb they grew was a leg, even those that formed in the anterior region, which would normally become wings. This confirms the role of T-box proteins in the type of limb that develops. #Knocking out Tbx4 or Tbx5 knockout prevents FGF10 expression in the lateral plate mesoderm in mice.
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They were originally classified as "constitutively expressed" and "Ca2+ sensitive" but it is now known that they are present in many different cell types and that expression is regulated under specific physiological conditions. In NOS1 and NOS3, physiological concentrations of Ca2+ in cells regulate the binding of calmodulin to the "latch domains", thereby initiating electron transfer from the flavins to the heme moieties. In contrast, calmodulin remains tightly bound to the inducible and Ca2+-insensitive isoform (iNOS or NOS2) even at a low intracellular Ca2+ activity, acting essentially as a subunit of this isoform. Nitric oxide may itself regulate NOS expression and activity.
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SLP-76 also contains a central proline-rich domain and a COOH-terminal SH2 domain. A number of additional proteins have been identified that associate with SLP-76 both constitutively and inducibly following receptor ligation, supporting the notion that SLP-76 functions as an adaptor or scaffold protein. Studies using SLP-76-deficient T cell lines or mice have provided strong evidence that SLP-76 plays a positive role in promoting T cell development and activation as well as mast cell and platelet function. SLP-76 might serve as an integration point for signals by activating NK cell receptors.
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Chemokine (C-X-C motif) ligand 14 (CXCL14) is a small cytokine belonging to the CXC chemokine family that is also known as BRAK (for breast and kidney- expressed chemokine). Mature CXCL14 has many of the conserved features of the CXC chemokine subfamily but has some differences too, such as a shorter N-terminus and five extra amino acids in the region between its third and fourth cysteines. CXCL14 is constitutively expressed at high levels in many normal tissues, where its cellular source is thought to be fibroblasts. However, it is reduced or absent from most cancer cells.
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Ribosomal RNA genes (rDNA) encodes for ribosomal RNA (rRNA) that constitutes the majority of the ribosome. These genes are not constitutively expressed and a mechanism of gene silencing is put in place to suppress rDNA gene expression when the ribosome isn’t required. Gene silencing of rDNA requires binding of the chromatin remodelling complex, NoRC to a non-coding RNA (ncRNA) molecule that is complementary to the rDNA promoter. The ncRNA that is involved in rDNA silencing is known as pRNA and has been shown to originate from a spacer promoter located upstream of the pre-ribosomal RNA transcription start site.
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In the PI3K/AKT/mTOR pathway, AKT1 (also known as Protein Kinase B or PKB) is an important driver of the tumor glycolytic phenotype and stimulates ATP generation. AKT1 stimulates glycolysis by increasing the expression and membrane translocation of glucose transporters and by phosphorylating key glycolytic enzymes, such as hexokinase and phosphofructokinase 2. This leads to inhibition of forkhead box subfamily O transcription factors, leading to the increase of glycolytic capacity. Activated mTOR stimulates protein and lipid biosynthesis and cell growth in response to sufficient nutrient and energy conditions and is often constitutively activated during tumorigenesis.
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Cardiac-specific overexpression of constitutively-active PKCε (9-fold increase in PKCε protein, 4-fold increase in activity) induced cardiac hypertrophy characterizes by enhanced anterior and posterior left ventricular wall thickness. A later study unveiled that the aging of PKCε transgenic mice brought on dilated cardiomyopathy and heart failure by 12 months of age,] characterized by a preserved Frank-Starling mechanism and exhausted contractile reserve. Crossing PKCε transgenic mice with mutant cTnI mice lacking PKCε phosphorylation sites (Serine-43/Serine-45 mutated to Alanine) attenuated the contractile dysfunction and hypertrophic marker expression, offering critical mechanistic insights.
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Furthermore, tyrosine kinases function in many signal transduction cascades wherein extracellular signals are transmitted through the cell membrane to the cytoplasm and often to the nucleus, where gene expression may be modified. Finally mutations can cause some tyrosine kinases to become constitutively active, a nonstop functional state that may contribute to initiation or progression of cancer. Tyrosine kinases function in a variety of processes, pathways, and actions, and are responsible for key events in the body. The receptor tyrosine kinases function in transmembrane signaling, whereas tyrosine kinases within the cell function in signal transduction to the nucleus.
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If after some time the fluorescence doesn't reach the initial level anymore, then some part of the fluorescence is caused by an immobile fraction (that cannot be replenished by diffusion). Similarly, if the fluorescent proteins bind to static cell receptors, the rate of recovery will be retarded by a factor related to the association and disassociation coefficients of binding. This observation has most recently been exploited to investigate protein binding. Similarly, if the GFP labeled protein is constitutively incorporated into a larger complex, the dynamics of fluorescence recovery will be characterized by the diffusion of the larger complex.
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The bioluminescent reaction is as follows: FMNH2 \+ O2 \+ R-CHO -> FMN + H2O + R-COOH + Light (~ 495 nm) Molecular oxygen reacts with FMNH2 (reduced flavin mononucleotide) and a long-chain aldehyde to produce FMN (flavin mononucleotide), water and a corresponding fatty acid. The blue-green light emission of bioluminescence, such as that produced by Photobacterium phosphoreum and Vibro harveyi, results from this reaction. Because light emission involves expending six ATP molecules for each photon, it is an energetically expensive process. For this reason, light emission is not constitutively expressed in bioluminescent bacteria; it is expressed only when physiologically necessary.
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IL-1α is constitutively produced by epithelial cells. It is found in substantial amounts in normal human epidermis and is distributed in a 1:1 ratio between living epidermal cells and stratum corneum. The constitutive production of large amounts of IL-1α precursor by healthy epidermal keratinocytes interfere with the important role of IL-1α in immune responses, assuming skin as a barrier, which prevents the entry of pathogenic microorganisms into the body. The essential role of IL-1α in maintenance of skin barrier function, especially with increasing age, is an additional explanation of IL-1α constitutive production in epidermis.
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IL-1α is a “dual-function cytokine”, which means it plays a role in the nucleus by affecting transcription, as well as its extracellular receptor-mediated effects as a classical cytokine. IL-33 also belongs in this group. IL-1α is synthesized as a precursor protein and it is constitutively stored in the cytoplasm of cells of mesenchymal origin and in epithelial cells. In contrast, monocytes and macrophages do not contain preformed IL-1α precursors, but instead rely on de novo synthesis. The IL-1α precursor is processed to its mature 17-kDa form by a Ca2+-activated protease, calpain.
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Inflammasome activation is known to trigger cleavage, activation and secretion of pro- inflammatory IL-1β and IL-18, which then recruit different types of effector cells and coordinate the innate immune response. Expression of pro-IL-1β is dependent on Toll-like-receptor signaling, and hence intestinal epithelial cells produce very low levels of IL-1β themselves. Pro-IL-18, on the other hand, is constitutively expressed by different kinds of epithelial cells, and readily secreted upon inflammasome activation. The IL-18 secreted by the epithelium can induce production of IFN-γ by different cell types.
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Once the initial cell plate forms at its center, the phragmoplast begins to expand outward to reach the cell edges. Actin filaments also localize to phragmoplast and accumulate greatly at late telophase. Evidence suggests that actin filaments serve phragmoplast expansion more than initial organization, given that disorganization of actin filaments via drug treatments lead to the delay of cell-plate expansion. Many microtubule- associated proteins (MAPs) have been localized to the phragmoplast, including both constitutively expressed ones (such as MOR1, katanin, CLASP, SPR2, and γ-tubulin complex proteins) and those expressed specifically during M-phase, such as EB1c, TANGLED1 and augmin complex proteins.
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These lysine residues are located within the DNA-binding domain; acetylation inhibits the ability of FOXO1 to interact with the glucose-6 phosphatase promoter by decreasing the stability of the FOXO1-DNA complex. Additionally, this acetylation increases the rate of phosphorylation on Ser-253 by Akt. Mutating Ser-253 to Ala-253 makes FOXO1 constitutively active. SIRT1 reverses this acetylation process; however, the exact mechanism by which SIRT1 deacetylates FOXO1 is still under investigation; presently, acetylation is thought to mitigate the transcriptional activity of FOXO1 and thereby provide an additional level of metabolic regulation that is independent of the insulin/PI3K pathway.
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CXCL1 exists as both monomer and dimer and both forms are able to bind chemokine receptor CXCR2. However, CXCL1 chemokine is able to dimerize only at higher (micromolar) concentrations and its concentrations are only nanomolar or picomolar upon normal conditions, which means that the form of WT CXCL1 is more likely monomeric while dimeric CXCL1 is present only during infection or injury. CXCL1 monomer consists of three antiparallel β-strands followed by C- terminal α-helix and this α-helix together with the first β-strand are involved in forming a dimeric globular structure. Upon normal conditions, CXCL1 is not expressed constitutively.
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Bcr-Abl tyrosine-kinase inhibitors (TKI) are the first-line therapy for most patients with chronic myelogenous leukemia (CML). More than 90% of CML cases are caused by a chromosomal abnormality that results in the formation of a so- called Philadelphia chromosome. This abnormality was discovered by Peter Nowell in 1960 and is a consequence of fusion between the Abelson (Abl) tyrosine kinase gene at chromosome 9 and the break point cluster (Bcr) gene at chromosome 22, resulting in a chimeric oncogene (Bcr-Abl) and a constitutively active Bcr-Abl tyrosine kinase that has been implicated in the pathogenesis of CML. Compounds have been developed to selectively inhibit the tyrosine kinase.
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CML has a well defined molecular target and relatively selective therapies aimed at that target, which is not the case for the majority of cancers and chemotherapies today. Bcr-Abl was regarded as highly attractive target for drug intervention since the Bcr-Abl fusion gene encodes a constitutively activated kinase. Drug discovery that specifically targeted the ATP binding site of a single kinase was regarded as quite a challenging task since hundreds of protein kinases were known in the human genome. In the presence of TKI the binding of ATP is blocked, phosphorylation is prevented and Bcr-Abl expressing cells either have a selective growth disadvantage or undergo apoptotic cell death.
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Chemokine (C-C motif) ligand 28 (CCL28), also known as mucosae-associated epithelial chemokine (MEC), CCK1 and SCYA28, is a chemokine. CCL28 regulates the chemotaxis of cells that express the chemokine receptors CCR3 and CCR10. CCL28 is expressed by columnar epithelial cells in the gut, lung, breast and the salivary glands and drives the mucosal homing of T and B lymphocytes that express CCR10, and the migration of eosinophils expressing CCR3. This chemokine is constitutively expressed in the colon, but its levels can be increased by pro-inflammatory cytokines and certain bacterial products implying a role in effector cell recruitment to sites of epithelial injury.
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O6-alkylguanine DNA alkyltransferase II (O6 AGT II) previously known as O6 Guanine transferase (ogt) is a bacterial protein that is involved in DNA repair together with Ada ( also known as O6 AGT I). Like AGT I, AGT II is responsible for the removal of alkyl groups from O6-alkyl guanine, O4-alkyl thymine and alkyl phosphotriester in the sugar-phosphate backbone of DNA. AGT II shows a greater preference for O4-alkyl thymine than O6-alkyl guanine and alkyl phosphotriester. Unlike Ada, AGT II is expressed constitutively in cells. Therefore, AGT II will repair alkylated DNA adducts even before Ada is fully induced.
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Regulation varies from species to species, and within an organism, chitinases with different physiological functions would be under different regulation mechanisms. For example, chitinases that are involved in maintenance, such as remodeling the cell wall, are constitutively expressed. However, chitinases that have specialized functions, such as degrading exogenous chitin or participating in cell division, need spatio-temporal regulation of the chitinase activity. The regulation of an endochitinase in Trichoderma atroviride is dependent on a N-acetylglucosaminidase, and the data indicates a feedback-loop where the break down of chitin produces N-acetylglucosamine, which would be possibly taken up and triggers up-regulation of the chitinbiosidases.
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Since the EF-hand and SAM (EF-SAM) domains are vital to STIM function and SOCE regulation, they are now discussed in detail. The EF-hand domain is a Ca2+ sensor used by STIM protein to detect changes in Ca2+ concentration inside the S/ER. STIM isoforms become activated when Ca2+ bound to the EF-hand motif is released as a result of a decrease in Ca2+ levels inside the S/ER store after IP3 receptor–mediated depletion. It has been reported that STIM EF-hand mutants that are not able to bind Ca2+ are constitutively active and continually activate SOCE independently of S/ER [Ca2+], in vitro and in vivo.
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Approximately 20% of all examined human tumor samples display a mutated B-Raf gene. The overwhelming majority of these mutations involve the exchange of a single amino acid: Val 600 into Glu, and this aberrant gene product (BRAF-V600E) can be visualized by immunohistochemistry for clinical molecular diagnostics The aberration can mimic the activation loop phosphorylation and - by jumping all control steps at normal activation - immediately render the kinase domain fully active. Since B-Raf can also activate itself by homodimerisation and c-Raf by heterodimerisation, this mutation has a catastrophic effect by turning the ERK1/2 pathway constitutively active, and driving an uncontrolled process of cell division.
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The model of budding yeast size control, in which a threshold size for Start entry is detected by a translational size sensor, required a "sizer" protein; the properties of Cln3 made it the prime candidate for that role from the time of its discovery. First, it was a critical Start activator, as G1 length varied inversely with Cln3 expression and activity levels. Second, it was expressed nearly constitutively throughout the cell cycle and in G1 in particular—unusual for cyclins, which (as their name suggests) oscillate in expression with the cell cycle. These two properties meant that Cln3 could serve as a Start activator that depended on total translation rate.
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PKMζ is an atypical isoform of PKC that lacks a regulatory subunit and thus remains constitutively active. Unlike other kinases that mediate LTP, PKMζ is active not just in the first 30 minutes following LTP induction; rather, PKMζ becomes a requirement for LTP maintenance only during the late phase of LTP. PKMζ thus appears important for the persistence of memory and would be expected to be important in the maintenance of long-term memory. Indeed, administration of a PKMζ inhibitor into the hippocampus of the rat results in retrograde amnesia with intact short-term memory; PKMζ does not play a role in the establishment of short- term memory.
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In the philosophy of mind, Jonardon Ganeri advances the view, in his book The Self, that our concept of self is constitutively grounded in the fact that subjects are beings who own their ideas, emotions, wishes, and feelings. He argues that the self is a unity of three strands of ownedness: normative, phenomenological, and subpersonal. In a different book, Attention, Not Self, he argues that when early Buddhists deny that there is a self, what they are rejecting is the conception of self as the willing agent, an inner origin of willed directives. For early Buddhists like Buddhaghosa the real nature of mental activity is in the ways we pay attention.
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Hence, both the cell wall-degrading enzymes are synthesized by the host grapevine plant specifically to target and degrade the cell walls of the oomycete pathogen. In addition, the upregulation of the PR-9 gene that encodes for peroxidase, which is a reactive oxygen species is associated with the systemic acquired defense of the grapevine host. The roles of other constitutively expressed PR genes during P.viticola infection such as PR-5, PR-1 and PR-10 genes remain ambiguous. PR-5 is involved in the synthesis of thaumatin-like proteins and osmotins, which are believed to inhibit the spore germination and germ tube growth of Plasmopara viticola by creating transmembrane pores.
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PKCε translocates to cardiac muscle sarcomeres and modulates contractility of the myocardium. PKCε binds RACK2 at Z-lines with an EC50 of 86 nM; PKCε also binds at costameres to syndecan-4. PKCε has been shown to bind F-actin in neurons, which modulates synaptic function and differentiation; however it is unknown whether PKCε binds sarcomeric actin in muscle cells. Sarcomeric proteins have been identified in PKCε signaling complexes, including actin, cTnT, tropomyosin, desmin, and myosin light chain-2; in mice expressing a constitutively-active PKCε, all sarcomeric proteins showed greater association with PKCε, and the cTnT, tropomyosin, desmin and myosin light chain-2 exhibited changes in post-translational modifications.
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Ciclosporin has been used experimentally to treat cardiac hypertrophy (an increase in cell volume). Inappropriate opening of the mitochondrial permeability transition pore (MPTP) manifests in ischemia (blood flow restriction to tissue) and reperfusion injury (damage occurring after ischemia when blood flow returns to tissue), after myocardial infarction (heart attack) and when mutations in mitochondrial DNA polymerase occur. The heart attempts to compensate for disease state by increasing the intracellular to increase the contractility cycling rates. Constitutively high levels of mitochondrial cause inappropriate MPTP opening leading to a decrease in the cardiac range of function, leading to cardiac hypertrophy as an attempt to compensate for the problem.
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This cycle is called the transcription-translation feedback loop as demonstrated in this video by the Howard Hughes Medical Institution. Though cyc is a clock gene and plays a role in setting and keeping rhythms, cyc is expressed constitutively (continuously) in Drosophila cells and is present in native Drosophila tissue culture cells, unlike clk, per, or tim. Regulation thus occurs primarily through the negative feedback by the PER-TIM protein complex in the transcription-translation feedback loop described above. The CYC-CLK also interacts with the Clockwork Orange (CWO) protein in such a way that increases the robustness in the generation of high amplitude oscillations.
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The identification of Rap1 effector proteins has provided important insights into mechanisms by which Rap1 regulates T-cell receptor (TCR) signaling to integrins. A constitutively active Rap1 construct, Rap1G12V, was used as a bait in a yeast two-hybrid screen to identify RAPL as a Rap1-binding protein. Overexpression of RAPL enhances LFA-1 clustering and adhesion, and RAPL-deficient lymphocytes and dendritic cells exhibit impaired adhesion and migration. RAPL is also an integrin-associated protein as RAPL polarizes to the immunological synapse following antigen stimulation of T cells, colocalizes with LFA-1 following TCR or chemokine stimulation, and co- immunoprecipitates with LFA-1 in a Rap1-dependent manner (108).
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In the absence of the inducer, the PTET promoter is repressed by the constitutively expressed tetracycline repressor protein (TetR). Therefore, the presence of TetR in the host cell prior to the introduction of both sgRNA and cas9 is a measure to avoid cell lethality. The first plasmid used in the pioneering work of Reisch and Prather is composed of: the cas9 gene under the control of the PTET promoter; the tetR gene, which codes for tetracycline repressor protein, under control of a constitutive promoter; and the cmr gene for chloramphenicol resistance. It was observed that leaky expression of Cas9 occurred even without induction of the PTET promoter.
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This chemical similarity can be exploited in cancer, where a protein may mutate into an "always on" (constitutively active) state. A mutation may occur to replace a tyrosine (which needs to be phosphorylated in order to activate the protein) with an aspartic acid (which would not need to be phosphorylated). In a laboratory setting, the use of recombinant proteins to artificially introduce phosphomimetics is a common tool for studying phosphorylation and protein activation. For example, the IRF3 protein must be phosphorylated for its normal activity (transcription of its target genes, like IFNβ), but when serine amino acid residues were mutated to aspartic acid, the activity increased 90-fold.
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Proliferation is restored completely by a selective agonist of D2-like (D2L) receptors. Neural stem cells have been identified in the neurogenic brain regions, where neurogenesis is constitutively ongoing, but also in the non-neurogenic zones, such as the midbrain and the striatum, where neurogenesis is not thought to occur under normal physiological conditions. Newer research has shown that there in fact is neurogenesis in the striatum.Neurogenesis in the Striatum of the Adult Human Brain A detailed understanding of the factors governing adult neural stem cells in vivo may ultimately lead to elegant cell therapies for neurodegenerative disorders such as Parkinson's disease by mobilizing autologous endogenous neural stem cells to replace degenerated neurons.
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Traditionally, it was thought that concepts can be truly representational, because ultimately they are related to intrinsically representational Platonic complexes of universals and particulars. However, once concepts and propositions are regarded as cognitive-event types, it is possible to claim that they are able to be representational, because they are constitutively related to intrinsically representational cognitive acts in the real world."Unlike the platonic epistemology required by the classic Frege- Russell account... the epistemology of naturalized propositions sees acquaintance with, and knowledge of, propositions as rooted in acquaintance with, and knowledge of, acts and events that make up one's cognitive life" - Scott Soames, What is meaning?. Princeton: Princeton University Press, 2010, p. 106.
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The constitutively active form of Ras oncoprotein is expressed in high levels in bladder carcinomas, leukemias, colon, breast, lung and skin cancers.Oncología Clínica, M González Some researchers have discovered that Ras and Ef-hand domain containing proteins are commonly overexpressed in primary lung cancers and its intervention is crucial for the proliferation and survival of cancerous cells. Apart from binding calcium ions in the N-terminus, RASEF plays a significant role in lung cancer cell-growth. This occurs because of its interaction with ERK (extracellular signal- regulated kinase) molecules involved in the regulation of meiosis, mitosis, and postmitotic functions in differentiated cells, whose pathway can be activated by carcinogens or viral infections. .
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The gene coding for human SAA1 is one of the 4 SAA genes mapped to a region in the short arm on Chromosome 15. Two of these genes, SAA1 and SAA2, are inducible during acute- phase response, whereas SAA3 is a pseudogene in humans and SAA4 is constitutively expressed in a variety of tissues and cells. Single nucleotide polymorphisms (SNPs) are found in SAA1 in both coding and non-coding sequences, with those located in the coding sequence defining 5 isoforms of SAA1 (SAA1.1 – 1.5). Genetic studies have shown association of some of these SNPs with the disposition to several human diseases including familiar Mediterranean fever, coronary artery diseases, cerebral infarction, and osteoporosis.
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Additionally, the p190 isoform can also be expressed as a splice variant of p210. The ABL1 gene expresses a membrane-associated protein, a tyrosine kinase, and the BCR-ABL1 transcript is also translated into a tyrosine kinase containing domains from both the BCR and ABL1 genes. The activity of tyrosine kinases is typically regulated in an auto-inhibitory fashion, but the BCR-ABL1 fusion gene codes for a protein that is "always on" or constitutively activated, leading to impaired DNA binding and unregulated cell division (i.e. cancer). This is due to the replacement of the myristoylated cap region, which when present induces a conformational change rendering the kinase domain inactive, with a truncated portion of the BCR protein.
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Also, like adaptive immunity, intrinsic immunity is specifically tailored to a single type or class of pathogens, notably retroviruses. Unlike adaptive and innate immunity, which must sense the infection to be turned on (and can take weeks to become effective in the case of adaptive immunity) intrinsic immune proteins are constitutively expressed and ready to shut down infection immediately following viral entry. This is particularly important in retroviral infections since viral integration into the host genome occurs quickly after entry and reverse transcription and is largely irreversible. Because the production of intrinsic immune mediating proteins cannot be increased during infection, these defenses can become saturated and ineffective if a cell is infected with a high level of virus.
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The β-subunit of the IL-5 receptor is responsible for signal transduction and contains several intracellular signaling domains. Unlike the α-chain, the β-chain does not bind IL-5, is not specific to this cytokine, and is expressed on practically all leukocytes. In fact, the β-subunit of the IL-5 receptor is also found in IL-3 and GM-CSF receptors where it is associated with IL-3Rα and GM-CSFRα subunits respectively. Therefore, it is known as the common β receptor or βc. As with the IL-5Rα subunit, the β subunit’s cytoplasmic domain is constitutively associated with JAK2, as well as LYN, another tyrosine kinase, which are both essential for IL-5 signal transduction.
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Laruelle argues that all forms of philosophy (from ancient philosophy to analytic philosophy to deconstruction and so on) are structured around a prior decision, and remain constitutively blind to this decision. The 'decision' that Laruelle is concerned with here is the dialectical splitting of the world in order to grasp the world philosophically. Examples from the history of philosophy include Immanuel Kant's distinction between the synthesis of manifold impressions and the faculties of the understanding; Martin Heidegger's split between the ontic and the ontological; and Jacques Derrida's notion of différance/presence. The reason Laruelle finds this decision interesting and problematic is because the decision itself cannot be grasped (philosophically grasped, that is) without introducing some further scission.
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N-cadherin showed no change, and there was no compensatory upregulation of plakoglobin at intercalated discs in the absence of beta-catenin. In a hamster model of cardiomyopathy and heart failure, cell–cell adhesions were irregular and disorganized, and expression levels of adherens junction/intercalated disc and nuclear pools of beta-catenin were decreased. These data suggest that a loss of beta-catenin may play a role in the diseased intercalated discs that have been associated with cardiac muscle hypertrophy and heart failure. In a rat model of myocardial infarction, adenoviral gene transfer of nonphosphorylatable, constitutively-active beta-catenin decreased MI size, activated the cell cycle, and reduced the amount of apoptosis in cardiomyocytes and cardiac myofibroblasts.
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Plants have co-evolved with their parasites for several hundred million years. This co-evolutionary process has resulted in the selection of a wide range of plant defences against microbial pathogens and herbivorous pests which act to minimise frequency and impact of attack. These defences include both physical and chemical adaptations, which may either be expressed constitutively, or in many cases, are activated only in response to attack. For example, utilization of high metal ion concentrations derived from the soil allow plants to reduce the harmful effects of biotic stressors (pathogens, herbivores etc.); meanwhile preventing the infliction of severe metal toxicity by way of safeguarding metal ion distribution throughout the plant with protective physiological pathways.
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Mouse models of RTT are available and the most studied are constitutively deleted Mecp2 mice developed by Adrian Bird or Rudolf Jaenisch laboratories. In accordance with the motor spectrum of the RTT phenotype, Mecp2-null mice show motor abnormalities from postnatal day 30 that worsen until death. These models offer a crucial substrate to elucidate the molecular and neuroanatomical correlates of an MeCP2-deficiency. Recently (2008), it was shown that the conditional deletion of Mecp2 in catecholaminergic neurons (by crossing of Th-Cre mice with loxP-flanked Mecp2 ones) recapitulates a motor symptomatology, it was further documented that brain levels of Th in mice lacking MeCP2 in catecholaminergic neurons only are reduced, participating to the motor phenotype.
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IFN-τ is constitutively secreted by trophoblast and endometrial cells during ovine pregnancy. Its secretion begins around tenth day and increases between days 13 and 16, when it reaches its peak, and then stopping after day 24 of pregnancy. IFN-τ is essential to maintain the levels of progesterone production by the corpus luteum for the maternal recognition of pregnancy, and together with progesterone increases expression of genes for transport of nutrients into the uterine lumen, growth factors for hematopoiesis and angiogenesis and other molecules that are crucial for implantation and placentation. It has both endocrine and paracrine effects, immunomodulatory influence on several types of cells including neutrophils, and antiproliferative, antiluteolytic and immunosuppressive effects on the endometrium.
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This interaction between RAPL and LFA-1 is dependent on lysine residues at positions 1097 and 1099 in the juxtamembrane region of the αL-subunit cytoplasmic domain. This is a functionally significant region of the αL cytoplasmic domain as deletion of the adjacent GFFKR motif results in a constitutively active LFA-1 integrin (124, 125). While lysines 1097 and 1099 are critical for Rap1-dependent activation of LFA-1, the β2-subunit cytoplasmic domain appears to be dispensable for activation of LFA-1 by Rap1 (126). Mutation of these lysine residues to alanine impairs the ability of LFA-1 to redistribute to the leading edge induced by Rap1 activation or overexpression of RAPL.
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Sib RNA regulates the expression of a toxic protein in a type I toxin-antitoxin system similar to that of hok/sok andldr-rdl genes. The constitutively expressed Sib transcript regulates the ibs (induction brings stasis) open reading frame which encodes a small 18–19 amino acid hydrophobic protein which slows growth at moderate levels of expression and is toxic when overexpressed. The ibs gene is on the opposite strand to sib and is completely complementary, so the antisense-binding of Sib RNA with the ibs mRNA brings about dsRNA-mediated degradation. When sib was deleted in multi-copy plasmids, the cells could not be maintained due to the toxicity of the unrepressed ibs protein.
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Marxists, communists, as well as some socialists and anarchists argue that liberal democracy under capitalist ideology is constitutively class-based and therefore can never be democratic or participatory. It is referred to as bourgeois democracy because ultimately politicians fight only for the rights of the bourgeoisie. According to Karl Marx, representation of the interests of different classes is proportional to the influence which a particular class can purchase (through bribes, transmission of propaganda through mass media, economic blackmail, donations for political parties and their campaigns and so on). Thus, the public interest in so-called liberal democracies is systematically corrupted by the wealth of those classes rich enough to gain the appearance of representation.
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The precise details of the PhK’s catalytic mechanism are still under study. While this may seem surprising given that it was isolated over 50 years ago, there are significant difficulties in studying the finer details of PhK’s structure and mechanism due to its large size and high degree of complexity. In the active site, there is significant homology between PhK and other so-called P-loop protein kinases such as protein kinase A (PKA, cAMP-dependent kinase). In contrast to these other proteins, which typically require phosphorylation of a serine or tyrosine residue in the catalytic site to be active, the catalytic γ subunit of PhK is constitutively active due to the presence of a negatively charged glutamate residue, Glu-182.
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This significant reduction in fitness, due to both increased mortality and age-related dropoff in fecundity, explains why the antibacterial activity of the exudate is only induced and not present constitutively. Further work revealed how a trade-off existed between investment in personal immunity vs investment in social immunity, i.e., upon injury, N. vespilloides upregulates its personal immune response whilst concomitantly reducing its social immune response. Recently, the Kilner Group identified a gene associated with social immunity in N. vespilloides: the expression rate of Lys6, a lysozyme, increases 1,409 times when breeding, and goes from the 5,967th most abundant transcript in the transcriptome of gut tissue to the 14th; it was also demonstrated that expression rates of Lys6 covary with the antibacterial activity of the anal exudate.
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CD49b provides only little contribution to the differentiation and function of Tr1 cells. They characteristically produce high levels of IL-10, IFNy, IL-5 and also TGF- β but no IL-4 nor IL-2 Production of IL-10 is also much more rapid than its production of other T-helper cell types. Tr1 cells do not constitutively express FOXP3 but only transiently, upon their activation and in smaller amounts than CD25+ FOXP3+ regulatory cells.Gregori et al.: Type 1 regulatory T (Tr1) cells: from the bench to the bedside. Journal of Translational Medicine 2012 10(Suppl 3):I7. FOXP3 is not required for Tr1 induction nor for its function. They also express repressor of GATA-3 (ROG), while CD25+ FOXP3+ regulatory cells do not.
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Transcription of the HSP90AA1 gene is currently understood to be induced by stress through binding of the master transcription factor (TF) HSF1 to the HSP90AA1 promoter. However, several focused studies of the HSP90AA1 promoter along with extensive global analysis of the human genome indicate that various other transcription complexes regulate HSP90AA1 gene expression. Mammalian HSP90AA1 along with HSP90AB1 gene expression was first characterized in transformed mouse cells where it was shown that HSP90AB1 is constitutively expressed 2.5-fold higher than HSP90AA1 under normal conditions. However upon heat shock, HSP90AA1 expression increased 7.0-fold while HSP90AB1 increases only 4.5-fold. Detailed analysis of the HSP90AA1 promoter shows that there are 2 heat shock elements (HSE) within 1200 bp of the transcription start site.
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This second CCR, which is allosterically activated by its preferred substrates but inhibited by feruloyl-CoA, is thought to act as part of a shunt pathway toward coniferaldehyde that enhances the pathway's overall flexibility and robustness in different conditions. In other cases though, the two homologs vary primarily by expression pattern. In the model plant Arabidopsis thaliana, for instance, the CCR1 and CCR2 homologs both display higher activity toward feruloyl-CoA than other substrates, but CCR2 is only expressed transiently during bacterial infection. The homolog pair in switchgrass (Panicum virgatum) differs in both ways: CCR2 prefers p-coumaroyl- and caffeoyl-CoA and is only expressed under specifically induced conditions, while CCR1 prefers feruloyl-CoA and is expressed constitutively in lignifying tissue.
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In fact, there is evidence that VDAC binding by the anti-apoptotic HK1 and by the pro-apoptotic creatine kinase are mutually exclusive, indicating that the absence of HK1 allows creatine kinase to bind and open VDAC. Furthermore, HK1 has demonstrated anti-apoptotic activity by antagonizing Bcl-2 proteins located at the OMM, which then inhibits TNF- induced apoptosis. In the prefrontal cortex, HK1 putatively forms a protein complex with EAAT2, Na+/K+ ATPase, and aconitase, which functions to remove glutamate from the perisynaptic space and maintain low basal levels in the synaptic cleft. In particular, HK1 is the most ubiquitously expressed isoform out of the four hexokinases, and constitutively expressed in most tissues, though it is majorly found in brain, kidney, and red blood cells (RBCs).
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Some members of the BMC-T protein family stack in a face-to-face fashion and form tiny cages. Based on crystal structures, these protein cages have relatively large gated pores on both sides, and it has been proposed that the opening and closing of the pore could be controlled in a manner similar to an air-lock. Such an air-lock, in contrast to BMC-H proteins with constitutively open pores, has been suggested to serve as a route for larger substrates (ribulose-1,5-bisphosphate) and products (3-phosphoglycerate) that must cross the shell. A number of viral capsids are also icosahedral, composed of hexameric and pentameric proteins, but currently there is no evidence suggesting any evolutionary relationship between the carboxysome shell and viral capsids.
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As opposed to humanist anthropologists, historians, sociologists, and political scientists who engage the history of Black subjectivity as one of entrenched political discrimination and social ostracization, afro-pessimists across disciplines have argued that Black people are constitutively excluded from the category of the self-possessing, rights-bearing human being of modernity. As Wilderson writes, “Blacks do not function as political subjects; instead, our flesh and energies are instrumentalized for postcolonial, immigrant, feminist, LGBT, and workers’ agendas.” Orlando Patterson's Slavery and Social Death forms a theoretical point of departure for almost all strands of Afropessimism. In an interview of the Kerner Report, Patterson had this to say about Afropessimism: > We’re going through a period of extreme despair about the situation of > African-Americans.
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DUT is a member of the dUTPase family, which is known for catalyzing the pyrophosphoralysis of dUTP into dUMP and inorganic pyrophosphate. This function contributes to DNA replication and repair via de novo thymidylate biosynthesis, as the dUMP product is methylated by thymidylate synthase (TS) to form dTMP, which is then phosphorylated to dTTP. DUT is also crucial for maintaining genome integrity by reducing cellular dUTP levels, thereby preventing the repeated cycles of uracil misincorporation into DNA and DNA repair-mediated strand breaks that would lead to cell death. In addition to their different localizations, the two DUT isoforms display different expression patterns: while DUT-M is constitutively expressed, DUT-N is under cell cycle control and notably upregulated during S phase.
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Stockinger and coworkers demonstrated the importance of CYP1A1 for the endogenous availability of FICZ. Th17 cells from mice expressing CYP1A1 constitutively metabolized FICZ rapidly and responded with lower production of IL-22 when treated with 0.01nM FICZ compared to wildtype Th17 cells. Metabolic clearance of FICZ in mice that overexpress Cyp1a1 in the gut epithelium led to a pseudo-AHR-deficient state and when infected with Citrobacter rodentium, these animals exhibited markedly reduced numbers of group 3 ILCs and Th17 cells and succumbed rapidly. Conversely, mice lacking CYP1A1 or when CYP1A1 is inhibited results in an elevate level of endogenous FICZ and conversely, mice lacking CYP1A1 or with inhibited CYP1A1 activity show elevated levels of endogenous FICZ and increased protection against intestinal infection.
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Findings suggest that Th3 cells are a different lineage from naturally arising CD25+CD4+ Treg cells, but it is still unclear whether Th3 cells are the same as induced Treg cells because of the lack of a specific marker for Th3 cells. It was previously shown that TGF-β was produced by intestinal dendritic cells, which has been considered to be the source of cytokines for the induction of Th3 cells in the intestine. Additionally, since TGF-β production was induced by cytotoxic T-lymphocyte antigen 4 (CTLA-4), which is constitutively expressed on naturally arising Treg cells, it is possible that TGF-β production from Treg cells through CTLA-4–mediated signaling may stimulate the differentiation of both induced Treg cells and Th3 cells.
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This triggers the activation of integrins from the cancer cells allowing their firmer adhesion to members of the Ig-CAM family such as ICAM, initiating the transendothelial migration and extravasation processes.[72] The appropriate set of endothelial receptors is sometimes not expressed constitutively and the cancer cells have to trigger their expression. In this context, the culture supernatants of cancer cells can trigger the expression of E- selectin by endothelial cells suggesting that cancer cells may release by themselves cytokines such as TNF-α, IL-1β or INF-γ that will directly activate endothelial cells to express E-selectin, P-selectin, ICAM-2 or VCAM. On the other hand, several studies further show that cancer cells may initiate the expression of endothelial adhesion molecules in a more indirect ways.
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J. G. Robson and J. B. Troy, "Nature of the maintained discharge of Q, X, and Y retinal ganglion cells of the cat", J. Opt. Soc. Am. A 4, 2301–2307 (1987)M.C.M. Wright, I.M. Winter, J.J. Forster, S. Bleeck "Response to best-frequency tone bursts in the ventral cochlear nucleus is governed by ordered inter-spike interval statistics", Hearing Research 317 (2014) In bacterial gene expression, the copy number of a constitutively expressed protein often follows the gamma distribution, where the scale and shape parameter are, respectively, the mean number of bursts per cell cycle and the mean number of protein molecules produced by a single mRNA during its lifetime.N. Friedman, L. Cai and X. S. Xie (2006) "Linking stochastic dynamics to population distribution: An analytical framework of gene expression", Phys. Rev. Lett.
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Endothelial NOS (eNOS), also known as nitric oxide synthase 3 (NOS3) or constitutive NOS (cNOS), is an enzyme that in humans is encoded by the NOS3 gene located in the 7q35-7q36 region of chromosome 7. This enzyme is one of three isoforms that synthesize nitric oxide (NO), a small gaseous and lipophilic molecule that participates in several biological processes. The other isoforms include neuronal nitric oxide synthase (nNOS), which is constitutively expressed in specific neurons of the brain and inducible nitric oxide synthase (iNOS), whose expression is typically induced in inflammatory diseases. eNOS is primarily responsible for the generation of NO in the vascular endothelium, a monolayer of flat cells lining the interior surface of blood vessels, at the interface between circulating blood in the lumen and the remainder of the vessel wall.
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Viral protein "u" (Vpu) is an oligomeric, 81-amino acid type I membrane protein (16 kDa) that is translated from vpu-env bicistronic mRNA. The N-terminus of Vpu encoding the transmembrane (TM) anchor represents an active domain important for the regulation of virus release but not CD4 degradation. The C-terminal cytoplasmic domain (54 residues) that contains a pair of serine residues (at positions 52 and 56) constitutively phosphorylated by casein kinase 2. The phosphorylation of two serine residues in the cytoplasmic domain is critical for CD4 degradation in the ER. Based on 2D 1H NMR spectroscopy of a peptide corresponding to the cytoplasmic domain of Vpu, it was proposed that the cytoplasmic domain of Vpu contains two α-helical domains, helix-1 and helix-2, which are connected by an unstructured region containing the two conserved phosphoseryl residues.
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As early as 1996, it was demonstrated that the expression of the GAST gene is required for the cellular tumorigenicity of human colorectal cancer. The GAST gene has been shown to be a downstream target of the ß-catenin/TCF-4 signalling pathway. Transfection of a construct expressing a constitutively active form of ß-catenin triples the activity of the GAST gene promoter.. This study establishes a link between progastrin and cancer across many cellular functions involving the Wnt pathway in a cancer cell, starting with its importance for cancer stem cell survival.. In pathological situations, progastrin is secreted by tumor cells into the bloodstream and is referred to as hPG80. The expression of progastrin in many cancers has been demonstrated.. It has been noted that in colorectal cancers, progastrin is more than 700 times more abundant than amidated gastrin.
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Mammalian oocytes are maintained in meiotic prophase arrest for a very long time -- months in mice, years in humans. Initially the arrest is due to lack of sufficient cell cycle proteins to allow meiotic progression. However, as the oocyte grows, these proteins are synthesized, and meiotic arrest becomes dependent on cyclic AMP Jaffe LA, Egbert JR. 2017. Regulation of Mammalian Oocyte Meiosis by Intercellular Communication Within the Ovarian Follicle. Ann. Rev. Physiol. 79:237-260.. The cyclic AMP is generated by the oocyte by adenylyl cyclase in the oocyte membrane. The adenylyl cyclase is kept active by a constitutively active G-protein-coupled receptor known as GPR3 and a G-protein, Gs, also present in the oocyte membrane Mehlmann LM, Saeki Y, Tanaka S, Brennan TJ, Evsikov AV, Pendola FL, Knowles BB, Eppig JJ, Jaffe LA. 2004.
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Many methods of transfection and transformation – two ways of expressing a foreign or modified gene in an organism – are effective in only a small percentage of a population subjected to the techniques. Thus, a method for identifying those few successful gene uptake events is necessary. Reporter genes used in this way are normally expressed under their own promoter (DNA regions that initiates gene transcription) independent from that of the introduced gene of interest; the reporter gene can be expressed constitutively (that is, it is "always on") or inducibly with an external intervention such as the introduction of Isopropyl β-D-1-thiogalactopyranoside (IPTG) in the β-galactosidase system. As a result, the reporter gene's expression is independent of the gene of interest's expression, which is an advantage when the gene of interest is only expressed under certain specific conditions or in tissues that are difficult to access.
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A central part of Gaskin's work focuses on the doctrine of linguistic idealism, the idea that the world is produced by, and depends on, language. Gaskin argues that the dependence of the world on language is a logical and constitutive one, rather than a temporal one: objects (such as tables and chairs) exist in virtue of, and are constituted as objects by, the existence of sentences about them; language 'makes the world', but not in the sense that there was a time at which it pre-existed the world. Although human language is a purely contingent product of evolution, there is a transcendental sense in which the existence of the world depends on the existence of language—more precisely, on the capacity of language to talk about the world. In Gaskin’s view the world is constitutively composed of propositions, which are referents of sentences; these propositions contain the ordinary objects of our discourse.
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The importance of some sequences of p22phox for its interaction with NOXs has been highlighted. The hydropathic profile of p22phox deduced from the gene sequence is compatible with at least two (possibly three or four) transmembrane passages. However, the most probable are the two or four transmembrane-spanning models because they are compatible with a cytosolic location of both the N- and the C-terminal tail of p22phox. A polyproline-rich region (PRR) (K149 to E162 sequence) in the C-terminus of p22phox contains a consensus motif PxxP that interacts with the SH3 (SRC homology 3) domains of p47phox during NADPH oxidase assembly in phagocytes. This PRR-rich sequence also interacts with the cytosolic organizer NOXO1 homologs to p47phox expressed in nonphagocytic cells, during the activation of NADPH oxidases (NOX1, NOX2 and NOX3), except for NOX4, which is constitutively expressed. Phosphorylation of Thr147 close to the PRR region of p22phox enhances NADPH oxidase activity by promoting p47phox binding in phagocytes.
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Professional antigen-presenting cells are primarily dendritic cells, macrophages and B cells, although dendritic cells are the only cell group that expresses MHC Class II constitutively (at all times). Some APCs also bind native (or unprocessed) antigens to their surface, such as follicular dendritic cells (these are not the same type of cell as the dendritic cell of the immune system but rather have a non-hematopoietic origin, and in general lack MHC Class II, meaning they are not true professional antigen-presenting cells; follicular dendritic cells may acquire MHC Class II proteins via exosomes that become attached to them, however). T cells require antigen to processed into short fragments that form linear epitopes on MHC Class II (in the case of helper T cells because they express CD4) or MHC class I (in the case of cytotoxic T cells which express CD8). MHC Class II binding pockets are flexible with respect to the length of the peptides they hold.
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Wiercinski has generated research accomplishments in his subject areas that demonstrate his scholarly expertise both in the range of his works as well as in their broad, contentful composition. He understands hermeneutics as a specific mind-set of openness that admits of neither a priori nor apodictic demarcations between domains of knowledge, but instead sits decidedly between them in order to overcome the compartmentalization of knowledge forms from each other. Despite the postmodern format of this hermeneutic in-between — which of course will not be raised to a trans- regional, conceptually achievable absolutism — Wiercinski positions hermeneutics within the horizon of man’s unmistakable ability to attain truth, which actualizes itself in the history of knowledge and its forms. He understands philosophy of religion as the hermeneutic mediation between the incommensurable knowledge forms of religion/theology and philosophy, which are not separated off from one another but rather allude to one another both genealogically and constitutively.
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In the past, antimetabolites (e.g., cytarabine, hydroxyurea), alkylating agents, interferon alfa 2b, and steroids were used as treatments of CML in the chronic phase, but since the 2000s have been replaced by Bcr-Abl tyrosine-kinase inhibitors drugs that specifically target BCR-ABL, the constitutively activated tyrosine kinase fusion protein caused by the Philadelphia chromosome translocation. Despite the move to replacing cytotoxic antineoplastics (standard anticancer drugs) with tyrosine kinase inhibitors sometimes hydroxyurea is still used to counteract the high leukocyte counts encountered during treatment with tyrosine kinase inhibitors like imatinib; in these situations it may be the preferred myelosuppressive agent due to its relative lack of leukemogenic effects and hence the relative lack of potential for secondary hematologic malignancies to result from treatment. IRIS, an international study that compared interferon/cytarabine combination and the first of these new drugs imatinib, with long-term follow up, demonstrated the clear superiority of tyrosine-kinase-targeted inhibition over existing treatments.
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Studies have further described a mechanistic cascade wherein cancer cells first bind E-selectin at shear flow rates: E-selectin binding results in a velcro-like interaction allowing the cancer cells to engage higher affinity integrin binding that eventually results in a tight binding between tumor cells and the activated endothelium. While numerous pieces of in vitro and clinical evidence continue to support this hypothesis of E-selectin-mediated cancer metastasis, in vivo studies of cancer metastasis have shown that E-selectin knockout only minimally affects leukemic cell adhesion to bone immediately following injection. while experimental lung metastasis is not affected by the genetic deletion of E-selectin. Furthermore, studies have also shown that primary tumor growth is increased in E-selectin knockout mice This paradox was more recently solved by a trio of studies showing that E-selectin is only constitutively expressed in the bone marrow endothelium where it is thought to perform functions vital to hematopoiesis.
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Second, the editing pattern controls the amount of the 5-HT2CR mRNA that leads to the expression of full-length protein through the modulation of alternative splice site selection 76,77. Among three alternative splice donor sites (GU1 to GU3; Fig. 4C), GU2 is the only site that forms the mature mRNA to produce the functional, full-length 5-HT2CR protein. Unedited pre-mRNAs tend to be spliced at the GU1 site, resulting in the truncated, non-functional protein if translated 76,77. However, most pre-mRNAs edited at more than one position are spliced at GU2 77. Thus, when editing is inefficient, increased splicing at GU1 may act as a control mechanism to decrease biosynthesis of the 5-HT2CR-INI and thereby limit serotonin response. Third, RNA editing controls the ultimate physiological output of constitutively active receptors by affecting the cell surface expression of the 5-HT2CR. The 5-HT2CR-VGV, which displays the lowest level of constitutive activity, is fully expressed at the cell surface under basal conditions and is rapidly internalized in the presence of agonist 78.
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"Disciplinary power," Miller wrote, "constitutively mobilizes a tactic of tact: it is the policing power that never passes for such, but is either invisible or visible only under cover of other, nobler or simply blander intentionalities (to educate, to cure, to produce, to defend)." Miller's book thus countered critical celebrations of the novel as inherently emancipatory. (Indeed, The Novel and the Police exposed these celebrations as "perpetuating the [novel’s] ruse".) Against this "subversion hypothesis", Miller called for attention to the novel's ability effectively to produce subjects, its capacity to form "a subject habituated to psychic displacements, evacuations, reinvestments, in a social order whose totalizing power circulates all the more easily for being pulverized". In Anal Rope(1990), his definitive reading of Alfred Hitchcock’s 1948 film Rope, and in his next books, Bringing Out Roland Barthes (1992) and Place for Us: Essay on the Broadway Musical (1998), Miller turned to more explicitly gay-themed works, even while insisting on the importance of the implicit in mainstream culture’s representations and disavowals of homosexuality.
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Retrieved on 13 September 2014. G. Philips argues that Palamas's distinction is not an "ontological" distinction but, rather, analogous to a "formal distinction" in the Scotist sense of the term.Michael J. Christensen, Jeffery A. Wittung (editors), Partakers of the Divine Nature: The History and Development of Deificiation in the Christian Traditions (Associated University Presses 2007 ), pp. 243–244, Fairleigh Dickinson Univ Press, 2007 . Retrieved on 13 September 2014. According to Dominican Catholic theological historian Fr. Aidan Nichols, Palamas's essence–energies distinction is not a mere "formal" distinction "demanded by the limited operating capacities of human minds". According to Anna N. Williams's study of Palamas, which is more recent than the assessments of Hart and Philips, in only two passages does Palamas state explicitly that God's energies are "as constitutively and ontologically distinct from the essence as are the three Hypostases," and in one place he makes explicit his view, repeatedly implied elsewhere, that the essence and the energies are not the same; but Williams contends that not even in these passages did Palamas intend to argue for an "ontological or fully real distinction," and that the interpretation of his teaching by certain polemical modern disciples of his is false.
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IL-18 receptor consists of the inducible component IL-18Rα, which binds the mature IL-18 with low affinity and the constitutively expressed co-receptor IL-18Rβ. IL-18 binds the ligand receptor IL-18Rα, inducing the recruitment of IL-18Rβ to form a high affinity complex, which signals through the toll/interleukin-1 receptor (TIR) domain. This signaling domain rectruits MyD88 adaptor protein that activates proinflammatory programes and NF-κB pathway. The activity of IL-18 can be suppressed by extracellular interleukin 18 binding protein (IL-18BP) that binds soluble IL-18 with a higher affinity than IL-18Rα thus prevents IL-18 binding to IL-18 receptor. IL-37 is another endogenous factor that suppresses the action of IL-18. IL-37 has high homology with IL-18 and can bind to IL-18Rα, which then forms a complex with IL-18BP, thereby reduces the activity of IL-18. Moreover, IL-37 binds to single immunoglobulin IL-1 receptor related protein (SIGIRR), also known as IL-1R8 or TIR8, which forms a complex with IL-18Rα and induces an anti-inflammatory response. The IL-37/IL-18Rα/IL-1R8 complex activates the STAT3 signaling pathway, decreases NF-κB and AP-1 activation and reduces IFNγ production.
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The first signal is provided by binding of the T cell receptor to its cognate peptide presented on MHCII on an APC. MHCII is restricted to so-called professional antigen-presenting cells, like dendritic cells, B cells, and macrophages, to name a few. The peptides presented to CD8+ T cells by MHC class I molecules are 8–13 amino acids in length; the peptides presented to CD4+ cells by MHC class II molecules are longer, usually 12–25 amino acids in length,Jennifer Rolland and Robyn O'Hehir, "Turning off the T cells: Peptides for treatment of allergic Diseases," Today's life science publishing, 1999, Page 32 as the ends of the binding cleft of the MHC class II molecule are open. The second signal comes from co-stimulation, in which surface receptors on the APC are induced by a relatively small number of stimuli, usually products of pathogens, but sometimes breakdown products of cells, such as necrotic-bodies or heat shock proteins. The only co-stimulatory receptor expressed constitutively by naïve T cells is CD28, so co-stimulation for these cells comes from the CD80 and CD86 proteins, which together constitute the B7 protein, (B7.1 and B7.2, respectively) on the APC.
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