7196 research outputs found
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Identification of Bacterial Metabolites that Modulate Endoplasmic Reticulum Stress
No full textMany inflammatory diseases are associated with dysbiosis of the human microbiota. The mechanisms by which these microbes influence diseases remain elusive. Since endoplasmic reticulum (ER) stress induced inflammation has been indicated in many diseases, gut microbes potentially influence inflammatory diseases through ER stress modulation. Using a colorectal adenocarcinoma cell line carrying GFP fusion reporter for XBP1, a key ER stress regulator, we performed a high content imaging screen to identify bacterial extracts and purified microbiome compounds that could modulate ER stress response. We did not identify ER stress modulation activity from extracts prepared from 30 bacterial species cultured across multiple growth media conditions. However, when a collection of microbiome metabolites were screened, several bacterial encoded natural products demonstrated ER stress response modulation activities. For instance, a Clostridium derived dipeptide aldehyde activates ER stress response, potentially through inhibition of proteases and proteosome. In contrast, soraphen A, a bacterial polyketide could inhibit ER stress response induced by tunicamycin. These findings indicates that commensal microbes encodes the potential to modulate ER stress response
MEB/NC3Rs Questionnaire on the optimal duration of non-clinical studies to assess the safety of monoclonal antibodies: Building an evidence-based approach to justify the duration of longer-term toxicity studies with monoclonal antibodies
No full textThe EPAA, the Netherlands Medicines Evaluation Board (MEB) and the UK National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) are collaborating on a project to investigate the optimal duration of non-clinical studies to assess the safety of monoclonal antibodies (mAbs). The NC3Rs (www.nc3rs.org.uk) are developing the survey, will collect and anonymise the data, which will then be analysed within the MEB.
An expert working group consisting of industry partners within Europe and USA has been convened. The aims of the working group are to share data from general regulatory toxicology studies for various mAb modalities and disease indications, to make evidence based recommendations on when it may (or may not) be appropriate to perform chronic toxicity studies (up to 6 month duration), to support longer-term clinical trials. This will include collecting information on species tested, NOAEL and differences between short and long-term toxicity study findings. Some of the data will serve to follow-up previous NC3Rs projects to track implementation of best-practice recommendations or to collect further information (e.g., group sizes, recovery animals etc) to promote further opportunities to reduce animal use and/or streamline processes.
All data collected in this survey will be treated in strict confidence and made anonymous. The NC3Rs data management policy is available on request. Please answer as many questions as possible with as much information as possible
Cell types of the human retina and its organoids at single cell resolution: developmental convergence, transcriptional identity, and disease map
No full textOrganoids are stem cell-derived artificial organs that mimic aspects of organ development, function and disease. How closely cell type diversity and cell type maturation in human organoids recapitulate that of their target organ is not well understood. We performed histochemistry and sequenced the RNA of 163,971 single cells from improved human retinal organoids at different developmental stages and from donated healthy adult human retinas and choroid. Cell types in mature organoids had morphologies and transcriptomes that resembled their adult equivalents. Remarkably, organoids developed at a similar rate to the developing human retina and the transcriptome trajectory of cell types contained a progression of key developmental markers. Mapping disease-associated genes to cell types revealed cellular targets for studying disease mechanism in organoids and performing targeted repair in adult retinas
Genomics and Nucleic Acid Therapeutics in Prevention & Treatment of Cardiometabolic Disease: A View from Pharma
No full textPresentation will include recent developments in human genetics and genomics of CVD and focus on nucleic acid therapies. WIll not cover any undisclosed therapies and will not promote novartis therapies that are discussed. Gene editing will be mentioned as one option in nucleic acid therapy but not discussed in any detail.
Overview:
Role of human genetics / genomics in etiology of risk factors and disease and discovery of cardio-metabolic disease biomarkers and targets
Genetic / genomic targets for cardio-metabolic disease and options for nucleic acid-based therapies for prevention, pre-emption and treatment of disease
Strengths, Weaknesses, Opportunies, Threats: Lessons from ASO and siRNA trials
Gaps and opportunities to leverage genetics and genomics in future trials for treatment and preventio
Matrix matching in quantitative bioanalysis by LC-MS/MS a dream or a reality?
No full textNot Availabl
Cryo-EM studies on Nav Channel - modulator complexes
No full textIn this talk I would be presenting my cryo EM results on the cockroach Nav channel(NavPas). I would detail the expression, purification and complex formation with Veratridine(Lily toxin) and LqhaIT(Scorpion toxin)