bluuebunny/crossref_metadata_2025_split huggingface dataset:
Improving diffusion-based protein backbone generation with global-geometry-aware latent encoding
Authors: Zhang Yuyang , Liu Yuhang , Ma Zinnia , Li Min , Xu Chunfu , Gong Haipeng 
Published: October 2024

AbstractRecent breakthroughs in diffusion-based generative models have promptedde novoprotein design, notably in generating diverse and realistic structures. Nevertheless, while existing models either excel at unconditional generation or employ residue-wise conditioning for topological control, explorations on a holistic, top-down approach to control the overall topological arrangements is still limited. In response, we introduce TopoDiff, a diffusion-based framework augmented by a structure encoder and a latent sampler. Our model can unsupervisedly learn a compact latent representation of protein global geometry, while simultaneously integrating a diffusion module to leverage this information for controlled structure generation. In benchmark against existing models, TopoDiff demonstrates comparable performance on established metrics and exhibits an improved coverage over the fold modes of natural proteins. Moreover, our method enables versatile control at the global-geometry level for structural generation, under the assistance of which we derived a number of novel folds of mainly-beta proteins with comprehensive experimental validation.
Uncovering large effect loci and epistasis for lifespan in standing genetic variation in the fruit flyDrosophila melanogaster
Authors: van den Heuvel Joost , Zandveld Jelle , Vrieling Klaas , Pannebakker Bart A. , Kammenga Jan , Zwaan Bas J. 
Published: October 2024

AbstractLifespan is a heritable trait with a polygenic architecture. Experimental evolution in combination with re-sequencing has often been used to identify candidate loci for lifespan inDrosophila melanogaster. Previous experiments showed thatDrosophilapopulations experimentally evolved to increase late-life reproduction showed a correlated responses in development time, body size, but also lifespan. Subsequent whole genome sequencing allowed for the identification of candidate loci that correlated to lifespan differentiation. However, it remains difficult to assess whether candidate loci affect lifespan and to what extent such loci pleiotropically underpin multiple traits. Furthermore, recent studies indicate that lifespan effects of loci are often context dependent, but genotype-by-genotype interactions remain understudied. Therefore, here, we report on a study where we genotyped 3210 individuals for 32 candidate loci that emerged from our evolve and re-sequence experiment and tested, (1) whether these loci significantly affected lifespan, (2) the effect size of each locus, and, (3) how these loci mutually interact, i.e. determine the level of epistasis in moulding lifespan. Of the 32 loci, six showed significant main effect associations, of which three loci showed effects of 6.6 days difference in lifespan or larger, while the overall average lifespan was 41.7 days. Eight additional significant pairwise interactions between loci were found, of which four (single) main effects and one three-way interaction was significant. Lastly, we found that alleles that increased lifespan did not necessarily have higher frequencies in populations that showed increased lifespan, indicating that lifespan itself had not been the major target of selection. Our study indicates that individual genotyping following an evolve and re-sequencing study is essential to understand the mechanistic basis of polygenetic adaptation.
Differentiating the mechanism of antibacterial activities of nano and ionic copper by usingEscherichia colias a model microorganism
Authors: Jose Gregor P. , Santra Subhankar , Saha Saurav Kumar , Mandal Swadhin K , Sengupta Tapas K. 
Published: October 2024

AbstractIn this study, the effect of polymer stabilized copper nanoparticles and ionic copper on the growth, nucleic acid pool, reactive oxygen species generation, cell surface lipopolysaccharide, outer membrane protein profile and cell surface morphology ofEscherichia coliwere investigated. Copper nanoparticles exhibited a superior bactericidal activity associated with increased nucleic acid degradation, reactive oxygen species generation and change in the outer membrane protein profile compared to ionic copper in a concentration dependent manner. Although, there was no change in the outer membrane lipopolysaccharide profile, inductively coupled plasma mass spectrometry analysis of nano- and ionic copper treatedEscherichia colicells revealed that more amounts of copper nanoparticles were transported inside the cells compared to the ionic counterpart up to 500 μM concentrations. Interestingly, copper nanoparticles at 1000 μM concentration could induce membrane pit formation whereas ionic copper failed to exhibit such property under the same experimental conditions. Based on these observations it can be concluded that both nano- and ionic copper exert their antibacterial action through the generation of reactive oxygen species, degradation of cellular nucleic acids and alteration of membrane protein profile, but with a significant difference in the effective concentration range due to the differential cellular transport.
Neural dynamics for working memory and evidence integration during olfactory navigation inDrosophila
Authors: Kathman Nicholas D. , Lanz Aaron J. , Freed Jacob D. , Nagel Katherine I. 
Published: October 2024

AbstractTo navigate towards an unknown food source, animals must accumulate evidence about the location of a goal and store this information in working memory. Here we identify a population of local neurons in the fan-shaped body ofDrosophilathat exhibits both evidence integration and working memory dynamics. Imaging from these neurons during virtual odor-guided navigation reveals a bump of activity that is activated by odor, but can outlast the odor stimulus by several seconds. Persistent bump activity is associated with persistent movement in the direction adopted during odor, arguing that these neurons represent a directional working memory. When the fly navigates a virtual odor plume, bump activity slowly ramps up with successive odor encounters, indicating that it integrates odor information over time. We do not observe these dynamics in a set of neighboring local neurons, although both populations show slow modulation correlated with engagement in the task. Silencing the first population impairs the integration of odor encounters and the persistence of upwind heading. Our work identifies a small group of genetically-identified neurons that integrate and store stochastic sensory evidence to support navigation in complex natural environments.
Object permanence in domestic cats (Felis catus) using violation-of-expectancy by owner and stranger
Authors: Forman Jemma , Rowe Jordan S. , Leavens David A. 
Published: October 2024

AbstractObject permanence, the understanding that objects continue to exist while out of sight, has been extensively researched in human infants and animals. Cats have been shown to reach Stage 5 object permanence by passing successive visible displacement tests, but their understanding of Stage 6 object permanence is less clear. We tested 18 domestic cats on their understanding of Stage 4 (single visible displacement; SVD) and Stage 6 (invisible displacement; IVD) of object permanence in their home environment. Additionally, we investigated how person familiarity may influence study engagement. In SVD tests, the box manipulator (owner or researcher) hid a toy in one of two cardboard boxes for the cat to find. In IVD tests, we implemented a violation-of-expectancy procedure in which the box manipulator showed a toy re-appearing out of either a) the same box it was hidden in (consistent trials) or b) the box it was not hidden in (violation trials). Approximately half of the cats (56%) did not find the hidden toy in SVD trials, with 42% of these cats not attempting to find the toy, despite previous research demonstrating that cats can retrieve hidden objects in successive SVD tests. No predictors significantly influenced whether cats found the toy, or which box was checked first (toy or empty box). In IVD trials, we unexpectedly found that cats were more likely to play with and had longer gaze durations towards the toy and display more toy box-directed behaviours in consistent trials than violation trials. Similarly, we found that cats were more likely to display toy and empty box- directed behaviours in trials where the researcher acted as the box manipulator. Other factors such as breed, outdoor access, cat sex and the first person to act as the box manipulator also influenced toy-directed behaviours. We discuss the complexity of person familiarity in research contexts and highlight some methodological challenges in studying cat cognition.
Differential Speed and Accuracy Trade-off in Working Memory Retrieval and Bilateral Precuneus between Older Men and Women
Authors: Esiaka Darlingtina K. , Strothkamp Stephanie , Banafsheh Aghayeeabianeh , Broster Lucas , Powell David K , Jicha Gregory , Jiang Yang 
Published: October 2024

AbstractBackgroundDespite various hypotheses, including differences in longevity, hormones, genetics, and neuroanatomy, the reasons for the higher prevalence of Alzheimer’s disease in older women compared to men remain unclear. Emerging evidence suggests that the precuneus, a key region of the default mode network, is linked to internally focused processes like memory retrieval. This study examined sex differences in the relationship between precuneus volumes and working memory retrieval speed in cognitively normal older adults, hypothesizing that disparities in precuneus size and function contribute to reduced working memory performance in older women.MethodA cohort of participants (N=45; 25 women; Mage=77) from the University of Kentucky Alzheimer’s Disease Research Center completed the Bluegrass Working Memory Task while undergoing 3T Siemens magnetic resonance imaging scans.ResultApplying Spearman correlation analyses, the results revealed correlations between working memory accuracy and volumes in the left (r=-.43, p<.01) and right (r=-.36, p<.05) precuneus across all subjects. Sex difference analysis indicated a tendency for the accuracy of the memory task to correlate more frequently with the left precuneus in women (r= 0.54; p < 0.05) than in men. Similarly, volumes in the left precuneus displayed a significant negative correlation with reaction time in response to memory target (r= -0.426; p < 0.05) and memory distractor (r= -0.549; p < 0.01) in women. There is a sex difference in accuracy and speed trade-off. While men were faster in reaction time, women were better in the accuracy of the memory task. Particularly noteworthy was the consistent association in women, where neurocognitive measures (Trail A, r= -.50, p<.01; Trail B, r= -.06, p<.01) reliably correlated with volumes in the left precuneus—a relationship not observed in men.DiscussionOur findings suggest that the left precuneus volume is associated with processing speed and accuracy of working memory performance, especially in women. Given that the left precuneus plays a key role in supporting various aspects of cognition, including memory retrieval, our findings point to the potential of reaction time serving as a surrogate marker for fMRI in predicting cognitive decline, particularly when considering sex differences.
Loss of killifish cGAS/STING function attenuates cellular senescence and age-related signatures but does not extend organismal life span
Authors: Ballhysa Eugen , Ripa Roberto , Hochhard Nadine , Nguyen Tin Tin Manh , Brazell Jennifer , Ferreri Baptiste , Hoffmann Elena , Steiner Joachim , Antebi Adam 
Published: October 2024

AbstractThe cGAS/STING pathway is a central innate immune signaling pathway whose chronic activation has been implicated in numerous age-related pathologies, yet its impact on life span itself is unknown. Here we engineered knockouts of this pathway in the killifishNothobranchius furzeri, and assessed physiology and aging.In vitro, loss of killifish cGAS or STING mitigated DNA damage-induced senescence in cultured fibroblasts.In vivo, cGAS knockout unexpectedly led to low-grade inflammation. It also attenuated changes in gene expression in response to DNA damage in young animals, and age-related changes in the old, suggesting dampening of senescence and aging. Necroscopy indicated that tissue pathology appeared milder overall in both mutants, though some tissues showed enhanced sterile macrophage infiltration. Despite an attenuated aging signature, however, longevity was not significantly different from wild type. Our findings reveal a potential tradeoff, where inhibiting the cGAS/STING pathway alleviates age-related signatures, but increases sterile inflammation, offsetting beneficial effects on lifespan.
Peripheral blood cytokines as markers of longitudinal recovery in white matter microstructure following inpatient treatment for opioid use disorders
Authors: Butelman Eduardo R , Huang Yuefeng , King Sarah G. , Gaudreault Pierre-Olivier , Ceceli Ahmet , Kronberg Greg , Cathomas Flurin , Roussos Panos , Russo Scott J. , Goldstein Rita Z. , Alia-Klein Nelly 
Published: October 2024

AbstractBackgroundHeroin and other opioid use disorders (HUD and OUD) cause massive public health morbidity and mortality. Although standard-of-care medication assisted treatment (MAT) exists, little is known about potential predictors of change during recovery. Recovery can include normalization of the brain’s white matter (WM) microstructure, which is sensitive to cytokine and immune signaling. Here we aimed to determine whether blood-based cytokine/immune markers can predict WM microstructure recovery following medication-assisted treatment.MethodsInpatient Individuals with HUD (iHUD; n=21) and healthy controls (HC; n=24) underwent magnetic resonance scans with diffusion tensor imaging (DTI) and provided ratings of drug cue-induced craving, arousal and valence twice, earlier in treatment and ≈14 weeks of inpatient MAT (with methadone or buprenorphine) thereafter. At this second session (MRI2), they also provided a peripheral blood sample for multiplex relative quantification of serum cytokine/immune proteins (with a proximity extension assay, Olink). We explored the correlation of a multi-target cytokine biomarker score (based on principal component analysis of 19 proteins that differed significantly between iHUD and HC) with change in whole-brain DTI (ΔDTI; MRI2 - MRI1) metrics (fractional anisotropy, mean diffusivity, and axial diffusivity) across the 14 weeks of MAT.ResultsThe cytokine biomarker score, obtained at the MRI2 stage, was correlated with ΔDTI metrics in frontal, fronto-parietal, and cortico-limbic WM tracts (e.g., including the genu of the corpus callosum, anterior corona radiata, and others). In a follow-up analysis, specific cytokines represented in the multi-target biomarker score, such as the interleukin oncostatin M (OSM), colony stimulating factor (CSF21), and the chemokine CCL7 were correlated with similar ΔDTI metrics in iHUD, but not in HC. Levels of other specific cytokines (i.e., CCL19 and CCL2) were negatively correlated with change in cue-induced craving or arousal. Thus, lower levels of the aforementioned cytokines were correlated with an increase in cue-induced craving or arousal across the two stages (MRI2 - MRI1).ConclusionsStudied as a multi-target biomarker score, or as individual targets, peripheral serum cytokines are highly accessible biomarkers of WM microstructure recovery in iHUD undergoing inpatient MAT.
Burnout and sleep problems among nurses working in a tertiary hospital in Kathmandu, Nepal
Authors: Kanak Manoj Panthi , Pant Smriti 
Published: October 2024

AbstractBurnout is defined as sustained response to chronic work-related stresses and is often measured in dimensions of emotional exhaustion, disengagement and feeling of low personal accomplishment. Burnout and sleep problems has been closely associated among healthcare providers, confirmed in many observational studies. However, there was a dearth in information regarding burnout and sleep problems among nurses from Nepal, hence this study was conducted. This was a cross-sectional study in which quantitative method was applied. Data was collected from 246 nurses working in the Tribhuvan University Teaching Hospital using simple random sampling method through self-administered questionnaire between March and April, 2022. Structured questions for personal and work-related characteristics were used while Oldenburg Burnout Inventory and Pittsburgh Sleep Quality Index were used to assess burnout and sleep problems, respectively. More than three out of four nurses (78.5%) were found to have burnout, with 88.3% disengaged and 83.0% exhausted. Likewise, almost half of the nurses (40.2%) were found to have a poor sleep quality. Using multivariate logistics regression analysis, factors like position of the nurse (AOR = 6.0, 95% CI; 1.9-18.8) and, slight problem (AOR = 6.6, 95% CI; 3.0-14.7) and somewhat to a big problem (AOR = 6.3, 95% CI; 1.9-20.9) of daytime dysfunction were found to be significantly associated with burnout. Similarly, age, work experience and beds-to-nurses ratio of the department was found to be significantly associated to burnout among the nurses using independent sample t-test. These results indicate the necessity to reduce work stress and manage sleep problems of the nurses prioritizing the nursing staffs occupying junior position. Similarly, establishment of interventions like psychological help desk and support groups for the nurses could be beneficial to mitigate the effects of burnout and sleep problems among nurses.
Multicomponent Thiolactone-Based Ionizable Lipid Screening Platform for an Efficient and Tunable mRNA Delivery to the Lungs
Authors: Peña Álvaro , Heredero Juan , Blandín Beatriz , Mata Elena , Miguel Diego De , Toro Alfonso , Alejo Teresa , Casabona Diego , López Alexandre , Gallego-Lleyda Ana , Pérez-Herrán Esther , Martínez-Oliván Juan , Giménez-Warren Javier 
Published: October 2024

ABSTRACTIonizable lipids are an essential component of lipid nanoparticles (LNPs) for an efficient mRNA delivery. However, optimizing their chemical structures for high protein expression, efficient endosomal escape, and selective organ targeting remains challenging due to complex structure-activity relationships and multistep synthesis. In this study, we introduce a rapid, high-throughput platform for screening ionizable lipids using a two-step, scalable synthesis involving a one-pot 3-component click-like reaction. This method, herein known as the STAAR approach, standing for Sequential Thiolactone Amine Acrylate Reaction, allowed for the combinatorial synthesis and in vivo screening of 91 novel lipids, followed by a structure-activity study. This led to the development of CP-LC-0729, an ionizable lipid that significantly surpasses the benchmark in protein expression while showing no in vivo toxicity. Additionally, the STAAR lipid platform was further validated by incorporating a one-step strategy to yield a permanently cationic lipid which was tested following a fifth-lipid formulation strategy. The in vivo results showed a highly selective lung delivery with a 32-fold increase in protein expression, outperforming current endogenous targeting strategies. All these findings underscore the potential of lipid CP-LC-0729 and the STAAR lipid platform in advancing the efficiency and specificity of mRNA delivery systems, while also advancing the development of new ionizable lipids.
assessPool: a flexible pipeline for population genomic analyses of pooled sequencing data
Authors: Freel Evan B , Conklin Emily E , Kraft Derek W , Whitney Jonathan L , Knapp Ingrid SS , Forsman Zac H , Toonen Robert J 
Published: October 2024

AbstractDespite the dramatic decrease in high-throughput sequencing costs over time, sequencing the ideal number of individuals for population genetic inference remains prohibitively expensive. When research questions require only population-level resolution, pooling individual samples before sequencing (pool-seq) can substantially reduce costs while still providing allele frequencies of Single Nucleotide Polymorphisms (SNPs). However, analyzing pooled data is comparatively difficult and less standardized than individual-based analyses. Although several programs have been developed to handle pool-seq data, most require extensive formatting or programming skills to operate. Here we introduce assessPool, an open-source R and Bash pipeline for pool- seq analyses with a focus on population structure. AssessPool accepts a Variant-Call Format (VCF) file and a FASTA-formatted reference, providing a straightforward transition from commonly used pipelines such as Stacks or dDocent. AssessPool handles varying numbers of pools and utilizes PoPoolation2 to generate locus-by-locus pairwiseFSTvalues and associated Fisher T-test values as measures of population structure. Starting with a VCF file containing all identified SNPs, assessPool facilitates several key functionalities for population genetic analyses: i) filtering SNPs based on adjustable criteria with parameter suggestions for pool-seq data, ii) organizing data structures for analysis based on input pools, iii) creating customizable run scripts for FSTcalculations using PoPoolation2 and/or the {poolfstat} R package, for all pairwise comparisons, iv) calculating locus-specificFSTvalues using PoPoolation2 and/or {poolfstat}, v) importingFSToutput into a format compatible with R, vi) producing population genomic summary statistics, and vii) generating interactive plots to visualize and explore data. A pooled dataset generated from wild populations is used here to showcase the features of the assessPool pipeline for population genomic analyses.
Amylin receptor subunit interactions are modulated by agonists and determine signaling
Authors: Gostynska Sandra E. , Karim Jordan A. , Ford Bailee E. , Gordon Peyton H. , Babin Katie M. , Inoue Asuka , Lambert Nevin A. , Pioszak Augen A. 
Published: October 2024

AbstractThree amylin receptors (AMYRs) mediate the metabolic actions of the peptide hormone amylin and are drug targets for diabetes and obesity. AMY1R, AMY2R, and AMY3R are heterodimers consisting of the G protein-coupled calcitonin receptor (CTR) paired with a RAMP1, -2, or -3 accessory subunit, respectively, which increases amylin potency. Little is known about AMYR subunit interactions and their role in signaling. Here, we show that the AMYRs have distinct basal subunit equilibriums that are modulated by peptide agonists and determine the cAMP signaling phenotype. Using a novel biochemical assay that resolves the AMYR heterodimers and free subunits, we found that the AMY1/2R subunit equilibriums favored free CTR and RAMP1/2, and rat amylin and αCGRP agonists promoted subunit association. A stronger CTR-RAMP3 transmembrane domain interface yielded a more stable AMY3R, and human and salmon calcitonin agonists promoted AMY3R dissociation. Similar changes in subunit association-dissociation were observed in live cell membranes, and G protein coupling and cAMP signaling assays showed how these altered signaling. Our findings reveal regulation of heteromeric GPCR signaling through subunit interaction dynamics.