The document discusses how AP-2α induces apoptosis in cancer cells. It finds that AP-2α activates the intrinsic apoptosis pathway by binding to the Bcl-2 promoter and repressing its transcription. This allows Bax to translocate to mitochondria, disrupt membrane potential, and release cytochrome c, activating caspase-9 and caspase-3. Downregulation of anti-apoptotic Bcl-2 is important for AP-2α-induced apoptosis. Overexpressing AP-2α enhances cancer cell chemosensitivity to various drugs.
BioROIS Co., Ltd is a Japanese venture company established in 2006 to commercialize bio-related technologies developed at the National Institute of Genetics. The company developed the Auxin Inducible Degron (AID) system, which allows for rapid degradation of target proteins in mammalian cells through the addition of auxin. The AID system allows target proteins to be degraded within 30 minutes, much faster than other gene expression control systems. BioROIS licenses the AID system technology and sells AID system kits to support life science research.
The document describes using peptidomics to monitor protease inhibition in vivo by analyzing peptides as surrogates for protease activity. Peptidomics allows the comprehensive analysis of endogenous peptides from biological samples. The study demonstrates inhibiting different proteases in rats, including DPPIV and FXA, and analyzing changes in peptide levels. Several novel protease substrates were identified, including an ITM2B peptide for DPPIV. Collagen peptide levels were also strongly affected by DPPIV inhibition, indicating its importance in collagen metabolism. Peptidomics can thus non-invasively monitor protease activity and inhibition in vivo by analyzing surrogate peptide markers.
This document discusses translational models of drug-induced liver injury. It begins by outlining the integrated mechanistic drug safety approach, which investigates chemicals, patients, and the interaction between the two. A key part of this approach is understanding the mechanisms of drug bioactivation and the consequences for cellular toxicity. Paracetamol is used as a case study, as it is a common cause of drug-induced liver injury. The document explores the mechanisms of paracetamol toxicity, including how its reactive metabolite NAPQI causes oxidative stress and depletion of glutathione, leading to liver cell damage through both necrosis and inflammation. It also discusses the role of the Nrf2 transcription factor in regulating the antioxidant response and adapting cells to
RT2 Profiler PCR Arrays allow researchers to analyze gene expression in biological pathways or disease states using real-time PCR. The document discusses:
1. PCR Arrays focus on profiling genes relevant to specific pathways or disease states. They provide a simple, reproducible, and sensitive way to simultaneously profile expression of many genes related to a pathway.
2. Examples are provided demonstrating how PCR Arrays have been used in cancer research to discover breast cancer biomarkers, in immunology research to monitor cytokine induction, and in toxicity research to determine drug toxicity profiles.
3. Key advantages of PCR Arrays are highlighted, including their simplicity, performance, relevance to specific pathways, and ability to analyze gene expression from small amounts
The DTExtm method allows simultaneous analysis of changes in gene expression levels of 145 ADME-associated genes using a microarray. Total RNA is converted to cDNA and labeled before being hybridized to the DTExtm microarray. The method can survey basal gene expression levels and coordinated changes in expression levels caused by drug treatment in various cell lines and tissues. Rifampicin treatment of human hepatocytes showed induction of genes such as CYP3A4, UGT1A1, and ABCB1 in a coordinated manner mediated by PXR activation. Benzoflavone treatment also coordinately induced CYP1A2, UGT1A1, and ABCC2 through AHR activation. DTE
The document describes research sequencing the human lymph peptidome using various mass spectrometry techniques. Over 900 peptides were identified from over 480 proteins. The peptides came from intracellular, extracellular, and membrane proteins. Some peptides bound strongly to MHC II molecules, indicating they could be immunologically relevant. Analysis of the molecular functions and pathways identified acute phase response and coagulation proteins. Protease processing pathways generating the peptidome involved matrix metalloproteases, cathepsins, and enzymes from innate immunity and coagulation. The study provides new insights into self-antigens and peptides presented by immune cells.
This document summarizes a study that analyzed the frequency of the CYP4F2 rs2108622 genetic variant among 90 healthy Jordanian volunteers. The study found:
- The frequency of the C allele was 0.55 and of the T allele was 0.45.
- The most common genotype was heterozygous CT at 0.55 frequency.
- The frequencies in Jordanians were similar to Caucasians but different from other groups like Africans.
- This variant may influence cardiovascular diseases and warfarin response in Jordanians.
BioROIS Co., Ltd is a Japanese venture company established in 2006 to commercialize bio-related technologies developed at the National Institute of Genetics. The company developed the Auxin Inducible Degron (AID) system, which allows for rapid degradation of target proteins in mammalian cells through the addition of auxin. The AID system allows target proteins to be degraded within 30 minutes, much faster than other gene expression control systems. BioROIS licenses the AID system technology and sells AID system kits to support life science research.
The document describes using peptidomics to monitor protease inhibition in vivo by analyzing peptides as surrogates for protease activity. Peptidomics allows the comprehensive analysis of endogenous peptides from biological samples. The study demonstrates inhibiting different proteases in rats, including DPPIV and FXA, and analyzing changes in peptide levels. Several novel protease substrates were identified, including an ITM2B peptide for DPPIV. Collagen peptide levels were also strongly affected by DPPIV inhibition, indicating its importance in collagen metabolism. Peptidomics can thus non-invasively monitor protease activity and inhibition in vivo by analyzing surrogate peptide markers.
This document discusses translational models of drug-induced liver injury. It begins by outlining the integrated mechanistic drug safety approach, which investigates chemicals, patients, and the interaction between the two. A key part of this approach is understanding the mechanisms of drug bioactivation and the consequences for cellular toxicity. Paracetamol is used as a case study, as it is a common cause of drug-induced liver injury. The document explores the mechanisms of paracetamol toxicity, including how its reactive metabolite NAPQI causes oxidative stress and depletion of glutathione, leading to liver cell damage through both necrosis and inflammation. It also discusses the role of the Nrf2 transcription factor in regulating the antioxidant response and adapting cells to
RT2 Profiler PCR Arrays allow researchers to analyze gene expression in biological pathways or disease states using real-time PCR. The document discusses:
1. PCR Arrays focus on profiling genes relevant to specific pathways or disease states. They provide a simple, reproducible, and sensitive way to simultaneously profile expression of many genes related to a pathway.
2. Examples are provided demonstrating how PCR Arrays have been used in cancer research to discover breast cancer biomarkers, in immunology research to monitor cytokine induction, and in toxicity research to determine drug toxicity profiles.
3. Key advantages of PCR Arrays are highlighted, including their simplicity, performance, relevance to specific pathways, and ability to analyze gene expression from small amounts
The DTExtm method allows simultaneous analysis of changes in gene expression levels of 145 ADME-associated genes using a microarray. Total RNA is converted to cDNA and labeled before being hybridized to the DTExtm microarray. The method can survey basal gene expression levels and coordinated changes in expression levels caused by drug treatment in various cell lines and tissues. Rifampicin treatment of human hepatocytes showed induction of genes such as CYP3A4, UGT1A1, and ABCB1 in a coordinated manner mediated by PXR activation. Benzoflavone treatment also coordinately induced CYP1A2, UGT1A1, and ABCC2 through AHR activation. DTE
The document describes research sequencing the human lymph peptidome using various mass spectrometry techniques. Over 900 peptides were identified from over 480 proteins. The peptides came from intracellular, extracellular, and membrane proteins. Some peptides bound strongly to MHC II molecules, indicating they could be immunologically relevant. Analysis of the molecular functions and pathways identified acute phase response and coagulation proteins. Protease processing pathways generating the peptidome involved matrix metalloproteases, cathepsins, and enzymes from innate immunity and coagulation. The study provides new insights into self-antigens and peptides presented by immune cells.
This document summarizes a study that analyzed the frequency of the CYP4F2 rs2108622 genetic variant among 90 healthy Jordanian volunteers. The study found:
- The frequency of the C allele was 0.55 and of the T allele was 0.45.
- The most common genotype was heterozygous CT at 0.55 frequency.
- The frequencies in Jordanians were similar to Caucasians but different from other groups like Africans.
- This variant may influence cardiovascular diseases and warfarin response in Jordanians.
The document discusses experiments to better understand regulation of the GADD45a gene and improve the GreenScreen HC assay. It found some chemicals induced GADD45a through non-genotoxic mechanisms, including flavonoids, glucocorticoids, retinoids and HDAC inhibitors. Arsenite was found to induce GADD45a possibly through JNK and ROS pathways, and this effect could be reduced by DMSO or a JNK inhibitor. Future work aims to investigate the importance of p53 and mutation of response elements in the GADD45a reporter.
The document summarizes research on knockout rat models lacking key drug transporter genes. It describes the development of knockout rats for the drug transporters Mdr1a, Bcrp, Mrp1, Mrp2, and p53 using zinc finger nuclease technology. This allows for improved prediction of drug absorption, distribution, metabolism, and excretion (ADME) properties. Data is presented comparing substrate drug levels and expression of other transporters in knockout versus wild type rats for several of these models. The goal is to enable more efficient drug development by identifying safety issues earlier in the process using a more human-relevant species.
This document summarizes a study investigating the relationship between activation of the alpha7 nicotinic acetylcholine receptor (α7nAChR) and the nuclear factor erythroid 2–related factor 2 (Nrf2) in antagonizing renal ischemia-reperfusion injury. The study examined the effects of a selective α7nAChR agonist on apoptosis and apoptotic signaling in renal epithelial cells subjected to hypoxia-reoxygenation injury. It was found that the agonist attenuated apoptosis and modulated levels of apoptotic proteins like caspase-3 and Bax. Inhibition of Nrf2 partially blocked these effects, indicating Nrf2 mediates the anti-apoptotic effects of α7nAChR activation
- TP53 somatic mutations are frequent in many types of human cancer, occurring in approximately 50% of cancers.
- The TP53 gene encodes the p53 protein, which functions as a tumor suppressor by inducing cell cycle arrest or apoptosis in response to DNA damage. Mutations in TP53 lead to a non-functional or dominant negative "mutant p53" protein (mp53).
- The study found that mp53 can bind to and activate the promoter of the ID4 gene, inducing its expression. ID4 is involved in processes like cell proliferation, differentiation and angiogenesis.
Farnesoid x receptor (fxr) and intestinal mucosa - Stefano FiorucciAttività scientifica
Bile acids activated receptors regulate the integrity of gastrointestinal mucosafocus on FXR.
Stefano Fiorucci,
MD Department of Surgical and Biomedical Sciences
University of Perugia
For The Japanese Society of Gastroenterology (JSGE) COI Disclosure
The document describes research into identifying potent inhibitors of the SHP2 protein tyrosine phosphatase. Several small molecule inhibitors were discovered, including NSC-87877, which was shown to selectively inhibit SHP2 activity in vitro and in cell-based assays. It was the first evidence that SHP2 phosphatase is involved in growth factor-stimulated ERK activation. Further screening of a chemical library identified additional SHP2 inhibitors, such as HLM002903 and HLM019544, which were shown to inhibit SHP2-dependent cell growth and signaling. The goal of finding SHP2 inhibitors is to develop potential anti-cancer agents, as SHP2 mutations have been implicated in various cancers and
The document describes a research study aimed at developing biomarkers for detecting potential allergenicity of novel foods, including genetically modified foods. The researcher conducted experiments challenging mice with known food allergens (egg ovomucoid protein and peanut protein) and analyzed gene expression profiles in the mice spleens. Several hundred genes were found to be differentially expressed. After validating some genes, the researcher identified potential biomarker genes that could help detect allergenicity of GM foods. The study provides insights into transcriptomic responses to food allergens and biomarkers that may help evaluate allergenicity of novel foods like GM crops.
Discriminating Facts from Artefacts in the Secreted Ly-6 Protein FamilyChris Southan
The document discusses several issues related to accurately characterizing the secreted Ly-6 protein family based on bioinformatic analysis. It describes the discovery of novel rat Ly-6 proteins from urine samples and EST data, but also finds chimeric mRNA sequences that combined portions of unrelated genes with Ly-6 sequences, complicating the analysis. Genome mapping showed the chimeras did not represent real gene fusions but likely arose from artifacts. While many rat and mouse homologs were identified, clear orthologs between species were difficult to determine due to high sequence divergence over time.
Fiorucci presents research on the role of bile acids and their activation of nuclear receptors such as FXR in regulating gastrointestinal mucosa integrity. Bile acids are endogenous ligands for FXR and other receptors that modulate inflammation. Activation of FXR was shown to reduce markers of colitis and inflammation in mouse models of inflammatory bowel disease. FXR deficient mice had increased inflammation and tissue damage compared to controls in response to colitis induction. Pharmacological FXR activation also reduced inflammation. This suggests FXR plays an important role in innate immunity and protection of the GI tract from inflammation.
This document discusses the role of the TLR4 ligand EDA-Fn in mediating signal transduction during skin fibrosis. It notes that EDA-Fn is an alternatively spliced form of fibronectin that is expressed during tissue repair and fibrosis. Experiments showed that TGF-β promotes the inclusion of the EDA exon into fibronectin pre-mRNA and increases EDA-Fn expression. Inhibiting the TGF-β pathways with SB431542 or MEK/ERK inhibitors reduced EDA-Fn mRNA levels, suggesting these pathways mediate TGF-β induced EDA-Fn expression. Overall, the document examines the role of EDA-Fn downstream of TGF-β
Control of liver fibrosis by nuclear receptors - Prof Stefano FiorucciAttività scientifica
The document discusses the role of nuclear receptors in controlling liver fibrosis. It describes several nuclear receptors expressed in hepatic stellate cells, including PPARβ/γ, PXR, FXR, and SHP. Activation of these receptors reduces stellate cell proliferation and the expression of fibrotic markers. Studies show that ligands for PPARγ, FXR, and PXR decrease liver fibrosis in rodent models by inducing a phenotypic switch in stellate cells from an activated to quiescent state.
The document describes the establishment of immortalized human amniotic epithelial cell (iHAE) lines. HAE cells were extracted from placentas and infected with retroviruses containing HPV16 E6/E7 and hTERT genes to extend their lifespan. The iHAE lines showed extended proliferation ability and expression of stem cell markers. They maintained multipotent differentiation potential as demonstrated by their ability to differentiate into adipocytes, osteocytes, neurons, and cardiac cell types. The iHAE cells represent a promising new cell source for applications in regenerative medicine and cell therapy due to their immunosuppressive properties and differentiation potential.
The document summarizes the development of a Ganoderma lucidum extract herbal tea product with higher triterpene content. Key steps included:
1) Cloning the MVD gene from G. lucidum and constructing an overexpression vector containing the MVD gene driven by the gpd promoter.
2) Transforming Agrobacterium tumefaciens containing the overexpression vector and selecting strains with increased triterpene production.
3) Optimizing cultivation and extraction methods to produce a herbal tea product with concentrated triterpenes for potential health benefits. Efficacy and safety testing were also discussed to support marketing and commercialization of the product.
Small molecule inhibitors of PI4 KinaseDavid Andrews
Potent, selective small molecule inhibitors of type III phosphatidylinositol-4-kinase α- and β- and their effects on phosphatidylinositol signalling. The importance of small molecule probes to help us understand cellular pathways in cancer
A reading report for <A Secreted Slit2 Fragment Regulates Adipose Tissue Ther...星云 王
A reading report for <A Secreted Slit2 Fragment Regulates Adipose Tissue Thermogenesis and Metabolic Function
>, only for private study use, please do not use it for profit or public.
NHERF1 regulates the membrane retention and recycling of the parathyroid hormone receptor PTH1R. Specifically:
1) NHERF1 inhibits the endocytosis of PTH1R in response to parathyroid hormone by binding to the receptor via its PDZ domains.
2) This prevents the internalization and delays the recycling of PTH1R after endocytosis.
3) Both the PDZ and MERM domains of NHERF1, as well as the PDZ-binding domain of PTH1R, are required for this effect of reduced endocytosis and delayed recycling.
2015 - Cdk5 promotes DNA replication stress checkpoint activation through RPA...Simon Gemble
Cdk5 promotes DNA replication stress checkpoint activation through RPA-32 phosphorylation, and impacts metastasis free survival in breast cancer patients. The study found that depletion of Cdk5 in cells results in increased sensitivity to agents that cause replication stress, slower DNA replication, and impaired activation of the intra-S phase DNA damage checkpoint. Cdk5 was shown to directly phosphorylate RPA32 on residues necessary for checkpoint activation. Analysis of breast cancer patient data revealed that lower levels of Cdk5 correlated with longer metastasis free survival after treatment. The results suggest that Cdk5 plays a role in DNA replication and repair, and that its depletion could enhance killing of tumor cells by therapies like radiation and PARP inhibitors.
IRJET- Silencing of hnRNP A1 and hnRNP A2/B1 Downregulates the Expression of ...IRJET Journal
The document summarizes a study that examined the effect of silencing hnRNP A1 and hnRNP A2/B1 splice factors on the expression of CD44v6 and CD44v10 exons in glioma cells. The researchers found that knockdown of hnRNP A1 and hnRNP A2/B1 led to decreased expression of CD44v6 and CD44v10 exons based on qRT-PCR analysis. Specifically, cells with silenced splice factors had lower expression of the two exons compared to non-silenced control cells. Therefore, hnRNP A1 and hnRNP A2/B1 may positively regulate the expression of
The document discusses cytometry techniques for analyzing apoptosis. It describes measuring mitochondrial changes, caspase activation, and DNA fragmentation to identify and quantify apoptotic cells. Specific techniques summarized include using fluorescent probes to detect mitochondrial membrane potential loss, caspase activation via cleavage of targets like PARP, and DNA strand breaks.
In this webinar, Dr. Augusto Montezano will share his research that investigates the role of endothelial inflammation and ACE2 biology in COVID-19 infections and long-term effects.
COVID-19 association with cardiovascular disease is thought to be due to endothelial cell inflammation. ACE2 interactions with SARS-CoV-2 spike protein S1 subunit are important to viral infection. In Dr. Montezano’s group, they questioned whether SARS-CoV-2 induces vascular inflammation via ACE2 and whether this is related to viral infection. By exposing human microvascular endothelial cells to recombinant S1p (rS1p), they observed that rS1p induces a potent inflammatory response via an ACE2-dependent manner, without affecting ACE2 activity. Their findings suggest that vascular inflammation in COVID-19 involves activation of ACE2-mediated pro-inflammatory signaling that may be unrelated to viral replication.
Key Topics Include:
- Learn a new facet of ACE2 biology
- Understand a novel mechanism whereby SARS-CoV-2 spike protein induces endothelial cell inflammation
The document discusses experiments to better understand regulation of the GADD45a gene and improve the GreenScreen HC assay. It found some chemicals induced GADD45a through non-genotoxic mechanisms, including flavonoids, glucocorticoids, retinoids and HDAC inhibitors. Arsenite was found to induce GADD45a possibly through JNK and ROS pathways, and this effect could be reduced by DMSO or a JNK inhibitor. Future work aims to investigate the importance of p53 and mutation of response elements in the GADD45a reporter.
The document summarizes research on knockout rat models lacking key drug transporter genes. It describes the development of knockout rats for the drug transporters Mdr1a, Bcrp, Mrp1, Mrp2, and p53 using zinc finger nuclease technology. This allows for improved prediction of drug absorption, distribution, metabolism, and excretion (ADME) properties. Data is presented comparing substrate drug levels and expression of other transporters in knockout versus wild type rats for several of these models. The goal is to enable more efficient drug development by identifying safety issues earlier in the process using a more human-relevant species.
This document summarizes a study investigating the relationship between activation of the alpha7 nicotinic acetylcholine receptor (α7nAChR) and the nuclear factor erythroid 2–related factor 2 (Nrf2) in antagonizing renal ischemia-reperfusion injury. The study examined the effects of a selective α7nAChR agonist on apoptosis and apoptotic signaling in renal epithelial cells subjected to hypoxia-reoxygenation injury. It was found that the agonist attenuated apoptosis and modulated levels of apoptotic proteins like caspase-3 and Bax. Inhibition of Nrf2 partially blocked these effects, indicating Nrf2 mediates the anti-apoptotic effects of α7nAChR activation
- TP53 somatic mutations are frequent in many types of human cancer, occurring in approximately 50% of cancers.
- The TP53 gene encodes the p53 protein, which functions as a tumor suppressor by inducing cell cycle arrest or apoptosis in response to DNA damage. Mutations in TP53 lead to a non-functional or dominant negative "mutant p53" protein (mp53).
- The study found that mp53 can bind to and activate the promoter of the ID4 gene, inducing its expression. ID4 is involved in processes like cell proliferation, differentiation and angiogenesis.
Farnesoid x receptor (fxr) and intestinal mucosa - Stefano FiorucciAttività scientifica
Bile acids activated receptors regulate the integrity of gastrointestinal mucosafocus on FXR.
Stefano Fiorucci,
MD Department of Surgical and Biomedical Sciences
University of Perugia
For The Japanese Society of Gastroenterology (JSGE) COI Disclosure
The document describes research into identifying potent inhibitors of the SHP2 protein tyrosine phosphatase. Several small molecule inhibitors were discovered, including NSC-87877, which was shown to selectively inhibit SHP2 activity in vitro and in cell-based assays. It was the first evidence that SHP2 phosphatase is involved in growth factor-stimulated ERK activation. Further screening of a chemical library identified additional SHP2 inhibitors, such as HLM002903 and HLM019544, which were shown to inhibit SHP2-dependent cell growth and signaling. The goal of finding SHP2 inhibitors is to develop potential anti-cancer agents, as SHP2 mutations have been implicated in various cancers and
The document describes a research study aimed at developing biomarkers for detecting potential allergenicity of novel foods, including genetically modified foods. The researcher conducted experiments challenging mice with known food allergens (egg ovomucoid protein and peanut protein) and analyzed gene expression profiles in the mice spleens. Several hundred genes were found to be differentially expressed. After validating some genes, the researcher identified potential biomarker genes that could help detect allergenicity of GM foods. The study provides insights into transcriptomic responses to food allergens and biomarkers that may help evaluate allergenicity of novel foods like GM crops.
Discriminating Facts from Artefacts in the Secreted Ly-6 Protein FamilyChris Southan
The document discusses several issues related to accurately characterizing the secreted Ly-6 protein family based on bioinformatic analysis. It describes the discovery of novel rat Ly-6 proteins from urine samples and EST data, but also finds chimeric mRNA sequences that combined portions of unrelated genes with Ly-6 sequences, complicating the analysis. Genome mapping showed the chimeras did not represent real gene fusions but likely arose from artifacts. While many rat and mouse homologs were identified, clear orthologs between species were difficult to determine due to high sequence divergence over time.
Fiorucci presents research on the role of bile acids and their activation of nuclear receptors such as FXR in regulating gastrointestinal mucosa integrity. Bile acids are endogenous ligands for FXR and other receptors that modulate inflammation. Activation of FXR was shown to reduce markers of colitis and inflammation in mouse models of inflammatory bowel disease. FXR deficient mice had increased inflammation and tissue damage compared to controls in response to colitis induction. Pharmacological FXR activation also reduced inflammation. This suggests FXR plays an important role in innate immunity and protection of the GI tract from inflammation.
This document discusses the role of the TLR4 ligand EDA-Fn in mediating signal transduction during skin fibrosis. It notes that EDA-Fn is an alternatively spliced form of fibronectin that is expressed during tissue repair and fibrosis. Experiments showed that TGF-β promotes the inclusion of the EDA exon into fibronectin pre-mRNA and increases EDA-Fn expression. Inhibiting the TGF-β pathways with SB431542 or MEK/ERK inhibitors reduced EDA-Fn mRNA levels, suggesting these pathways mediate TGF-β induced EDA-Fn expression. Overall, the document examines the role of EDA-Fn downstream of TGF-β
Control of liver fibrosis by nuclear receptors - Prof Stefano FiorucciAttività scientifica
The document discusses the role of nuclear receptors in controlling liver fibrosis. It describes several nuclear receptors expressed in hepatic stellate cells, including PPARβ/γ, PXR, FXR, and SHP. Activation of these receptors reduces stellate cell proliferation and the expression of fibrotic markers. Studies show that ligands for PPARγ, FXR, and PXR decrease liver fibrosis in rodent models by inducing a phenotypic switch in stellate cells from an activated to quiescent state.
The document describes the establishment of immortalized human amniotic epithelial cell (iHAE) lines. HAE cells were extracted from placentas and infected with retroviruses containing HPV16 E6/E7 and hTERT genes to extend their lifespan. The iHAE lines showed extended proliferation ability and expression of stem cell markers. They maintained multipotent differentiation potential as demonstrated by their ability to differentiate into adipocytes, osteocytes, neurons, and cardiac cell types. The iHAE cells represent a promising new cell source for applications in regenerative medicine and cell therapy due to their immunosuppressive properties and differentiation potential.
The document summarizes the development of a Ganoderma lucidum extract herbal tea product with higher triterpene content. Key steps included:
1) Cloning the MVD gene from G. lucidum and constructing an overexpression vector containing the MVD gene driven by the gpd promoter.
2) Transforming Agrobacterium tumefaciens containing the overexpression vector and selecting strains with increased triterpene production.
3) Optimizing cultivation and extraction methods to produce a herbal tea product with concentrated triterpenes for potential health benefits. Efficacy and safety testing were also discussed to support marketing and commercialization of the product.
Small molecule inhibitors of PI4 KinaseDavid Andrews
Potent, selective small molecule inhibitors of type III phosphatidylinositol-4-kinase α- and β- and their effects on phosphatidylinositol signalling. The importance of small molecule probes to help us understand cellular pathways in cancer
A reading report for <A Secreted Slit2 Fragment Regulates Adipose Tissue Ther...星云 王
A reading report for <A Secreted Slit2 Fragment Regulates Adipose Tissue Thermogenesis and Metabolic Function
>, only for private study use, please do not use it for profit or public.
NHERF1 regulates the membrane retention and recycling of the parathyroid hormone receptor PTH1R. Specifically:
1) NHERF1 inhibits the endocytosis of PTH1R in response to parathyroid hormone by binding to the receptor via its PDZ domains.
2) This prevents the internalization and delays the recycling of PTH1R after endocytosis.
3) Both the PDZ and MERM domains of NHERF1, as well as the PDZ-binding domain of PTH1R, are required for this effect of reduced endocytosis and delayed recycling.
2015 - Cdk5 promotes DNA replication stress checkpoint activation through RPA...Simon Gemble
Cdk5 promotes DNA replication stress checkpoint activation through RPA-32 phosphorylation, and impacts metastasis free survival in breast cancer patients. The study found that depletion of Cdk5 in cells results in increased sensitivity to agents that cause replication stress, slower DNA replication, and impaired activation of the intra-S phase DNA damage checkpoint. Cdk5 was shown to directly phosphorylate RPA32 on residues necessary for checkpoint activation. Analysis of breast cancer patient data revealed that lower levels of Cdk5 correlated with longer metastasis free survival after treatment. The results suggest that Cdk5 plays a role in DNA replication and repair, and that its depletion could enhance killing of tumor cells by therapies like radiation and PARP inhibitors.
IRJET- Silencing of hnRNP A1 and hnRNP A2/B1 Downregulates the Expression of ...IRJET Journal
The document summarizes a study that examined the effect of silencing hnRNP A1 and hnRNP A2/B1 splice factors on the expression of CD44v6 and CD44v10 exons in glioma cells. The researchers found that knockdown of hnRNP A1 and hnRNP A2/B1 led to decreased expression of CD44v6 and CD44v10 exons based on qRT-PCR analysis. Specifically, cells with silenced splice factors had lower expression of the two exons compared to non-silenced control cells. Therefore, hnRNP A1 and hnRNP A2/B1 may positively regulate the expression of
The document discusses cytometry techniques for analyzing apoptosis. It describes measuring mitochondrial changes, caspase activation, and DNA fragmentation to identify and quantify apoptotic cells. Specific techniques summarized include using fluorescent probes to detect mitochondrial membrane potential loss, caspase activation via cleavage of targets like PARP, and DNA strand breaks.
In this webinar, Dr. Augusto Montezano will share his research that investigates the role of endothelial inflammation and ACE2 biology in COVID-19 infections and long-term effects.
COVID-19 association with cardiovascular disease is thought to be due to endothelial cell inflammation. ACE2 interactions with SARS-CoV-2 spike protein S1 subunit are important to viral infection. In Dr. Montezano’s group, they questioned whether SARS-CoV-2 induces vascular inflammation via ACE2 and whether this is related to viral infection. By exposing human microvascular endothelial cells to recombinant S1p (rS1p), they observed that rS1p induces a potent inflammatory response via an ACE2-dependent manner, without affecting ACE2 activity. Their findings suggest that vascular inflammation in COVID-19 involves activation of ACE2-mediated pro-inflammatory signaling that may be unrelated to viral replication.
Key Topics Include:
- Learn a new facet of ACE2 biology
- Understand a novel mechanism whereby SARS-CoV-2 spike protein induces endothelial cell inflammation
Identifying candidate targets for Cancer Therapy with Integrated Text Mining ...Ann-Marie Roche
In this 60 minute webinar, Philip L. Lorenzi Ph.D. talked to us about autophagy, a programmed process in which cell contents are delivered to lysosomes for degradation and which appears to have both tumor-suppressive and tumor-promoting functions. Phillip and his colleagues have compiled a comprehensive, curated inventory of autophagy modulators by integrating information from published siRNA screens, multiple pathway analysis algorithms, and extensive text-mining of the literature and he will provide extensive analysis of their sources of information and their complex relationships with each other.
El martes 26 de septiembre del 2017 organizamos en la Fundación Ramón Areces un Simposio Internacional sobre nuevas perspectivas en la investigación sobre el cáncer. En colaboración con el Centro Nacional de Investigaciones Oncológicas (CNIO) y Weizmann Institute for Science.
The document is a reference guide for pathway maps and related QIAGEN products. It includes a table of contents listing over 40 signaling pathways. For each pathway, it lists related RT2 Profiler PCR Arrays and Cignal Reporter Assay Kits from QIAGEN that can be used to study gene expression and transcription factor activity for that pathway. It also provides brief descriptions of the PCR array and reporter assay products and directs readers to QIAGEN websites for more information.
Many key signaling pathways determine how cells respond to stress from various sources like inflammation, nutrient imbalance, hypoxia, and protein misfolding. Dysregulation of these pathways can lead to diseases such as diabetes, cancer, cardiovascular disease, COPD, Alzheimer's, and depression. Researchers use products from Enzo Life Sciences to study how cellular stress signaling pathways are involved in these conditions.
Chemokines are small proteins, usually ~70–80 amino acid residues, with conserved sequence and structural features and expressed in tissues during normal immune surveillance or in response to injury or infection.
This is the Powerpoint presentation from my recent presentation at the TTP LabTech US Acumen Users Group Meeting (UGM) held at the British Consulate-General in Cambridge, MA on May 18, 2010
This document discusses stem cell niches and the microenvironment that supports stem cells. It outlines various cell types that make up stem cell niches in the bone marrow including mesenchymal stem cells, endothelial cells, and osteoblasts. It describes markers that characterize these cell types and factors they secrete like cytokines, growth factors, and extracellular matrix proteins that regulate stem cell self-renewal and differentiation. Pathways involved in maintaining stem cells like the Wnt signaling pathway are also summarized.
1. The document discusses systems biology approaches to modeling the endothelial cell response to fluid shear stress. It describes experimental techniques to apply controlled fluid shear stress and measure downstream cellular responses.
2. Mathematical models are formulated to represent molecular interactions and pathways involved in the shear stress response. Model predictions are compared to experimental data to validate and refine the models.
3. The models can provide insights into critical components, feedback loops, and how external perturbations may influence the cellular response to shear stress. Further experimental validation of model predictions is needed.
This document summarizes three genomic approaches: 1) Profiling downstream target genes of the Runx3 transcription factor in gastric cancer cells, identifying both up- and downregulated genes. 2) Constructing an shRNA library targeting the mouse kinome to discover regulators of osteogenesis through screening. 3) Investigating the protein interaction between Bmi1 and Pontin52, linking them to hematopoietic stem cell self-renewal and exploring their roles in cancer cell death.
A study using a novel matrix analysis (called “PiSCES”) to observe the network activity of TCR signaling proteins in alopecia areata that revealed a subnetwork of basal T cell signaling complexes which could provide new molecular candidates for pharmacologic targeting.
JC Fall 2009-Role of TNFalpha-Converting Enzyme (TACE) Inhibition on Amyloid ...Nisha Rizvi
This document summarizes the findings of a study investigating the effects of BMS-561392, a TNFα converting enzyme (TACE) inhibitor, on amyloid beta (Aβ) production. The study found that BMS-561392 selectively inhibited TACE without affecting BACE or increasing Aβ levels. This suggests that while TACE and BACE reside in the same compartment, they do not compete for the same pool of amyloid precursor protein and target distinct pathways. Therefore, TACE-targeted anti-inflammatory drugs may not increase Aβ generation in Alzheimer's disease patients as previously thought. The authors conclude that BMS-561392 is an unlikely AD drug candidate but that further research into centrally-acting
The document discusses microRNAs (miRNAs) and their dysregulation in cancer. It summarizes a study that identified a miRNA signature associated with prognostic factors and disease progression in chronic lymphocytic leukemia (CLL) patients. The signature included upregulated miRNAs such as miR-15a, miR-16-1, and miR-155, and downregulated miRNAs such as miR-29b-2. Genetic variations were also found in miRNA genes of CLL patients.
This document discusses advances in multiplexed genotyping and its impact on the treatment of lung cancers. Key points include:
1) The era of "one size fits all" treatment of lung cancers is over due to advances in identifying oncogenic drivers through multiplexed testing of tumor samples.
2) Identifying these drivers through comprehensive genomic profiling allows for matching patients to targeted therapies, improving outcomes over previous untargeted approaches.
3) The MSK-IMPACT assay profiles 341 cancer genes and has identified targets for both approved and investigational targeted therapies, improving personalized treatment of lung cancer patients.
How to Build a Module in Odoo 17 Using the Scaffold MethodCeline George
Odoo provides an option for creating a module by using a single line command. By using this command the user can make a whole structure of a module. It is very easy for a beginner to make a module. There is no need to make each file manually. This slide will show how to create a module using the scaffold method.
This document provides an overview of wound healing, its functions, stages, mechanisms, factors affecting it, and complications.
A wound is a break in the integrity of the skin or tissues, which may be associated with disruption of the structure and function.
Healing is the body’s response to injury in an attempt to restore normal structure and functions.
Healing can occur in two ways: Regeneration and Repair
There are 4 phases of wound healing: hemostasis, inflammation, proliferation, and remodeling. This document also describes the mechanism of wound healing. Factors that affect healing include infection, uncontrolled diabetes, poor nutrition, age, anemia, the presence of foreign bodies, etc.
Complications of wound healing like infection, hyperpigmentation of scar, contractures, and keloid formation.
How to Manage Your Lost Opportunities in Odoo 17 CRMCeline George
Odoo 17 CRM allows us to track why we lose sales opportunities with "Lost Reasons." This helps analyze our sales process and identify areas for improvement. Here's how to configure lost reasons in Odoo 17 CRM
ISO/IEC 27001, ISO/IEC 42001, and GDPR: Best Practices for Implementation and...PECB
Denis is a dynamic and results-driven Chief Information Officer (CIO) with a distinguished career spanning information systems analysis and technical project management. With a proven track record of spearheading the design and delivery of cutting-edge Information Management solutions, he has consistently elevated business operations, streamlined reporting functions, and maximized process efficiency.
Certified as an ISO/IEC 27001: Information Security Management Systems (ISMS) Lead Implementer, Data Protection Officer, and Cyber Risks Analyst, Denis brings a heightened focus on data security, privacy, and cyber resilience to every endeavor.
His expertise extends across a diverse spectrum of reporting, database, and web development applications, underpinned by an exceptional grasp of data storage and virtualization technologies. His proficiency in application testing, database administration, and data cleansing ensures seamless execution of complex projects.
What sets Denis apart is his comprehensive understanding of Business and Systems Analysis technologies, honed through involvement in all phases of the Software Development Lifecycle (SDLC). From meticulous requirements gathering to precise analysis, innovative design, rigorous development, thorough testing, and successful implementation, he has consistently delivered exceptional results.
Throughout his career, he has taken on multifaceted roles, from leading technical project management teams to owning solutions that drive operational excellence. His conscientious and proactive approach is unwavering, whether he is working independently or collaboratively within a team. His ability to connect with colleagues on a personal level underscores his commitment to fostering a harmonious and productive workplace environment.
Date: May 29, 2024
Tags: Information Security, ISO/IEC 27001, ISO/IEC 42001, Artificial Intelligence, GDPR
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Find out more about ISO training and certification services
Training: ISO/IEC 27001 Information Security Management System - EN | PECB
ISO/IEC 42001 Artificial Intelligence Management System - EN | PECB
General Data Protection Regulation (GDPR) - Training Courses - EN | PECB
Webinars: https://pecb.com/webinars
Article: https://pecb.com/article
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Website: https://pecb.com/
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Slideshare: http://www.slideshare.net/PECBCERTIFICATION
Reimagining Your Library Space: How to Increase the Vibes in Your Library No ...Diana Rendina
Librarians are leading the way in creating future-ready citizens – now we need to update our spaces to match. In this session, attendees will get inspiration for transforming their library spaces. You’ll learn how to survey students and patrons, create a focus group, and use design thinking to brainstorm ideas for your space. We’ll discuss budget friendly ways to change your space as well as how to find funding. No matter where you’re at, you’ll find ideas for reimagining your space in this session.
A review of the growth of the Israel Genealogy Research Association Database Collection for the last 12 months. Our collection is now passed the 3 million mark and still growing. See which archives have contributed the most. See the different types of records we have, and which years have had records added. You can also see what we have for the future.
Chapter wise All Notes of First year Basic Civil Engineering.pptxDenish Jangid
Chapter wise All Notes of First year Basic Civil Engineering
Syllabus
Chapter-1
Introduction to objective, scope and outcome the subject
Chapter 2
Introduction: Scope and Specialization of Civil Engineering, Role of civil Engineer in Society, Impact of infrastructural development on economy of country.
Chapter 3
Surveying: Object Principles & Types of Surveying; Site Plans, Plans & Maps; Scales & Unit of different Measurements.
Linear Measurements: Instruments used. Linear Measurement by Tape, Ranging out Survey Lines and overcoming Obstructions; Measurements on sloping ground; Tape corrections, conventional symbols. Angular Measurements: Instruments used; Introduction to Compass Surveying, Bearings and Longitude & Latitude of a Line, Introduction to total station.
Levelling: Instrument used Object of levelling, Methods of levelling in brief, and Contour maps.
Chapter 4
Buildings: Selection of site for Buildings, Layout of Building Plan, Types of buildings, Plinth area, carpet area, floor space index, Introduction to building byelaws, concept of sun light & ventilation. Components of Buildings & their functions, Basic concept of R.C.C., Introduction to types of foundation
Chapter 5
Transportation: Introduction to Transportation Engineering; Traffic and Road Safety: Types and Characteristics of Various Modes of Transportation; Various Road Traffic Signs, Causes of Accidents and Road Safety Measures.
Chapter 6
Environmental Engineering: Environmental Pollution, Environmental Acts and Regulations, Functional Concepts of Ecology, Basics of Species, Biodiversity, Ecosystem, Hydrological Cycle; Chemical Cycles: Carbon, Nitrogen & Phosphorus; Energy Flow in Ecosystems.
Water Pollution: Water Quality standards, Introduction to Treatment & Disposal of Waste Water. Reuse and Saving of Water, Rain Water Harvesting. Solid Waste Management: Classification of Solid Waste, Collection, Transportation and Disposal of Solid. Recycling of Solid Waste: Energy Recovery, Sanitary Landfill, On-Site Sanitation. Air & Noise Pollution: Primary and Secondary air pollutants, Harmful effects of Air Pollution, Control of Air Pollution. . Noise Pollution Harmful Effects of noise pollution, control of noise pollution, Global warming & Climate Change, Ozone depletion, Greenhouse effect
Text Books:
1. Palancharmy, Basic Civil Engineering, McGraw Hill publishers.
2. Satheesh Gopi, Basic Civil Engineering, Pearson Publishers.
3. Ketki Rangwala Dalal, Essentials of Civil Engineering, Charotar Publishing House.
4. BCP, Surveying volume 1
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How to Add Chatter in the odoo 17 ERP ModuleCeline George
In Odoo, the chatter is like a chat tool that helps you work together on records. You can leave notes and track things, making it easier to talk with your team and partners. Inside chatter, all communication history, activity, and changes will be displayed.
How to Setup Warehouse & Location in Odoo 17 InventoryCeline George
In this slide, we'll explore how to set up warehouses and locations in Odoo 17 Inventory. This will help us manage our stock effectively, track inventory levels, and streamline warehouse operations.
Leveraging Generative AI to Drive Nonprofit InnovationTechSoup
In this webinar, participants learned how to utilize Generative AI to streamline operations and elevate member engagement. Amazon Web Service experts provided a customer specific use cases and dived into low/no-code tools that are quick and easy to deploy through Amazon Web Service (AWS.)
1. Chemoresistance and Transformation -ABC family- membrane transport protein MDR1-P-gp 48 different ABC transporters extrude many types of drugs from cancer cells, thereby conferring multidrug resistance Is there something common? -Oncogenic signal -Defect in apoptotic pathway -Many drugs induce apoptotic pathways that defects in this pathway also results in multidrug resistancc Myc and ras Myc and bcl-2 Myc and mutant p53 E1A and E1B Increasing our knowledge of the components involved in the pathways that mediate cell death and survival….. Gives us the hope is that targeting specific molecules ( Targeted therapy ) will impart sensitivity to Chemotherapy — a combination therapy is possible Chemoresistance Transformation
7. Are caspases activated ? If yes, how important they are? How important caspase 3 is? Caspase 8 or 9 or both are important! Apoptosis Two broad pathways that lead to apoptosis: Apoptosis Extrinsic Intrinsic Adapter
18. Mitochondrial membrane potential Mitochondrial Outer Membrane Permeabilization Pro-apoptotic Bcl-2 member Bax translocates to Mitochondria Cytochrome C is released into cytoplasm
28. Does AP-2 has any role in cancer cell Chemosensitivity ?
29. p53 50% of primary tumor have mutated p53 Need for identification of other determinants Major chemosensitivity determinant Gets activated upon DNA damage and induces apoptosis irradiation Chemotherapy
30. Chemosensitivity of cancer cells over expressing AP-2 - Chemodrug - Ad-LacZ + Chemodrug - Ad-AP2 + Chemodrug 0 20 40 60 80 100 120 Adriamycin Etoposide Cisplatin Taxol Carboplatin Percent IC 50 Cells O/N Mock/ Ad-LacZ/ Ad-AP-2 6 hrs Add chemo 48 hrs % Live cells
31. Tet-Off system Transcription is turned off by tet tTA expressing adenovirus tTA – tetracyclin controlled transactivator - Tet AP-2 under Tet-responsive element P min CMV TRE AP-2 tTA active pCMV tetR VP16 tTA Tet bound tTA Tet + Tet inactive
33. AP-2 expression sensitizes cells to undergo apoptosis upon chemotherapy Adria tTA Tet IC25 IC50 B + - - + + 1 g + + 0.1 g Control/ 0 hr tTA - + Tet - 0.1 g MOCK AP-2 A G1 G2 A S S
34. AP-2 expression sensitizes cells to undergo apoptosis upon chemotherapy Adria tTA Tet - - - - + 0.1 g 0 5 10 15 20 25 30 35 40 45 1 2 3 4 5 6 7 8 IC 25 - - IC 50 - - IC 25 + 1.0 g IC 50 + 1.0 g IC 25 + 0.1 g IC 50 + 0.1 g AP-2 Adria Adria Adria+ AP-2 - % <G1 - % S % Apoptosis/ % DNA synthesis 0 10 20 30 40 50 60 70 Chemo tTA Tet - - - - + 0.1 g IC 25 - - IC 50 - - IC 25 + 1.0 g IC 50 + 1.0 g IC 25 + 0.1 g IC 50 + 0.1 g AP-2 Chemo Chemo Chemo+ AP-2 - Cisplatin - Taxol - Etoposide 1 2 3 4 5 6 7 8 % Apoptosis
35. What is the role of endogenous AP-2 in chemosensitivity ? Taxol Cisplatin Adriamycin 0 24 48 72 hrs AP2 Actin Etoposide AP2 Actin AP2 Actin AP2 Actin 48 hrs GPDH AP-2 72 hrs Untreated Adriamycin Cisplatin Etoposide Taxol Marker Untreated Adriamycin Cisplatin Etoposide Taxol
36. What is the role of Chemotherapy induced AP-2 in Cancer cell chemosensitvity? Chemotherapy induced AP-2 contributes to chemosensitivity - Control - Mock - Lamin siRNA - AP-2 siRNA 0 10 20 30 40 50 60 70 80 90 Etoposide Adria Cisplatin Taxol % Viability GAPDH AP-2 Control Mock siRNA LaminA/C siRNA AP-2 1 2 3 4 Lamin A/C - Mock siRNA Lamin A/C siRNA AP-2 Control AP-2 Actin - + + + + Adria 1 2 3 4 5 AP-2 Actin - + + + + Cisplatin AP-2 Actin - + + + + Taxol
37. Chemotherapy induced AP-2 contributes to chemosensitivity Plate cells Transfect siRNA Add Adria Stain the colonies O/N 2 days 2 weeks Control Mock Lamin/ siRNA AP-2 siRNA 0 0.1 0.2 0.4 0.8 1 Adriamycin g/ml
38. In cell culture, silenced AP-2 is re-expressed by methylation inhibitor (5-aza-2 deoxycytidine) AP-2 expression and Breast Cancer progression Effect of re-expression of silenced AP-2 on chemosensitivity ? AP-2 expression + + - Normal breast epithelium Ductal carcinoma in situ (DCIS) Invasive breast tumors Hypermethylation of AP-2 promoter - + 75% (12/16) (Douglas et al., 2004) + 16% (3/19)
42. 5aza2dC treatment inhibits the tumorigenicity of MDA-MB-231 cells upon chemotherapy in an AP-2 dependent manner Treatment No of tumors/ Mean volume (%) No of mice mm 3 ± SE Control 3/3 6426 ± 1118 100 5aza2dC 3/3 5100 ± 291 79 Adria 3/3 2348 ± 1172 37 Mock + 5aza2dC + Adria 0/4 0 ± 0 0 Lamin siRNA + 5aza2dC+ Adria 0/4 0 ± 0 0 AP-2 siRNA + 5aza2dC + Adria 5/5 1832 ± 300 29
43. AP-2 overexpression increases the chemosensitivity of cancer cells Conclusions 5aza2dC induced re-expression of AP-2 in breast cancer cells increases chemosensitivity and inhibits tumorigenicity upon chemotherapy Chemotherapy induces endogenous AP-2 , which contributes to chemosensitivity AP-2 sensitizes cancer cells undergo apoptosis upon chemotherapy
44. AP-2 inhibits cancer cell growth by inducing cell cycle arrest and apoptosis Wajapeyee and Somasundaram, 2003 JBC 0 20 40 60 80 100 120 0 20 40 60 - Ad-LacZ - Ad-AP2 % Viability MOI Hrs 24 48 24 48 %A %G1 %S %G2 2.04 57.32 26.19 14.45 1.08 58.52 25.48 14.92 1.71 82.45 3.24 12.60 42.44 32.51 6.30 16.75 Ad-LacZ Ad-AP2 Virus 24 hr 48 hr Ad-LacZ Ad-AP2 G1 A G2 S S PI-DNA content Brdu-DNA synthesis
45. Apoptosis Intrinsic Apoptosis induction-two pathways Wajapeyee and Somasundaram, 2006 JBC Extrinsic Adapter AP-2 Bcl-2 Bax Bax Bax How does AP-2 induce apoptosis?
65. Forced AP-2 expression induces myogenic differentiation GM GM+ AP-2 10X 100X a b c d
66. AP-2 downregulates c-Myc mediated induction of cyclin D2 DM DM + Cyclin D2 DM + cMYC 10X 100X a g b h c i DM + MYC + AP-2 DM + Cyclin D2 + AP-2 DM + MYC + Cyclin D2 siRNA d j e k f l 10X 100X
67. Cancer of striated muscle tissue There are three major forms: alveolar rhabdosarcoma - most often afflicts adolescents, typically develops in the extremities, body or eye cavities. embryonal rhabdosarcoma – occurs in infants and young children, develops in the head, neck, extremities or lower genitourinary tract. pleiomorphic rhabdosarcoma – occurs in adults and typically develops in the extremities Rhabdosarcoma AP-2 is induced during muscle differentiation De-differentiation results in cancer Loss of AP-2 leads to rhabdosarcoma !!!
68. N P1 P2 P3 P4 AP-2 fold downregulation 0 5 10 15 20 25 30 AP-2 AP-2 is silenced by promoter methylation -1000 +800 1 47 N P1 P2 P3 P4 Bisulfite sequencing