Western Diet-Fed, Aortic-Banded Ossabaw Swine: A Preclinical Model of Cardio-Metabolic Heart Failure.

The development of new treatments for heart failure lack animal models that encompass the increasingly heterogeneous disease profile of this patient population. This report provides evidence supporting the hypothesis that Western Diet-fed, aortic-banded Ossabaw swine display an integrated physiological, morphological, and genetic phenotype evocative of cardio-metabolic heart failure. This new preclinical animal model displays a distinctive constellation of findings that are conceivably useful to extending the understanding of how pre-existing cardio-metabolic syndrome can contribute to developing HF

The Continued Need for Modeling and Scaled Testing to Advance the Hanford Tank Waste Mission

Hanford tank wastes are chemically complex slurries of liquids and solids that can exhibit changes in rheological behavior during retrieval and processing. The Hanford Waste Treatment and Immobilization Plant (WTP) recently abandoned its planned approach to use computational fluid dynamics (CFD) supported by testing at less than full scale to verify the design of vessels that process these wastes within the plant. The commercial CFD tool selected was deemed too difficult to validate to the degree necessary for use in the design of a nuclear facility. Alternative, but somewhat immature, CFD tools are available that can simulate multiphase flow of non-Newtonian fluids. Yet both CFD and scaled testing can play an important role in advancing the Hanford tank waste mission—in supporting the new verification approach, which is to conduct testing in actual plant vessels; in supporting waste feed delivery, where scaled testing is ongoing; as a fallback approach to design verification if the Full Scale Vessel Testing Program is deemed too costly and time-consuming; to troubleshoot problems during commissioning and operation of the plant; and to evaluate the effects of any proposed changes in operating conditions in the future to optimize plant performance

Comparison of Waste Feed Delivery Small Scale Mixing Demonstration Simulant to Hanford Waste

The Hanford double-shell tank (DST) system provides the staging location for waste that will be transferred to the Hanford Tank Waste Treatment and Immobilization Plant (WTP). Specific WTP acceptance criteria for waste feed delivery describe the physical and chemical characteristics of the waste that must be met before the waste is transferred from the DSTs to the WTP. One of the more challenging requirements relates to the sampling and characterization of the undissolved solids (UDS) in a waste feed DST because the waste contains solid particles that settle and their concentration and relative proportion can change during the transfer of the waste in individual batches. A key uncertainty in the waste feed delivery system is the potential variation in UDS transferred in individual batches in comparison to an initial sample used for evaluating the acceptance criteria. To address this uncertainty, a number of small-scale mixing tests have been conducted as part of Washington River Protection Solutions' Small Scale Mixing Demonstration (SSMD) project to determine the performance of the DST mixing and sampling systems. A series of these tests have used a five-part simulant composed of particles of different size and density and designed to be equal or more challenging than AY-102 waste. This five-part simulant, however, has not been compared with the broad range of Hanford waste, and thus there is an additional uncertainty that this simulant may not be as challenging as the most difficult Hanford waste. The purpose of this study is to quantify how the current five-part simulant compares to all of the Hanford sludge waste, and to suggest alternate simulants that could be tested to reduce the uncertainty in applying the current testing results to potentially more challenging wastes

S-102 Transfer Pump Restriction Modeling Results

It was determined that a radioactive waste leak in the Hanford S Farm in the vicinity of the S-102 retrieval pump discharge occurred because of over-pressurization and failure of the S-102 dilution water supply hose while operating the retrieval pump in reverse with an obstructed suction cavity and an unobstructed flow path to the dilution water supply hose. This report describes efforts to identify plausible scenarios for the waste leak to occur

Preliminary Scaling Estimate for Select Small Scale Mixing Demonstration Tests

The Hanford Site double-shell tank (DST) system provides the staging location for waste that will be transferred to the Hanford Tank Waste Treatment and Immobilization Plant (WTP). Specific WTP acceptance criteria for waste feed delivery describe the physical and chemical characteristics of the waste that must be met before the waste is transferred from the DSTs to the WTP. One of the more challenging requirements relates to the sampling and characterization of the undissolved solids (UDS) in a waste feed DST because the waste contains solid particles that settle and their concentration and relative proportion can change during the transfer of the waste in individual batches. A key uncertainty in the waste feed delivery system is the potential variation in UDS transferred in individual batches in comparison to an initial sample used for evaluating the acceptance criteria. To address this uncertainty, a number of small-scale mixing tests have been conducted as part of Washington River Protection Solutions’ Small Scale Mixing Demonstration (SSMD) project to determine the performance of the DST mixing and sampling systems

Omics-squared: human genomic, transcriptomic and phenotypic data for genetic analysis workshop 19

Background The Genetic Analysis Workshops (GAW) are a forum for development, testing, and comparison of statistical genetic methods and software. Each contribution to the workshop includes an application to a specified data set. Here we describe the data distributed for GAW19, which focused on analysis of human genomic and transcriptomic data. Methods GAW19 data were donated by the T2D-GENES Consortium and the San Antonio Family Heart Study and included whole genome and exome sequences for odd-numbered autosomes, measures of gene expression, systolic and diastolic blood pressures, and related covariates in two Mexican American samples. These two samples were a collection of 20 large families with whole genome sequence and transcriptomic data and a set of 1943 unrelated individuals with exome sequence. For each sample, simulated phenotypes were constructed based on the real sequence data. ‘Functional’ genes and variants for the simulations were chosen based on observed correlations between gene expression and blood pressure. The simulations focused primarily on additive genetic models but also included a genotype-by-medication interaction. A total of 245 genes were designated as ‘functional’ in the simulations with a few genes of large effect and most genes explaining \u3c 1 % of the trait variation. An additional phenotype, Q1, was simulated to be correlated among related individuals, based on theoretical or empirical kinship matrices, but was not associated with any sequence variants. Two hundred replicates of the phenotypes were simulated. The GAW19 data are an expansion of the data used at GAW18, which included the family-based whole genome sequence, blood pressure, and simulated phenotypes, but not the gene expression data or the set of 1943 unrelated individuals with exome sequence

Amphiphilic shuttle peptide delivers base editor ribonucleoprotein to correct the CFTR R553X mutation in well-differentiated airway epithelial cells.

Base editing could correct nonsense mutations that cause cystic fibrosis (CF), but clinical development is limited by the lack of delivery methods that efficiently breach the barriers presented by airway epithelia. Here, we present a novel amphiphilic shuttle peptide based on the previously reported S10 peptide that substantially improved base editor ribonucleoprotein (RNP) delivery. Studies of the S10 secondary structure revealed that the alpha-helix formed by the endosomal leakage domain (ELD), but not the cell penetrating peptide (CPP), was functionally important for delivery. By isolating and extending the ELD, we created a novel shuttle peptide, termed S237. While S237 achieved lower delivery of green fluorescent protein, it outperformed S10 at Cas9 RNP delivery to cultured human airway epithelial cells and to pig airway epithelia in vivo, possibly due to its lower net charge. In well-differentiated primary human airway epithelial cell cultures, S237 achieved a 4.6-fold increase in base editor RNP delivery, correcting up to 9.4% of the cystic fibrosis transmembrane conductance regulator (CFTR) R553X allele and restoring CFTR channel function close to non-CF levels. These findings deepen the understanding of peptide-mediated delivery and offer a translational approach for base editor RNP delivery for CF airway disease

The mitochondrial multi-omic response to exercise training across rat tissues

Mitochondria have diverse functions critical to whole-body metabolic homeostasis. Endurance training alters mitochondrial activity, but systematic characterization of these adaptations is lacking. Here, the Molecular Transducers of Physical Activity Consortium mapped the temporal, multi-omic changes in mitochondrial analytes across 19 tissues in male and female rats trained for 1, 2, 4, or 8 weeks. Training elicited substantial changes in the adrenal gland, brown adipose, colon, heart, and skeletal muscle. The colon showed non-linear response dynamics, whereas mitochondrial pathways were downregulated in brown adipose and adrenal tissues. Protein acetylation increased in the liver, with a shift in lipid metabolism, whereas oxidative proteins increased in striated muscles. Exercise-upregulated networks were downregulated in human diabetes and cirrhosis. Knockdown of the central network protein 17-beta-hydroxysteroid dehydrogenase 10 (HSD17B10) elevated oxygen consumption, indicative of metabolic stress. We provide a multi-omic, multi-tissue, temporal atlas of the mitochondrial response to exercise training and identify candidates linked to mitochondrial dysfunction

Agricultural Research Service Weed Science Research: Past, Present, and Future

The U.S. Department of Agriculture-Agricultural Research Service (USDA-ARS) has been a leader in weed science research covering topics ranging from the development and use of integrated weed management (IWM) tactics to basic mechanistic studies, including biotic resistance of desirable plant communities and herbicide resistance. ARS weed scientists have worked in agricultural and natural ecosystems, including agronomic and horticultural crops, pastures, forests, wild lands, aquatic habitats, wetlands, and riparian areas. Through strong partnerships with academia, state agencies, private industry, and numerous federal programs, ARS weed scientists have made contributions to discoveries in the newest fields of robotics and genetics, as well as the traditional and fundamental subjects of weed-crop competition and physiology and integration of weed control tactics and practices. Weed science at ARS is often overshadowed by other research topics; thus, few are aware of the long history of ARS weed science and its important contributions. This review is the result of a symposium held at the Weed Science Society of America\u27s 62nd Annual Meeting in 2022 that included 10 separate presentations in a virtual Weed Science Webinar Series. The overarching themes of management tactics (IWM, biological control, and automation), basic mechanisms (competition, invasive plant genetics, and herbicide resistance), and ecosystem impacts (invasive plant spread, climate change, conservation, and restoration) represent core ARS weed science research that is dynamic and efficacious and has been a significant component of the agency\u27s national and international efforts. This review highlights current studies and future directions that exemplify the science and collaborative relationships both within and outside ARS. Given the constraints of weeds and invasive plants on all aspects of food, feed, and fiber systems, there is an acknowledged need to face new challenges, including agriculture and natural resources sustainability, economic resilience and reliability, and societal health and well-being