The Kaiser Permanente Research Program on Genes, Environment, and Health (RPGEH) Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort includes DNA specimens extracted from saliva ...samples of 110,266 individuals. Because of its relationship to aging, telomere length measurement was considered an important biomarker to develop on these subjects. To assay relative telomere length (TL) on this large cohort over a short time period, we created a novel high throughput robotic system for TL analysis and informatics. Samples were run in triplicate, along with control samples, in a randomized design. As part of quality control, we determined the within-sample variability and employed thresholds for the elimination of outlying measurements. Of 106,902 samples assayed, 105,539 (98.7%) passed all quality control (QC) measures. As expected, TL in general showed a decline with age and a sex difference. While telomeres showed a negative correlation with age up to 75 years, in those older than 75 years, age positively correlated with longer telomeres, indicative of an association of longer telomeres with more years of survival in those older than 75. Furthermore, while females in general had longer telomeres than males, this difference was significant only for those older than age 50. An additional novel finding was that the variance of TL between individuals increased with age. This study establishes reliable assay and analysis methodologies for measurement of TL in large, population-based human studies. The GERA cohort represents the largest currently available such resource, linked to comprehensive electronic health and genotype data for analysis.
•Admixing vermicompost and thermophilic compost increases nutrient availability.•Synergistic increases in N, P, K and electrical conductivity were observed.•Coir was an important addition to the ...blends increasing synergistic effects.•Enzyme activity increased linearly with vermicompost addition.
Composting is a common waste management strategy for recycling nutrients from organic household or agricultural wastes. However, thermophilic (e.g. windrow) composting and vermicomposting (using earthworms) produce different nutrient and enzyme profiles. Vermicompost is purported to have greater fertility benefits, but is also more expensive than thermophilic compost. The objective of this study was to examine a novel approach to designing organic fertility amendments by blending mature vermicompost and thermophilic compost. To examine the effect of blending, vermicompost was admixed to thermophilic compost at 20, 50 and 70 % by mass, with and without the addition of coir (cocopeat). Electric conductivity, water-extractable, immediately available N, P and K were measured. Vermicompost and coir synergistically affected the availability of these nutrients. Synergistic effects were between 15 and 40 % for total inorganic N in blends with coir. Without coir, synergism occurred only at vermicompost additions ≥50 %. Synergism for available P and K was present in all blends and ranged from 10% to 35%. Electrical conductivity measurements suggest that blending affected compost within three days of starting the incubation. The activity of five of seven measured enzymes were linearly and positively related to the fraction of vermicompost in the blend. Blending mature composts with differing properties may be another tool, in addition to adjusting feedstock and process parameters, to affect positively the fertility properties of composts.
Reports of disease suppression by compost are inconsistent likely because there are no established standards for feedstock material, maturity age for application, and application rate. The overall ...goal of the study was to evaluate a suite of biological indicators for their ability to predict disease suppression. Indicators included both commercial available methods for compost stability (Solvita™, respiration) and metrics of soil ecology not yet adopted by the compost industry (e.g., ecoenzymes, nematode community index). Damping-off by Rhizoctonia solani on radish was chosen as a model system given its global importance, competitiveness affected by carbon quality, and lack of disease management options for organic production. Biological indicators were evaluated for their ability to consistently differentiate among curing process, maturity, and feedstock material as a function of disease severity of a seedling bioassay and a compost extract assay to test competition with R. solani growth. Compost processed as vermicompost and anaerobic digestate were more suppressive against R. solani than windrow or aerated static pile. Mature composts were more suppressive than immature components. Feedstocks containing dairy manure and/or hardwood bark tended to have suppressive qualities. In contrast, poultry manure-based components were conducive to disease. Microbial ecoenzymes active on chitin and cellulose and nematode community indices were better predictors of disease suppressiveness than microbial respiration. These indicators are quicker than plant bioassays and could be adopted as tools to certify commercial products.
Compost can suppress soilborne plant pathogens that cause significant damage on globally important food crops. However, reports of plant pathogen suppression are inconsistent likely because there are ...no established standards for feedstock material, application rate, and maturity age upon application. Excellent results can be achieved in greenhouse trials, but field applications are much less reliable. Disease suppression occurs through the activity of biocontrol organisms (direct antagonism), and general microbial competition. Biocontrol species are hypothesized to colonize the pile during the curing phase, but single species may not be as important as microbial consortia. Substrate composition during maturation may give rise to a suppressive microbial community. More research is needed to understand the relationships between feedstock, maturity, and production process on compost microbial ecology. The thesis had two main objectives: 1) identify biological indicators in compost that could (a) characterize maturity, process, and feedstock, and (b) predict disease suppression against R. solani, and 2) identify bacterial and fungal community composition and/or structure that is associated with suppression of soilborne disease. Rhizoctonia solani is a facultative saprophytic fungus and soilborne plant pathogen that attacks many globally important food crops and turfgrass. Prior research suggests that managing carbon quality and compost maturity will alter relative competition between biological control microbes and the R. solani pathogen. The pathogen is responsible for economic losses to organic vegetable production in Vermont and there are no available methods to manage the disease that meet organic certification. R. solani on radish was chosen as a model system given its global importance, competitiveness affected by carbon quality, and lack of disease management options for organic production. Compost samples were most abundant in the bacterial phyla Proteobacteria and Bacteroidetes, and known biocontrol species were not detected in abundance. Compost samples did not differ significantly in fungal community composition, suggesting a dominance effect from the native soil fungal community. Overall, anaerobic digestate and vermicompost were most suppressive against R. solani. Thermophilic composts were not very suppressive overall, though a specially made hardwood bark compost was comparable to the suppressiveness of vermicompost application. Ecoenzyme analysis was able to integrate information on environmental substrate composition, microbial nutrient acquisition, and microbial community metabolism, offering the best view of current ecological conditions in compost. Ecoenzyme analysis showed that the most suppressive composts, anaerobic digestate and vermicompost, were most nutrient limited. All compost samples were severely nitrogen (N) limited, and anaerobic digestate and vermicompost were severely limited in both N and phosphorus (P). The additional P limitation may support non-pathogenic species to outcompete R. solani. The key to disease suppression may lie in matching up the ecology of the plant pathogen with the ecology of biocontrol, which may be engineered in compost.
Compost can suppress soilborne plant pathogens that cause significant damage on globally important food crops. However, reports of plant pathogen suppression are inconsistent likely because there are ...no established standards for feedstock material, application rate, and maturity age upon application. Excellent results can be achieved in greenhouse trials, but field applications are much less reliable. Disease suppression occurs through the activity of biocontrol organisms (direct antagonism), and general microbial competition. Biocontrol species are hypothesized to colonize the pile during the curing phase, but single species may not be as important as microbial consortia. Substrate composition during maturation may give rise to a suppressive microbial community. More research is needed to understand the relationships between feedstock, maturity, and production process on compost microbial ecology. The thesis had two main objectives: 1) identify biological indicators in compost that could (a) characterize maturity, process, and feedstock, and (b) predict disease suppression against R. solani, and 2) identify bacterial and fungal community composition and/or structure that is associated with suppression of soilborne disease.
Rhizoctonia solani is a facultative saprophytic fungus and soilborne plant pathogen that attacks many globally important food crops and turfgrass. Prior research suggests that managing carbon quality and compost maturity will alter relative competition between biological control microbes and the R. solani pathogen. The pathogen is responsible for economic losses to organic vegetable production in Vermont and there are no available methods to manage the disease that meet organic certification. R. solani on radish was chosen as a model system given its global importance, competitiveness affected by carbon quality, and lack of disease management options for organic production.
Compost samples were most abundant in the bacterial phyla Proteobacteria and Bacteroidetes, and known biocontrol species were not detected in abundance. Compost samples did not differ significantly in fungal community composition, suggesting a dominance effect from the native soil fungal community.
Overall, anaerobic digestate and vermicompost were most suppressive against R. solani. Thermophilic composts were not very suppressive overall, though a specially made hardwood bark compost was comparable to the suppressiveness of vermicompost application. Ecoenzyme analysis was able to integrate information on environmental substrate composition, microbial nutrient acquisition, and microbial community metabolism, offering the best view of current ecological conditions in compost. Ecoenzyme analysis showed that the most suppressive composts, anaerobic digestate and vermicompost, were most nutrient limited. All compost samples were severely nitrogen (N) limited, and anaerobic digestate and vermicompost were severely limited in both N and phosphorus (P). The additional P limitation may support non-pathogenic species to outcompete R. solani. The key to disease suppression may lie in matching up the ecology of the plant pathogen with the ecology of biocontrol, which may be engineered in compost.
Prized for their ability to rapidly generate chemical complexity by building new ring systems and stereocentres
, cycloaddition reactions have featured in numerous total syntheses
and are a key ...component in the education of chemistry students
. Similarly, carbon-carbon (C-C) cross-coupling methods are integral to synthesis because of their programmability, modularity and reliability
. Within the area of drug discovery, an overreliance on cross-coupling has led to a disproportionate representation of flat architectures that are rich in carbon atoms with orbitals hybridized in an sp
manner
. Despite the ability of cycloadditions to introduce multiple carbon sp
centres in a single step, they are less used
. This is probably because of their lack of modularity, stemming from the idiosyncratic steric and electronic rules for each specific type of cycloaddition. Here we demonstrate a strategy for combining the optimal features of these two chemical transformations into one simple sequence, to enable the modular, enantioselective, scalable and programmable preparation of useful building blocks, natural products and lead scaffolds for drug discovery.
Current efforts in the proteolysis targeting chimera (PROTAC) field mostly focus on choosing an appropriate E3 ligase for the target protein, improving the binding affinities towards the target ...protein and the E3 ligase, and optimizing the PROTAC linker. However, due to the large molecular weights of PROTACs, their cellular uptake remains an issue. Through comparing how different warhead chemistry, reversible noncovalent (RNC), reversible covalent (RC), and irreversible covalent (IRC) binders, affects the degradation of Bruton's Tyrosine Kinase (BTK), we serendipitously discover that cyano-acrylamide-based reversible covalent chemistry can significantly enhance the intracellular accumulation and target engagement of PROTACs and develop RC-1 as a reversible covalent BTK PROTAC with a high target occupancy as its corresponding kinase inhibitor and effectiveness as a dual functional inhibitor and degrader, a different mechanism-of-action for PROTACs. Importantly, this reversible covalent strategy is generalizable to improve other PROTACs, opening a path to enhance PROTAC efficacy.
Engineering materials that can store electrical energy in structural load paths can revolutionize lightweight design across transport modes. Stiff and strong batteries that use solid‐state ...electrolytes and resilient electrodes and separators are generally lacking. Herein, a structural battery composite with unprecedented multifunctional performance is demonstrated, featuring an energy density of 24 Wh kg−1 and an elastic modulus of 25 GPa and tensile strength exceeding 300 MPa. The structural battery is made from multifunctional constituents, where reinforcing carbon fibers (CFs) act as electrode and current collector. A structural electrolyte is used for load transfer and ion transport and a glass fiber fabric separates the CF electrode from an aluminum foil‐supported lithium–iron–phosphate positive electrode. Equipped with these materials, lighter electrical cars, aircraft, and consumer goods can be pursued.
Structural battery composites offer mass‐less energy storage for electrical vehicles and devices. Structural batteries are enabled by the recently discovered multifunctional properties of carbon fibers and the development of a structural electrolyte matrix material. The emergent multifunctional properties reach a level that allows lightweight vehicles and innovations across and beyond all transport modes.
Integrative analysis of multi-omics layers at single cell level is critical for accurate dissection of cell-to-cell variation within certain cell populations. Here we report scCAT-seq, a technique ...for simultaneously assaying chromatin accessibility and the transcriptome within the same single cell. We show that the combined single cell signatures enable accurate construction of regulatory relationships between cis-regulatory elements and the target genes at single-cell resolution, providing a new dimension of features that helps direct discovery of regulatory patterns specific to distinct cell identities. Moreover, we generate the first single cell integrated map of chromatin accessibility and transcriptome in early embryos and demonstrate the robustness of scCAT-seq in the precise dissection of master transcription factors in cells of distinct states. The ability to obtain these two layers of omics data will help provide more accurate definitions of "single cell state" and enable the deconvolution of regulatory heterogeneity from complex cell populations.
Abstract Objective Genomic studies of ovarian cancer (OC) cell lines frequently used in research revealed that these cells do not fully represent high-grade serous ovarian cancer (HGSOC), the most ...common OC histologic type. However, OC lines that appear to genomically resemble HGSOC have not been extensively used and their growth characteristics in murine xenografts are essentially unknown. Methods To better understand growth patterns and characteristics of HGSOC cell lines in vivo, CAOV3, COV362, KURAMOCHI, NIH–OVCAR3, OVCAR4, OVCAR5, OVCAR8, OVSAHO, OVKATE, SNU119 and UWB1.289 cells were assessed for tumor formation in nude mice. Cells were injected intraperitoneally (i.p.) or subcutaneously (s.c.) in female athymic nude mice and allowed to grow (maximum of 90 days) and tumor formation was analyzed. All tumors were sectioned and assessed using H&E staining and immunohistochemistry for p53, PAX8 and WT1 expression. Results Six lines (OVCAR3, OVCAR4, OVCAR5, OVCAR8, CAOV3, and OVSAHO) formed i.p xenografts with HGSOC histology. OVKATE and COV362 formed s.c. tumors only. Rapid tumor formation was observed for OVCAR3, OVCAR5 and OVCAR8, but only OVCAR8 reliably formed ascites. Tumors derived from OVCAR3, OVCAR4, and OVKATE displayed papillary features. Of the 11 lines examined, three (Kuramochi, SNU119 and UWB1.289) were non-tumorigenic. Conclusions Our findings help further define which HGSOC cell models reliably generate tumors and/or ascites, critical information for preclinical drug development, validating in vitro findings, imaging and prevention studies by the OC research community.
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