N-acetyl-D-glucosamine kinase (NAGK) interacts with dynein light-chain roadblock type 1 (DYNLRB1) at dendritic branch points in neurons. Immunocytochemistry and proximity ligation assays showed colocalization of NAGK and DYNLRB1 on microtubule fibers at dendritic branches. NAGK was also found to interact with Golgi outposts and DYNLRB1 at branch points, indicating a tripartite interaction between NAGK, dynein, and Golgi that regulates dendritic growth and branching. Introduction of a peptide derived from DYNLRB1 stunted dendrite development in cultured neurons.
Presentation PPT The 55 kDa Tissue Transglutaminase Cross-Linking Active Isof...Danstan Arasa
The study aimed to demonstrate that the 55 kDa isoform of tissue transglutaminase (TG) plays a significant role in cell apoptosis. Experiments showed higher rates of cell death with increased TG expression in retinoic acid-treated cells and cells transfected with the TG isoform. This supports the hypothesis that the cross-linking active TG isoform is a potent inducer of apoptosis, helping to clarify the role of TG isoforms in transglutaminase activity and cell death. The 55 kDa TG isoform may have significant roles in physiological and disease-related tissue events.
Taxol and 10-deacetylbaccatinIII induce distinct changesNeesar Ahmed
The document summarizes a study comparing the effects of Taxol, 10-deacetylbaccatinIII (10-DAB), and BaccatinIII (BacIII) on caveolae dynamics in HeLa cells expressing GFP-Caveolin-1. The key findings are:
1) Taxol treatment caused a transient recruitment of Caveolin-1 to the cell surface followed by internalization, while 10-DAB increased the "kiss and run" dynamics of caveolae.
2) Sustained Caveolin-1 phosphorylation was observed with both Taxol and 10-DAB treatments, with Taxol also inducing phosphorylation of Raf-1, ERK1/2,
Oncology: Spatial Localization of Ras proteinsNachiket Vartak
This is a presentation of work done at the MPI Dortmund from 2008-2013 on the mechanism through with localization of the Ras protein in generated in cells. It presents the inhibiton Palmostatin-B, which inhibits this mechanism, leading to reveral of oncogenic signaling and cancerous phenotypes.
The document discusses methylation processes and their role in human pathogenesis. It first describes how the MeCP2 protein functions in gene silencing through methyl-DNA binding and transcription repression, but that its role is more complex as a regulator rather than strict silencer of transcription. It also discusses how MeCP2 mutations cause Rett syndrome and interactions with other proteins. The role of DNA methylation in cancer is then covered, including global hypomethylation in cancer and hypermethylation of tumor suppressor genes. Finally, the potential of epigenetic therapies targeting DNA methyltransferases and histone deacetylases for cancer treatment is presented.
The document discusses the cause of Fragile X syndrome, which is a genetic condition associated with intellectual disabilities and certain physical characteristics. There has been some debate around whether deletion or expansion of the CGG trinucleotide in the FMR1 gene causes the syndrome. Some research has found that a substitution of G>C in the CGG trinucleotide leads to gene silencing and causes the syndrome. However, other research from a study of a healthy family found that a CGG>CCG substitution is a non-coding polymorphism and does not affect gene expression or cause the syndrome. The purpose is to analyze which findings are correct regarding the molecular basis of Fragile X syndrome.
This study aims to analyze the distribution of 5-hydroxymethylcytosine (5-hmC) in the hippocampus of an Alzheimer's mouse model compared to healthy mice. DNA will be isolated from the hippocampus and analyzed using a microarray containing over 20,000 promoters and 15,000 CpG islands. Antibodies specific to 5-methylcytosine and 5-hmC will isolate DNA fragments containing these modifications, which will then be amplified and compared between the transgenic and healthy mice to assess epigenetic changes associated with Alzheimer's Disease. The results are expected to show increases, decreases, or no change in 5-hmC levels in the transgenic mouse model compared to controls.
Temp-Sensitive Inhibition of Development in Dictyostelium - Dev Bio 251 18-26...James Silverman
1) The Dictyostelium mutant HSB1 is temperature-sensitive for development, aggregating and forming fruiting bodies below 18°C but not above.
2) HSB1 cells have a defective G protein-linked adenylyl cyclase that is not stimulated by GTPγS in vitro but can be rescued by adding wild-type cytosol.
3) Transfection with the wild-type piaA gene rescued the HSB1 mutant phenotype, and sequencing revealed a point mutation in the HSB1 piaA gene resulting in a single amino acid change.
N-acetyl-D-glucosamine kinase (NAGK) interacts with dynein light-chain roadblock type 1 (DYNLRB1) at dendritic branch points in neurons. Immunocytochemistry and proximity ligation assays showed colocalization of NAGK and DYNLRB1 on microtubule fibers at dendritic branches. NAGK was also found to interact with Golgi outposts and DYNLRB1 at branch points, indicating a tripartite interaction between NAGK, dynein, and Golgi that regulates dendritic growth and branching. Introduction of a peptide derived from DYNLRB1 stunted dendrite development in cultured neurons.
Presentation PPT The 55 kDa Tissue Transglutaminase Cross-Linking Active Isof...Danstan Arasa
The study aimed to demonstrate that the 55 kDa isoform of tissue transglutaminase (TG) plays a significant role in cell apoptosis. Experiments showed higher rates of cell death with increased TG expression in retinoic acid-treated cells and cells transfected with the TG isoform. This supports the hypothesis that the cross-linking active TG isoform is a potent inducer of apoptosis, helping to clarify the role of TG isoforms in transglutaminase activity and cell death. The 55 kDa TG isoform may have significant roles in physiological and disease-related tissue events.
Taxol and 10-deacetylbaccatinIII induce distinct changesNeesar Ahmed
The document summarizes a study comparing the effects of Taxol, 10-deacetylbaccatinIII (10-DAB), and BaccatinIII (BacIII) on caveolae dynamics in HeLa cells expressing GFP-Caveolin-1. The key findings are:
1) Taxol treatment caused a transient recruitment of Caveolin-1 to the cell surface followed by internalization, while 10-DAB increased the "kiss and run" dynamics of caveolae.
2) Sustained Caveolin-1 phosphorylation was observed with both Taxol and 10-DAB treatments, with Taxol also inducing phosphorylation of Raf-1, ERK1/2,
Oncology: Spatial Localization of Ras proteinsNachiket Vartak
This is a presentation of work done at the MPI Dortmund from 2008-2013 on the mechanism through with localization of the Ras protein in generated in cells. It presents the inhibiton Palmostatin-B, which inhibits this mechanism, leading to reveral of oncogenic signaling and cancerous phenotypes.
The document discusses methylation processes and their role in human pathogenesis. It first describes how the MeCP2 protein functions in gene silencing through methyl-DNA binding and transcription repression, but that its role is more complex as a regulator rather than strict silencer of transcription. It also discusses how MeCP2 mutations cause Rett syndrome and interactions with other proteins. The role of DNA methylation in cancer is then covered, including global hypomethylation in cancer and hypermethylation of tumor suppressor genes. Finally, the potential of epigenetic therapies targeting DNA methyltransferases and histone deacetylases for cancer treatment is presented.
The document discusses the cause of Fragile X syndrome, which is a genetic condition associated with intellectual disabilities and certain physical characteristics. There has been some debate around whether deletion or expansion of the CGG trinucleotide in the FMR1 gene causes the syndrome. Some research has found that a substitution of G>C in the CGG trinucleotide leads to gene silencing and causes the syndrome. However, other research from a study of a healthy family found that a CGG>CCG substitution is a non-coding polymorphism and does not affect gene expression or cause the syndrome. The purpose is to analyze which findings are correct regarding the molecular basis of Fragile X syndrome.
This study aims to analyze the distribution of 5-hydroxymethylcytosine (5-hmC) in the hippocampus of an Alzheimer's mouse model compared to healthy mice. DNA will be isolated from the hippocampus and analyzed using a microarray containing over 20,000 promoters and 15,000 CpG islands. Antibodies specific to 5-methylcytosine and 5-hmC will isolate DNA fragments containing these modifications, which will then be amplified and compared between the transgenic and healthy mice to assess epigenetic changes associated with Alzheimer's Disease. The results are expected to show increases, decreases, or no change in 5-hmC levels in the transgenic mouse model compared to controls.
Temp-Sensitive Inhibition of Development in Dictyostelium - Dev Bio 251 18-26...James Silverman
1) The Dictyostelium mutant HSB1 is temperature-sensitive for development, aggregating and forming fruiting bodies below 18°C but not above.
2) HSB1 cells have a defective G protein-linked adenylyl cyclase that is not stimulated by GTPγS in vitro but can be rescued by adding wild-type cytosol.
3) Transfection with the wild-type piaA gene rescued the HSB1 mutant phenotype, and sequencing revealed a point mutation in the HSB1 piaA gene resulting in a single amino acid change.
This document discusses how the transcription elongation complex (TEC), comprising the growing nascent RNA and RNA polymerase traversing chromatin, serves as a nexus for various nuclear processes including mRNA biogenesis, DNA repair, chromatin modification, and gene silencing. The TEC allows these processes to occur cotranscriptionally by localizing various protein complexes and factors to the site of transcription. In particular, the phosphorylated C-terminal domain of RNA polymerase II functions as a landing pad that recruits mRNA processing factors and chromatin modifiers to couple transcription with downstream events. This cotranscriptional coupling enhances the efficiency and coordination of gene expression and nuclear transactions organized around the transcription machinery.
The document discusses various topics related to DNA methylation and its role in human pathology. It begins by describing the MeCP2 protein and its involvement in Rett syndrome through mutations in the MECP2 gene. It then discusses how alterations in DNA methylation levels and patterns are common in cancer and can lead to genomic instability. Finally, it examines the use of epigenetic therapies like DNA methyltransferase inhibitors and histone deacetylase inhibitors to treat cancer by reversing aberrant DNA methylation and histone modifications.
The document discusses various topics related to DNA methylation and its role in human pathology. It begins by describing the MeCP2 protein and its involvement in Rett syndrome through mutations in the MECP2 gene. It then discusses how alterations in DNA methylation levels and patterns are common in cancer and can lead to genomic instability. Finally, it examines the use of epigenetic therapies like DNA methyltransferase inhibitors and histone deacetylase inhibitors to treat cancer by reversing aberrant DNA methylation and histone modifications.
1) The study examines the role of tissue plasminogen activator (tPA) and plasmin in promoting axonal regrowth after spinal cord injury (SCI) via degradation of chondroitin sulfate proteoglycans (CSPGs).
2) It finds that tPA and plasmin are upregulated after SCI and can degrade CSPG core proteins. Mice lacking tPA show attenuated neurite outgrowth and recovery after SCI, even with chondroitinase ABC (ChABC) treatment to degrade CSPG sugar chains.
3) Coadministration of ChABC and plasmin enhanced recovery in tPA-deficient mice and further supported recovery in wild-type mice with S
This document summarizes a study that investigated how mechanical stressing of integrin receptors affects tyrosine phosphorylation in osteoblastic cells. The key findings were:
1) Mechanical stressing of both the β1 and α2 integrin subunits induced enhanced tyrosine phosphorylation of proteins compared to integrin clustering alone.
2) Applying cyclic forces at 1 Hz was more effective at inducing tyrosine phosphorylation than continuous stress.
3) Mechanically stressed cells showed tyrosine-phosphorylated proteins becoming anchored to the cytoskeleton in a calcium-dependent manner.
4) Mechanical stressing of integrins also increased phosphorylation of MAP kinases, suggesting it can induce downstream signaling events.
The document discusses strategies used in cell cycle research. It describes the history of cell cycle research from the 1970s discovery of MPF (Maturation Promoting Factor) to current understanding of complex regulation involving cyclins and CDKs (Cyclin-Dependent Kinases). Key developments include identifying homologs of cdc2/CDC28 genes and establishing their role in controlling the cell cycle as catalytic subunits of MPF/H1 kinase complexes with cyclins. Understanding cell cycle regulation provides insights into uncontrolled proliferation in diseases like cancer.
Epigenetic regulation of rice flowering and reproductionRoshan Parihar
This document summarizes a doctoral seminar on epigenetic regulation of rice flowering reproduction. It begins by defining epigenetics and epigenomics. It then discusses various epigenetic modifications in rice including DNA methylation/demethylation, histone methylation/demethylation, polycomb silencing, histone acetylation, and the role of small/long non-coding RNAs. It outlines key genes involved in these modifications and their functions. The document reviews the regulation of chromatin modifications in rice and describes networks of genetic and epigenetic control of rice flowering under different photoperiod conditions. Finally, it presents a schematic of rice reproduction structures and lists chromatin modifier genes playing roles in floral organogenesis,
This study investigated whether S-methylcysteine (SMC), a metabolite of monohalomethanes, contributes to their neurotoxicity. The researchers found that:
1) High concentrations of SMC (10-2 M) reduced synaptic responses in hippocampal slices, an effect that was partially reversible.
2) In organotypic hippocampal cultures, 24 hour exposure to 5x10-5 M SMC compromised membrane integrity in the dentate gyrus, while lower concentrations increased population spike amplitudes and repetitive discharges without affecting membrane integrity.
3) In dissociated hippocampal neurons, SMC reduced GABA-induced currents, acting as a competitive GABAA receptor antagonist with
This study aimed to identify proteins that interact with PlzC, a c-di-GMP receptor important for controlling motility, biofilm formation, and virulence in Vibrio cholerae. The researchers used transposon mutagenesis to introduce random mutations in a ΔplzC genetic background. They then screened for secondary mutations that restored wild-type motility on soft agar plates. Several motility-suppressing mutants were selected, sequenced, and further analyzed to identify interacting proteins and understand how they regulate motility through PlzC and c-di-GMP signaling.
TP receptors augment cellular immune responses and inflammatory tissue injury. Mice lacking the TP receptor, which binds thromboxane A2, show reduced T cell proliferation in response to mitogens and alloantigens. They also show attenuated tissue injury in a cardiac transplant model of inflammation. Thus, thromboxane signaling through the TP receptor enhances immune responses and inflammation, suggesting that specific inhibition of this receptor may reduce inflammation without the side effects of broad COX inhibition by NSAIDs.
This document summarizes a study examining the role of protein arginine methyltransferases (PRMTs) in small nuclear ribonucleoprotein particle (snRNP) assembly in Drosophila melanogaster. The key findings are:
1) Both Dart5 (PRMT5 ortholog) and Dart7 (PRMT7 ortholog) are required for symmetric dimethylation of Sm proteins in Drosophila, as they are in humans.
2) Loss of Dart7 is lethal, whereas loss of Dart5 alone has little effect, and flies lacking Dart5 are viable.
3) Expression of a mutant form of SmD1 that cannot be symmetrically dimethylated does not affect viability or
2016 - A balanced pyrimidine pool is required for optimal Chk1 activation to ...Simon Gemble
This document summarizes a study investigating how a decrease in poly(ADP-ribose) polymerase 1 (PARP-1) activity in cells deficient for cytidine deaminase (CDA) leads to impaired activation of checkpoint kinase 1 (Chk1) and less efficient DNA damage checkpoints. The study found that CDA deficiency results in lower levels of Chk1 bound to chromatin and reduced phosphorylation/activation of Chk1 in response to genotoxic stress. This compromised Chk1 activation leads to less efficient S-phase and G2-M checkpoints and accumulation of unreplicated DNA during mitosis, resulting in ultrafine anaphase bridge formation. The results reveal an unexpected link between nucleotide pool balance
This document summarizes a study that investigated how mechanical forces applied to integrin receptors control intracellular signaling in osteoblasts. The researchers found that cyclic forces applied to the beta-1 integrin subunit at 1 Hz were more effective at stimulating calcium responses in osteoblasts than continuous forces. Cyclic forces also induced increased tyrosine phosphorylation of cytoskeleton-anchored proteins and greater activation of focal adhesion kinase and mitogen-activated protein kinase compared to continuous forces. These responses depended on an intact cytoskeleton and the presence of intracellular calcium. Analysis of spatial calcium signals revealed they originated near the stressed receptors, indicating cells can sense local stress via integrins.
1) The protein SAMP1 localizes to both the endoplasmic reticulum (ER) and microtubules, suggesting it may associate the ER with microtubules.
2) RNAi treatments to stop SAMP1 synthesis in HeLa cells resulted in changes to cell morphology, including the presence of stress fibers and abnormal mitotic cell shapes.
3) This indicates SAMP1 likely plays a role in cell adhesion and cytoplasmic structure.
This document summarizes a study examining the role of the μ2 subunit of the clathrin adaptor protein AP-2 in receptor-mediated endocytosis. The researchers constructed an epitope-tagged version of μ2 that incorporated into AP-2 complexes and localized to clathrin-coated pits. Using this tagged μ2, they identified amino acids D176 and W421 as important for interacting with internalization motifs. They then generated a mutant μ2 unable to bind these motifs. Overexpression of this mutant μ2 replaced endogenous μ2 in AP-2 complexes and blocked AP-2's interaction with internalization signals. This resulted in impaired endocytosis of the transferrin receptor but not the EGF receptor, demonstrating that
This document summarizes a study on using nanocurcumin to mitigate toxicities caused by the chemotherapy drug cisplatin in rats. The study synthesized nanocurcumin particles between 10-20nm in size and tested their ability to reduce cisplatin-induced damage in brain, bone marrow, sperm, and blood cells of treated rats. Results showed nanocurcumin was effective in reducing oxidative stress, genetic damage and abnormalities caused by cisplatin, demonstrating its potential for managing cisplatin side effects. Further analysis of liver, kidney, heart and histopathological effects is ongoing.
Plant epigenetic memory in plant growth behavior and stress response. Sally M...CIAT
Speaker: Sally Mackenzie, Lloyd and Dottie Huck Chair for Functional Genomics, Department of Biology, Pennsylvania State University. Fellow in the American Society of Plant Biologists and the American Association for the Advancement of Science (AAAS).
Event: Robert D. Havener Seminar on “Innovations for Crop Productivity”.
http://ciat.cgiar.org/event/robert-d-havener-seminar-on-innovations-for-crop-productivity/
KDM5 epigenetic modifiers as a focus for drug discoveryChristopher Wynder
A summary presentation of my scientific work.
My laboratory focused on an enzyme KDM5b (aka PLU-1, JARID1b) that was widely expressed during development and played a key role in progression of breast cancer through HER-2.
My lab focused on understanding the key biochemical activity of the enzyme through dissecting the proteomic and genomic interactors.
Our results were confirmed through the use of ES cells, adult stem cells and mouse models.
Much of this work remains unpublished, please contact me for more information and/or access to any reagents that I still have as part of this work.
crwynder@gmail.com
Matthew Wheeler is producing a 10-minute documentary about gluten intolerance titled "Gluten documentary". His crew includes Alex Goodall as cameraman, James Sinton as sound technician and health and safety officer. The documentary will discuss what gluten is, who is affected, the effects of eating gluten, and advice from experts. It must be completed by June 24th and involves interviewing people about living gluten-free. The production is managed across pre-production, filming, and post-production phases on a budget of £6,702.
Demographic data refers to statistical information about populations and groups, including characteristics like age, occupation, and lifestyle. Businesses use demographics for audience research and analysis to identify their target markets. Demographic groups are divided by class to provide more details about audiences' lifestyles. Media producers analyze demographics to discover and directly appeal to their target audiences through tailored advertising. Psychographics focus more on individuals' attitudes, aspirations, and psychological traits rather than just occupation. Psychographics are useful for media companies because they provide insight into the best approaches for appealing to specific personality types and lifestyles.
The document summarizes two documentaries - "Gluten" and "Supersize Me". "Gluten" discusses what gluten is, its effects, and includes an expert interview. It aims to inform viewers on gluten. "Supersize Me" shows the presenter eating only fast food for a month to display its health impacts. It is seen as more entertaining. While "Supersize Me" is more interactive, "Gluten" is viewed as more educational by providing facts about gluten. Both target wide audiences but discuss different topics and use varying techniques.
This document discusses how the transcription elongation complex (TEC), comprising the growing nascent RNA and RNA polymerase traversing chromatin, serves as a nexus for various nuclear processes including mRNA biogenesis, DNA repair, chromatin modification, and gene silencing. The TEC allows these processes to occur cotranscriptionally by localizing various protein complexes and factors to the site of transcription. In particular, the phosphorylated C-terminal domain of RNA polymerase II functions as a landing pad that recruits mRNA processing factors and chromatin modifiers to couple transcription with downstream events. This cotranscriptional coupling enhances the efficiency and coordination of gene expression and nuclear transactions organized around the transcription machinery.
The document discusses various topics related to DNA methylation and its role in human pathology. It begins by describing the MeCP2 protein and its involvement in Rett syndrome through mutations in the MECP2 gene. It then discusses how alterations in DNA methylation levels and patterns are common in cancer and can lead to genomic instability. Finally, it examines the use of epigenetic therapies like DNA methyltransferase inhibitors and histone deacetylase inhibitors to treat cancer by reversing aberrant DNA methylation and histone modifications.
The document discusses various topics related to DNA methylation and its role in human pathology. It begins by describing the MeCP2 protein and its involvement in Rett syndrome through mutations in the MECP2 gene. It then discusses how alterations in DNA methylation levels and patterns are common in cancer and can lead to genomic instability. Finally, it examines the use of epigenetic therapies like DNA methyltransferase inhibitors and histone deacetylase inhibitors to treat cancer by reversing aberrant DNA methylation and histone modifications.
1) The study examines the role of tissue plasminogen activator (tPA) and plasmin in promoting axonal regrowth after spinal cord injury (SCI) via degradation of chondroitin sulfate proteoglycans (CSPGs).
2) It finds that tPA and plasmin are upregulated after SCI and can degrade CSPG core proteins. Mice lacking tPA show attenuated neurite outgrowth and recovery after SCI, even with chondroitinase ABC (ChABC) treatment to degrade CSPG sugar chains.
3) Coadministration of ChABC and plasmin enhanced recovery in tPA-deficient mice and further supported recovery in wild-type mice with S
This document summarizes a study that investigated how mechanical stressing of integrin receptors affects tyrosine phosphorylation in osteoblastic cells. The key findings were:
1) Mechanical stressing of both the β1 and α2 integrin subunits induced enhanced tyrosine phosphorylation of proteins compared to integrin clustering alone.
2) Applying cyclic forces at 1 Hz was more effective at inducing tyrosine phosphorylation than continuous stress.
3) Mechanically stressed cells showed tyrosine-phosphorylated proteins becoming anchored to the cytoskeleton in a calcium-dependent manner.
4) Mechanical stressing of integrins also increased phosphorylation of MAP kinases, suggesting it can induce downstream signaling events.
The document discusses strategies used in cell cycle research. It describes the history of cell cycle research from the 1970s discovery of MPF (Maturation Promoting Factor) to current understanding of complex regulation involving cyclins and CDKs (Cyclin-Dependent Kinases). Key developments include identifying homologs of cdc2/CDC28 genes and establishing their role in controlling the cell cycle as catalytic subunits of MPF/H1 kinase complexes with cyclins. Understanding cell cycle regulation provides insights into uncontrolled proliferation in diseases like cancer.
Epigenetic regulation of rice flowering and reproductionRoshan Parihar
This document summarizes a doctoral seminar on epigenetic regulation of rice flowering reproduction. It begins by defining epigenetics and epigenomics. It then discusses various epigenetic modifications in rice including DNA methylation/demethylation, histone methylation/demethylation, polycomb silencing, histone acetylation, and the role of small/long non-coding RNAs. It outlines key genes involved in these modifications and their functions. The document reviews the regulation of chromatin modifications in rice and describes networks of genetic and epigenetic control of rice flowering under different photoperiod conditions. Finally, it presents a schematic of rice reproduction structures and lists chromatin modifier genes playing roles in floral organogenesis,
This study investigated whether S-methylcysteine (SMC), a metabolite of monohalomethanes, contributes to their neurotoxicity. The researchers found that:
1) High concentrations of SMC (10-2 M) reduced synaptic responses in hippocampal slices, an effect that was partially reversible.
2) In organotypic hippocampal cultures, 24 hour exposure to 5x10-5 M SMC compromised membrane integrity in the dentate gyrus, while lower concentrations increased population spike amplitudes and repetitive discharges without affecting membrane integrity.
3) In dissociated hippocampal neurons, SMC reduced GABA-induced currents, acting as a competitive GABAA receptor antagonist with
This study aimed to identify proteins that interact with PlzC, a c-di-GMP receptor important for controlling motility, biofilm formation, and virulence in Vibrio cholerae. The researchers used transposon mutagenesis to introduce random mutations in a ΔplzC genetic background. They then screened for secondary mutations that restored wild-type motility on soft agar plates. Several motility-suppressing mutants were selected, sequenced, and further analyzed to identify interacting proteins and understand how they regulate motility through PlzC and c-di-GMP signaling.
TP receptors augment cellular immune responses and inflammatory tissue injury. Mice lacking the TP receptor, which binds thromboxane A2, show reduced T cell proliferation in response to mitogens and alloantigens. They also show attenuated tissue injury in a cardiac transplant model of inflammation. Thus, thromboxane signaling through the TP receptor enhances immune responses and inflammation, suggesting that specific inhibition of this receptor may reduce inflammation without the side effects of broad COX inhibition by NSAIDs.
This document summarizes a study examining the role of protein arginine methyltransferases (PRMTs) in small nuclear ribonucleoprotein particle (snRNP) assembly in Drosophila melanogaster. The key findings are:
1) Both Dart5 (PRMT5 ortholog) and Dart7 (PRMT7 ortholog) are required for symmetric dimethylation of Sm proteins in Drosophila, as they are in humans.
2) Loss of Dart7 is lethal, whereas loss of Dart5 alone has little effect, and flies lacking Dart5 are viable.
3) Expression of a mutant form of SmD1 that cannot be symmetrically dimethylated does not affect viability or
2016 - A balanced pyrimidine pool is required for optimal Chk1 activation to ...Simon Gemble
This document summarizes a study investigating how a decrease in poly(ADP-ribose) polymerase 1 (PARP-1) activity in cells deficient for cytidine deaminase (CDA) leads to impaired activation of checkpoint kinase 1 (Chk1) and less efficient DNA damage checkpoints. The study found that CDA deficiency results in lower levels of Chk1 bound to chromatin and reduced phosphorylation/activation of Chk1 in response to genotoxic stress. This compromised Chk1 activation leads to less efficient S-phase and G2-M checkpoints and accumulation of unreplicated DNA during mitosis, resulting in ultrafine anaphase bridge formation. The results reveal an unexpected link between nucleotide pool balance
This document summarizes a study that investigated how mechanical forces applied to integrin receptors control intracellular signaling in osteoblasts. The researchers found that cyclic forces applied to the beta-1 integrin subunit at 1 Hz were more effective at stimulating calcium responses in osteoblasts than continuous forces. Cyclic forces also induced increased tyrosine phosphorylation of cytoskeleton-anchored proteins and greater activation of focal adhesion kinase and mitogen-activated protein kinase compared to continuous forces. These responses depended on an intact cytoskeleton and the presence of intracellular calcium. Analysis of spatial calcium signals revealed they originated near the stressed receptors, indicating cells can sense local stress via integrins.
1) The protein SAMP1 localizes to both the endoplasmic reticulum (ER) and microtubules, suggesting it may associate the ER with microtubules.
2) RNAi treatments to stop SAMP1 synthesis in HeLa cells resulted in changes to cell morphology, including the presence of stress fibers and abnormal mitotic cell shapes.
3) This indicates SAMP1 likely plays a role in cell adhesion and cytoplasmic structure.
This document summarizes a study examining the role of the μ2 subunit of the clathrin adaptor protein AP-2 in receptor-mediated endocytosis. The researchers constructed an epitope-tagged version of μ2 that incorporated into AP-2 complexes and localized to clathrin-coated pits. Using this tagged μ2, they identified amino acids D176 and W421 as important for interacting with internalization motifs. They then generated a mutant μ2 unable to bind these motifs. Overexpression of this mutant μ2 replaced endogenous μ2 in AP-2 complexes and blocked AP-2's interaction with internalization signals. This resulted in impaired endocytosis of the transferrin receptor but not the EGF receptor, demonstrating that
This document summarizes a study on using nanocurcumin to mitigate toxicities caused by the chemotherapy drug cisplatin in rats. The study synthesized nanocurcumin particles between 10-20nm in size and tested their ability to reduce cisplatin-induced damage in brain, bone marrow, sperm, and blood cells of treated rats. Results showed nanocurcumin was effective in reducing oxidative stress, genetic damage and abnormalities caused by cisplatin, demonstrating its potential for managing cisplatin side effects. Further analysis of liver, kidney, heart and histopathological effects is ongoing.
Plant epigenetic memory in plant growth behavior and stress response. Sally M...CIAT
Speaker: Sally Mackenzie, Lloyd and Dottie Huck Chair for Functional Genomics, Department of Biology, Pennsylvania State University. Fellow in the American Society of Plant Biologists and the American Association for the Advancement of Science (AAAS).
Event: Robert D. Havener Seminar on “Innovations for Crop Productivity”.
http://ciat.cgiar.org/event/robert-d-havener-seminar-on-innovations-for-crop-productivity/
KDM5 epigenetic modifiers as a focus for drug discoveryChristopher Wynder
A summary presentation of my scientific work.
My laboratory focused on an enzyme KDM5b (aka PLU-1, JARID1b) that was widely expressed during development and played a key role in progression of breast cancer through HER-2.
My lab focused on understanding the key biochemical activity of the enzyme through dissecting the proteomic and genomic interactors.
Our results were confirmed through the use of ES cells, adult stem cells and mouse models.
Much of this work remains unpublished, please contact me for more information and/or access to any reagents that I still have as part of this work.
crwynder@gmail.com
Matthew Wheeler is producing a 10-minute documentary about gluten intolerance titled "Gluten documentary". His crew includes Alex Goodall as cameraman, James Sinton as sound technician and health and safety officer. The documentary will discuss what gluten is, who is affected, the effects of eating gluten, and advice from experts. It must be completed by June 24th and involves interviewing people about living gluten-free. The production is managed across pre-production, filming, and post-production phases on a budget of £6,702.
Demographic data refers to statistical information about populations and groups, including characteristics like age, occupation, and lifestyle. Businesses use demographics for audience research and analysis to identify their target markets. Demographic groups are divided by class to provide more details about audiences' lifestyles. Media producers analyze demographics to discover and directly appeal to their target audiences through tailored advertising. Psychographics focus more on individuals' attitudes, aspirations, and psychological traits rather than just occupation. Psychographics are useful for media companies because they provide insight into the best approaches for appealing to specific personality types and lifestyles.
The document summarizes two documentaries - "Gluten" and "Supersize Me". "Gluten" discusses what gluten is, its effects, and includes an expert interview. It aims to inform viewers on gluten. "Supersize Me" shows the presenter eating only fast food for a month to display its health impacts. It is seen as more entertaining. While "Supersize Me" is more interactive, "Gluten" is viewed as more educational by providing facts about gluten. Both target wide audiences but discuss different topics and use varying techniques.
Psychographic profiling refers to studying personality, attitudes, values, lifestyles, and interests to group individuals and understand what they may like. Marketers find it useful for targeting advertising as it provides insight into appealing to different audiences. The document discusses various psychographic segments including Mainstreamers who prefer mainstream brands and trends, and Explorers who seek new experiences. It indicates the marketing campaign will target Mainstreamers and Explorers as pop music appeals to Mainstreamers' preferences, and Explorers include young people like the target age group.
Demographics categorize people based on factors like age, gender, job, income, education, and location to classify audiences. The NRS social demographic scale divides the population into categories like ABC1 and C2DE based on jobs and incomes, though these classes sometimes overlap and may not reflect all groups. Psychographics instead categorizes people based on personality and lifestyle, allowing for more variety within groups but some individuals could overlap multiple categories. Both systems have advantages in segmentation but also limitations around overgeneralization or changes in society.
The document provides guidance on developing story concepts and pitching ideas for screenplays. It discusses Syd Field's method for describing a story concept as "A person in a place doing his or her thing." Examples are given to illustrate this method. Techniques for generating story ideas like research, brainstorming and teamwork are covered. Students are instructed to develop 3 story concepts and pitch one of the ideas to their peers. They are also told to conduct secondary research on their chosen concept and develop an outline of the story for next week's lesson on narrative planning.
Audience research involves gathering information about audience segments to understand their attitudes, interests, and behaviors regarding a topic. It is important to conduct audience research before finalizing a project to understand the target audience and design something that will appeal to them. There are many ways to categorize audiences, such as by demographics like age, gender, income level, and occupation. Gathering this information through surveys, interviews, and focus groups can provide insights into what the audience wants. Internet forums, social media, and online ratings are also effective research methods because many younger audiences spend time online.
How media producers define their target audiencemattwako
The document discusses different methods that media producers use to define their target audiences for documentaries. It describes several profiling methods such as quantitative research using viewing figures, qualitative research through focus groups and interviews, socio-economic status research, demographics research using charts to categorize audiences, psychographics research examining audience behavior and personality, and considering audience age and gender. The document evaluates which methods are most useful for documentary producers, with qualitative research and demographics and psychographics charts seen as providing the most detailed audience information.
The document discusses audience profiling, which media companies use to define their target audiences. It explains that factors like age, gender, race, education level, income, lifestyle, culture and interests should be considered. Two common methods are described - demographics, which categorizes people by occupation and income, and psychographics, which examines behavior and personality traits to group people. An example reader profile for a music magazine is presented to show the type of information advertisers would find useful. The document prompts the reader to create their own target audience profile considering relevant demographics, psychographics, lifestyle brands and media consumption habits.
Demographic information classifies audiences by age, gender, race and other attributes and breaks them into bands based on jobs or status, as shown in a sample demographic table. While thriller movies could appeal to wide audiences, psychological thrillers may not appeal to those with lower education levels who are unemployed and would not understand the psychological aspects. Psychographics divides the market into groups based on social class, lifestyle, and personality, and the products or brands purchased reflect those characteristics and patterns of living. Thrillers can appeal to varied psychographic groups more so than other genres like rom-coms that target more specific psychographics.
Set7/9 is a lysine methyltransferase that interacts with the transcription factor Pdx1. This study found that:
1) Set7/9 methylates two lysine residues (Lys-123 and Lys-131) on Pdx1. Methylation only occurred with full-length Pdx1, indicating structural requirements.
2) Lys-131 methylation by Set7/9 augments Pdx1's transcriptional activity in luciferase reporter assays.
3) Mice with beta-cell specific deletion of Set7/9 (SetΔβ mice) showed glucose intolerance and impaired insulin secretion from islets, similar to Pdx1-deficient mice. Target genes
Abstract
Aberrant mucin-type O-glycosylation by glycosyltransferases is a well-described hallmark of many cancers and is also associated with additional non-cancerous developmental and metabolic disorders. The current review focuses on N-acetylgalactosaminyltransferase genes (GALNT) and proteins (GalNAcTs) to illustrate their importance in cancer biology. Aberrant O-glycosylation by GalNAcTs activates a wide range of proteins that carry out interactions of sessile and motile cells affecting organogenesis, responses to agonists and stimulating hyperproliferation and metastatisation of neoplastic cells. As genome-wide analyses have provided abundant clues regarding under- or over-expressed genes that characterize different types of cancers, GALNTs and their transferase products have attracted attention by being unexpected actors in neoplastic contexts. We intend to review the current knowledge on GALNTs and their encoded transferases in cancer and suggest what could be the significance of such information in cancer pathogenesis and management.
A major focus of the current research underway is to develop disease models which may then be used to study the pathophysiology of CDG at the cellular level as well as the broader level of the organism as a whole. These disease models may also be used to investigate possible therapeutics. One of the models being used is a yeast model employing brewer's yeast or Saccharomyces cerevisiae. The process of protein glycosylation occurs in all domains of life and is highly conserved. As such the process of glycosylation in eukaryotic yeast cells provides insight into the same process in human cells.
The poster was presented at the 17th Annual ID Research Day & the 4th Annual CCfV Symposium in Halifax, Nova Scotia on April 23rd, 2012.
The document discusses various topics related to DNA methylation and its roles in human pathology. It begins by describing the MeCP2 protein and its involvement in Rett syndrome through mutations in the MECP2 gene. It then discusses how alterations in DNA methylation levels and patterns are common in cancer and can lead to genomic instability. Finally, it examines the use of epigenetic therapies like DNA methyltransferase inhibitors and histone deacetylase inhibitors to treat cancer by reversing aberrant DNA methylation and histone modifications.
This document discusses various topics related to DNA methylation and its roles in human pathology. It begins by describing the MeCP2 protein and Rett syndrome, where mutations in the MECP2 gene cause the condition. It then discusses how alterations in DNA methylation levels and patterns are common in cancer and can cause genome instability and gene silencing. Finally, it examines the roles of DNA methyltransferases and histone deacetylases, and how inhibitors of these enzymes show promise as epigenetic cancer therapies.
NAD-Glycohydrolase Depletes Intracellular NAD+ and Inhibits Acidification of Autophagosomes to Enhance Multiplication of Group A Streptococcus in Endothelial Cells
The document summarizes research into the effects of the 55 kDa tissue transglutaminase (TG) isoform on inducing apoptosis in human breast cancer cell lines. The study found that cells transfected with the TG isoform had higher rates of apoptosis than cells transfected with the full-length 80 kDa TG precursor or control cells. Calcium ionophore treatment, which triggers transamidation, promoted cell death, while a TG inhibitor blocked TG-induced apoptosis. The results indicate that TG-dependent protein cross-linking represents an important biochemical event in apoptosis induction.
This document describes a study that used proteomic techniques to characterize the proteome of human insulin secretory granules (ISGs). Two analytical methods were used: one-dimensional gel electrophoresis coupled with mass spectrometry identified 253 proteins from ISGs. Pathway analysis showed many proteins involved in carbohydrate metabolism and signaling pathways related to oxidative stress and membrane fusion. Stimulation with glucose induced changes related to exocytosis and secretion. The proteomic data provides insights into ISG biogenesis, maturation and the mechanisms governing insulin secretion and diabetes.
This document summarizes a study on the effects of antimicrobial and anti-cancer therapies on Alzheimer's disease pathogenesis. The study examines how inhibiting alpha-secretase affects p53 status in cultured human neuroblastoma cells. The results suggest targeting both beta-amyloid precursor protein processing and p53 levels could serve as a therapeutic approach by alleviating multiple pathological processes leading to neuronal vulnerability and death. Methodologies included western blot analyses, real-time quantitative PCR, cell viability assays, and flow cytometry. The conclusions determined certain medical therapies could potentially trigger Alzheimer's disease, highlighting the importance of prevention. Studying the consequences of alpha-secretase inhibition provided insights to advance treatment approaches.
1) The study investigated the effects of dopamine (DA), dihydroxyphenylacetaldehyde (DOPAL), and dihydroxyphenylacetic acid (DOPAC) on oligomerization of wild-type α-synuclein and mutated forms (A53T, A30P).
2) DOPAL was found to potently oligomerize α-synuclein, around 10 times more than DA. DOPAC had little effect.
3) DOPAL also oligomerized the mutated forms of α-synuclein and appeared to aggregate the A53T form to the point that it did not migrate in gels.
C3G overexpression induces long, actin-rich neurite-like extensions in aggressive breast cancer cell lines MDA-MB-231 and BT549, but not in other cancer cell lines tested. These extensions resemble neuronal processes and contain nodes, branches, and microspikes. C3G expression is associated with stabilization of microtubules and reduced motility of MDA-MB-231 cells compared to control cells. Both the catalytic and protein interaction domains of C3G contribute to its ability to induce these neurite-like extensions.
The document discusses DNA repair mechanisms in human lymphocytes. It describes how oxidized purines in DNA are repaired through the base excision repair pathway involving the OGG1 glycosylase. This repair requires activation by the transcription factor NF-YA, which upregulates OGG1 expression when DNA is at risk of oxidation. The repair of oxidized bases by OGG1 in human lymphocytes is slow but can be activated by phytohemagglutinin. Disruption of this global repair of oxidized purines may be due to downregulation of OGG1. A second document discusses how green tea acts as an antioxidant to protect against oxidative stress and influence DNA damage and repair through activation of the Nrf2 transcription factor and upreg
When DNA is attacked by oxidative stress such as ROS, ultraviolet light, or genotoxic agents, guanine is easily oxidized into 8-hydroxydeoxyguanosine (8-OHdG).
The interaction of Nrf2 and Glyoxalase I in response to lipid loading in Hepa...Farya Mubarik
This document summarizes a study that examined the interaction between Nrf2 and glyoxalase I in response to lipid loading in hepatocytes. The study first optimized the dose and duration of MG132 treatment, a proteasomal inhibitor, to induce accumulation of Nrf2 protein in HepG2 cells. It then examined the effects of oleic acid and palmitic acid on cell viability and found no significant effects. The study aims to determine if inhibition of proteasomal degradation leads to accumulation of Nrf2 and subsequent upregulation of glyoxalase I expression in response to lipid accumulation.
The document discusses DNA damage and repair. It describes various types of DNA damage including those caused by replication errors, chemicals, radiation and intercalating agents. The main DNA repair pathways discussed are mismatch repair, base excision repair, nucleotide excision repair and recombinational repair. Mismatch repair corrects errors in DNA replication while the other pathways help repair different types of DNA damage through mechanisms such as removal of damaged bases and filling in of DNA strands. Defects in DNA repair pathways can lead to genetic disorders and cancer.
1) The document examines how elevating O-GlcNAc levels through OGA inhibition or increasing OGT substrate availability affects mitochondrial function.
2) Experiments found that elevated O-GlcNAc levels decreased mitochondrial respiration and ATP production, while reducing reactive oxygen species levels.
3) Pathway analysis predicted that the NRF2-mediated oxidative stress response, a key regulator of antioxidants, was downregulated with elevated O-GlcNAc. Protein expression of antioxidant genes regulated by NRF2, such as TXNRD1, were also reduced.
4) Together, the results demonstrate that prolonged alterations to cellular O-GlcNAc homeostasis impact mitochondrial function and metabolism.
The document discusses epigenetic factors that contribute to imprinting diseases. It describes how epigenetic modifications like DNA and histone methylation establish parental imprints and regulate gene expression in a parent-of-origin specific manner. Alterations in these epigenetic marks can lead to imprinting disorders like Prader-Willi syndrome and Angelman syndrome, which are associated with changes in imprinted genes on chromosome 15. The authors investigate these diseases using methods like MS-PCR to analyze DNA methylation patterns.
Decreases Expression of PGC-1α in the Alzheimer Disease Brain Impaire Mitocho...rana alhakimi
Alzheimer is the most neurodegenerative disorder in the aged people. It is characterized by senile, accumulation of amyloid plaque, neurofibrillary tangle and progressive decline in brain memory cells.
Alzheimer disease is associated with inflammatory response, synaptic damage and mitochondrial dysfunctions which are a prominent and early feature of Alzheimer disease.
This document contains summaries of 4 poster presentations from a conference on Alzheimer's disease and dementia research.
The first poster discusses findings that the ER stress transcription factor XBP1s protects against amyloid-beta neurotoxicity in a fruit fly model of Alzheimer's and in human neuroblastoma cells. XBP1s prevents the accumulation of free calcium in the cytosol, explaining its neuroprotective effects.
The second poster reports that amyloid-beta oligomers impair neuronal function and morphology in rat and mouse neuronal cultures and hippocampal slices through a mechanism linked to NMDA receptor signaling and activation of the protein Jacob.
The third poster examines the role of O-GlcNAc glycosylation in hippocampal synaptic
Similar to Might Might - Cambridge Rare Disease Summit 2015 (20)
At CamRARE's RAREsummit23 on 12 Oct, Chair of the Trustees, Dr Gemma Chandratillake, presented a visual slideshow of CamRARE's highlights, achievements and impact since our last in person RAREsummit in 2019.
This document outlines wishes for increased knowledge and treatments for Bardet-Biedl syndrome (BBS) through research collaboration and access to care coordinators. It wants all young people with BBS to be better understood and supported in their education and care through educating professionals, student passports, and coordinated family support.
This document discusses Pitt-Hopkins syndrome, a rare genetic condition characterized by distinctive facial features like wide mouth and prominent eyebrows. It causes severe learning disabilities, motor delays, and breathing issues. The wish list calls for increased geneticist awareness of Pitt-Hopkins syndrome to aid diagnosis, more research on autonomic nervous system effects like breathing anomalies and constipation, and establishing a specialized UK clinic for comprehensive Pitt-Hopkins syndrome care and management guidance.
This document discusses red flags that may indicate a rare disease. It notes that 1 in 700 births and 9 in 1000 births involve a major congenital abnormality, which could be a sign of a rare syndrome. Multiple minor abnormalities, especially more than two, also increase the risk of a major abnormality. Specific rare conditions discussed include Marfan syndrome, Birt-Hogg-Dube syndrome, and neurofibromatosis type 1. The document also covers red flags in pregnancy, such as short fetal long bones indicating conditions like achondroplasia. It discusses genetic testing and calculations for determining disease risk. Finally, it notes unexpected patterns of inheritance can be a red flag, such as lethal conditions in males for
The document discusses drug repurposing for rare diseases. Drug repurposing involves finding new uses for existing drugs to treat different patient populations. The document provides examples of repurposing drugs to treat rare conditions like Wolfram syndrome and CDKL5. It also discusses using 'omics data to identify repurposing opportunities and describes a potential social impact bond model to fund repurposing clinical trials through healthcare savings.
Alström syndrome is a rare genetic disease characterized by childhood obesity, insulin resistance, and fibrosis of multiple organs. There are currently no approved treatments. PBI-4050, a drug candidate from Prometic being developed for fibrosis, has potential as a novel treatment for Alström syndrome given its multi-organ anti-fibrotic activity. An ongoing proof-of-concept study of PBI-4050 in the UK represents the first clinical trial in Alström syndrome patients. Regulatory pathways like orphan drug designation and the EMA's PRIME program aim to facilitate development of treatments for rare diseases by providing scientific advice, accelerated assessment, and incentives for further research.
This document summarizes a presentation given by Neil Dugdale of Sobi (Swedish Orphan Biovitrum) at the 2017 Cambridge Rare Disease Network Summit. The presentation discusses Sobi's work in rare diseases, including developing orphan drugs, partnering with patient advocacy groups, and donating factor therapy to expand treatment access for hemophilia in developing countries. Sobi aims to pioneer new approaches to rare disease management through multi-stakeholder engagement and community co-creation.
This document discusses the utility and benefits of receiving a diagnosis for a family struggling with an evident medical condition. A diagnosis can provide (1) an explanation for the condition, (2) access to targeted treatments and services, and (3) allow families to make informed decisions about family planning, research participation, and testing of extended family members. A diagnosis also provides closure and access to support groups, clinical trials, education resources, and financial assistance programs.
This document discusses vasculitis, a group of rare diseases that cause inflammation of the blood vessels. It describes one patient's experience with Behcet's Disease, a type of vasculitis, including their symptoms since age 13, diagnosis at age 34, and failed treatment attempts. The patient expresses 3 wishes: 1) more understanding from medical professionals and society about chronic illnesses, 2) to remove the anguish experienced by patients and their families, and 3) to have support centers similar to Maggie's Centers for cancer patients, which provide practical advice, emotional support, and a community for rare disease patients.
This document discusses the history of Alstrom syndrome, a rare genetic disorder, and the journey to developing effective treatments. It describes:
- Carl Alstrom's initial identification and description of the syndrome in 1946 based on his observations of three related patients.
- Key characteristics of Alstrom syndrome including childhood obesity, insulin resistance, hearing loss, and multi-organ fibrosis.
- The experiences of two patients, Matthew and Charlotte, who experienced multiple misdiagnoses before receiving a correct Alstrom syndrome diagnosis in their late teens. Both ultimately died due to heart and organ failure.
- Milestones in establishing patient organizations and clinical networks in the late 1990s and 2000s that helped increase understanding and care for Al
The document discusses the evolving role of patient advocacy groups in orphan drug development. It notes that historical barriers to orphan drug research included limited funding, lack of researcher interest, and few patient groups. The 1983 Orphan Drug Act and similar European regulations aimed to incentivize orphan drug development by providing tax credits, reduced fees, and extended market exclusivity for sponsors. Both the FDA and EMA have increasingly engaged with patient groups over the past few decades. Industry and patient groups both seek collaboration to advance research, though their needs differ. Frameworks like the EFPIA and CTTI guidelines provide recommendations for transparent and ethical partnerships between stakeholders.
This document summarizes a presentation about Mendelian, a company that uses artificial intelligence to help diagnose rare diseases. Mendelian analyzes patients' phenotypes and returns differential diagnoses and the top potential diseases in real-time. The presentation describes a case study where Mendelian correctly diagnosed a patient based on their clinical features. It also discusses Mendelian's goals of improving diagnosis rates for rare diseases by streamlining the diagnosis process, aggregating clinical data, and reducing the need for multiple specialist referrals and tests. Finally, it provides an overview of Mendelian's progress since its founding in 2015 and calls for collaboration to further its mission.
The 100,000 Genomes Project aims to sequence 100,000 genomes from 70,000 people in the UK. For rare diseases, the project seeks to provide genetic diagnoses for patients by comprehensively analyzing their full genome. It also aims to kickstart genomic medicine in the NHS and a UK genomics industry. The East of England Genomic Medicine Centre is one of several centers that recruits participants and returns results as part of this large national project.
This document discusses rare diseases and proposes three ways to improve the patient journey: 1) earlier diagnosis of rare diseases to help patients receive timely treatment; 2) using IGF-1 and OGTT tests to help diagnose acromegaly; 3) continuing efforts to raise awareness of rare diseases to help more patients get diagnosed.
This document discusses empowering patients to take a more active role in drug discovery and development. It notes that for many rare diseases, the science is incomplete and drug development is slow. However, patient organizations are already leading many scientific and medical advances. The document advocates for a more collaborative approach where patients work with researchers and companies. It presents examples where patient groups have helped identify new patients, generated data to help trials, and invested in research. It argues that patients need more access to tools and technologies to drive diagnosis and drug development themselves for ultra-rare diseases. An envisioned "23andMe of drug development" could help facilitate this.
The document discusses the potential for a telemedicine pilot program to serve patients with rare diseases. It summarizes surveys that found over 50% of patients would be receptive to telemedicine and over 90% are willing to learn video call applications. The document estimates a 3-year pilot program could save £6.8 million in healthcare costs while costing approximately £975,000 to implement. Key operational requirements for the pilot include videoconferencing capabilities and secure data protection.
The document summarizes the history and work of a charity focused on Tay-Sachs and Sandhoff diseases. It describes how the charity was formed in 2011 in response to a research team's need for funding and patient identification support. The charity provides equipment, respite trips, and other support to families, and works closely with researchers conducting a gene therapy trial for the diseases. Its goals are to complete the current trial and eventually develop treatments that could eliminate the need for the charity.
The CATS Foundation was founded in 2011 to support families affected by Tay-Sachs and Sandhoff diseases. It provides equipment, respite trips, and a support network for these families. The foundation also supports research for potential treatments for these currently terminal illnesses that cause children to lose abilities like walking, speaking, and hearing. Currently, the foundation is working with Professor Cox and is close to starting a clinical trial for an potential enzyme replacement therapy treatment.
Teddington Trust is encouraging people to join the #RareRevolution by tapping into the talent, creativity, and passion of the rare disease community through patient education, peer education, and raising awareness. The document discusses the rare diseases of the author's father and nephew to inspire others that with preparation and belief, achieving your goals is possible, even when facing a rare condition. It directs people to the Rare Revolution magazine website and social media accounts to get involved.
Students 4 Rare Diseases is an organization founded by Dr. Lucy McKay that aims to educate medical students and future doctors about rare diseases. It coordinates with 33 medical schools in the UK, which have almost 7,000 medical student places each year. The organization's educational coordinator works to keep its website and social media updated, contacts medical schools consistently, and organizes an annual symposium, with the goal of ensuring future doctors are prepared to consider and diagnose rare diseases.
- Video recording of this lecture in English language: https://youtu.be/kqbnxVAZs-0
- Video recording of this lecture in Arabic language: https://youtu.be/SINlygW1Mpc
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
Here is the updated list of Top Best Ayurvedic medicine for Gas and Indigestion and those are Gas-O-Go Syp for Dyspepsia | Lavizyme Syrup for Acidity | Yumzyme Hepatoprotective Capsules etc
NVBDCP.pptx Nation vector borne disease control programSapna Thakur
NVBDCP was launched in 2003-2004 . Vector-Borne Disease: Disease that results from an infection transmitted to humans and other animals by blood-feeding arthropods, such as mosquitoes, ticks, and fleas. Examples of vector-borne diseases include Dengue fever, West Nile Virus, Lyme disease, and malaria.
Title: Sense of Taste
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
Basavarajeeyam is an important text for ayurvedic physician belonging to andhra pradehs. It is a popular compendium in various parts of our country as well as in andhra pradesh. The content of the text was presented in sanskrit and telugu language (Bilingual). One of the most famous book in ayurvedic pharmaceutics and therapeutics. This book contains 25 chapters called as prakaranas. Many rasaoushadis were explained, pioneer of dhatu druti, nadi pareeksha, mutra pareeksha etc. Belongs to the period of 15-16 century. New diseases like upadamsha, phiranga rogas are explained.
Rasamanikya is a excellent preparation in the field of Rasashastra, it is used in various Kushtha Roga, Shwasa, Vicharchika, Bhagandara, Vatarakta, and Phiranga Roga. In this article Preparation& Comparative analytical profile for both Formulationon i.e Rasamanikya prepared by Kushmanda swarasa & Churnodhaka Shodita Haratala. The study aims to provide insights into the comparative efficacy and analytical aspects of these formulations for enhanced therapeutic outcomes.
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
share - Lions, tigers, AI and health misinformation, oh my!.pptxTina Purnat
• Pitfalls and pivots needed to use AI effectively in public health
• Evidence-based strategies to address health misinformation effectively
• Building trust with communities online and offline
• Equipping health professionals to address questions, concerns and health misinformation
• Assessing risk and mitigating harm from adverse health narratives in communities, health workforce and health system
TEST BANK For Community Health Nursing A Canadian Perspective, 5th Edition by...Donc Test
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Tests for analysis of different pharmaceutical.pptx
Might Might - Cambridge Rare Disease Summit 2015
1. Matthew Might, Ph.D.
Associate Professor
University of Utah
Visiting Assoc. Professor
Harvard Medical School
Treating the Rarest of Diseases
What do you do when you’re one of a kind?
President
NGLY1.org
151. Endo-β-N-acetylglucosaminidase forms N-GlcNAc
protein aggregates during ER-associated degradation
in Ngly1-defective cells
Chengcheng Huanga,b
, Yoichiro Haradaa
, Akira Hosomia
, Yuki Masahara-Negishia
, Junichi Seinoa
, Haruhiko Fujihiraa
,
Yoko Funakoshia
, Takehiro Suzukic
, Naoshi Dohmaec
, and Tadashi Suzukia,b,1
a
Glycometabolome Team, Systems Glycobiology Research Group, RIKEN–Max Planck Joint Research Center for Systems Chemical Biology, RIKEN Global
Research Cluster, Wako, Saitama 351-0198, Japan; b
Graduate School of Science and Engineering, Saitama University, Saitama, Saitama 338-8570, Japan;
and c
Collaboration Promotion Unit, RIKEN Global Research Cluster, Wako, Saitama 351-0198, Japan
Edited by David W. Russell, University of Texas Southwestern Medical Center, Dallas, TX, and approved December 30, 2014 (received for review
August 1, 2014)
The cytoplasmic peptide:N-glycanase (PNGase; Ngly1 in mice) is
a deglycosylating enzyme involved in the endoplasmic reticulum
(ER)-associated degradation (ERAD) process. The precise role of
Ngly1 in the ERAD process, however, remains unclear in mammals.
The findings reported herein, using mouse embryonic fibroblast
(MEF) cells, that the ablation of Ngly1 causes dysregulation of the
ERAD process. Interestingly, not only delayed degradation but also
the deglycosylation of a misfolded glycoprotein was observed in
Ngly1−/−
MEF cells. The unconventional deglycosylation reaction
was found to be catalyzed by the cytosolic endo-β-N-acetylgluco-
saminidase (ENGase), generating aggregation-prone N-GlcNAc pro-
teins. The ERAD dysregulation in cells lacking Ngly1 was restored
by the additional knockout of ENGase gene. Thus, our study under-
scores the functional importance of Ngly1 in the ERAD process and
provides a potential mechanism underlying the phenotypic conse-
quences of a newly emerging genetic disorder caused by mutation
of the human NGLY1 gene.
PNGase (Ngly1) | ENGase | protein aggregates | glycoprotein | ERAD
Endoplasmic reticulum (ER)-associated degradation (ERAD)
constitutes one of the quality control mechanisms for newly
synthesized proteins in the ER. The ERAD process involves
a series of events, including aberrant domain recognition, ubiq-
uitination, translocation from the ER to the cytosol, and deg-
radation by proteasomes. Numerous lines of evidence point to
the existence of an ERAD system dedicated to N-linked glyco-
proteins; in this system, specific N-glycan structures dictate the
folding status of client glycoproteins (1, 2). Once glycoproteins in
the ER lumen are targeted for degradation, they are retro-
translocated into the cytosol, where the 26S proteasome plays
a central role in their degradation (3). During the degradation
process, N-glycans are removed by the action of the cytoplasmic
peptide:N-glycanase (PNGase) (4–6).
Activity of the cytoplasmic PNGase was first described in mam-
malian cells (7, 8), and the gene encoding cytoplasmic PNGase
(PNG1 in yeast; Ngly1/NGLY1 in mice/human) is widely dis-
tributed throughout eukaryotes (9). The functional importance
of cytoplasmic PNGase in the ERAD process is evident in yeast
(10–13). On the other hand, the suppression of Ngly1 gene ex-
pression by siRNA in mammalian cells resulted in a reduced
deglycosylation of T-cell receptor α subunit (TCRα) or MHC class
I heavy chain, whereas no significant delay in their degradation
was observed (14, 15). Moreover, Z-VAD-fmk, a pan-caspase in-
hibitor, was shown to inhibit cytoplasmic PNGase activity in vivo,
but it did not impede the degradation of MHC class I heavy chain
(16). Consequently, the functional importance of the cytoplasmic
PNGase remains elusive in mammalian cells.
PNGase-mediated deglycosylation generates free oligosaccharides
in the cytosol (17). Recent evidence suggests that a nonlysosomal
degradation pathway exists for these cytosolic free glycans (17).
This degradation process involves cytosolic endo-β-N-acetylglu-
cosaminidase (ENGase) (18, 19). Although the ENGase is believed
to be involved in the catabolism of cytosolic free oligosaccharides,
recent evidence shows that it can deglycosylate glycoproteins in vivo
to generate N-GlcNAc–bearing proteins in Arabidopsis thaliana
(20), raising the possibility that this enzyme may also act as a
deglycosylation enzyme for misfolded glycoproteins in the cytosol
(21, 22) (Fig. 1A).
Recently, patients harboring mutations on the NGLY1 gene, an
ortholog of the cytoplasmic PNGase in mammalian cells (23), have
been described (24, 25). Although this observation emphasizes the
functional importance of this protein in mammalian cells, mecha-
nistic insight into the phenotypic consequences of these patients
remains unclarified. In this study, we established an ERAD model
substrate, RTAΔm, and demonstrated that the delay in its degra-
dation was evident in Ngly1−/−
mouse embryonic fibroblast (MEF)
cells. Interestingly, the delay was canceled by additional gene
knockout of ENGase. The degradation of RTAΔm in double-
knockout cells remains proteasome-dependent, clearly indicating
that the presence of an N-glycan on RTAΔm did not affect the
efficiency of proteasomal degradation. Moreover, the occurrence
of N-GlcNAc–modified RTAΔm in Ngly1−/−
MEF cells was iden-
tified by MS analysis, demonstrating that the ENGase-mediated
Significance
In the endoplasmic reticulum (ER), N-glycans on glycoproteins
play important roles in dictating the folding status of proteins
by a sophisticated N-glycan–dependent protein quality control
machinery. In this study we identified the dysregulation of ER-
associated degradation (ERAD) in cells that were defective in
the cytosolic deglycosylating enzyme, Ngly1. ERAD dysregula-
tion was caused by an unexpected deglycosylating activity of
endo-β-N-acetylglucosaminidase, another cytosolic deglycosy-
lation enzyme, and this action resulted in the intracellular
formation of protein aggregates. Our results clearly point to
the critical role of N-glycans even in cytosolic events of the
ERAD process by controlling the conformation/solubility of
proteins. This study may also provide a potential mechanism
for explaining the pathology of a human genetic disorder
caused by mutations in the NGLY1 gene.
Author contributions: C.H. and Tadashi Suzuki designed research; C.H., Y.H., A.H., Y.M.-N.,
J.S., H.F., Y.F., Takehiro Suzuki, and N.D. performed research; Y.H., A.H., Y.M.-N., and Y.F.
contributed new reagents/analytic tools; C.H., Y.H., A.H., J.S., H.F., Y.F., Takehiro Suzuki,
N.D., and Tadashi Suzuki analyzed data; and C.H. and Tadashi Suzuki wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
1
To whom correspondence should be addressed. Email: tsuzuki_gm@riken.jp.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.
1073/pnas.1414593112/-/DCSupplemental.
1398–1403 | PNAS | February 3, 2015 | vol. 112 | no. 5 www.pnas.org/cgi/doi/10.1073/pnas.1414593112