bluuebunny/crossref_metadata_2025_split huggingface dataset:
Microbial community changes correlate with impaired host fitness ofAurelia auritaafter environmental challenge
Authors: Pinnow Nicole , Chibani Cynthia M. , Güllert Simon , Weiland-Bräuer Nancy 
Published: March 2023

AbstractClimate change globally endangers certain marine species, but at the same time, such changes may promote species that can tolerate and adapt to varying environmental conditions. Such acclimatization can be accompanied or possibly even be enabled by a host’s microbiome; however, few studies have so far directly addressed this process. Here we show that acute, individual rises in seawater temperature and salinity to sub-lethal levels diminished host fitness of the benthicAurelia auritapolyp, demonstrated by up to 34 % reduced survival rate, shrinking of the animals, and almost halted asexual reproduction. Changes in the fitness of the polyps to environmental stressors coincided with microbiome changes, mainly within the phyla Proteobacteria and Bacteroidota. The absence of bacteria amplified these effects, pointing to the crucial importance of a balanced microbiota to cope with a changing environment. In a future ocean scenario, mimicked by a combined but milder rise of temperature and salinity, the fitness of polyps was severely less impaired, together with condition-specific changes in the microbiome composition. Our results show that the effects on host fitness correlate with the strength of environmental stress, while salt-conveyed thermotolerance might be involved. Further, a specific, balanced microbiome ofA. auritapolyps is essential for the host’s acclimatization. Microbiomes may provide a means for acclimatization, and microbiome flexibility can be a fundamental strategy for marine animals to adapt to future ocean scenarios and maintain biodiversity and ecosystem functioning.
Transcriptional buffering and 3ʹUTR lengthening are shaped during human neurodevelopment by shifts in mRNA stability and microRNA load
Authors: Mufteev Marat , Rodrigues Deivid C. , Yuki Kyoko E. , Narula Ashrut , Wei Wei , Piekna Alina , Liu Jiajie , Pasceri Peter , Rissland Olivia S. , Wilson Michael D. , Ellis James 
Published: March 2023

AbstractThe contribution of mRNA half-life is commonly overlooked when examining changes in mRNA abundance during development. mRNA levels of some genes are regulated by transcription rate only, but others may be regulated by mRNA half-life only shifts. Furthermore, transcriptional buffering is predicted when changes in transcription rates have compensating shifts in mRNA half-life resulting in no change to steady-state levels. Likewise, transcriptional boosting should result when changes in transcription rate are accompanied by amplifying half-life shifts. During neurodevelopment there is widespread 3ʹUTR lengthening that could be shaped by differential shifts in the stability of existing short or long 3ʹUTR transcript isoforms. We measured transcription rate and mRNA half-life changes during induced human Pluripotent Stem Cell (iPSC)-derived neuronal development using RATE-seq. During transitions to progenitor and neuron stages, transcriptional buffering occurred in up to 50%, and transcriptional boosting in up to 15%, of genes with changed transcription rates. The remaining changes occurred by transcription rate only or mRNA half-life only shifts. Average mRNA half-life decreased two-fold in neurons relative to iPSCs. Short gene isoforms were more destabilized in neurons and thereby increased the average 3ʹUTR length. Small RNA sequencing captured an increase in microRNA copy number per cell during neurodevelopment. We propose that mRNA destabilization and 3ʹUTR lengthening are driven in part by an increase in microRNA load in neurons. Our findings identify mRNA stability mechanisms in human neurodevelopment that regulate gene and isoform level abundance and provide a precedent for similar post-transcriptional regulatory events as other tissues develop.
Subset-specific and temporal control of effector and memory CD4+ T cell survival
Authors: Shanmuganad Sharmila , Ferguson Autumn , Paranjpe Aditi , Cianciolo Eileen Elfers , Katz Jonathan D. , Herold Marco J , Hildeman David A. 
Published: March 2023

AbstractFollowing their proliferative expansion and differentiation into effector cells like Th1, Tfh, and T central memory precursors (Tcmp), most effector CD4+ T cells die, while some survive and become memory cells. Here, we explored how Bcl-2 family members controlled the survival of CD4+ T cells during distinct phases of mouse acute LCMV infection. During expansion, we found that Th1 cells dominated the response, downregulated expression of Bcl-2, and did not require Bcl-2 for survival. Instead, they relied on the anti-apoptotic protein, A1 for survival. Similarly, Th17 cells in an EAE model also depended on A1 for survival. However, after the peak of the response, CD4+ effector T cells required Bcl-2 to counteract Bim to aid their transition into memory. This Bcl-2 dependence persisted in established memory CD4+ T cells. Combined, these data show a temporal switch in Bcl-2 family-mediated survival of CD4+ T cells over the course of an immune response. This knowledge can help improve T cell survival to boost immunity and conversely, target pathogenic T cells.
The emergence of tuning to global shape properties of radial frequency patterns in the ventral visual pathway
Authors: Lawrence Samuel J. D. , Zamboni Elisa , Vernon Richard J. W. , Gouws André D. , Wade Alex R. , Morland Antony B. 
Published: March 2023

AbstractRadial frequency patterns - created by sinusoidal modulations of a circle’s radius - are processed globally when radial frequency is low. These closed shapes therefore offer a useful way to interrogate the human visual system for global processing of curvature. Radial frequency patterns elicit greater responses than those to radial gratings in V4 and more anterior face selective regions of the ventral visual pathway. This is largely consistent with work on non-human primates showing curvature processing emerges in V4, but is evident also higher up the ventral visual stream. Rather than contrasting radial frequency patterns with other stimuli, we presented them at varied frequencies in a regimen that allowed tunings to radial frequency to be derived from 8 human participants (3 female). We found tuning to low radial frequency in lateral occipital areas and to some extent in V4. In a control experiment we added a high frequency ripple to the stimuli disrupting the local contour. Low frequency tuning to these stimuli remained in the ventral visual stream underscoring its role in global processing of shape curvature. We then used representational similarity analysis to show that in lateral occipital areas the neural representation was related to stimulus similarity, when it was computed with a model that captured how stimuli are perceived. We show therefore that global processing of shape curvature emerges in the ventral visual stream as early as V4, but is found more strongly in lateral occipital regions, which exhibit responses and representations that relate well to perception.
“Conformational dynamics of C1r inhibitor proteins from Lyme disease and relapsing fever spirochetes”
Authors: Roy Sourav , Booth Charles E. , Powell-Pierce Alexandra D. , Schulz Anna M. , Skare Jon T. , Garcia Brandon L. 
Published: March 2023

AbstractBorrelial pathogens are vector-borne etiological agents of Lyme disease, relapsing fever, andBorrelia miyamotoidisease. These spirochetes each encode several surface-localized lipoproteins that bind to components of the human complement system. BBK32 is an example of a borrelial lipoprotein that protects the Lyme disease spirochete from complement-mediated attack. The complement inhibitory activity of BBK32 arises from an alpha helical C-terminal domain that interacts directly with the initiating protease of the classical pathway, C1r.Borrelia miyamotoispirochetes encode BBK32 orthologs termed FbpA and FbpB, and these proteins also inhibit C1r, albeit via distinct recognition mechanisms. The C1r-inhibitory activities of a third ortholog termed FbpC, which is found exclusively in relapsing fever spirochetes, remains unknown. Here we report the crystal structure of the C-terminal domain ofB. hermsiiFbpC to a limiting resolution of 1.5 Å. Surface plasmon resonance studies and assays of complement function demonstrate that FbpC retains potent BBK32-like anti-complement activities. Based on the structure of FbpC, we hypothesized that conformational dynamics of the complement inhibitory domains of borrelial C1r inhibitors may differ. To test this, we utilized the crystal structures of the C-terminal domains of BBK32, FbpA, FbpB, and FbpC to carry out 1 µs molecular dynamics simulations, which revealed borrelial C1r inhibitors adopt energetically favored open and closed states defined by two functionally critical regions. This study advances our understanding of how protein dynamics contribute to the function of bacterial immune evasion proteins and reveals a surprising plasticity in the structures of borrelial C1r inhibitors.
Brain-wide neural activity underlying memory-guided movement
Authors: Chen Susu , Liu Yi , Wang Ziyue , Colonell Jennifer , Liu Liu D. , Hou Han , Tien Nai-Wen , Wang Tim , Harris Timothy , Druckmann Shaul , Li Nuo , Svoboda Karel 
Published: March 2023

SummaryBehavior requires neural activity across the brain, but most experiments probe neurons in a single area at a time. Here we used multiple Neuropixels probes to record neural activity simultaneously in brain-wide circuits, in mice performing a memory-guided directional licking task. We targeted brain areas that form multi-regional loops with anterior lateral motor cortex (ALM), a key circuit node mediating the behavior. Neurons encoding sensory stimuli, choice, and actions were distributed across the brain. However, in addition to ALM, coding of choice was concentrated in subcortical areas receiving input from ALM, in an ALM-dependent manner. Choice signals were first detected in ALM and the midbrain, followed by the thalamus, and other brain areas. At the time of movement initiation, choice-selective activity collapsed across the brain, followed by new activity patterns driving specific actions. Our experiments provide the foundation for neural circuit models of decision-making and movement initiation.
Brain state dynamics reflect emotion transitions induced by music
Authors: Sachs Matthew E. , Ochsner Kevin N. , Baldassano Christopher 
Published: March 2023

AbstractOur ability to shift from one emotion to the next allows us to adapt our behaviors to a constantly-changing and often uncertain environment. Although previous studies have identified cortical and subcortical regions involved in affective responding, no studies have asked whether and how these regions track and represent transitionsbetweendifferent emotional states and modulate their responses based on the recent emotional context. To this end, we commissioned new musical pieces designed to systematically move participants through different emotional states during fMRI. Using a combination of data-driven (Hidden Markov Modeling) and hypothesis-driven methods, we show that spatiotemporal patterns of activation along the temporoparietal axis reflect transitions between music-evoked emotions. Furthermore, self-reported emotions and the subsequent neural response patterns were sensitive to the emotional context in which the music was heard. The findings highlight the role of temporal and parietal brain regions in not only processing low-level auditory signals, but in linking changes in these signals with our on-going, contextually-dependent emotional responses.
Early striatal hyperexcitability in anin vitrohuman striatal microcircuit model carrying the Parkinson’sGBA-N370Smutation
Authors: Do Quyen B. , Ng Bryan , Gomez Ricardo Marquez , Beccano-Kelly Dayne , Ibarra-Aizpura Naroa , Caiazza Maria-Claudia , Lang Charmaine , Baleriola Jimena , Bengoa-Vergniory Nora , Wade-Martins Richard 
Published: March 2023

AbstractUnderstanding medium spiny neuron (MSN) physiology is essential to understand motor impairments in Parkinson’s disease (PD) given the architecture of the basal ganglia. Here, we developed a custom three-chamber microfluidic platform and established a cortico-striato-nigral microcircuit recapitulating the striatal presynaptic triadin vitrousing induced pluripotent stem cell (iPSC)-derived neurons. We found that, although cortical glutamatergic projections facilitated MSN synaptic activity, dopaminergic transmission was essential for excitability maturation of MSNsin vitro. Replacement of wild-type iPSC-dopamine neurons (iPSC-DaNs) in the striatal microcircuit with those carrying the PD-relatedGBA-N370Smutation induced early hyperexcitability in iPSC-MSNs through reduction of voltage-gated sodium and potassium intrinsic currents. Such deficits were resolved in aged cultures or with antagonism of protein kinase A activity in nigrostriatal iPSC-DaNs. Hence, our results highlight the unique utility of modelling striatal neurons in a modular and highly physiological circuit which is essential to reveal mechanistic insights of the loss of electrical functional integrity in the striata ofGBA1PD patients.
Clinical Antibiotic-Resistance Plasmids Have Small Effects on Biofilm Formation and Population Growth inEscherichia coliin vitro
Authors: Brülisauer Laura , Leon-Sampedro Ricardo , Hall Alex R. 
Published: March 2023

AbstractAntimicrobial resistance (AR) mechanisms encoded on plasmids can affect other phenotypic traits in bacteria, including biofilm formation. These effects may be important contributors to the spread of AR and the evolutionary success of plasmids, but it is not yet clear how common such effects are for clinical plasmids/bacteria, and how they vary among different plasmids and host strains. Here, we used a combinatorial approach to test the effects of clinical AR plasmids on biofilm formation and population growth in clinical and laboratoryEscherichia colistrains. In most of the 25 plasmid-bacterium combinations tested, we observed no significant change in biofilm formation upon plasmid introduction, contrary to the notion that plasmids frequently alter biofilm formation. In a few cases we detected altered biofilm formation, and these effects were specific to particular plasmid-bacterium combinations. By contrast, we found a relatively strong effect of a chromosomal streptomycin-resistance mutation (inrpsL) on biofilm formation. Further supporting weak and host-strain-dependent effects of clinical plasmids on bacterial phenotypes in the combinations we tested, we found growth costs associated with plasmid carriage (measured in the absence of antibiotics) were moderate and varied among bacterial strains. These findings suggest some key clinical resistance plasmids cause only mild phenotypic disruption to their host bacteria, which may contribute to the persistence of plasmids in the absence of antibiotics.
Probabilistic inference of epigenetic age acceleration from cellular dynamics
Authors: Dabrowski Jan. K. , Yang Emma. J. , Crofts Samuel. J. C. , Hillary Robert. F. , Simpson Daniel. J. , Mccartney Daniel. L. , Marioni Riccardo. E. , Latorre-Crespo Eric , Chandra Tamir 
Published: March 2023

AbstractThe emergence of epigenetic predictors was a pivotal moment in geroscience, propelling the measurement and concept of biological ageing into a quantitative era. However, while current epigenetic clocks have shown strong predictive power, they do not reflect the underlying biological mechanisms driving methylation changes with age. Consequently, biological interpretation of their estimates is limited. Furthermore, our findings suggest that clocks trained on chronological age are confounded by non-age-related phenomena.To address these limitations, we developed a probabilistic model that describes methylation transitions at the cellular level. Our approach reveals two measurable components, acceleration and bias, that directly relate to perturbations of the underlying cellular dynamics. Acceleration is the proportional increase in the speed of methylation transitions across CpG sites, whereas bias is the degree of global change in methylation affecting all CpG sites uniformly. Using data from 7,028 participants from the Generation Scotland study, we found the age acceleration parameter to be associated with physiological traits known to impact healthy ageing. Furthermore, a genome-wide association study of age acceleration identified four genomic loci previously linked with ageing.
A Systems Serology Approach to the Investigation of Infection-Induced Antibody Responses and Protection in Trachoma
Authors: Barton Amber , Rosenkrands Ida , Pickering Harry , Faal Nkoyo , Harte Anna , Joof Hassan , Makalo Pateh , Ragonnet Manon , Weinreich Olsen Anja , Bailey Robin L. , Mabey David CW , Follmann Frank , Dietrich Jes , Holland Martin J 
Published: March 2023

AbstractBackgroundOcular infections withChlamydia trachomatisserovars A-C cause the neglected tropical disease trachoma. As infection does not confer complete immunity, repeated infections are common, leading to long term sequelae such as scarring and blindness. Here we apply a systems serology approach to investigate whether systemic antibody features are associated with susceptibility to infection.MethodsSera from children in five trachoma endemic villages in The Gambia were assayed for 23 antibody features: IgG responses towards twoChlamydia trachomatisantigens and three serovars (elementary bodies and major outer membrane protein MOMP, serovars A-C), IgG responses towards five MOMP peptides (serovars A-C), neutralization and antibody-dependent phagocytosis. Participants were considered resistant if they subsequently developed infection only when over 70% of other children in the same compound were infected.ResultsThe antibody features assayed were not associated with resistance to infection (false discovery rate < 0.05). Anti-MOMP SvA IgG and neutralization titer were higher in susceptible individuals (p < 0.05 before multiple testing adjustment). Classification using partial least squares performed only slightly better than chance in distinguishing between susceptible and resistant participants based on systemic antibody profile (specificity 71%, sensitivity 36%).ConclusionsSystemic infection-induced IgG and functional antibody responses do not appear to be protective against subsequent infection. This may be due to confounding factors increasing both past and future exposure toC. trachomatis, or antibody-dependent enhancement. Ocular responses, IgA, avidity or cell-mediated responses may play a greater role in protective immunity than systemic IgG.
Musashi-2 causes cardiac hypertrophy and heart failure by inducing mitochondrial dysfunction through destabilizingCluhandSmyd1mRNA
Authors: Singh Sandhya , Gaur Aakash , Kumari Renu , Prakash Shakti , Kumari Sunaina , Chaudhary Ayushi Devendrasingh , Sharma Rakesh Kumar , Prasun Pankaj , Pant Priyanka , Thum Thomas , Jagavelu Kumaravelu , Bharati Pragya , Hanif Kashif , Chitkara Pragya , Kumar Shailesh , Mitra Kalyan , Gupta Shashi Kumar 
Published: March 2023

AbstractRegulation of RNA stability and translation by RNA-binding proteins (RBPs) is a crucial process altering gene expression. Musashi family of RBPs comprisingMsi1andMsi2are known to control RNA stability and translation. However, despite the presence of MSI2 in the heart, its function remains entirely unknown. Here, we aim to explore the cardiac functions of MSI2. We confirmed the presence of MSI2 in the adult mouse, rat heart, and neonatal rat cardiomyocytes. Furthermore,Msi2was significantly enriched in the heart’s cardiomyocyte fraction. Next, using RNA-seq data and isoform-specific PCR primers, we identified,Msi2isoforms 1, 4, and 5 and two novel putative isoforms labeled asMsi2isoforms 6 and 7 to be expressed in the heart. Overexpression ofMsi2isoforms led to cardiac hypertrophy in cultured cardiomyocytes. Additionally,Msi2was also found to be significantly increased in a pressure-overload model of cardiac hypertrophy. To validate the hypertrophic effects, we selected isoforms 4 and 7 due to their unique alternative splicing patterns. AAV9-mediated overexpression ofMsi2isoforms 4 and 7 in murine hearts led to cardiac hypertrophy, dilation, heart failure, and eventually early death, confirming a pathological function forMsi2. Using global proteomics, gene ontology, transmission electron microscopy, and transmembrane potential measurement assays increased MSI2 was found to cause mitochondrial dysfunction in the heart. Mechanistically, we identifiedCluhandSmyd1as direct downstream targets ofMsi2. Overexpression ofCluhorSmyd1inhibitedMsi2-induced hypertrophy and mitochondrial dysfunction in cardiomyocytes. Collectively, we show thatMsi2induces hypertrophy, mitochondrial dysfunction, and heart failure.
Spatiotemporal regulation ofde novoand salvage purine synthesis during brain development
Authors: Mizukoshi Tomoya , Yamada Seiya , Sakakibara Shin-ichi 
Published: March 2023

AbstractThe levels of purines, essential molecules to sustain eukaryotic cell homeostasis, are regulated by the coordination of thede novoand salvage synthesis pathways. In the embryonic central nervous system (CNS), thede novopathway is considered crucial to meet the requirements for the active proliferation of neural stem/progenitor cells (NSPCs). However, how these two pathways are balanced or separately utilized during CNS development remains poorly understood. In this study, we showed a dynamic shift in pathway utilization, with greater reliance on thede novopathway during embryonic stages and on the salvage pathway at postnatal–adult stages. The pharmacological effects of various purine synthesis inhibitorsin vitroand the expression profile of purine synthesis enzymes indicated that NSPCs in the embryonic cerebrum mainly utilize thede novopathway. Simultaneously, NSPCs in the cerebellum require both thede novoand the salvage pathways.In vivoadministration ofde novoinhibitors resulted in severe hypoplasia of the forebrain cortical region, indicating a gradient of purine demand along the anteroposterior axis of the embryonic brain, with cortical areas of the dorsal forebrain having higher purine requirements than ventral or posterior areas such as the striatum and thalamus. This histological defect of the neocortex was accompanied by strong downregulation of the mechanistic target of rapamycin complex 1 (mTORC1)/ribosomal protein S6 kinase (S6K)/S6 signaling cascade, a crucial pathway for cell metabolism, growth, and survival. These findings indicate the importance of the spatiotemporal regulation of both purine pathways for mTORC1 signaling and proper brain development.Significance StatementBrain development requires a balance ofde novoand salvage purine synthetic pathways. However, the utilization of these pathways during brain development remains poorly understood. This study provides evidence that the spatiotemporal regulation of these two purine synthesis pathways is essential for normal brain development. We revealed that inhibition ofde novopurine synthesis results in the downregulation of mammalian/mechanistic target of rapamycin (mTOR) signaling, leading to malformations in specific embryonic brain regions such as the cerebral neocortex. These results suggest a temporal and spatial gradient of purine demand during embryonic brain development. These findings could improve our understanding of neurological diseases caused by defects in purine metabolism.