bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparative Analysis of Housing Temperature Impact on Heart Failure with Preserved Ejection Fraction in J vs N Strain C57BL/6 Mice
Authors: Chaudhary Rajesh , Suhan Tahra K. , Wu Chao , Alzamrooni Afnan , Abdel-Latif Ahmed 
Published: August 2024

AbstractIntroductionHeart failure studies are conducted in preclinical animal models with different genotypic strains, 7-times higher metabolic rate, 5 to 6 times higher heart rate, and are housed in a cold-stressed environment of 23°C, unlike humans. These differences severely affect how animals respond to interventions, particularly those that lead to the development of metabolic syndrome, such as the two-hit model of diet-induced obesity (DIO) and Nμ-nitro-L-arginine methyl ester (L-NAME) administration. A two-hit model of diet-induced obesity (DIO) and L-NAME administration has been proposed to induce heart failure with preserved ejection fraction (HFpEF) and mimic the hallmarks of metabolic syndrome and inflammation-induced heart failure in humans [1]. However, studies have reported conflicting results using this model. In this study, we examined the influence of mouse strain and environmental temperature on the development of metabolic syndrome and HFpEF using a two-hit model.MethodsEight-week-old, C57BL/6 mice (n=30) from the J and N strains were randomized to receive a high-fat diet (HFD) plus L-NAME versus a regular chow diet; and were randomized to be housed at a regular temperature of 23 °C versus a thermoneutral temperature of 30 °C. Glucose tolerance test (GTT, 2g/kg body weight), blood pressure via tail cuff, and echocardiography were conducted at baseline and, then at 5 and 15 weeks. Metabolic phenotyping was conducted at week 15 by using the Promethion Sable System.ResultsOur study revealed the significant effects of housing temperature and strain on the development of metabolic syndrome and HFpEF following the initiation of HFD +L-NAME over 5 and 15 weeks. At 5 weeks, both strains showed thermoneutral housing-induced attenuation of the effects of HFD + L-NAME on blood pressure and glucose tolerance, with the J strain exhibiting reduced diastolic dysfunction. By week 15, thermoneutral housing decreased energy expenditure (EE) and fat oxidation in both strains, while specifically reducing the respiratory exchange ratio (RER)_and glucose oxidation in J strain. Ejection fraction increased in both strains compared with the Chow group, except for J strain at 23 °C. Notably, physical activity levels remained constant across the groups, suggesting that the observed metabolic changes were not activity related. These findings highlight the complex physiological adaptations of these strains to different housing temperatures.ConclusionsThermoneutral housing conditions elicited strain-specific metabolic and cardiac effects in mice, with the J strain showing more pronounced responses. These findings highlight the critical influence of ambient temperature on experimental outcomes in rodent models, emphasizing the need to consider housing conditions when interpreting the results of metabolic and cardiovascular research.
Micro to macro scale anatomical analysis of the human hippocampal arteries with synchrotron Hierarchical Phase-Contrast Tomography
Authors: Bellier A. , Tafforeau P. , Bouziane A. , Angelloz-Nicoud T. , Lee P.D. , Walsh C. 
Published: August 2024

AbstractPurposeTo date, no non-invasive imaging modality has been employed to profile the structural intricacies of the hippocampal arterial microvasculature in humans. We hypothesised that synchrotron-based imaging of the human hippocampus would enable precise characterisation of the arterial microvasculature.MethodsTwo preserved human brains from, a 69-year-old female and a 63-year-old male body donors were imaged using hierarchical phase-contrast tomography (HiP-CT) with synchrotron radiation at multiple voxel resolutions from 25.08 μm down to 2.45 μm. Subsequent manual and semi-automatic artery segmentation were performed followed by morphometric analyses. These data were compared to published data from alternative methodologies.ResultsHiP-CT made it possible to segment in context the arterial architecture of the human hippocampus. Our analysis identified anterior, medial and posterior hippocampal arteries arising from the P2 segment of the posterior cerebral artery on the image slices. We mapped arterial branches with external diameters greater than 50 μm in the hippocampal region. We visualised vascular asymmetry and quantified arterial structures with diameters as small as 7 μm.ConclusionsThrough the application of HiP-CT, we have provided the first imaging visualisation and quantification of the arterial system of the human hippocampus at high resolution in the context of whole brain imaging. Our results bridge the gap between anatomical and histological scales.
Defining the cardiac fibroblast secretome in the healthy and infarcted mouse heart
Authors: Bahr Jasmin , Poschmann Gereon , Jungmann Andreas , Busch Martin , Ding Zhaoping , Zalfen Ria , Steinhausen Julia , Wachtmeister Thorsten , Rickert Daniel , Lautwein Tobias , Alter Christina , Amrute Junedh M. , Lavine Kory J. , Köhrer Karl , Most Patrick , Stühler Kai , Hesse Julia , Schrader Jürgen 
Published: August 2024

AbstractCardiac fibroblasts (CF) are key players after myocardial infarction (MI), but their signaling is only incompletely understood. Here we report a first secretome atlas of CF in control (cCF) and post-MI hearts (miCF), combining a rapid cell isolation technique with SILAC and click chemistry. In CF, numerous paracrine factors involved in immune homeostasis were identified. Comparing secretome, transcriptome (SLAMseq), and cellular proteome disclosed protein turnover. In miCF at day 5 post-MI, significantly upregulated proteins included SLIT2, FN1, and CRLF1 in mouse and human samples. Comparing the miCF secretome at day 3 and 5 post-MI showed the dynamic nature of protein secretion. Specific in-vivo labeling of miCF proteins via biotin ligase TurboID using the POSTN promotor mirrored the in-vitro data. In summary, we have identified numerous paracrine factors specifically secreted from CF in mice and humans. This secretome atlas may lead to new biomarkers and/or therapeutic targets for the activated CF.
VUStruct: a compute pipeline for high throughput and personalized structural biology
Authors: Moth Christopher W. , Sheehan Jonathan H. , Mamun Abdullah Al , Sivley R. Michael , Gulsevin Alican , Rinker David , Capra John A. , Meiler Jens 
Published: August 2024

AbstractEffective diagnosis and treatment of rare genetic disorders requires the interpretation of a patient’s genetic variants of unknown significance (VUSs). Today, clinical decision-making is primarily guided by gene-phenotype association databases and DNA-based scoring methods. Our web-accessible variant analysis pipeline, VUStruct, supplements these established approaches by deeply analyzing the downstream molecular impact of variation in context of 3D protein structure. VUStruct’s growing impact is fueled by the co-proliferation of protein 3D structural models, gene sequencing, compute power, and artificial intelligence.Contextualizing VUSs in protein 3D structural models also illuminates longitudinal genomics studies and biochemical bench research focused on VUS, and we created VUStruct for clinicians and researchers alike. We now introduce VUStruct to the broad scientific community as a mature, web-facing, extensible, High Performance Computing (HPC) software pipeline.VUStruct maps missense variants onto automatically selected protein structures and launches a broad range of analyses. These include energy-based assessments of protein folding and stability, pathogenicity prediction through spatial clustering analysis, and machine learning (ML) predictors of binding surface disruptions and nearby post-translational modification sites. The pipeline also considers the entire input set of VUS and identifies genes potentially involved in digenic disease.VUStruct’s utility in clinical rare disease genome interpretation has been demonstrated through its analysis of over 175 Undiagnosed Disease Network (UDN) Patient cases. VUStruct-leveraged hypotheses have often informed clinicians in their consideration of additional patient testing, and we report here details from two cases where VUStruct was key to their solution. We also note successes with academic research collaborators, for whom VUStruct has informed research directions in both computational genomics and wet lab studies.
Local lateral connectivity is sufficient for replicating cortex-like topographical organization in deep neural networks
Authors: Qian Xinyu , Dehghani Amir Ozhan , Farahani Asa Borzabadi , Bashivan Pouya 
Published: August 2024

AbstractAcross the primate cortex, neurons that perform similar functions tend to be spatially grouped together. This biological principle extends to many other species as well, reflecting a common way of organizing sensory processing across diverse forms of life. In the visual cortex, this biological principle manifests itself as a modular organization of neuronal clusters, each tuned to a specific visual property. The tendency toward short connections is widely believed to explain the existence of such an organization in the brains of many animals. However, the neural mechanisms underlying this phenomenon remain unclear. Here, we use artificial deep neural network models to demonstrate that a topographical organization akin to that in the primary, intermediate, and high-level human visual cortex emerges when units in these models are locally laterally connected and their weight parameters are tuned by top-down credit assignment. The emergence of modular organization without explicit topography-inducing learning rules or objective functions challenges their necessity and suggests that local lateral connectivity alone may suffice for the formation of topographic organization across the cortex. Furthermore, the incorporation of lateral connections in deep convolutional networks enhances their robustness to subtle alterations in visual inputs, such as those designed to deceive the model (i.e. adversarial examples), indicating an additional role for these connections in learning robust representations.
Engineered Protein-G variants for plug-and-play applications
Authors: Slezak Tomasz , O’Leary Kelly M. , Li Jinyang , Rohaim Ahmed , Davydova Elena K. , Kossiakoff Anthony A. 
Published: August 2024

AbstractWe have developed a portfolio of antibody-based modules that can be prefabricated as standalone units and snapped together in plug-and-play fashion to create uniquely powerful multifunctional assemblies. The basic building blocks are derived from multiple pairs of native and modified Fab scaffolds and protein G (PG) variants engineered by phage display to introduce high pair-wise specificity. The variety of possible Fab-PG pairings provides a highly orthogonal system that can be exploited to perform challenging cell biology operations in a straightforward manner. The simplest manifestation allows multiplexed antigen detection using PG variants fused to fluorescently labeled SNAP-tags. Moreover, Fabs can be readily attached to a PG-Fc dimer module which acts as the core unit to produce plug-and-play IgG-like assemblies, and the utility can be further expanded to produce bispecific analogs using the “knobs into holes” strategy. These core PG-Fc dimer modules can be made and stored in bulk to produce off-the-shelf customized IgG entities in minutes, not days or weeks by just adding a Fab with the desired antigen specificity. In another application, the bispecific modalities form the building block for fabricating potent Bispecific T-cell Engagers (BiTEs), demonstrating their efficacy in cancer cell-killing assays. Additionally, the system can be adapted to include commercial antibodies as building blocks, greatly increasing the target space. Crystal structure analysis reveals that a few strategically positioned interactions engender the specificity between the Fab-PG variant pairs, requiring minimal changes to match the scaffolds for different possible combinations. This plug-and-play platform offers a user-friendly and versatile approach to enhance the functionality of antibody-based reagents in cell biology research.
PAI-1 Interaction with Sortilin Related Receptor-1 is Required for Lung Fibrosis
Authors: Sisson Thomas H. , Osterholzer John J. , Leung Lisa , Basrur Venkatesha , Nesvizhskii Alexey , Subbotina Natalya , Warnock Mark , Torrente Daniel , Virk Ammara Q , Horowitz Jeffrey C. , Migliorini Mary , Strickland Dudley K. , Kim Kevin K. , Huang Steven K. , Lawrence Daniel A. 
Published: August 2024

AbstractPlasminogen activator inhibitor-1 (PAI-1) has been previously shown to promote lung fibrosis via a mechanism that requires an intact vitronectin (VTN) binding site. In the present study, employing two distinct murine fibrosis models, we find that VTN is not required for PAI-1 to drive lung scarring. This result suggested the existence of a previously unrecognized profibrotic PAI-1-protein interaction involving the VTN-binding site for PAI-1. Using an unbiased proteomic approach, we identified sortilin related receptor 1 (SorlA) as the most highly enriched PAI-1 interactor in the fibrosing lung. We next investigated the role of SorlA in pulmonary fibrosis and found that SorlA deficiency protected against lung scarring in a murine model. We further show that, while VTN deficiency does not influence fibrogenesis in the presence or absence of PAI-1, SorlA is required for PAI-1 to promote scarring. These results, together with data showing increased SorlA levels in human IPF lung tissue, support a novel mechanism through which the potent profibrotic mediator PAI-1 drives lung fibrosis and implicate SorlA as a new therapeutic target in IPF treatment.
Variability of 7K and 11K SomaScan plasma proteomics assays
Authors: Candia Julián , Fantoni Giovanna , Delgado-Peraza Francheska , Shehadeh Nader , Tanaka Toshiko , Moaddel Ruin , Walker Keenan A. , Ferrucci Luigi 
Published: August 2024

AbstractSomaScan is an aptamer-based proteomics assay designed for the simultaneous measurement of thousands of human proteins with a broad range of endogenous concentrations. The 7K SomaScan assay has been recently expanded into the new 11K version. Following up on our previous assessment of the 7K assay, here we expand our work on technical replicates from donors enrolled in the Baltimore Longitudinal Study of Aging. By generating SomaScan data from a second batch of technical replicates in the 7K version, as well as additional intra- and inter-plate replicate measurements in the new 11K version using the same donor samples, this work provides useful precision benchmarks for the SomaScan user community. Beyond updating our previous technical assessment of the 7K assay with increased statistics, here we estimate inter-batch variability, we assess inter- and intra-plate variability in the new 11K assay, we compare the observed variability between the 7K and 11K assays (leveraging the use of overlapping pairs of technical replicates), and explore the potential effects of sample storage time (ranging from 2 to 30 years) in the assays’ precision.
The Influence of Shoreline Residential Development on Riparian and Littoral Habitats in the Belgrade Lakes of Maine
Authors: Bevier Catherine R. , Cole F. Russell , Gimond Manuel , Rueger Bruce F. 
Published: August 2024

AbstractResidential development of lake shoreland can be accomplished with minimal negative impact to riparian and littoral habitat complexity, biological diversity, lake water quality, and general ecosystem health by using landscaping best practices. Preserving a heterogeneous and stratified vegetated buffer along the shoreline helps reduce erosion and nutrient runoff. In our study, we compared characteristics of undisturbed reference, developed but buffered, and developed but unbuffered properties along shorelines of three lakes in the Belgrade Lakes region of south central Maine, USA. Features of riparian habitats associated with reference and buffered developed sites were generally more similar to each other than to unbuffered developed sites. Significantly less shading along the shoreline, fewer trees and tall shrubs in buffer areas, and narrower buffer strips along the shoreline occurred on unbuffered developed sites compared to buffered developed sites. The degree of substrate embeddedness, aufwuchs cover, and amount of woody structure were more similar for littoral habitats adjacent to undeveloped reference and buffered developed sites than for unbuffered developed sites. These findings represent important validation for the use of landscaping best management practices that mimic natural landscape patterns to minimize the influence of shoreland residential development on lake ecosystem health. These practices should be promoted by lake protection programs and communicated to shoreline property owners.
Female Túngara Frogs Discriminate against the Call of Males Infected by Chytridiomycosis
Authors: Rodríguez-Brenes Sofía , Garza Sylvia F. , Ryan Michael J. 
Published: August 2024

AbstractSpecies worldwide are disappearing in the most devastating mass extinction in human history and one of the six most profound extinctions in the history of life. Amphibians are greatly affected, approximately one third of living species are threatened, and many others are extinct. One of the main causes of amphibian species extinctions and population declines is the emerging infectious disease chytridiomycosis, caused by the fungusBatrachochytrium dendrobatidis(Bd). Although some species are somewhat tolerant of the disease, the non-lethal effects of the infection with Bd and their short or long term consequences are poorly understood. In these species there is the potential for behavioral responses to mitigate the spread of the fungus. Here we show that in túngara frogs, infection status influences the males’ mating calls. These infection-induced changes in the quality of males’ mating calls ultimately reduce the calls’ attractiveness to females making females less likely to respond to and thus mate with infected males. More broadly, our results imply that females might avoid mating with disease-infected males by assessing the acoustic signal only, and that such recruitment of behavioral responses might potentially ameliorate some of the effects of this sixth mass extinction.Lay summaryChytridiomycosis is an amphibian disease well known for its lethal effects. Túngara frogs are infected in nature, but seem to be resistant to the disease. Here we show that chytridiomycosis has non-lethal behavioral effects on túngara frogs. Females discriminate against infected males by assessing only their acoustic signal. The mating call of a male that is not infected with the disease is more attractive to females than the call of that same male when he is infected.
Turning microglia neuroprotective: Towards connexin43-specific therapy of Alzheimer’s disease
Authors: Su Yixun , Li Hui , Zhang Wenjie , Tao Shi , Wang Qi , Zhou Mi , Tang Yong , Chen Hui , Verkhratsky Alexei , Zha Zhengbao , Niu Jianqin , Yi Chenju 
Published: August 2024

AbstractAlzheimer’s disease (AD) is the major cause of senile dementia without effective therapeutic strategies. The fundamental role of microglia in AD pathology, particularly in the early stages, is well acknowledged, although cell-specific therapeutic targets were not identified. Here we show that microglial connexin 43 (Cx43) hemichannels controls microglial reactivity in AD, thus being a promising therapeutic target. We discovered a marked increase in Cx43 protein in the periplaque microglia in the post-mortem tissue from AD patients. Subsequently, using the APPswe/PS1dE9mouse model of AD, we demonstrated that microglial Cx43 operating as hemichannels influences microglial function, which in turn affects β-amyloid pathology. Ablation of microglial Cx43 hemichannels by genetic knockout shifted microglia to neuroprotective phenotype, which promoted the microglia-plaque interaction while suppressing the neurotoxic microglial signature, thereby mitigating the progression of AD. Following this lead, we developed a novel formulation of a small molecule peptide, lipid nanoparticle-delivered molecule TAT-Cx43266-283(TAT-CX43@LNPs), which selectively blocks Cx43 hemichannels. Our preclinical trial demonstrated its efficacy in delaying and rescuing β-amyloid-related neuropathology and cognitive impairment in AD mice. This study provides strong evidence to progress our novel drug into clinical trials and translate it to disease-preventing (when administered in the early disease stages) and disease-modifying agents.
Unifying regulatory motifs in endocrine circuits
Authors: Raz Moriya , Glass David S. , Milo Tomer , Kohanim Yael Korem , Karin Omer , Tendler Avichai , Mayo Avi , Alon Uri 
Published: August 2024

AbstractIn this study we identify unifying design principles in human endocrine systems. We find that 43 hormone systems, controlling diverse physiological functions, fall into 5 classes of circuits with shared structure – thus only a small number of the possible circuits actually occur. Each class uses a different regulatory logic to perform specific dynamical functions, such as homeostasis, acute input-output response or adjustable set points. The circuits employ interactions on two timescales: hormone secretion on the scale of minutes-hours and growth and shrinkage of endocrine gland mass on the scale of months, which impacts the amount of hormone the glands secrete. This two-timescale principle recurs in several classes of circuits, including the most complex class, which has an intermediate gland, the pituitary. We analyze the pituitary circuit in detail and find tradeoffs between endocrine amplification, buffering of hypersecreting tumors, and rapid response times. These unifying principles of regulation build a foundation for systems endocrinology.
Towards Principled Modeling Of Coronary Artery Calcium Scores With Zero-Inflated Regression
Authors: Shrikumar Avanti , Fathieh Sina , Figtree Gemma A. , Grieve Stuart M. 
Published: August 2024

AbstractThe Coronary Artery Calcium Score (CACS) is a widely-used measure of Coronary Artery Disease (CAD). The primary use of CACS is to identify subclinical CAD and estimate risk of future cardiovascular events such as acute myocardial infarction. The development of coronary atherosclerosis is well known to be accelerated in response to risk factors such as age, hypertension, hypercholeterolaemia and smoking. However, there is substantial variability in an individual’s susceptibility or resistance to CAD against these risk factors. Quantifiying the deviation from “expected” CACS provides an novel opportunity to inform multi-omic and similar unbiased discovery of new markers and mechanisms of CAD trained against CT imaging. Standard linear regression struggles to model CACS due to the high prevalence of zeros (which reflect the absence of measurable coronary plaque). Prior works have variously handled this by discarding measurements with CACS of zero or by binning the CACS into broad categorical groups. Such approaches discard meaningful data, motivating the need for a more principled approach to handling the data distribution. In this work, we explored zero-inflated regression as a possible approach to modeling CACS using a cohort of patients from the BioHEART-CT study, and devised metrics to validate performance. We identified zero-inflated negative binomial regression, zero-inflated gamma regression and zero-inflated lognormal regression as promising approaches for handling the distributional properties of CACS, where the best method to use can vary depending on the dataset considered. A key contribution of our work is to demonstrate how these models can also estimate the percentile of the observed CACS relative to the distribution that would be expected after controlling for the inputs, thereby avoiding the need for data-hungry binning-based approaches.