The Cellular Thermal Shift Assay (CETSA) enables the study of protein-ligand interactions in a cellular context. It provides valuable information on the binding affinity and specificity of both small and large molecule ligands in a relevant physiological context, hence forming a unique tool in drug discovery. Though high-throughput lab protocols exist for scaling up CETSA, subsequent data analysis and quality control remain laborious and limit experimental throughput.
View Article and Find Full Text PDFRecent efforts for increasing the success in drug discovery focus on an early, massive, and routine mechanistic and/or kinetic characterization of drug-target engagement as part of a design-make-test-analyze strategy. From an experimental perspective, many mechanistic assays can be translated into a scalable format on automation platforms and thereby enable routine characterization of hundreds or thousands of compounds. However, now the limiting factor to achieve such in-depth characterization at high-throughput becomes the quality-driven data analysis, the sheer scale of which outweighs the time available to the scientific staff of most labs.
View Article and Find Full Text PDFBiopharmaceutical drug discovery, as of today is a highly automated, high throughput endeavor, where many screening technologies produce a high-dimensional measurement per sample. A striking example is High Content Screening (HCS), which utilizes automated microscopy to systematically access the wealth of information contained in biological assays. Exploiting HCS to its full potential traditionally requires extracting a high number of features from the images to capture as much information as possible, then performing algorithmic analysis and complex data visualization in order to render this high-dimensional data into an interpretable and instructive information for guiding drug development.
View Article and Find Full Text PDFIon channels are drug targets for neurologic, cardiac, and immunologic diseases. Many disease-associated mutations and drugs modulate voltage-gated ion channel activation and inactivation, suggesting that characterizing state-dependent effects of test compounds at an early stage of drug development can be of great benefit. Historically, the effects of compounds on ion channel biophysical properties and voltage-dependent activation/inactivation could only be assessed by using low-throughput, manual patch clamp recording techniques.
View Article and Find Full Text PDFDrug discovery programs are moving increasingly toward phenotypic imaging assays to model disease-relevant pathways and phenotypes in vitro. These assays offer richer information than target-optimized assays by investigating multiple cellular pathways simultaneously and producing multiplexed readouts. However, extracting the desired information from complex image data poses significant challenges, preventing broad adoption of more sophisticated phenotypic assays.
View Article and Find Full Text PDFis a highly infectious Gram-negative bacterium that is the etiologic agent of tularemia in animals and humans and a Tier 1 select agent. The natural incidence of pneumonic tularemia worldwide is very low; therefore, it is not feasible to conduct clinical efficacy testing of tularemia medical countermeasures (MCM) in human populations. Development and licensure of tularemia therapeutics and vaccines need to occur under the Food and Drug Administration's (FDA's) Animal Rule under which efficacy studies are conducted in well-characterized animal models that reflect the pathophysiology of human disease.
View Article and Find Full Text PDFDeep Learning has boosted artificial intelligence over the past 5 years and is seen now as one of the major technological innovation areas, predicted to replace lots of repetitive, but complex tasks of human labor within the next decade. It is also expected to be 'game changing' for research activities in pharma and life sciences, where large sets of similar yet complex data samples are systematically analyzed. Deep learning is currently conquering formerly expert domains especially in areas requiring perception, previously not amenable to standard machine learning.
View Article and Find Full Text PDFSurface plasmon resonance (SPR) is a powerful method for obtaining detailed molecular interaction parameters. Modern instrumentation with its increased throughput has enabled routine screening by SPR in hit-to-lead and lead optimization programs, and SPR has become a mainstream drug discovery technology. However, the processing and reporting of SPR data in drug discovery are typically performed manually, which is both time-consuming and tedious.
View Article and Find Full Text PDFContamination of pet food with is a serious public health concern, and several disease outbreaks have recently occurred due to human exposure to tainted pet food. The problem is especially challenging for raw pet foods (which include raw meats, seafood, fruits, and vegetables). These foods are becoming increasingly popular because of their nutritional qualities, but they are also more difficult to maintain -free because they lack heat-treatment.
View Article and Find Full Text PDFRNA interference (RNAi), a naturally occurring phenomenon in eukaryotic organisms, is an extremely valuable tool that can be utilized in the laboratory for functional genomic studies. The ability to knockdown individual genes selectively via this reverse genetic technique has allowed many researchers to rapidly uncover the biological roles of numerous genes within many organisms, by evaluation of loss-of-function phenotypes. In the major human malaria vector Anopheles gambiae, the predominant method used to reduce the function of targeted genes involves injection of double-stranded (dsRNA) into the hemocoel of the adult mosquito.
View Article and Find Full Text PDFHuman salmonellosis has been associated with contaminated pet foods and treats. Therefore, there is interest in identifying novel approaches for reducing the risk of Salmonella contamination within pet food manufacturing environments. The use of lytic bacteriophages shows promise as a safe and effective way to mitigate Salmonella contamination in various food products.
View Article and Find Full Text PDFTetrahymena telomeres are protected by a protein complex composed of Pot1, Tpt1, Pat1, and Pat2. Pot1 binds the 3' overhang and serves multiple roles in telomere maintenance. Here we describe Pot2, a paralog of Pot1 which has evolved a novel function during Tetrahymena sexual reproduction.
View Article and Find Full Text PDFBacterially derived lipopolysaccharide (LPS) stimulates naive B lymphocytes to differentiate into immunoglobulin (Ig)-secreting plasma cells. Differentiation of B lymphocytes is characterized by a proliferative phase followed by expansion of the intracellular membrane secretory network to support Ig production. A key question in lymphocyte biology is how naive B cells reprogram metabolism to support de novo lipogenesis necessary for proliferation and expansion of the endomembrane network in response to LPS.
View Article and Find Full Text PDFA cocktail of six lytic bacteriophages, SalmoFresh™, significantly (p < 0.05) reduced the number of surface-applied Kentucky and Brandenburg from stainless steel and glass surfaces by > 99% (2.1-4.
View Article and Find Full Text PDFRecent technological advances in high-content screening instrumentation have increased its ease of use and throughput, expanding the application of high-content screening to the early stages of drug discovery. However, high-content screens produce complex data sets, presenting a challenge for both extraction and interpretation of meaningful information. This shifts the high-content screening process bottleneck from the experimental to the analytical stage.
View Article and Find Full Text PDFCurr Opin Drug Discov Devel
May 2005
Lead discovery is a complex process that is intimately linked to chemistry, but which is also increasingly driven by biological sciences. In an industrial pharmaceutical research environment the process is defined by highly automated technologies for target identification and validation, compound library screening, and compound efficacy assessment. The huge volumes and complex dependencies of data produced by such large-scale experiments have led to a reassessment of data analysis processes, resulting in the development of novel data analysis strategies tailored to drug discovery.
View Article and Find Full Text PDFObjectives: To determine the relative severity and compare the clinical expression of spondyloarthropathy (SpA) in men and women.
Methods: A clinical study was conducted in 43 women and 40 men who made up 80% of all individuals identified as having SpA in a community-wide epidemiologic study of Alaskan Eskimos. The study included interviews, physical, laboratory, radiographic and electrocardiographic examinations, record reviews, and functional assessments.
G protein-coupled receptors (GPCRs) constitute an abundant family of membrane receptors of high pharmacological interest. Cell-based assays are the predominant means of assessing GPCR activation, but are limited by their inherent complexity. Functional molecular assays that directly and specifically report G protein activation by receptors could offer substantial advantages.
View Article and Find Full Text PDFObjective: To evaluate global statistical tests (GSTs) of treatment effectiveness for rheumatoid arthritis (RA) trials measuring multiple outcomes.
Methods: Using outcome measures from American College of Rheumatology (ACR) core set variables available in 3 RA trials, GSTs were calculated using the O'Brien ranking procedure and a procedure for binary data. GSTs take correlations among outcomes into account.
A cross-national study of hip fracture incidence was carried out in five geographic areas--Beijing, China; Budapest, Hungary; Hong Kong; Porto Alegre, Brazil; and Reykjavik, Iceland--during the years 1990-1992. Cases of hip fracture among women and men of age 20 years and older were identified using hospital discharge data in conjunction with medical records, operating room logs, and radiology logs. Estimated incidence rates varied widely, with Beijing reporting the lowest rates (age-adjusted rate per 100,000 population for men 20 years and older = 45.
View Article and Find Full Text PDFObjective: To define the clinical spectrum and disease manifestations of spondyloarthropathy (SpA) as seen in a community, rather than a referral setting.
Methods: Eighty percent (83/104) of all individuals identified as having SpA in a community wide epidemiologic study of Alaskan Eskimos and 83 age and sex matched controls from the same regions participated in a 5 year clinical study. The study included baseline and followup interviews, physical, radiographic, and electrocardiographic examinations, record reviews, and functional assessment.
This paper describes data on bone mineral levels in the proximal femur of US adults based on the nationally representative sample examined during both phases of the third National Health and Nutrition Examination Survey (NHANES III, 1988-94), and updates data previously presented from phase 1 only. The data were collected from 14,646 men and women aged 20 years and older using dual-energy X-ray absorptiometry, and included bone mineral density (BMD), bone mineral content (BMC) and area of bone scanned in four selected regions of interest (ROI) in the proximal femur: femur neck, trochanter, intertrochanter and total. These variables are provided separately by age and sex for non-Hispanic whites (NHW), non-Hispanic blacks (NHB) and Mexican Americans (MA).
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