bluuebunny/crossref_metadata_2025_split huggingface dataset:
DNA methylation carries signatures of sublethal effects under thermal stress in loggerhead sea turtles
Authors: Yen Eugenie C. , Gilbert James D. , Balard Alice , Afonso Inês O. , Fairweather Kirsten , Newlands Débora , Lopes Artur , Correia Sandra M. , Taxonera Albert , Rossiter Stephen J. , Martín-Durán José M. , Eizaguirre Christophe 
Published: November 2023

AbstractRising global temperatures are a major threat to biodiversity. Whilst research generally focuses on thermal tolerance and mortality, sublethal effects may alter population dynamics and subsequently the adaptive potential of species. However, detecting such effects in the wild can be challenging, particularly for endangered and long-lived species with cryptic life histories. This necessitates the development of molecular tools to identify their signatures. In a split-clutch design experiment, we relocated clutches of wild, nesting loggerhead sea turtles (Caretta caretta) to a protected,in-situhatchery. Eggs were then split into two sub-clutches incubated under shallow (35cm) or deep (55cm) conditions, with those in the shallow treatment experiencing significantly higher temperatures. Whilst no difference in hatching success was observed between treatments, hatchlings that emerged from the shallow, warmer treatment had altered length-mass relationships, and were weaker at fitness tests of locomotion capacity than their siblings incubated in the deep, cooler treatment. To characterise the molecular signatures of these thermal effects, we performed whole genome bisulfite sequencing on blood samples collected upon emergence. This identified 714 differentially methylated sites between treatments, including on genes with neuronal development, cytoskeleton, and sex determination functions. Taken together, our results show that higher incubation temperatures can induce sublethal effects in hatchlings, which are reflected in their DNA methylation status at identified sites. Such sites could be used as biomarkers of thermal stress, especially if they are retained across life stages. Overall, this study suggests that global warming may have population-level consequences for loggerhead sea turtles, by reducing hatchling quality, dispersal capacity and the adaptive potential of this species. Conservation efforts for climate-threatened taxa like endangered sea turtles will therefore benefit from strategies that monitor and mitigate exposure to incubation temperatures that lead to sublethal effects.
Multi-protein chimeric antigens, a novel combined approach for efficiently targeting and blocking the blood stage ofPlasmodium falciparum
Authors: Deshmukh Bhagyashree , Khatri Dhruv , Kochar Sanjay Kumar , Athale Chaitanya , Karmodiya Krishanpal 
Published: November 2023

AbstractPlasmodium falciparum-induced malaria remains a fatal disease affecting millions of people worldwide. Mainly, the blood stage of malaria is highly pathogenic and symptomatic, rapidly damaging the host organs and occasionally leading to death. Currently, no vaccines are approved for use against the blood stage of malaria. Canonical vaccines in the past have selected the most immunodominant or essential protein to block the growth of the parasite. This strategy works efficiently for low-complexity organisms such as viruses and a few bacteria but has not shown promising results for a malaria vaccine.Plasmodiumhas a complex life cycle and vaccine candidates especially during blood stage are ineffective due to multiple gene families showing redundancy, immune evasion, and insufficient antibody titer. Herein, we demonstrate a novel strategy of combining multiple antigens from the blood stage ofPlasmodium falciparumusing only the most immunodominant peptide sequences as a way of tackling polymorphism and redundancy. We created three chimeric antigens targeting eight PfEMP1 proteins (chimeric varB) and eight merozoite surface proteins (chimeric MSP and InvP) by selecting and stitching B-cell epitopes. Our chimeric constructs show naturally circulating antibodies against individual peptides using epitope-mapping microarray as well as entire proteins in malaria-infected patients. We demonstrate that anti-varB antibodies are neutralizing in nature and significantly reduce the cytoadhesion on an organ-on-chip system with a microfluidic device mimicking physiological conditions. We have applied a Deep Learning based method to quantify the number of adhered RBCs under fluidic conditions that is used to study cytoadhesion. Furthermore, the anti-MSP and InvP antibodies show complete growth inhibition in a single cycle at a combined concentration of 0.13 mg/ml. Overall, our results show that a combination of antigenic peptides from multiple antigens can function as a next-generation vaccine and effectively block the blood stage by reducing cytoadhesion and inhibiting the parasite growth.
Group-common and individual-specific effects of structure-function coupling in human brain networks with graph neural networks
Authors: Chen Peiyu , Yang Hang , Zheng Xin , Jia Hai , Hao Jiachang , Xu Xiaoyu , Li Chao , He Xiaosong , Chen Runsen , Okubo Tatsuo S. , Cui Zaixu 
Published: November 2023

ABSTRACTThe human cerebral cortex is organized into functionally segregated but synchronized regions bridged by the structural connectivity of white matter pathways. While structure-function coupling has been implicated in cognitive development and neuropsychiatric disorders, it remains unclear to what extent the structure-function coupling reflects a group-common characteristic or varies across individuals, at both the global and regional brain levels. By leveraging two independent, high-quality datasets, we found that the graph neural network accurately predicted unseen individuals’ functional connectivity from structural connectivity, reflecting a strong structure-function coupling. This coupling was primarily driven by network topology and was substantially stronger than that of the correlation approaches. Moreover, we observed that structure-function coupling was dominated by group-common effects, with subtle yet significant individual-specific effects. The regional group and individual effects of coupling were hierarchically organized across the cortex along a sensorimotor-association axis, with lower group and higher individual effects in association cortices. These findings emphasize the importance of considering both group and individual effects in understanding cortical structure-function coupling, suggesting insights into interpreting individual differences of the coupling and informing connectivity-guided therapeutics.
Sec7 regulatory domains scaffold autoinhibited and active conformations
Authors: Brownfield Bryce A. , Richardson Brian C. , Halaby Steve L. , Fromme J. Christopher 
Published: November 2023

AbstractThe late stages of Golgi maturation involve a series of sequential trafficking events in which cargo-laden vesicles are produced and targeted to multiple distinct subcellular destinations. Each of these vesicle biogenesis events requires activation of an Arf GTPase by the Sec7/BIG guanine nucleotide exchange factor (GEF). Sec7 localization and activity is regulated by autoinhibition, positive feedback, and interaction with other GTPases. Although these mechanisms have been characterized biochemically, we lack a clear picture of how GEF localization and activity is modulated by these signals. Here we report the cryoEM structure of full-length Sec7 in its autoinhibited form, revealing the architecture of its multiple regulatory domains. We use functional experiments to determine the basis for autoinhibition and use structural predictions to produce a model for an active conformation of the GEF that is supported empirically. This study therefore elucidates the conformational transition that Sec7 undergoes to become active on the organelle membrane surface.
Modulation of dysbiotic vaginal complications by cervical mucus revealed in linked human vagina and cervix chips
Authors: Gutzeit Ola , Gulati Aakanksha , Izadifar Zohreh , Stejskalova Anna , Rhbiny Hassan , Cotton Justin , Budnik Bogdan , Shahriar Sanjid , Goyal Girija , Junaid Abidemi , Ingber Donald E. 
Published: November 2023

ABSTRACTBackgroundThe cervicovaginal mucus that coats the upper surface of the vaginal epithelium is thought to serve as a selective barrier that helps to clear pathogens, however, its role in modulating the physiology and pathophysiology of the human vagina is poorly understood. Bacterial vaginosis (BV), a common disease of the female reproductive tract that increases susceptibility to sexually transmitted infections, pelvic inflammatory disease, infertility, preterm birth, and both maternal and neonatal infections is characterized by the presence of a wide array of strict and facultative anaerobes, often includingGardnerella vaginalis.ObjectiveTo assess the role of cervical mucus in preventing dysbiosis-associated complications and preserving vaginal health.Study DesignTo better understand the role of cervicovaginal mucus in vaginal health, we used human organ-on-a-chip (Organ Chip) microfluidic culture technology to analyze the effects of cervical mucus produced in a human Cervix Chip when transferred to a human Vagina Chip BV model. Both chips are lined by primary human organ-specific (cervical or vaginal) epithelium interfaced with organ-specific stromal fibroblasts.ResultsOur data show that mucus-containing effluents from Cervix Chips protect Vagina Chips from inflammation and epithelial cell injury caused by co-culture with dysbiotic microbiome containingG. vaginalis. Proteomic analysis of proteins produced by the Vagina Chip following treatment with the Cervix Chip mucus also revealed a collection of differentially abundant proteins that may contribute to the vaginal response to dysbiotic microbiome, which could represent potential diagnostic biomarkers or therapeutic targets for management of BV.ConclusionsThis study highlights the importance of cervical mucus in control of human vaginal physiology and pathophysiology, and demonstrates the potential value of Organ Chip technology for studies focused on health and diseases of the female reproductive tract.
A Simple Strategy for Identifying Conserved Features across Non-independent Omics Studies
Authors: Reed Eric , Sebastiani Paola 
Published: November 2023

AbstractFalse discovery is an ever-present concern in omics research, especially for burgeoning technologies with unvetted specificity of their biomolecular measurements, as such unknowns obscure the ability to characterize biologically informative features from studies performed with any single platform. Accordingly, performing replication studies of the same samples using different omics platforms is a viable strategy for identifying high-confidence molecular associations that are conserved across studies. However, an important caveat of replication studies that include the same samples is that they are inherently non-independent, leading to overestimating conservation if studies are treated otherwise. Strategies for accounting for such inter-study dependencies have been proposed for meta-analysis methods devised to increase statistical power to detect molecular associations in one or more studies. Still, they are not immediately suited for identifying conserved molecular associations across multiple studies. Here, we present a unifying strategy for performing inter-study conservation analysis as an alternative to meta-analysis strategies for aggregating summary statistical results of shared features across complementary studies while accounting for inter-study dependency. This method, which we call “adjusted maximum p-value” (AdjMaxP), is easy to implement with inter-study dependency and conservation estimated directly from the p-values from each study’s molecular feature-level association testing results. Through simulation-based assessment, we demonstrate AdjMaxP’s improved performance for accurately identifying conserved features over a related meta-analysis strategy for non-independent studies. AdjMaxP offers an easily implementable strategy for improving the precision of analyses for biomarker discovery from cross-platform omics study designs, thereby facilitating the adoption of such protocols for robust inference from emerging omics technologies.
Structure guided mutagenesis of Henipavirus Receptor Binding Proteins reveals molecular determinants of receptor usage and antibody binding epitopes
Authors: Oguntuyo KY , Haas GD , Azarm KD , Stevens CS , Brambilla L , Kowdle S , Avanzato VA , Pryce R , Freiberg AN , Bowden TA , Lee B 
Published: November 2023

AbstractNipah virus (NiV) is a highly lethal, zoonotic henipavirus (HNV) that causes respiratory and neurological signs and symptoms in humans. Similar to other paramyxoviruses, HNVs mediate entry into host cells through the concerted actions of two surface glycoproteins: a receptor binding protein (RBP) that mediates attachment and a fusion glycoprotein (F) that triggers fusion in an RBP-dependent manner. NiV uses ephrin-B2 (EFNB2) and ephrin-B3 (EFNB3) as entry receptors. Ghana virus (GhV), a novel HNV identified in a Ghanaian bat, use EFNB2 but not EFNB3. In this study, we employ a structure-informed approach to identify receptor interfacing residues and systematically introduce GhV-RBP residues into a NiV-RBP backbone to uncover the molecular determinants of EFNB3 usage. We reveal two regions that severely impair EFNB3 binding by NiV-RBP and EFNB3-mediated entry by NiV pseudotyped viral particles. Further analyses uncovered two point mutations (NiVN557SGhVandNiVY581TGhV) pivotal for this phenotype. Moreover, we identify NiV interaction with Y120 of EFNB3 as important for usage of this receptor. Beyond these EFNB3-related findings, we reveal two domains that restrict GhV binding of EFNB2, identify the HNV-head as an immunodominant target for polyclonal and monoclonal antibodies, and describe putative epitopes for GhV and NiV-specific monoclonal antibodies. Cumulatively, the work presented here generates useful reagents and tools that shed insight to residues important for NiV usage of EFNB3, reveals regions critical for GhV binding of EFNB2, and describes putative HNV antibody binding epitopes.
Exposure to sounds during sleep impairs hippocampal sharp wave ripples and memory consolidation
Authors: Salgado-Puga Karla , Rothschild Gideon 
Published: November 2023

SummarySleep is critical for the consolidation of recent experiences into long-term memories. As a key underlying neuronal mechanism, hippocampal sharp-wave ripples (SWRs) occurring during sleep define periods of hippocampal reactivation of recent experiences and have been causally linked with memory consolidation. Hippocampal SWR-dependent memory consolidation during sleep is often referred to as occurring during an “offline” state, dedicated to processing internally generated neural activity patterns rather than external stimuli. However, the brain is not fully disconnected from the environment during sleep. In particular, sounds heard during sleep are processed by a highly active auditory system which projects to brain regions in the medial temporal lobe, reflecting an anatomical pathway for sound modulation of hippocampal activity. While neural processing of salient sounds during sleep, such as those of a predator or an offspring, is evolutionarily adaptive, whether ongoing processing of environmental sounds during sleep interferes with SWR-dependent memory consolidation remains unknown. To address this question, we used a closed-loop system to deliver non-waking sound stimuli during or following SWRs in sleeping rats. We found that exposure to sounds during sleep suppressed the ripple power and reduced the rate of SWRs. Furthermore, sounds delivered during SWRs (On-SWR) suppressed ripple power significantly more than sounds delivered 2 seconds after SWRs (Off-SWR). Next, we tested the influence of sound presentation during sleep on memory consolidation. To this end, SWR-triggered sounds were applied during sleep sessions following learning of a conditioned place preference paradigm, in which rats learned a place-reward association. We found that On-SWR sound pairing during post-learning sleep induced a complete abolishment of memory retention 24 h following learning, while leaving memory retention immediately following sleep intact. In contrast, Off-SWR pairing weakened memory 24 h following learning as well as immediately following learning. Notably, On-SWR pairing induced a significantly larger impairment in memory 24 h after learning as compared to Off-SWR pairing. Together, these findings suggest that sounds heard during sleep suppress SWRs and memory consolidation, and that the magnitude of these effects are dependent on sound-SWR timing. These results suggest that exposure to environmental sounds during sleep may pose a risk for memory consolidation processes.
Individual cell fate and population dynamics revealed by a mathematical model linking telomere length and replicative senescence
Authors: Rat Anaïs , Doumic Marie , Teixeira Maria Teresa , Xu Zhou 
Published: November 2023

AbstractProgressive shortening of telomeres ultimately causes replicative senescence and is linked with aging and tumor suppression. Studying the intricate link between telomere shortening and senescence at the molecular level and its population-scale effects over time is challenging with current approaches but crucial for understanding behavior at the organ or tissue level. In this study, we developed a mathematical model for telomere shortening and the onset of replicative senescence using data fromSaccharomyces cerevisiaewithout telomerase. Our model tracks individual cell states, their telomere length dynamics, and lifespan over time, revealing selection forces within a population. We discovered that both cell genealogy and global telomere length distribution are key to determine the population proliferation capacity. We also discovered that cell growth defects unrelated to telomeres also affect subsequent proliferation and may act as confounding variables in replicative senescence assays. Overall, while there is a deterministic limit for the shortest telomere length, the stochastic occurrence of non-terminal arrests drive cells into a totally different regime, which may promote genome instability and senescence escape. Our results offer a comprehensive framework for investigating the implications of telomere length on human diseases.One-sentence SummaryKey determinants of population proliferation capacity in the context of telomere shortening.
Focal adhesion-derived liquid-liquid phase separations regulate mRNA translation
Authors: Kumar Abhishek , Tanaka Keiichiro , Schwartz Martin A 
Published: November 2023

AbstractLiquid-liquid phase separation (LLPS) has emerged as a major organizing principle in cells. Recent work showed that multiple components of integrin-mediated focal adhesions including p130Cas can form LLPS, which govern adhesion dynamics and related cell behaviors. In this study, we found that the focal adhesion protein p130Cas drives formation of structures with the characteristics of LLPS that bud from focal adhesions into the cytoplasm. Condensing concentrated cytoplasm around p130Cas-coated beads allowed their isolation, which were enriched in a subset of focal adhesion proteins, mRNAs and RNA binding proteins, including those implicated in inhibiting mRNA translation. Plating cells on very high concentrations of fibronectin to induce large focal adhesions inhibited message translation which required p130Cas and correlated with droplet formation. Photo-induction of p130Cas condensates using the Cry2 system also reduced translation. These results identify a novel regulatory mechanism in which high adhesion limits message translation via induction of p130Cas-dependent cytoplasmic LLPS. This mechanism may contribute to the quiescent state of very strongly adhesive myofibroblasts and senescent cells.
Homologies and evolution of male tail characters in rhabditid and diplogastrid nematodes
Authors: Kiontke Karin , Kolysh Simone , Ng Rocio , Fitch David H. A. 
Published: November 2023

AbstractA major question in evolutionary biology is how often the same developmental events, mechanisms and genes are reused in the recurrent evolution of similar phenotypes. If this happens frequently, it would suggest that evolution is often constrained by developmental genetic mechanisms. To help address this question, we used adherens junction staining and laser ablation to analyze the development underlying several features of nematode male tails have evolved recurrently. We find that recurrent evolution has sometimes employed similar developmental events (parallel evolution) and sometimes different events (convergent evolution). Specifically, phasmid position changed four times via cell migration and never by switches in cell lineage polarity; different genital papillae are missing in species with less than nine; and tail tip morphogenesis was gained at least twice (once with tail tip cell fusions and once without) and lost at least twice. As in previous analyses, we also find that genital papilla positions have shifted differently in different lineages relative to their conserved positions of origin in the lateral hypodermis. In particular, the v1 papilla homolog in diplogastrids has moved dorsally relative to the other v-papillae and lies posterior to the v2 papilla. The prevalence of recurrently evolved characters (homoplasy) suggests that caution should be exercised when using these characters for phylogenetic inference. On the other hand, because of their recurrent evolution, these characters provide good models for investigating how developmental and genetic systems may bias, constrain or allow phenotypic evolution.
Anodal M1 tDCS enhances online learning of rhythmic timing videogame skill
Authors: Meek Anthony W. , Greenwell Davin , Poston Brach , Riley Zachary A. 
Published: November 2023

AbstractTranscranial direct current stimulation (tDCS) has been shown to modify excitability of the primary motor cortex (M1) and influence online motor learning. However, research on the effects of tDCS on motor learning has focused predominantly on simplified motor tasks. The purpose of the present study was to investigate whether anodal stimulation of M1 over a single session of practice influences online learning of a relatively complex rhythmic timing video game. Fifty-eight healthy young adults were randomized to either a-tDCS or SHAM conditions and performed 2 familiarization blocks, a 20-minute 5 block practice period while receiving their assigned stimulation, and a post-test block with their non-dominant hand. To assess performance, a performance index was calculated that incorporated timing accuracy elements and incorrect key inputs. The results showed that M1 a-tDCS enhanced the learning of the video game based skill more than SHAM stimulation during practice, as well as overall learning at the post-test. These results provide evidence that M1 a-tDCS can enhance acquisition of skills where quality or success of performance depends on optimized timing between component motions of the skill, which could have implications for the application of tDCS in many real-world contexts.