bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of Treatment of Methicillin-ResistantStaphylococcus aureusBiofilms with Intermittent Electrochemically-Generated H2O2or HOCl
Authors: Anoy Md Monzurul Islam , Kim Won-Jun , Gelston Suzanne , Fleming Derek , Patel Robin , Beyenal Haluk 
Published: March 2024

AbstractChronic wound infections can be difficult to treat and may lead to impaired healing and worsened patient outcomes. Novel treatment strategies are needed. This study evaluated effects of intermittently produced H2O2and HOCl, generated via an electrochemical bandage (e-bandage), against methicillin-resistantStaphylococcus aureusbiofilms in an agar membrane biofilm model. By changing the working electrode potential, the e-bandage generated either HOCl (1.5 VAg/AgCl) or H2O2(−0.6 VAg/AgCl). The degree of biocidal activity of intermittent treatment with HOCl and H2O2correlated with HOCl treatment time; HOCl treatment durations of 0, 1.5, 3, 4.5, and 6 hours (with the rest of the 6 hour total treatment time devoted to H2O2generation) resulted in mean biofilm reductions of 1.36±0.2, 2.22±0.16, 3.46±0.38, 4.63±0.74 and 7.66±0.5 log CFU/cm2, respectively vs. non-polarized controls, respectively. However, application of H2O2immediately after HOCl treatment was detrimental to biofilm removal. For example, 3-hours HOCl treatment followed by 3-hours H2O2resulted in a 1.90±0.84 log CFU/cm2lower mean biofilm reduction than 3-hours HOCl treatment followed by 3-hours non-polarization. HOCl generated over 3-hours exhibited biocidal activity for at least 7.5-hours after e-bandage operation ceased; 3-hours of HOCl generation followed by 7.5-hours of non-polarization resulted in a biofilm cell reduction of 7.92±0.12 log CFU/cm2vs. non polarized controls. Finally, intermittent treatment with HOCl (i.e., interspersed with periods of e-bandage non-polarization) for various intervals showed similar effects (approximately 6 log CFU/cm2reduction vs. non-polarized control) to continuous treatment with HOCl for 3-hours, followed by 3-hours of non-polarization. These findings suggest that timing and sequencing of HOCl and H2O2treatments are crucial for maximizing biofilm control.
Modeling responses of macaque and human retinal ganglion cells to natural images using a convolutional neural network
Authors: Gogliettino Alex R. , Cooler Sam , Vilkhu Ramandeep S. , Brackbill Nora J. , Rhoades Colleen , Wu Eric G. , Kling Alexandra , Sher Alexander , Litke Alan M. , Chichilnisky E.J. 
Published: March 2024

AbstractLinear-nonlinear (LN) cascade models provide a simple way to capture retinal ganglion cell (RGC) responses to artificial stimuli such as white noise, but their ability to model responses to natural images is limited. Recently, convolutional neural network (CNN) models have been shown to produce light response predictions that were substantially more accurate than those of a LN model. However, this modeling approach has not yet been applied to responses of macaque or human RGCs to natural images. Here, we train and test a CNN model on responses to natural images of the four numerically dominant RGC types in the macaque and human retina – ON parasol, OFF parasol, ON midget and OFF midget cells. Compared with the LN model, the CNN model provided substantially more accurate response predictions. Linear reconstructions of the visual stimulus were more accurate for CNN compared to LN model-generated responses, relative to reconstructions obtained from the recorded data. These findings demonstrate the effectiveness of a CNN model in capturing light responses of major RGC types in the macaque and human retinas in natural conditions.
Exploring ligands that target von Willebrand factor selectively under oxidizing conditions through docking and molecular dynamics simulations
Authors: Interlandi Gianluca 
Published: March 2024

AbstractThe blood protein von Willebrand factor (VWF) is a large multimeric protein that, when activated, binds to blood platelets tethering them to the site of vascular injury initiating blood coagulation. This process is critical for the normal haemostatic response, but especially under inflammatory conditions it is thought to be a major player in pathological thrombus formation. For this reason, VWF has been the target for the development of anti-thrombotic therapeutics. However, it is challenging to prevent pathological thrombus formation while still allowing normal physiological blood coagulation as currently available anti-thrombotic therapeutics are known to cause unwanted bleeding in particular intracranial haemorrhage. This work explores the possibility of inhibiting VWF selectively under the inflammatory conditions present during pathological thrombus formation. In particular, the A2 domain of VWF is known to inhibit the neighboring A1 domain from binding to the platelet surface receptor GpIbα and this auto-inhibitory mechanism has been shown to be removed by oxidizing agents released during inflammation. Hence, finding drug molecules that bind at the interface between A1 and A2 only under oxidizing conditions could restore such auto-inhibitory mechanism. Here, by using a combination of computational docking, molecular dynamics simulations and free energy perturbation calculations, a ligand from the ZINC15 database was identified that binds at the A1A2 interface with the interaction being stronger under oxidizing conditions. The results provide a framework for the discovery of drug molecules that bind to a protein selectively in inflammatory conditions.
Dynamic fibrillar assembly of αB-crystallin induced by perturbation of the conserved NT-IXI motif resolved by cryo-EM
Authors: McFarland Russell , Reichow Steve 
Published: March 2024

ABSTRACTαB-crystallin is an archetypical member of the small heat-shock proteins (sHSPs) vital for cellular proteostasis and mitigating protein misfolding diseases. Gaining insights into the principles defining their molecular organization and chaperone function have been hindered by intrinsic dynamic properties and limited high-resolution structural analysis. To disentangle the mechanistic underpinnings of these dynamical properties, we mutated a conserved IXI-motif located within the N-terminal (NT) domain of human αB-crystallin. This resulted in a profound structural transformation, from highly polydispersed caged-like native assemblies into a comparatively well-ordered helical fibril state amenable to high-resolution cryo-EM analysis. The reversible nature of the induced fibrils facilitated interrogation of functional effects due to perturbation of the NT-IXI motif in both the native-like oligomer and fibril states. Together, our investigations unveiled several features thought to be key mechanistic attributes to sHSPs and point to a critical significance of the NT-IXI motif in αB-crystallin assembly, dynamics and chaperone activity.
Switching between newly learned motor skills
Authors: Kita Kahori , Du Yue , Haith Adrian M. 
Published: March 2024

AbstractStudies of cognitive flexibility suggest that switching between different tasks can entail a transient switch cost. Here, we asked whether analogous switch costs exist in the context of switching between different motor skills. We tested whether participants could switch between a newly learned skill associated with a novel visuomotor mapping, and an existing skill associated with an intuitive mapping. Participants showed increased errors in trials immediately following a switch between mappings. These errors were attributable to persisting with the pre-switch policy, rather than imperfect implementation or retrieval of the post-switch policy. A subset of our participants further learned a second new skill. Switching between these two novel skills was initially very challenging, but improved with further training. Our findings suggest that switching between newly learned motor skills can be challenging, and that errors in the context of switching between skills are primarily attributable to perseveration with the wrong control policy.
ELO-6 expression predicts longevity in isogenic populations ofCaenorhabditis elegans
Authors: Kong Weilin , Gu Guoli , Dai Tong , Chen Beibei , Pu Mintie 
Published: March 2024

AbstractVariations of individual lifespans within genetically identical populations in homogenous environments are remarkable, with the cause largely unknown. Gene expression changes with age, and the transcriptome changes correlate with chronological aging. Here, we show that inCaenorhabditis elegans, the expression dynamic of the fatty acid elongase ELO-6 during aging predicts individual longevity in isogenic populations. The expression ofelo-6is reduced with age. From adult day 5, ELO-6 expression level exhibits variation between individuals, and the expression level is positively correlated with adult lifespan and health span. Interventions that prolong longevity enhance the expression stability of ELO-6 during aging from adult day 4 to adult day 8, indicating ELO-6 is also a populational lifespan predictor. We performed transcriptome analysis in short-lived and long-lived isogenic worms and identified differentially expressed genes, which are enriched for PQM-1 binding sites. Decreasingpqm-1expression in young adults improved the homogeneity of ELO-6 levels between individuals and enhanced health span. Furthermore, we found reducing the expression of genes that are highly expressed in short-lived individuals, including PQM-1 target genes, enhanced ELO-6 expression stability with age and extended lifespan. Thus, our study identified ELO-6 as a predictor of individual and populational lifespan and revealed the role ofpqm-1in restricting health span and possibly causing individual lifespan variation.
Molecular Dynamics Study of α-Synuclein Domain Deletion Mutant Monomers
Authors: Onishi Noriyo , Mazzaferro Nicodemo , Kunstelj Špela , Alvarado Daisy A. , Muller Anna M. , Vázquez Frank X. 
Published: March 2024

AbstractAggregates of misfolded α-synuclein proteins (asyn) are key markers of Parkinson’s disease. Asyn proteins have three domains: an N-terminal domain, a hydrophobic NAC core implicated in aggregation, and a proline-rich C-terminal domain. Proteins with truncated C-terminal domains are known to be prone to aggregation and suggest that understanding domain-domain interactions in asyn monomers could help elucidate the role of the flanking domains in modulating protein structure. To this end, we used Gaussian accelerated molecular dynamics (GAMD) to simulate wild-type (WT), N-terminal truncated (ΔN), C-terminal truncated (ΔC), and isolated NAC domain asyn protein variants (isoNAC). Using clustering and contact analysis, we found that removal of the N-terminal domain led to increased contacts between NAC and C-terminal domains and the formation of interdomain Δ-sheets. Removal of either flanking domain also resulted in increased compactness of every domain. We also found that the contacts between flanking domains in the WT protein result in an electrostatic potential (ESP) that may lead to favorable interactions with anionic lipid membranes. Removal of the C-terminal domain disrupts the ESP in a way that could result in over-stabilized protein-membrane interactions. These results suggests that cooperation between the flanking domains may modulate the protein’s structure in a way that helps maintain elongation and creates an ESP that may aid favorable interactions with the membrane.
[mixglm]: A tool for modelling ecosystem resilience
Authors: Klimeš Adam , Chipperfield Joseph Daniel , Töpper Joachim Paul , Macias-Fauria Marc , Spiegel Marcus , Vandvik Vigdis , Velle Liv Guri , Robin Seddon Alistair William 
Published: March 2024

AbstractAimsA number of modelling frameworks exist to aid in the identification and exploration of stable states and the assessment of resilience from ecological datasets. However, because such models are complex to implement there is a substantial barrier for the application in ecological research. Here we develop a flexible model of ecological resilience based on Bayesian approximation of the “stability landscape”. We illustrate its usage on a tropical area where variation in tree cover has been previously interpreted as alternative stable states.MethodsThe stability landscape, from which stable states and resilience parameters are computed, is modelled using a mixture of multiple distributions, each representing a regression between the system state variable and the environmental covariates. Our “mixglm” model allows the mean, precision, and probability parameters of these distributions in the landscape to be dependent on multiple external covariates. “Mixglm” is implemented as a function in R package with the same name, internally using Bayesian inference via NIMBLE. We also conducted a power analysis to provide guidance regarding required sample size.ResultsWe illustrate the use of the “mixglm” on a published case of tree cover in South America which reports a stability landscape with three distinct stable states. Using “mixglm”, we were able to replicate the identification of these states. Moreover, we quantified uncertainty of our estimates, and computed resilience of South America’s forests.Conclusions“Mixglm” can be readily used for description of stability landscapes and identification of stable states in most spatial datasets of system state variables, and it is accompanied by tools for calculation of resilience metrics. It can also be further expanded using regression framework to account for more complex data structures such as spatio-temporal data.
Multi-trait genome-wide analysis identified novel risk loci and candidate drugs for heart failure
Authors: Yu Zhengyang , Lin Maohuan , Liang Zhanyu , Ren Bozhen , Yang Ying , Chen Wen , Wang Yonghua , Lin Xiaoling , Chen Yangxin , Ning Kaida , Xia Li C. 
Published: March 2024

AbstractHeart failure (HF) is a common cardiovascular syndrome that poses significant morbidity and mortality risks. While genome-wide association studies reporting on HF abound, its genetic etiology remains poorly elucidated, primarily due to its inherent polygenic nature. Furthermore, these genetic insights have not been fully leveraged for the development of effective primary treatment strategies for HF. In this study, we conducted a large-scale integrated multi-trait analysis using European-ancestry GWAS summary statistics of coronary artery disease and HF, involving near 2 million samples to identify novel risk loci associated with HF. 72 loci were newly identified with HF, of which 44 were validated in the replication phase. Transcriptome association analysis revealed 215 HF risk genes, includingEDNRAandFURIN. Pathway enrichment analysis of risk genes revealed their enrichment in pathways closely related to HF, such as response to endogenous stimulus (adjusted P = 8.83×10-3), phosphate-containing compound metabolic process (adjusted P = 1.91×10-2). Single-cell analysis indicated significant enrichments of these genes in smooth muscle cells, fibroblast of cardiac tissue, and cardiac endothelial cells. Additionally, our analysis of HF risk genes identified 74 potential drugs for further pharmacological evaluation. These findings provide novel insights into the genetic determinants of HF, highlighting new genetic loci as potential interventional targets to HF treatment, with significant implications for public health and clinical practice.
Five millennia of mitochondrial introgression in Atlantic bluefin tuna identified using ancient DNA
Authors: Eriksen Emma Falkeid , Andrews Adam Jon , Nielsen Svein Vatsvåg , Persson Per , Malca Estrella , Onar Vedat , Aniceti Veronica , Piquès Gäel , Piattoni Federica , Fontani Francesco , Wiech Martin , Ferter Keno , Kersten Oliver , Ferrari Giada , Cariani Alessia , Tinti Fausto , Cilli Elisabetta , Atmore Lane M. , Star Bastiaan 
Published: March 2024

AbstractMitogenomic (MT) introgression between species is readily documented in marine fishes. Such introgression events may either be long-term natural phenomena or the result of human-driven shifts in spatial distributions of previously separated species. Determining the drivers behind MT introgression is stymied by the difficulty of directly observing patterns of interbreeding over long timescales. Using ancient DNA spanning five millennia, we here investigate the long-term presence of MT introgression from Pacific bluefin tuna (Thunnus orientalis) and albacore (Thunnus alalunga) into Atlantic bluefin tuna (Thunnus thynnus), a species with extensive exploitation history and observed shifts in abundance, and demographic distribution. Comparing ancient (n=130) and modern (n=78) mitogenomes of specimens covering most of the range of Atlantic bluefin tuna we detect no significant spatial or temporal population structure. This lack of spatiotemporal genomic differentiation is indicative of ongoing gene flow between populations and large effective population sizes over millennia. Moreover, we identify introgressed MT genomes in ancient specimens up to 5000 years old and find that this rate of introgression has remained similar through time. We therefore conclude that MT introgression in the Atlantic bluefin tuna is to date unaffected by anthropogenic impacts. By providing the oldest example of directly observed MT introgression in the marine environment, our results highlight the utility of ancient DNA to obtain temporal insights in the long-term persistence of such phenomena.
Does Vibrotactile Stimulation of the Auricular Vagus Nerve Enhance Working Memory? A Behavioral and Physiological Investigation
Authors: Tan Gansheng , Adams Josh , Donovan Kara , Demarest Phillip , Willie Jon T. , Brunner Peter , Gorlewicz Jenna L. , Leuthardt Eric C. 
Published: March 2024

AbstractBackgroundWorking memory is essential to a wide range of cognitive functions and activities. Transcutaneous auricular VNS (taVNS) is a promising method to improve working memory performance. However, the feasibility and scalability of electrical stimulation are constrained by several limitations, such as auricular discomfort and inconsistent electrical contact.ObjectiveWe aimed to develop a novel and practical method, vibrotactile taVNS, to improve working memory. Further, we investigated its effects on arousal, measured by skin conductance and pupil diameter.MethodThis study included 20 healthy participants. Behavioral response, skin conductance, and eye tracking data were concurrently recorded while the participants performed N-back tasks under three conditions: vibrotactile taVNS delivered to the cymba concha, earlobe (sham control), and no stimulation (baseline control).ResultsIn 4-back tasks, which demand maximal working memory capacity, active vibrotactile taVNS significantly improved the performance metricd’ compared to the baseline but not to the sham. Moreover, we found that the reduction rate ofd’ with increasing task difficulty was significantly smaller during vibrotactile taVNS sessions than in both baseline and sham conditions. Arousal, measured as skin conductance and pupil diameter, declined over the course of the tasks. Vibrotactile taVNS rescued this arousal decline, leading to arousal levels corresponding to optimal working memory levels. Moreover, pupil diameter and skin conductance level were higher during high-cognitive-load tasks when vibrotactile taVNS was delivered to the concha compared to baseline and sham.ConclusionOur findings suggest that vibrotactile taVNS modulates the arousal pathway and could be a potential intervention for enhancing working memory.HighlightsVibrotactile stimulation of the auricular vagus nerve increases general arousal.Vibrotactile stimulation of the auricular vagus nerve mitigates arousal decreases as subjects continuously perform working memory tasks.6 Hz Vibrotactile auricular vagus nerve stimulation is a potential intervention for enhancing working memory performance.
Mutation bias alters the distribution of fitness effects of mutations
Authors: Sane Mrudula , Parveen Shazia , Agashe Deepa 
Published: March 2024

ABSTRACTMutation bias is an important factor determining the diversity of genetic variants available for selection, and can therefore constrain the genetic paths to adaptation. An additional constraint emerges over the course of evolution. As adaptation proceeds and some beneficial mutations are fixed, new beneficial mutations become rare, limiting further adaptation. Recent theoretical work predicts that these constraints may be alleviated by a change in the direction of mutation bias (i.e., a bias reversal). As populations sample previously underexplored types of mutations, the distribution of fitness effects (DFE) of mutations should shift towards more beneficial mutations. Here, we test this prediction usingEscherichia coli, which has a transition mutation bias, with ∼55% of single-nucleotide mutations being transitions compared to the unbiased expectation of ∼33% transitions. We generated mutant strains with a wide range of mutation biases from 96% transitions to 98% transversions, either reinforcing or reversing the wild type transition bias. Quantifying DFEs of hundreds of single mutations obtained from mutation accumulation experiments for each strain, we find strong support for the theoretical prediction. Strains that oppose the ancestral bias (i.e., with a strong transversion bias) have DFEs with the highest proportion of beneficial mutations, whereas strains that exacerbate the ancestral transition bias have up to 10-fold fewer beneficial mutations. Such dramatic differences in the DFE should drive large variation in the rate and outcome of adaptation. Our results thus strongly suggest an important and generalized evolutionary role for mutation bias shifts.
Complete telomere-to-telomere assemblies of two sorghum genomes to guide biological discovery
Authors: Wei Chuanzheng , Gao Lei , Xiao Ruixue , Wang Yanbo , Chen Bingru , Zou Wenhui , Li Jihong , Mace Emma , Jordan David , Tao Yongfu 
Published: March 2024

ABSTRACTSorghum is a C4 crop well-known for its high efficiency of biomass accumulation and adaptation to drought and hot environments. This study reports the assembly of complete genome sequence of two sorghum genomes using a combination of ultra-long reads from Oxford Nanopore Technology, high-fidelity long reads from Pacbio and Hi-C reads. The accuracy and completeness of the T2T assemblies were comprehensively validated using a range of parameters, including coverage depth assessment, BUSCO, LTR assembly index, ect. Our T2T assembly of BTx623 identified 36.25 Mb of new sequence, in addition to dozens of misoritation and mispositioning of large DNA segments in the BTx623-v3. Correcting these assembly errors in the reference genome is critical for exploiting genetic information in these complex regions in sorghum. Comparison of the two T2T genomes shed new insights on variation of centromeres in sorghum. The two high-quality T2T genomes represent an important resource for sorghum improvement and gene discovery. They would serve as the new reference genomes to unlock the full potential of global sequence variation of this valuable crop.