bluuebunny/crossref_metadata_2025_split huggingface dataset:
Epistasis regulates genetic control of cardiac hypertrophy
Authors: Wang Qianru , Tang Tiffany M. , Youlton Nathan , Weldy Chad S. , Kenney Ana M. , Ronen Omer , Weston Hughes J. , Chin Elizabeth T. , Sutton Shirley C. , Agarwal Abhineet , Li Xiao , Behr Merle , Kumbier Karl , Moravec Christine S. , Wilson Tang W. H. , Margulies Kenneth B. , Cappola Thomas P. , Butte Atul J. , Arnaout Rima , Brown James B. , Priest James R. , Parikh Victoria N. , Yu Bin , Ashley Euan A. 
Published: November 2023

AbstractThe combinatorial effect of genetic variants is often assumed to be additive. Although genetic variation can clearly interact non-additively, methods to uncover epistatic relationships remain in their infancy. We develop low-signal signed iterative random forests to elucidate the complex genetic architecture of cardiac hypertrophy. We derive deep learning-based estimates of left ventricular mass from the cardiac MRI scans of 29,661 individuals enrolled in the UK Biobank. We report epistatic genetic variation including variants close toCCDC141,IGF1R,TTN, andTNKS.Several loci where variants were deemed insignificant in univariate genome-wide association analyses are identified. Functional genomic and integrative enrichment analyses reveal a complex gene regulatory network in which genes mapped from these loci share biological processes and myogenic regulatory factors. Through a network analysis of transcriptomic data from 313 explanted human hearts, we found strong gene co-expression correlations between these statistical epistasis contributors in healthy hearts and a significant connectivity decrease in failing hearts. We assess causality of epistatic effects via RNA silencing of gene-gene interactions in human induced pluripotent stem cell-derived cardiomyocytes. Finally, single-cell morphology analysis using a novel high-throughput microfluidic system shows that cardiomyocyte hypertrophy is non-additively modifiable by specific pairwise interactions betweenCCDC141and bothTTNandIGF1R. Our results expand the scope of genetic regulation of cardiac structure to epistasis.
Glucose-6-phosphate dehydrogenase deficiency accelerates pancreatic acinar-to-ductal metaplasia
Authors: Radyk Megan D. , Nelson Barbara S. , Halbrook Christopher J. , Wood Alexander , Lavoie Brooke , Salvatore Lucie , Corfas Gabriel , Colacino Justin A. , Shah Yatrik M. , Crawford Howard C. , Lyssiotis Costas A. 
Published: November 2023

ABSTRACTActivating mutations inKRASextensively reprogram cellular metabolism to support the continuous growth, proliferation, and survival of pancreatic tumors. Targeting these metabolic dependencies are promising approaches for the treatment of established tumors. However, metabolic reprogramming is required early during tumorigenesis to provide transformed cells selective advantage towards malignancy. Acinar cells can give rise to pancreatic tumors through acinar-to-ductal metaplasia (ADM). Dysregulation of pathways that maintain acinar homeostasis accelerate tumorigenesis. During ADM, acinar cells transdifferentiate to duct-like cells, a process driven by oncogenicKRAS. The metabolic reprogramming that is required for the transdifferentiation in ADM is unclear. We performed transcriptomic analysis on mouse acinar cells undergoing ADM and found metabolic programs are globally enhanced, consistent with the transition of a specialized cell to a less differentiated phenotype with proliferative potential. Indeed, we and others have demonstrated how inhibiting metabolic pathways necessary for ADM can prevent transdifferentiation and tumorigenesis. Here, we also find NRF2-target genes are differentially expressed during ADM. Among these, we focused on the increase in the gene coding for NADPH-producing enzyme, Glucose-6-phosphate dehydrogenase (G6PD). Using established mouse models ofKrasG12D-driven pancreatic tumorigenesis and G6PD-deficiency, we find that mutantG6pdaccelerates ADM and pancreatic intraepithelial neoplasia. Acceleration of cancer initiation with G6PD-deficiency is dependent on its NADPH-generating function in reactive oxygen species (ROS) management, as opposed to other outputs of the pentose phosphate pathway. Together, this work provides new insights into the function of metabolic pathways during early tumorigenesis.
Antagonistic functions of CTL1 and SUH1 mediate cell wall assembly inArabidopsis
Authors: Thuy Nguyen Thi , Kim Hyun-Jung , Hong Suk-Whan 
Published: November 2023

AbstractPlant genomes contain numerous genes encoding chitinase-like (CTL) proteins, which have a similar protein structure to chitinase but lack the chitinolytic activity to cleave theβ-1,4-glycosidic bond in chitins, polymers ofN-acetylglucosamine. Mutations inCTL1in rice andArabidopsishave been found to cause pleiotropic developmental defects, including altered cell wall composition and decreased abiotic stress tolerance, likely due to a reduction in cellulose content. In this study, we identifiedsuppressor of hot2-1(suh1) as a genetic suppressor of thectl1hot2-1mutation inArabidopsis. The mutation inSUH1restored almost allctl1hot2-1defects examined to nearly wild-type levels, with the exception of partial recovery of cellulose content inctl1hot2-1mutants.SUH1encodes a Golgi-located type II membrane protein with glycosyltransferase (GT) activity, and its mutations lead to reduction in cellulose content and hypersensitivity to cellulose biosynthesis inhibitors, although to a lesser extent thanctl1hot2-1mutation. TheSUH1promoter fused with the GUS reporter gene exhibited GUS activity in interfascicular fibers and xylem in stems, and this activity was significantly increased by thectl1hot2-1mutation. Our findings provide genetic and molecular evidence that the antagonistic activities of CTL1 and SUH1 play an essential role in cell wall assembly inArabidopsis.HighlightThis study reports mutations insuppressor of hot2-1(SUH1) gene that rescues the defects caused by mutations inCTL1, which are characterized by stunted growth due to decreased cellulose levels.
Arousal as a universal embedding for spatiotemporal brain dynamics
Authors: Raut Ryan V. , Rosenthal Zachary P. , Wang Xiaodan , Miao Hanyang , Zhang Zhanqi , Lee Jin-Moo , Raichle Marcus E. , Bauer Adam Q. , Brunton Steven L. , Brunton Bingni W. , Kutz J. Nathan 
Published: November 2023

AbstractNeural activity in awake organisms shows widespread and spatiotemporally diverse correlations with behavioral and physiological measurements. We propose that this covariation reflects in part the dynamics of a unified, multidimensional arousal-related process that regulates brain-wide physiology on the timescale of seconds. By framing this interpretation within dynamical systems theory, we arrive at a surprising prediction: that a single, scalar measurement of arousal (e.g., pupil diameter) should suffice to reconstruct the continuous evolution of multidimensional, spatiotemporal measurements of large-scale brain physiology. To test this hypothesis, we perform multimodal, cortex-wide optical imaging and behavioral monitoring in awake mice. We demonstrate that spatiotemporal measurements of neuronal calcium, metabolism, and brain blood-oxygen can be accurately and parsimoniously modeled from a low-dimensional state-space reconstructed from the time history of pupil diameter. Extending this framework to behavioral and electrophysiological measurements from the Allen Brain Observatory, we demonstrate the ability to integrate diverse experimental data into a unified generative model via mappings from an intrinsic arousal manifold. Our results support the hypothesis that spontaneous, spatially structured fluctuations in brain-wide physiology—widely interpreted to reflect regionally-specific neural communication—are in large part reflections of an arousal-related process. This enriched view of arousal dynamics has broad implications for interpreting observations of brain, body, and behavior as measured across modalities, contexts, and scales.
Bacterial Diversity and Chemical Ecology of Natural Product-Producing Bacteria from Great Salt Lake Sediment
Authors: Bring Horvath Elijah R. , Brazelton William J. , Kim Min Cheol , Cullum Reiko , Mulvey Matthew A. , Fenical William , Winter Jaclyn M. 
Published: November 2023

AbstractGreat Salt Lake (GSL), located northwest of Salt Lake City, UT, is the largest terminal lake in the United States. While the average salinity of seawater is ∼3.3%, the salinity in GSL ranges between 5-28%. In addition to being a hypersaline environment, GSL also contains toxic concentrations of heavy metals, such as arsenic, mercury, and lead. The extreme environment of GSL makes it an intriguing subject of study, both for its unique microbiome and its potential to harbor novel natural product-producing bacteria, which could be used as resources for the discovery of biologically active compounds. Though work has been done to survey and catalogue bacteria found in GSL, the Lake’s microbiome is largely unexplored, and little-to-no work has been done to characterize the natural product potential of GSL microbes. Here, we investigate the bacterial diversity of two important regions within GSL, describe the first genomic characterization of Actinomycetota isolated from GSL sediment, including the identification of a newSaccharomonosporaspecies, and provide the first survey of the natural product potential of GSL bacteria.
Fast-slow traits predict competition network structure and its response to resources and enemies
Authors: Daniel Caroline , Allan Eric , Saiz Hugo , Godoy Oscar 
Published: November 2023

AbstractPlants interact in complex networks but how their structure depends on resources, natural enemies and species resource-use strategy remains poorly understood. Here, we quantified competition networks among 18 plants varying in fast-slow strategy, by testing how increased nutrient availability and reduced foliar pathogens affected intra- and inter-specific interactions. Our results show that nitrogen and pathogens altered several aspects of network structure, often in unexpected ways due to fast and slow growing species responding differently. Nitrogen addition increased competition asymmetry in slow growing networks, as expected, but decreased it in fast growing networks. Pathogen reduction made networks more even and less skewed because pathogens targeted weaker competitors. Surprisingly, pathogens and nitrogen dampened each other’s effect. Our results show that plant growth strategy is key to understand how competition respond to resources and enemies, a prediction from classic theories which has rarely been tested by linking functional traits to competition networks.
X-ray-driven chemistry and conformational heterogeneity in atomic resolution crystal structures of bacterial dihydrofolate reductases
Authors: Smith Nathan , Horswill Alexander R. , Wilson Mark A. 
Published: November 2023

AbstractDihydrofolate reductase (DHFR) catalyzes the NADPH-dependent reduction of dihydrofolate to tetrahydrofolate. Bacterial DHFRs are targets of several important antibiotics as well as model enzymes for the role of protein conformational dynamics in enzyme catalysis. We collected 0.93 Å resolution X-ray diffraction data from bothBacillus subtilis(Bs) andE. coli(Ec) DHFRs bound to folate and NADP+. These oxidized ternary complexes should not be able to perform chemistry, however electron density maps suggest hydride transfer is occurring in both enzymes. Comparison of low- and high-dose EcDHFR datasets show that X-rays drive partial production of tetrahydrofolate. Hydride transfer causes the nicotinamide moiety of NADP+to move towards the folate as well as correlated shifts in nearby residues. Higher radiation dose also changes the conformational heterogeneity of Met20 in EcDHFR, supporting a solvent gating role during catalysis. BsDHFR has a different pattern of conformational heterogeneity and an unexpected disulfide bond, illustrating important differences between bacterial DHFRs. This work demonstrates that X-rays can drive hydride transfer similar to the native DHFR reaction and that X-ray photoreduction can be used to interrogate catalytically relevant enzyme dynamics in favorable cases.
Nanoscale cellular organization of viral RNA and proteins in SARS-CoV-2 replication organelles
Authors: Andronov Leonid , Han Mengting , Zhu Yanyu , Balaji Ashwin , Roy Anish R. , Barentine Andrew E. S. , Patel Puja , Garhyan Jaishree , Qi Lei S. , Moerner W.E. 
Published: November 2023

AbstractThe SARS-CoV-2 viral infection transforms host cells and produces special organelles in many ways, and we focus on the replication organelle where the replication of viral genomic RNA (vgRNA) occurs. To date, the precise cellular localization of key RNA molecules and replication intermediates has been elusive in electron microscopy studies. We use super-resolution fluorescence microscopy and specific labeling to reveal the nanoscopic organization of replication organelles that contain vgRNA clusters along with viral double-stranded RNA (dsRNA) clusters and the replication enzyme, encapsulated by membranes derived from the host endoplasmic reticulum (ER). We show that the replication organelles are organized differently at early and late stages of infection. Surprisingly, vgRNA accumulates into distinct globular clusters in the cytoplasmic perinuclear region, which grow and accommodate more vgRNA molecules as infection time increases. The localization of ER labels and nsp3 (a component of the double-membrane vesicle, DMV) at the periphery of the vgRNA clusters suggests that replication organelles are enclosed by DMVs at early infection stages which then merge into vesicle packets as infection progresses. Precise co-imaging of the nanoscale cellular organization of vgRNA, dsRNA, and viral proteins in replication organelles of SARS-CoV-2 may inform therapeutic approaches that target viral replication and associated processes.
Evaluation of Prompts to Simplify Cardiovascular Disease Information Using a Large Language Model
Authors: Mishra Vishala , Sarraju Ashish , Kalwani Neil M. , Dexter Joseph P. 
Published: November 2023

AbstractAI chatbots powered by large language models (LLMs) are emerging as an important source of public-facing medical information. Generative models hold promise for producing tailored guidance at scale, which could advance health literacy and mitigate well-known disparities in the accessibility of health-protective information. In this study, we highlight an important limitation of basic approaches to AI-powered text simplification: when given a zero-shot or one-shot simplification prompt, GPT-4 often responds by omitting critical details. To address this limitation, we developed a new prompting strategy, which we term rubric prompting. Rubric prompts involve a combination of a zero-shot simplification prompt with brief reminders about important topics to address. Using rubric prompts, we generate recommendations about cardiovascular disease prevention that are more complete, more readable, and have lower syntactic complexity than baseline responses produced without prompt engineering. This analysis provides a blueprint for rigorous evaluation of AI model outputs in medicine.
Reach and public health implications of proposed new food marketing regulation in Germany: an updated analysis
Authors: Leibinger Anna , Holliday Nicole , Huizinga Oliver , von Philipsborn Peter 
Published: November 2023

AbstractIntroductionAdvertising of unhealthy foods to children is a key public health concern as exposure to such advertising has been shown to adversely affect children’s food preferences, choices, purchases and intake. The proposed Children’s Food Advertising Act (Kinder-Lebensmittel-Werbegesetz or KLWG) in Germany aims to regulate such marketing by using an adapted version of the World Health Organization Regional Office for Europe Nutrient Profile Model (WHO NPM). Since the first announcement of the proposed new legislation in February 2023, several revisions to the proposed law have been made. In the present study, we evaluate the reach and public health implications of the planned law’s latest draft proposed in June 2023, updating a previously published analysis of the initial proposal.MethodsOur analysis is based on a dataset from the open-source online database Open Food Facts, comprising 660 food products randomly selected from the German market. We assigned these products to the 22 food and beverage categories covered the WHO NPM. We then applied the nutrient and ingredient thresholds of the the June 2023 version of the KLWG to this sample to assess the share of products permitted for marketing to children under the proposed legislation.ResultsApplying the adjustments from the June 2023 KLWG version increased the proportion of products allowed for marketing to children in three product categories, namely plant-based milks (from 70% to 73%), yogurt and cream (from 13% to 73%) and fresh and frozen meat, fish and eggs (from 93% to 100%). Overall, this raised the median share of products across all 22 product categories permitted for marketing to children from 38% to 55%, with an interquartile range of 11%-73%.ConclusionOur previous study found the use of the WHO NPM, as part of the KLWG, to be feasible in the German context and suggested additional threshold adjustments. The latest draft of the KLWG from June 2023 incorporated several of these, substantially increasing the proportion of products allowed for marketing to children. This analysis provides an updated perspective on the evolving debate and its implications for public health.
East-West mortality disparities during the COVID-19 pandemic widen the historical longevity divide in Europe: an international comparative study
Authors: Shkolnikov Vladimir M. , Timonin Sergey , Jdanov Dmitry , Medina-Jaudes Naomi , Islam Nazrul , Leon David A. 
Published: November 2023

ABSTRACTIntroductionFor over half a century, life expectancy in the former communist countries of Eastern Europe has been noticeably lower than in Western Europe. Since 2000 this gap has narrowed. We examined the impact of the COVID-19 pandemic on these long-term mortality trends and differences.MethodsNationally reported mortality data were used to estimate East-West differences in excess mortality and life expectancy losses. Regression and decomposition methods were employed to examine the contribution of vaccination, trust in government, regulatory enforcement, and air connectivity between populations to these differences.ResultsDuring the pandemic, the East-West life expectancy gap widened to its highest level in more than two decades. Moreover, the trajectory of excess mortality during the pandemic differed between East and West, with levels of excess mortality in the East being minimal until autumn 2020. Cumulative excess mortality in weeks 10-18 of 2020 was correlated with an index of air connectivity, which was appreciably lower in Eastern compared to Western European countries in the immediate pre-pandemic period. From October 2020 onwards, the East suffered greater losses in life expectancy, especially in 2021. This could not be explained by greater frailty of the Eastern European populations, as indicated by higher pre-pandemic mortality levels. Half of the difference between East and West in 2021 was jointly explained by COVID-19 vaccination levels and trust in government.ConclusionsEast-West contrasts in the timing and magnitude of life expectancy losses during the COVID-19 pandemic appear to have their ultimate origins in differences between societies that were established during the Cold War. These include differences in the connectivity of populations, levels of trust in science and authorities and the related capacity of Eastern countries to mount effective vaccination campaigns.
SPATEs promote the survival ofShigellato the plasma complement system upon local hemorrhage and bacteremia
Authors: Debande Lorine , Sabbah Ahmad , Kuhn Laurianne , Ngondo Patryk , André Antonin C , Roche Béatrice , Laborde Matthieu , Cantalapiedra-Mateo Victoria , Thahouly Tamou , Milinski Ana , Bianchetti Laurent , Allmang-Cura Christine , Frugier Magali , Marteyn Benoit S 
Published: November 2023

AbstractShigellaspp. are the causative agents of shigellosis, which remains a leading cause of death in children under the age of five. Shigellosis is characterized by fever and results in hemorrhagic diarrhea; in more severe cases,Shigellabacteremia has been reported. These clinical features strongly suggest thatShigellasurvive exposure to plasma, although this has not yet been studied at the molecular level. In this report, we confirmed in a guinea pig model of shigellosis that local hemorrhages were induced byS. flexneri5a andS. sonnei, and we demonstrated thatShigellareached mucosal CD31+/CD34+ blood vessels during the late stages of infection and further disseminated in the bloodstream. These results confirmed the exposure ofShigellato plasma components within the hemorrhagic colonic mucosa and in the bloodstream. We demonstrated that all the testedShigellastrains survived plasma exposurein vitro, and we showed that Serine Protease Autotransporters of Enterobacteriaceae (SPATEs) are essential forShigelladissemination within the colonic mucosa. We have confirmed that SPATEs are expressed and secreted in poorly oxygenated environments encountered byShigellafrom hypoxic foci of infection to the bloodstream. We further demonstrated that SPATEs promotedShigellasurvival in plasma, by cleaving complement component 3 (C3), thereby impairing complement system activation. We have shown here that the ability ofShigellato survive plasma exposure is a key factor in its virulence, both within primary foci and systemically.Significance StatementIn this study we aimed to better understand the significance of the ability ofShigellato survive plasma exposure, as we observed that non-pathogenicE. colirapidly lysed upon exposure. Indeed, we reported thatShigellawas already exposed to plasma components within the colonic mucosa, as we reported in a guinea pig model of shigellosis that hemorrhages were induced, that were associated with local diffusion of plasma components in the infected colonic mucosa.Shigellawas obviously exposed to plasma during bacteremia. The ability ofShigellato survive in plasma has not been previously reported. Here we have shown, first, thatShigellawas able to divide and grow in the presence of human plasma, and second, we found that SPATEs played a central role in this process by impairing with the activation of the complement system.