bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multiple behavioural mechanisms shape development in a highly social cichlid fish
Authors: Harmon Isabela P. , McCabe Emily A. , Vergun Madeleine R. , Weinstein Julia , Graves Hannah L. , Bradley Deijah D. , Boldt Clare M. , Lee June , Maurice Jessica M. , Solomon-Lane Tessa K. 
Published: April 2023

ABSTRACTEarly-life social experiences shape adult phenotype, yet the underlying behavioural mechanisms remain poorly understood. We manipulated early-life social experience in the highly social African cichlid fishAstatotilapia burtonito investigate the effects on behaviour and neuroendocrine stress axis function. Juveniles experienced different numbers of early-life social partners in stable pairs (1 partner), stable groups (6 fish; 5 partners), and socialized pairs (a novel fish was exchanged every 5 days; 5 partners). Treatments differed in group size (groups vs. pairs) and stability (stable vs. socialized). We then measured behaviour in multiple contexts and collected water-borne cortisol. We found effects of treatment on behaviour across all assays: open field exploration, social cue investigation, dominant behaviour, and subordinate behaviour. Cortisol did not differ across treatments. Principal components (PC) analysis revealed robust co- variation of behaviour across contexts, including with cortisol, to form behavioural syndromes sensitive to early-life social experience. PC1 (25.1%) differed by numbers of social partners: juveniles with more social partners were more active during the social cue investigation, spent less time in the territory, and were more interactive as dominants. Differences in PC5 (8.5%) were based on stability: socialized pairs were more dominant, spent less time in and around the territory, were more socially investigative, and had lower cortisol than stable groups or pairs. Behaviour observations in the home tanks provided further insights into the behavioural mechanisms underlying these effects. These results contribute to our understanding of how early- life social experiences are accrued and exert strong, lasting effects on adult phenotype.
Modeling synaptic integration of bursty and beta oscillatory inputs in ventromedial motor thalamic neurons in normal and parkinsonian states
Authors: Cavarretta Francesco , Jaeger Dieter 
Published: April 2023

AbstractThe Ventromedial Motor Thalamus (VM) is implicated in multiple motor functions and occupies a central position in the cortico-basal ganglia-thalamocortical loop. It integrates glutamatergic inputs from motor cortex (MC) and motor-related subcortical areas, and it is a major recipient of inhibition from basal ganglia. Previous experiments in vitro showed that dopamine depletion enhances the excitability of thalamocortical cells (TC) in VM due to reduced M-type potassium currents. To understand how these excitability changes impact synaptic integration in vivo, we constructed biophysically detailed VM TC models fit to normal and dopamine-depleted conditions, using the NEURON simulator. These models allowed us to assess the influence of excitability changes with dopamine depletion on the integration of synaptic inputs expected in vivo. We found that VM TCs in the dopamine-depleted state showed increased firing rates with the same synaptic inputs. Synchronous bursting in inhibitory input from the substantia nigra pars reticulata (SNR), as observed in parkinsonian conditions, evoked a post-inhibitory firing rate increase with a longer duration in dopamine-depleted than control conditions, due to different M-type potassium channel densities. With beta oscillations in the inhibitory inputs from SNR and the excitatory inputs from drivers and modulators, we observed spike-phase locking in the activity of the models in normal and dopamine-depleted states, which relayed and amplified the oscillations of the inputs, suggesting that the increased beta oscillations observed in VM of parkinsonian animals are predominantly a consequence of changes in the presynaptic activity rather than changes in intrinsic properties.Significance StatementThe Ventromedial Motor Thalamus is implicated in multiple motor functions. Experiments in vitro showed this area undergoes homeostatic changes following dopamine depletion (parkinsonian state). Here we studied the impact of these changes in vivo, using biophysically detailed modeling. We found that dopamine depletion increased firing rate in the ventromedial thalamocortical neurons and changed their responses to synchronous inhibitory inputs from substantia nigra reticulata. All thalamocortical neuron models relayed and amplified beta oscillations from substantia nigra reticulata and cortical/subcortical inputs, suggesting that increased beta oscillations observed in parkinsonian animals predominantly reflect changes in presynaptic activity.
Stromal netrin-1 coordinates renal arteriogenesis and mural cell differentiation
Authors: Luo Peter M. , Gu Xiaowu , Chaney Christopher , Carroll Thomas , Cleaver Ondine 
Published: April 2023

AbstractThe kidney vasculature has a uniquely complex architecture that is essential to proper renal function. Little is known about the molecular mechanisms that direct where and when blood vessels form during kidney development. We identified a regionally-restricted, stroma-derived signaling molecule, netrin-1 (Ntn1), as a putative regulator of vascular patterning. We generated a stromal progenitor-specific knockout of netrin-1 (Ntn1SPKO) that resulted in smaller postnatal kidneys with altered epithelial development and profound defects in arterial and capillary architecture. We also found significant loss of arterial vascular smooth muscle cell (vSMC) coverage and ectopic smooth muscle cell deposition at the kidney cortex. Transcriptomic analysis ofNtn1SPKOkidneys revealed downregulation of Klf4, which we find expressed in stromal progenitors. Deletion of Klf4 in the stroma largely phenocopies loss of Ntn1, and expression of Klf4 inNtn1SPKOkidneys rescues ectopic vSMC deposition. Vascular defects observed inNtn1SPKOare transient, as both arterial and smooth muscle coverage defects resolve late in development, however ectopic peripheral smooth muscle perdures perinatally. These data suggest a stromal-intrinsic Ntn1-Klf4 axis acting as an essential mediator of stromal crosstalk and vascular progenitor differentiation.
Computational Models Suggest that Human Memory Judgments Exhibit Interference due to the Use of Distributed Representations
Authors: Huffman Derek J. , Guan Ruijia 
Published: April 2023

AbstractEpisodic memory is a core function that allows us to remember the events of our lives. Given that many events in our life contain overlapping elements (e.g., similar people and places), it is critical to understand how well we can remember the specific events of our lives vs. how susceptible we are to interference between similar memories. Several prominent theories converged on the notion that pattern separation in the hippocampus causes it to play a greater role in processes such as recollection, associative memory, and memory for specific details, while distributed representations in the neocortex cause it to play a stronger role in domain-specific memory. We propose that studying memory performance on tasks with targets and similar lures provides a critical testbed for comparing the extent to which human memory is driven by hippocampal pattern separation vs. more distributed representations (e.g., neocortex) vs. a blend thereof. We generated predictions from several computational models and then tested these predictions in a large sample of human participants. We found a linear relationship between memory performance and target-lure pattern similarity within a neural network simulation of area IT, an object-processing region of the brain. We also observed strong effects of test format on performance and consistent relationships between test formats. Altogether, our results were better accounted for by distributed memory models than the pattern-separated representations of the hippocampus; therefore, our results provide important insight into prominent memory theories by suggesting that memory performance is primarily driven by distributed representations (e.g., neocortex).
Discovery of novel multi-functional peptides by using protein language models and graph-based deep learning
Authors: Luo Jiawei , Zhao Kejuan , Chen Junjie , Yang Caihua , Qu Fuchuan , Yan Ke , Zhang Yang , Liu Bin 
Published: April 2023

AbstractFunctional peptides are one kind of short protein fragments that have a wide range of beneficial functions for living organisms. The majority of previous research focused on mono-functional peptides, but a growing number of multi-functional peptides have been discovered. Although enormous experimental efforts endeavor to assay multi-functional peptides, only a small fraction of millions of known peptides have been explored. Effective and precise techniques for identifying multi-functional peptides can facilitate their discovery and mechanistic understanding. In this article, we presented a novel method, called iMFP-LG, for identifying multi-functional peptides based on protein language models (pLMs) and graph attention networks (GATs). Comparison results showed iMFP-LG significantly outperforms state-of-the-art methods on both multifunctional bioactive peptides and multi-functional therapeutic peptides datasets. The interpretability of iMFP-LG was also illustrated by visualizing attention patterns in pLMs and GATs. Regarding to the outstanding performance of iMFP-LG on the identification of multi-functional peptides, we employed iMFP-LG to screen novel candidate peptides with both ACP and AMP functions from millions of known peptides in the UniRef90. As a result, 8 candidate peptides were identified, and 1 candidate that exhibits significant antibacterial and anticancer effect was confirmed through molecular structure alignment and biological experiments. We anticipate iMFP-LG can assist in the discovery of multi-functional peptides and contribute to the advancement of peptide drug design.Availability and implementationThe models and associated code are available at:https://github.com/chen-bioinfo/iMFP-LG.Supplementary informationSupplementary data are available online.
Early-life stress and ovarian hormones alter transcriptional regulation in the nucleus accumbens resulting in sex-specific responses to cocaine
Authors: Rocks Devin , Jaric Ivana , Bellia Fabio , Cham Heining , Greally John M. , Suzuki Masako , Kundakovic Marija 
Published: April 2023

AbstractEarly-life stress and ovarian hormones contribute to increased female vulnerability to cocaine addiction. Here we reveal molecular substrates in the key reward area, the nucleus accumbens, through which these female-specific factors affect immediate and conditioning responses to cocaine in mice. We find shared involvement of X chromosome and estrogen signaling gene regulation in enhanced conditioning responses seen after early-life stress and during the low-estrogenic state in females. During the low-estrogenic state, females respond to acute cocaine exposure by increasing the accessibility of neuronal chromatin enriched for the binding sites of ΔFosB, a transcription factor implicated in chronic cocaine response and addiction. Conversely, high-estrogenic females respond to cocaine by preferential closing of neuronal chromatin, providing a mechanism for limiting cocaine-driven chromatin and synaptic plasticity. We find that physiological estrogen withdrawal, exposure to early-life stress, and absence of the second X chromosome all nullify the protective effect of high-estrogenic state on cocaine conditioning in females. Our findings offer a molecular framework to understand sex-specific neuronal mechanisms underlying cocaine use disorder.
Longitudinal Survey of Astrovirus infection in different bat species in Zimbabwe: Evidence of high genetic Astrovirus diversity
Authors: Vimbiso Chidoti , Hélène De Nys , Malika Abdi , Getrude Mashura , Valérie Pinarello , Ngoni Chiweshe , Gift Matope , Laure Guerrini , Davies Pfukenyi , Julien Cappelle , Ellen Mwandiringana , Dorothée Missé , Elizabeth Gori , Mathieu Bourgarel , Florian Liégeois 
Published: April 2023

AbstractAstroviruses (AstVs) have been discovered in over 80 animal species including diverse bat species and avian species. A study on Astrovirus circulation and diversity in different insectivorous and frugivorous chiropteran species roosting in trees, caves and building basements was carried out at 11 different sites across Zimbabwe. Pooled and individual faecal sampling methods were used for this study, with collection dates ranging from June 2016 to July 2021. In two sites, Magweto and Chirundu, sampling was carried out at monthly intervals from August 2020 to July 2021. Astroviruses and bat mitochondrial genes were amplified using pan-AstVs and CytB /12S RNA PCR systems respectively. Phylogenetic analysis of theRdRpAstrovirus sequences revealed a high genetic diversity of astroviruses. All the bat astroviruses tested in this study clustered with theMamastrovirusgenus. Two distinct groups of amplified sequences were identified. One group was comprised of sequences isolated fromHipposideros, RhinolophusandEidolon helvumspp. clustered with Human Astrovirus strains:HuAstVtypes1-6,HuAstV-MLB1-3 andHuAstV-VA-1. The second group comprising the majority of the sequences clustered with different strains of Bat AstVs. Results from the longitudinal study at Magweto and Chirundu showed an overall AstV prevalence of 13.7% and 10.4% respectively. Peaks of AstV infection at Chirundu coincided with the period when juveniles are 4-6 months old. By combining data from our previous work on Coronaviruses, we also anaylzed co-infection of bats with Coronaviruses and Astroviruses at Magweto and Chirundu sites for which the prevalence of co-infection was 2.6% and 3.5% respectively.
There and back again: when and how the world’s richest snake family (Dipsadidae) dispersed and speciated across the Neotropical region
Authors: Serrano Filipe C. , Pontes-Nogueira Matheus , Sawaya Ricardo J. , Alencar Laura R.V. , Nogueira Cristiano C. , Grazziotin Felipe G. 
Published: April 2023

ABSTRACTAimThe widespread megadiverse Neotropical snake family Dipsadidae occurs in a large range of diverse habitats. Thus it represents an excellent model to study the diversification of Neotropical biota. Herein, by generating a time-calibrated species-level phylogeny, we investigate the origin and historical biogeography of Dipsadidae and test if its two main Neotropical subfamilies, Xenodontinae and Dipsadinae, have different geographical origins.LocationNeotropical region.TaxonDipsadidae (Serpentes).MethodsWe generated a new Bayesian time-calibrated phylogeny including sequences from six genes for 344 species, including 287 species of Dipsadidae. We subsequently estimated ancestral areas of distribution by comparing models in BioGeoBEARS: DEC (subset sympatry, narrow vicariance), DIVALIKE (narrow and wide vicariance), BAYAREALIKE (no vicariance and widespread sympatry), also testing jump dispersal.ResultsThe best models show that Dipsadidae likely originated approximately 50 million years ago (mya) in Asia. Dispersal was a fundamental process in its historical biogeography. The DEC model with jump dispersal indicated that this family underwent a range extension from Asia and posterior vicariance of North and Central America ancestors. Both Xenodontinae and Dipsadinae originated in Central America and dispersed to South America during Middle Eocene, but did so to different regions (cis and trans-Andean South America, respectively). Xenodontinae entered cis-Andean South America around 39 mya and jump dispersed to the West Indies around 33 mya, while Dipsadinae entered trans-Andean South America multiple times 20 – 38 mya.Main conclusionsOur results show that Dipsadidae has an Asian origin and that the two main Neotropical subfamilies originated in Central America, later dispersing to South America in different time periods. The current biogeographical patterns of the family Dipsadidae, the most species-rich snake family in the world, have likely been shaped by complex evolutionary and geological processes such as Eocene land bridges, Andean uplift and the formation of the Panama isthmus.
Temporal Effects of Galactose and Manganese Supplementation on Monoclonal Antibody N-Linked Glycosylation in Fed-Batch and Perfusion Bioreactor Operation
Authors: Gyorgypal Aron , Fratz-Berilla Erica , Kohnhorst Casey , Powers David N. , Chundawat Shishir P. S. 
Published: April 2023

AbstractMonoclonal antibodies (mAbs) represent a majority of biotherapeutics on the market today. These glycoproteins undergo post-translational modifications, such as N-linked glycosylation, that influence the structural & functional characteristics of the antibody. Glycosylation is a heterogenous post-translational modification that may influence therapeutic glycoprotein stability and clinical efficacy, which is why it is often considered a critical quality attribute (CQA) of the mAb product. While much is known about the glycosylation pathways of Chinese Hamster Ovary (CHO) cells and how cell culture chemical modifiers may influence the N-glycosylation profile of the final product, this knowledge is often based on the final cumulative glycan profile at the end of the batch process. Building a temporal understanding of N-glycosylation and how mAb glycoform composition responds to real-time changes in the biomanufacturing process will help build integrated process models that may allow for glycosylation control to produce a more homogenous product. Here, we look at the effect of specific nutrient feed media additives (e.g., galactose, manganese) and feeding times on the N-glycosylation pathway to modulate N-glycosylation of a Herceptin biosimilar mAb (i.e., Trastuzumab). We deploy the N-GLYcanyzer process analytical technology (PAT) to monitor glycoforms in near real-time for bench-scale bioprocesses operated in both fed-batch and perfusion modes to build an understanding of how temporal changes in mAb N-glycosylation are dependent on specific media additives. We find that Trastuzumab terminal galactosylation is sensitive to media feeding times and intracellular nucleotide sugar pools. Temporal analysis reveals an increased desirable production of single and double galactose-occupied glycoforms over time under glucose-starved fed-batch cultures. Comparable galactosylation profiles were also observed between fed-batch (nutrient-limited) and perfusion (non-nutrient-limited) bioprocess conditions. In summary, our results demonstrate the utility of real-time monitoring of mAb glycoforms and feeding critical cell culture nutrients under fed-batch and perfusion bioprocessing conditions to produce higher-quality biologics.
Sterile Soil as Prebiotics Mitigate Intergenerational Loss of Gut Microbial Diversity and Anxiety-Like Behavior Induced by Antibiotics in mice
Authors: Li Na , Xiao Xiaoao , Zhang Honglin , Bai Zhimao , Li Mengjie , Sun Jia , Dong Yangyang , Zhu Wenyong , Fei Zhongjie , Sun Xiao , Xiao Pengfeng , Gao Yuanqing , Zhou Dongrui 
Published: April 2023

SummaryThe decline in gut microbial diversity of modern human is closely associated with the rising prevalence of various diseases. It is imperative to investigate the underlying causes of gut microbial loss and the rescue measures. Although the impact of non-perinatal antibiotic use on gut microbiota has been recognized, its intergenerational effects remain unexplored. Our previous research has highlighted soil in the farm environment as a key prebiotic for gut microbiome health by restoring gut microbial diversity and balance. In this study, we investigated the intergenerational consequences of antibiotic exposure and the therapeutic potential of soil prebiotics. We treated mice with vancomycin and streptomycin for 2 weeks continuously, followed by 4-8 weeks of withdrawal period before breeding. The process was repeated across 3 generations. Half of the mice in each generation received an oral soil prebiotic intervention. We assessed gut microbial diversity, anxiety behavior, microglia reactivity, and gut barrier integrity across generations. The antibiotics exposure led to a decrease in gut microbial diversity over generations, along with aggravated anxiety behavior, microglia abnormalityies, and altered intestinal tight junction protein expression. Notably, the third generation of male mice exhibited impaired reproductive capacity. Oral sterile soil intervention restored gut microbial diversity in adult mice across generations, concomitantly rescuing abnormalities in behavior, microglia activity, and intestinal barrier integrity. In conclusion, this study simulated an important process of the progressive loss gut microbiota diversity in modern human and demonstrated the potential of sterile soil as a prebiotic to reverse this process. The study provides a theoretical and experimental basis for the research and therapeutic interventions targeting multiple modern chronic diseases related to intestinal microorganisms.
Fever-like temperature bursts promote competence development via an HtrA-dependent pathway inStreptococcus pneumoniae
Authors: Maziero Mickaël , Lane David , Polard Patrice , Bergé Mathieu 
Published: April 2023

AbstractStreptococcus pneumoniae(the pneumococcus) is well known for its ability to develop competence for natural DNA transformation. Competence development is regulated by an autocatalytic loop driven by variations in the basal level of transcription of thecomCDEandcomABoperons. These genes are part of the early gene regulon that controls expression of the late competence genes known to encode the apparatus of transformation. Several stressful conditions are known to promote competence development, although the induction pathways are remain poorly understood so far. To date there have been no reports of the response of the pneumococcal competence regulon to changes in the physical conditions of the environment, oxidative potential and temperature. Here we demonstrate that transient temperature elevation induces an immediate increase in the basal expression level of thecomCDEoperon and early genes that, in turn, stimulates its full induction, including that of the late competence regulon. This thermal regulation depends on the HtrA chaperone/protease and its proteolytic activity. We find that certain other competence induction stimuli are not conveyed by the HtrA-dependent pathway. This finding strongly supports that competence can be induced by any of several independent pathways and thus reinforces the view that competence is a general stress response system in the pneumococcus.Authors’ summaryStreptococcus pneumoniaeis a commensal bacterium and an opportunistic pathogen of humans. Certain environmental stimuli, such as a variety of antibiotics targeting distinct cellular functions, trigger the induction of the distinct physiological state of competence, in which cells can, among other things, import and integrate external DNA. Competence is thus considered a general stress response in this highly adaptable species. To understand the role of competence in pneumococcal interaction with its host and in pathogenicity, we attempted to decipher the pathways that enable appropriate reactions to environmental stress, and have focused here on induction of competence by elevation of temperature to levels similar to that of a host in fever. We found that elevated temperature raises the basal expression level of the competence control operon, and thus lowers the threshold of transition to full competence induction. By genetic characterisation of the thermal induction pathway of competence, we demonstrated that the chaperone/protease HtrA is essential to relaying of the thermal signal but is not involved in transmitting other stimuli such as those arising from the presence of certain antibiotics. Our work supports the view that competence can be induced through various pathways in response to distinct aggressions, but also by fever-like bursts of temperature that the pneumococcus could face in its natural habitat.