bluuebunny/crossref_metadata_2025 huggingface dataset:
Structural and functional changes of pyramidal neurons at the site of an implanted microelectrode array in rat primary motor cortex
Authors: Gregory Bronson A. , Thompson Cort H. , Salatino Joseph W. , Railing Mia J. , Zimmerman Ariana F. , Gupta Bhavna , Williams Kathleen , Beatty Joseph A. , Cox Charles L. , Purcell Erin K.
Published: September 2022

Devices capable of recording or stimulating neuronal signals have created new opportunities to understand normal physiology and treat sources of pathology in the brain. However, it is possible that the initial surgical insertion and subsequent tissue response to implanted electrodes may influence the nature of the signals detected or stimulated. In this study, we characterized structural and functional changes in pyramidal neurons surrounding silicon or polyimide-based electrodes implanted in the motor cortex of rats. Devices were captured in 300 μm-thick tissue slices collected at the 1 or 6 week time point post-implantation, and individual neurons were assessed using a combination of whole-cell electrophysiology and 2-photon imaging. We observed disruption of the dendritic arbor of neurons near (<100 μm) the device surface at both time points, as well as a significant reduction in spine densities. These effects were accompanied by a decrease in the frequency of spontaneous excitatory post-synaptic currents (sEPSCs), a loss in sag amplitude, and an increase in spike frequency adaptation at the 6 week time point. Interestingly, we also noted a significant increase in filopodial density in neurons surrounding devices. Results were similar for polyimide and silicon-based electrodes. We hypothesize that the effects observed in this study may contribute to the signal loss and instability that often accompany chronically implanted electrodes.
Improved the Protein Complex Prediction with Protein Language Models
Authors: Chen Bo , Xie Ziwei , Qiu Jiezhong , Ye Zhaofeng , Xu Jinbo , Tang Jie
Published: September 2022

AlphaFold-Multimer has greatly improved protein complex structure prediction, but its accuracy also depends on the quality of the multiple sequence alignment (MSA) formed by the interacting homologs (i.e., interologs) of the complex under prediction. Here we propose a novel method, denoted as ESMPair, that can identify interologs of a complex by making use of protein language models (PLMs). We show that ESMPair can generate better interologs than the default MSA generation method in AlphaFold-Multimer. Our method results in better complex structure prediction than AlphaFold-Multimer by a large margin (+10.7% in terms of the Top-5 best DockQ), especially when the predicted complex structures have low confidence. We further show that by combining several MSA generation methods, we may yield even better complex structure prediction accuracy than Alphafold-Multimer (+22% in terms of the Top-5 best DockQ). We systematically analyze the impact factors of our algorithm and find out the diversity of MSA of interologs significantly affects the prediction accuracy. Moreover, we show that ESMPair performs particularly well on complexes in eucaryotes.
Parthenogenomics: insights on mutation rates and nucleotide diversity in parthenogeneticPanagrolaimusnematodes
Authors: Villegas Laura I. , Ferretti Luca , Wiehe Thomas , Waldvogel Ann-Marie , Schiffer Philipp H.
Published: September 2022

Asexual reproduction is assumed to lead to the accumulation of deleterious mutations, and reduced heterozygosity due to the absence of recombination. Panagrolaimid nematode species display different modes of reproduction. Sexual reproduction with distinct males and females, asexual reproduction through parthenogenesis in the genusPanagrolaimus, and hermaphroditism inPropanagrolaimus. Here, we compared genomic features of free-living nematode populations in populations and species isolated from geographically distant regions to study diversity, and genome-wide differentiation under different modes of reproduction. We firstly estimated genome-wide spontaneous mutation rates in a triploid parthenogeneticPanagrolaimuspopulation, and a diploid hermaphroditicPropanagrolaimusspecies via long-term mutation-accumulation-lines. Secondly, we calculated population genetic parameters including nucleotide diversity, and fixation index (FST) between populations of asexually and sexually reproducing nematodes. Thirdly, we used phylogenetic network methods on sexually and asexually reproducingPanagrolaimuspopulations to understand evolutionary relationships between them. The estimated mutation rate was slightly lower for the asexual population, as expected for taxa with this reproductive mode. Natural polyploid asexual populations revealed higher nucleotide diversity. Despite their common ancestor, a gene network revealed a high level of genetic differentiation among asexual populations. The elevated heterozygosity found in the triploid parthenogens could be explained by the third genome copy. Given their tendentially lower mutation rates it can be hypothesized that this is part of the mechanism to evade Muller’s ratchet. Our findings in parthenogenetic triploid nematode populations seem to challenge common expectations of evolution under asexuality.
Current sequence-based models capture gene expression determinants in promoters but mostly ignore distal enhancers
Authors: Karollus Alexander , Mauermeier Thomas , Gagneur Julien
Published: September 2022

Background

The largest sequence-based models of transcription control to date have been obtained by predicting genome-wide gene regulatory assays across the human genome. This setting is fundamentally correlative, as those models are exposed during training solely to the sequence variation between human genes that arose through evolution, questioning the extent to which those models capture genuine causal signals.

Results

Here we confront predictions of state-of-the-art models of transcription regulation against data from two large-scale observational studies and five deep perturbation assays. The most advanced of these sequence-based models, Enformer, by and large captures causal determinants of human promoters. However, models fail to capture the causal effects of enhancers on expression, notably in medium to long distances and particularly for highly expressed promoters. More generally, the predicted impact of distal elements on gene expression predictions is small and the ability to correctly integrate long-range information is significantly more limited than the receptive fields of the models suggest. This is likely caused by the escalating class imbalance between actual and candidate regulatory elements as distance increases.

Conclusions

Our results suggest that sequence-based models have advanced to the point that in-silico study of promoter regions and promoter variants can provide meaningful insights and we provide practical guidance on how to use them. Moreover, we foresee that it will require significantly more and particularly new kinds of data to train models accurately accounting for distal elements.
Toward Improving Immunotolerance for Stem Cell-Derived Islets
Authors: Zhou Quan , Li Hongfei , Gerace Dario , Nikolskly Igor , Wang Xi , Kenty-Ryu Jennifer , Zhang Jingping , Hinderhofer Matthew , Robinson Elaine , Melton Douglas A.
Published: September 2022

Transplanting human stem cell-derived islets (SC-islets) is a promising therapy for insulin-dependent diabetes. While functional SC-islets have been produced for clinical application, immune rejection by the host remains a challenge. Present attempts, including chronic immunosuppression and/or physical encapsulation, have some disadvantages. Here we explore a strategy to induce an immune-tolerant environment based on the immune privilege observed in the male gonad. Sperm appears after the maturation of the immune system and development of systemic self-tolerance and the testis protects these autoreactive germ cells by the physical structure of blood-testis-barrier (BTB) and active local immunosuppression. Human SC-islets transplanted into the mouse testis can be physically protected by the BTB and we find that the testis secretes cytokines that induce a population of regulatory T cells (Tregs) that express both CD4 and CD8. We identified cytokines secreted by testis and used a cocktail of IL-2, IL-10, and TGF-β for in vitro co-culture and in vivo transplantation demonstrating improved survival of SC-islets and the induction of Tregs.

One Sentence Summary

Inducing local immunotolerance by suppressive cytokines for islet Transplantation.
Evaluating Working Memory Representations during the Attentional Blink: A Comparative Modeling Approach
Authors: Wang Shuyao , Karabay Aytaç , Akyürek Elkan G.
Published: September 2022

The nature of working memory (WM) limitations has long been debated, with several models proposed to elucidate this issue. In this study, we conducted a systematic comparison of seven visual WM models to assess their ability to account for target consolidation during the attentional blink (AB). The AB phenomenon refers to where participants often fail to encode the second of two targets when there is a short time interval of ∼500 msec or less between them, providing an opportunity to evaluate commensurate WM limitations. Despite the growing consensus on the applicability of some WM models, such as the standard mixture model and the variable precision model, to the AB domain, no study has systematically evaluated these models in this context. We addressed this gap by comparing the performance of seven widely adopted visual WM models in four different AB datasets from three separate laboratories. We fitted each model and computed the Akaike Information Criterion (AIC) values at an individual level across different conditions and experiments, based on which we compared the models. We found that most models, excluding the variable precision model, fit well to AB datasets. We nevertheless also observed that experimental properties, such as the choice of stimuli or the spatial arrangement of targets resulted in different model rankings. This systematic evaluation of WM models in the AB context can help AB researchers select the most appropriate models, and thereby enhance the understanding of WM consolidation under time constraints and the mechanisms behind the AB phenomenon.
Functional connectivity across the human subcortical auditory system using an autoregressive matrix-Gaussian copula graphical model approach with partial correlations
Authors: Chandra Noirrit Kiran , Sitek Kevin R. , Chandrasekaran Bharath , Sarkar Abhra
Published: September 2022

Abstract/Summary

The auditory system comprises multiple subcortical brain structures that process and refine incoming acoustic signals along the primary auditory pathway. Due to technical limitations of imaging small structures deep inside the brain, most of our knowledge of the subcortical auditory system is based on research in animal models using invasive methodologies. Advances in ultra-high field functional magnetic resonance imaging (fMRI) acquisition have enabled novel non-invasive investigations of the human auditory subcortex, including fundamental features of auditory representation such as tonotopy and periodotopy. However, functional connectivity across subcortical networks is still underexplored in humans, with ongoing development of related methods. Traditionally, functional connectivity is estimated from fMRI data with full correlation matrices. However, partial correlations reveal the relationship between two regions after removing the effects of all other regions, reflecting more direct connectivity. Partial correlation analysis is particularly promising in the ascending auditory system, where sensory information is passed in an obligatory manner, from nucleus to nucleus up the primary auditory pathway, providing redundant but also increasingly abstract representations of auditory stimuli. While most existing methods for learning conditional dependency structures based on partial correlations assume independently and identically Gaussian distributed data, fMRI data exhibit significant deviations from Gaussianity as well as high temporal autocorrelation. In this paper, we developed an autoregressive matrix-Gaussian copula graphical model (ARMGCGM) approach to estimate the partial correlations and thereby infer the functional connectivity patterns within the auditory system while appropriately accounting for autocorrelations between successive fMRI scans. Our results show strong positive partial correlations between successive structures in the primary auditory pathway on each side (left and right), including between auditory midbrain and thalamus, and between primary and associative auditory cortex. These results are highly stable when splitting the data in halves according to the acquisition schemes and computing partial correlations separately for each half of the data, as well as across cross-validation folds. In contrast, full correlation-based analysis identified a rich network of interconnectivity that was not specific to adjacent nodes along the pathway. Overall, our results demonstrate that unique functional connectivity patterns along the auditory pathway are recoverable using novel connectivity approaches and that our connectivity methods are reliable across multiple acquisitions.
Bet hedging is not sufficient to explain germination patterns of a winter annual plant
Authors: Siegmund Gregor-Fausto , Moeller David A. , Eckhart Vincent M. , Geber Monica A.
Published: September 2022

Bet hedging consists of life history strategies that buffer against environmental variability by trading off immediate and long-term fitness. Delayed germination in annual plants is a classic example of bet hedging, and is often invoked to explain low germination fractions. We examined whether bet hedging explains low and variable germination fractions among 20 populations of the winter annual plantClarkia xantianassp.xantianathat experience substantial variation in reproductive success among years. Leveraging 15 years of demographic monitoring and 3 years of field germination experiments, we assessed the fitness consequences of seed banks and compared optimal germination fractions from a density-independent bet-hedging model to observed germination fractions. We did not find consistent evidence of bet hedging or the expected trade-off between arithmetic and geometric mean fitness, though delayed germination increased long-term fitness in 7 of 20 populations. Optimal germination fractions were 2 to 5 times higher than observed germination fractions, and among-population variation in germination fractions was not correlated with risks across the life cycle. Our comprehensive test suggests that bet hedging is insufficient to explain the observed germination patterns. Understanding variation in germination strategies will likely require integrating bet hedging with complementary forces shaping the evolution of delayed germination.
Topographically driven microclimatic gradients shape patterns of forest structure, diversity, and composition at a forest-grassland transition zone
Authors: McNichol Bailey H. , Wang Ran , Hefner Amanda , Helzer Chris , McMahon Sean M. , Russo Sabrina E.
Published: September 2022

Globally, forests provide important ecosystem services, but anthropogenic change may shift the boundaries of forested biomes, because small-scale environmental changes govern biome transitions. This is especially true in semi-arid forests, where minor topographic and microclimatic changes influence forest functioning and transitions to open biomes such as grasslands. However, we lack quantitative descriptions of topographically driven microclimate variation and how it shapes forest structure, diversity, and composition in these transition zones.

Leveraging a 20.2-ha forest inventory plot (Niobrara plot) at a semi-arid forest-grassland transition zone in the Niobrara River valley (Nebraska, USA), we paired data on abundances and distributions of seedlings, saplings, and adults of woody species with topographic and microclimate data to test the hypothesis that if topographic variation causes variation in microclimate that affects forest function, then forest structure, diversity, and composition should vary significantly with topography and microclimate.

Microclimatic variation within the Niobrara plot strongly corresponded with topography, creating a sharp water availability and exposure gradient from the river floodplain to the forest-grassland transition zone. The magnitude of microclimate variation corresponded to that of regional macroclimate variation. Mean soil moisture was 10.2% lower along the higher-elevation transition zone than in the canyon bottoms, corresponding to variation across approximately 2.5 degrees of longitude. Mean air temperature increased by 2.2 °C from the canyon bottoms to upper canyon, corresponding to variation across approximately 3 degrees of latitude.

Forest structure, diversity, and composition correlated strongly with topographic and microclimatic gradients. More complex forest structure and higher species richness of adults and saplings occurred in moister, less exposed habitats with steeper slopes and lower elevations, whereas seedling stem density and richness were higher in higher-light, moister habitats at lower elevations. Species occupied well-defined topographic niches, promoting high beta diversity along topographic and microclimatic gradients and high species turnover from the floodplain to the transition zone.

Synthesis: Microclimatic and topographic variation drive patterns of structure, diversity, and composition in the forests at this forest-grassland transition zone. As the macroclimate becomes warmer and drier, topographically mediated microclimatic refuges supporting diverse, structurally complex forested ecosystems may shrink in semi-arid regions.
Leishmania major centrinknock-out parasites alter the kynurenine- aryl hydrocarbon receptor signaling to produce a pro-inflammatory response
Authors: Oljuskin Timur , Azodi Nazli , Volpedo Greta , Bhattacharya Parna , Ismail Nevien , Hamano Shinjiro , Matlashewski Greg , Satoskar Abhay R. , Gannavaram Sreenivas , Nakhasi Hira L.
Published: September 2022

Leishmaniasis is a parasitic disease that is prevalent in approximately 88 countries, and yet no licensed human vaccine exists against it. Towards control of leishmaniasis, we have developedLeishmania major centringene deletion mutant strains (LmCen-/-) as a live attenuated vaccine, which induces a strong Th1 response to provide IFN-γ-mediated protection to the host. However, the immune mechanisms of such protection remain to be understood. Metabolomic reprogramming of the host cells followingLeishmania-infection has been shown to play a critical role in pathogenicity and shaping the immune response following infection. Here, we applied untargeted mass spectrometric analysis to study the metabolic changes induced by infection withLmCen-/-and compared those with virulentL. majorparasite infection to identify the immune mechanism of protection. Our data shows that immunization withLmCen-/-parasites, in contrast to virulentL. majorinfection, alters tryptophan metabolism to down-regulate kynurenine-AhR signaling and promote a pro-inflammatory response.
Dimethyl fumarate modulates the Duchenne muscular dystrophy disease program following short-term treatment inmdxmice
Authors: Timpani Cara A. , Kourakis Stephanie , Debruin Danielle A. , Campelj Dean G. , Pompeani Nancy , Dargahi Narges , Bautista Angelo P. , Bagaric Ryan M. , Ritenis Elya J. , Sahakian Lauren , Hafner Patricia , Arthur Peter G. , Terrill Jessica R. , Apostolopoulos Vasso , de Haan Judy B. , Guven Nuri , Fischer Dirk , Rybalka Emma
Published: September 2022

New medicines are urgently required to treat the fatal neuromuscular disease, Duchenne muscular dystrophy (DMD). DMD involves progressive muscle damage and weakness, which are preceded by oxidative stress, inflammation, and mitochondrial dysfunction. Dimethyl fumarate (DMF) is a potent small molecule nuclear erythroid 2-related factor 2 (Nrf2) activator with current clinical utility in the treatment of multiple sclerosis and psoriasis. Pharmaceutical targeting of Nrf2 by DMF has strong translational potential for DMD, given it: (1) promotes antioxidant defence systems; (2) has a potent immuno-modulatory profile; and (3) can be rapidly re-purposed into clinical care strategies for DMD patients. Here, we tested two weeks of daily 100mg/kg DMF versus 5mg/kg standard care prednisone (PRED) treatment during the peak muscle degeneration period in juvenilemdxmice, the gold standard murine DMD model. Both drugs modulated seed genes driving the DMD disease program and improved muscle force production in fast-twitch muscle. However, only DMF showed pro-mitochondrial effects that protected contracting muscles from fatigue, improved histopathology and augmented clinically compatible muscle function tests. In contrast, PRED treatment stunted mouse growth, worsened histopathology and modulated many normally expressed inflammatory and extracellular matrix (ECM) genes consistent with pan immunosuppression. These findings suggest DMF could be a more selective modulator of the DMD disease program with better efficacy and fewer side effects than standard care PRED therapy warranting follow-up studies to progress clinical translation.
Evolutionary conservation of sequence motifs at sites of protein modification
Authors: Li Shuang , Dohlman Henrik G.
Published: September 2022

Gene duplications are common in biology and are likely to be an important source of functional diversification and specialization. The yeast Saccharomyces cerevisiae underwent a whole genome duplication event early in evolution, and a substantial number of duplicated genes have been retained. We identified more than 3,500 instances where only one of two paralogous proteins undergoes post-translational modification despite having retained the same amino acid residue in both. We also developed a web-based search algorithm (CoSMoS.c.) that scores conservation of amino acid sequences based on 1011 wild and domesticated yeast isolates and used it to compare differentially-modified pairs of paralogous proteins. We found that the most common modifications – phosphorylation, ubiquitylation and acylation but not N-glycosylation – occur in regions of high sequence conservation. Such conservation is evident even for ubiquitylation and succinylation, where there is no established ‘consensus site’ for modification. Differences in phosphorylation were not associated with predicted secondary structure or solvent accessibility, but did mirror known differences in kinase-substrate interactions. By integrating data from large scale proteomics and genomics analysis, in a system with such substantial genetic diversity, we obtained a more comprehensive understanding of the functional basis for genetic redundancies that have persisted for 100 million years.
Feature similarity gradients detect alterations in the neonatal cortex associated with preterm birth
Authors: Galdi Paola , Cabez Manuel Blesa , Farrugia Christine , Vaher Kadi , Williams Logan ZJ , Sullivan Gemma , Stoye David Q , Quigley Alan J , Makropoulos Antonios , Thrippleton Michael J , Bastin Mark E , Richardson Hilary , Whalley Heather , Edwards A David , Bajada Claude J , Robinson Emma C , Boardman James P
Published: September 2022

The early life environment programmes cortical architecture and cognition across the life course. A measure of cortical organisation that integrates information from multi-modal MRI and is unbound by arbitrary parcellations has proven elusive, which hampers efforts to uncover the perinatal origins of cortical health. Here, we use the Vogt-Bailey index to provide a fine-grained description of regional homogeneities and sharp variations in cortical microstructure based on feature gradients, and we investigate the impact of being born preterm on cortical development. Preterm infants have a homogeneous microstructure in temporal and occipital lobes, and the medial parietal, cingulate, and frontal cortices, compared with term infants. These observations replicated across two independent datasets and were robust to differences that remain in the data after matching samples and alignment of processing and quality control strategies. We conclude that cortical microstructural architecture is altered in preterm infants in a spatially distributed rather than localised fashion.
An experimental and theoretical approach to understand the interaction between particles and mucosal tissues
Authors: Arzi Roni Sverdlov , Davidovich-Pinhas Maya , Cohen Noy , Sosnik Alejandro
Published: September 2022

Nanonization of poorly water-soluble drugs has shown great potential in improving their oral bioavailability by enhancing the dissolution rate and saturation solubility. Moreover, due to particle size reduction and larger surface area, the number of contact points with the gastrointestinal mucus favors adhesion. Similar phenomena could be anticipated when nano-pollutants come into direct contact with mucosal tissues. However, the fundamental features that govern the interaction of particles with mucus have not been investigated in a systematic and rational way before. In this work, we synthesize mucin hydrogels of different pore sizes with rheological properties that closely mimic the properties of freshly extracted porcine mucin. By using fluorescent pure curcumin particles, we characterize the effect of particle size (hydrodynamic diameter of 200 nm, and 1.2 and 1.3 μm), concentration (18, 35, and 71 μg mL−1), and hydrogel crosslinking density (which is directly related to the stiffness and governs the average pore size) on the diffusion-driven particle penetrationin vitro. Next, we derive a phenomenological model that describes the physics behind the diffusion-derived penetration of particles into the mucin network and considers the contributions of the particle size, the particle concentration, and the crosslinking density of the mucin hydrogel. Finally, we challenge our experimental-theoretical approach by preliminarily assessing the oral pharmacokinetics of an anti-cancer model drug, namely dasatinib, in pristine and nanonized forms and two clinically relevant doses in rats. For of a dose of 10 mg kg−1, drug nanonization leads to a significant ~8- and ~21-fold increase of the drug oral bioavailability and half-life, respectively, with respect to the unprocessed micron-sized drug. When the drug dose of pure drug nanoparticles (which is directly related to the local concentration of the drug in the gastrointestinal tract) was increased to 15 mg mL−1, the oral bioavailability increased though not significantly, suggesting the saturation of the penetration sites in the mucus, as demonstrated by thein vitromodel. Our overall results reveal the potential of this experimental-theoretical approach, shed light on the interaction of particulate matter and mucosal tissues, and pave the way for the development of tools that enable a more rational design of nano-drug delivery systems for mucosal administration and the assessment of risk factors related to the exposure of mucosal tissues to nano-pollutants.
Demographic History Inference and the Polyploid Continuum
Authors: Blischak Paul D. , Sajan Mathews , Barker Michael S. , Gutenkunst Ryan N.
Published: September 2022

Polyploidy is an important generator of evolutionary novelty across diverse groups in the Tree of Life, including many crops. However, the impact of whole-genome duplication (WGD) depends on the mode of formation: doubling within a single lineage (autopolyploidy) versus doubling after hybridization between two different lineages (allopolyploidy). Researchers have historically treated these two scenarios as completely separate cases based on patterns of chromosome pairing, but these cases represent ideals on a continuum of chromosomal interactions among duplicated genomes. Understanding the history of polyploid species thus demands quantitative inferences of demographic history and rates of exchange between subgenomes. To meet this need, we developed diffusion models for genetic variation in polyploids with subgenomes that cannot be bioinformatically separated and with potentially variable inheritance patterns, implementing them in the dadi software. We validated our models using forward SLiM simulations and found that our inference approach is able to accurately infer evolutionary parameters (timing, bottleneck size) involved with the formation of auto- and allotetraploids, as well as exchange rates in segmental allotetraploids. We then applied our models to empirical data for allotetraploid shepherd’s purse (Capsella bursa-pastoris), finding evidence for allelic exchange between the subgenomes. Taken together, our model provides a foundation for demographic modeling in polyploids using diffusion equations, which will help increase our understanding of the impact of demography and selection in polyploid lineages.
WikiGOA: Gene set enrichment analysis based on Wikipedia and the Gene Ontology
Authors: Lubiana Tiago , Dias Thomaz Lüscher , Peixe Débora Guerra , Nakaya Helder Takashi Imoto
Published: September 2022

Gene sets curated to Gene Ontology terms are widely used by the transcriptomics community

Presence in Wikipedia is a common proxy for the relevance of a concept.

In this work, we describe the use of Wikidata to generate a dataset comprising only gene sets with a corresponding Wikipedia page.

We refer to the dataset as “WikiGOA”, standing for “Wikipedia Gene Ontology Annotations”

We use the dataset to analyze gene expression data and show that it provides readily understandable results.

We envision WikiGOA to be useful for exploring complex biological datasets both in academic research and educational contexts.

Note

This report was written in a non-standard, experimental format, where assertions are expressed in bullet points. This was done to clarify statements and assumptions, simplify reading and pave the way for conversion to structured formats (e.g., nanopublications). [1]
Inflammation-mediated Upregulation of VCAM-1 but not KIM-1 during Acute Kidney Injury to Chronic Kidney Disease Transition
Authors: Melchinger Isabel , Guo Kailin , Guo Jiankan , Xu Leyuan
Published: September 2022

Background

Patients with acute kidney injury (AKI) have higher risks of developing chronic kidney disease (CKD). The basis for the AKI-to-CKD transition remains poorly understood, but studies in animal models suggest a linkage between the inflammatory response to injury and subsequent nephron loss and interstitial fibrosis. The proximal tubule is the primary venue of injury and progression of disease during this process.

Methods

Mouse unilateral ischemia/reperfusion injury (U-IRI) model was used to study the kinetics of proximal injury marker expression during AKI-to-CKD transition. Immortalized MPT cells and primary cultured renal cells were used to study factor(s) that induce vascular cell adhesion protein-1 (VCAM-1) expression in proximal tubule cells.

Results

Kidney injury molecule-1 (KIM-1) was rapidly upregulated on day 1 after injury and gradually reduced close to the baseline; whereas VCAM-1 was not upregulated on day 1 but markedly increased afterwards during AKI-to-CKD transition. The proximal tubular VCAM-1 expression is induced by proinflammatory cytokines including TNFα and IL-1β. Blockade of these signaling pathways by using NF-κB inhibitor or by using double null mutant Myd88 and Trif derived PCRC in vitro or decrease of immune cell recruitment using Ccr2 null mouse in vivo significantly suppressed VCAM-1 expression. Human single cell transcriptome analysis identified a distinct cluster of injured proximal tubules that highly expressed VCAM1 but not HAVCR1 (KIM1), and the population of these VCAM1-positive proximal tubule cells was associated with CKD progression and VCAM-1 levels were significantly higher in the patients with Stage 3 CKD as compared to the healthy references.

Conclusions

Proximal tubule cells upregulated KIM-1 and VCAM-1 in an orchestrated fashion after injury. Upregulation of VCAM-1 associated with chronic tubular injury and interstitial fibrosis and may mark the earliest molecular event during AKI-to-CKD transition.
Cardiomyocyte ploidy is dynamic during postnatal development and varies across genetic backgrounds
Authors: Swift Samantha K. , Purdy Alexandra L. , Kolell Mary E. , Flinn Michael A. , Lahue Caitlin , Buddell Tyler , Akins Kaelin A. , Foster Parker , O’Meara Caitlin C. , Rau Christoph D. , Patterson Michaela
Published: September 2022

Somatic polyploidization, an adaptation by which cells increase their DNA content to support cell and organ growth, is observed in many mammalian cell types, including cardiomyocytes. Although polyploidization is beneficial in many contexts, progression to a polyploid state is often accompanied by a loss of proliferative capacity. Recent work suggests that heterogeneity in cardiomyocyte ploidy is highly influenced by genetic diversity. However, the developmental course by which cardiomyocytes reach their final ploidy state has only been investigated in select genetic backgrounds. Here, we assessed cardiomyocyte number, cell cycle activity, and ploidy dynamics across two divergent inbred mouse strains; C57Bl/6J and A/J. Both strains are born and reach adulthood with a comparable number of cardiomyocytes, however the end composition of ploidy classes and developmental progression to reach the final state and number differ substantially. In addition to corroborating previous findings that identified Tnni3k as a mediator of cardiomyocyte ploidy, we also uncover a novel role for Runx1 and Tnni3k in ploidy dynamics and cardiomyocyte cytokinesis. These data provide novel insight into the developmental path to cardiomyocyte ploidy states and challenge the paradigm that polyploidization and hypertrophy are the only mechanisms for growth in the mouse heart after the first week of life.
The functional organization of retinal ganglion cell receptive fields across light levels
Authors: Ruda Kiersten , Rudzite Andra M. , Field Greg D.
Published: September 2022

Two major functions performed by the retina are to establish the parallel processing of visual information and to adapt visual encoding to the trillion-fold range of light intensities encountered in the environment. Previous work has highlighted many specialized cell types and circuits that instantiate parallel processing and light adaptation. However, fully understanding either process requires identifying how light adaptation and parallel processing interact. One possibility is that light adaptation causes uniform or proportional scaling to the receptive fields (RFs) of different retinal ganglion cell (RGC) types, the output neurons of the retina. Alternatively, light adaptation could cause a reorganization of RF structures across RGC types. A third possibility is that RFs across different RGC types are more similar under some conditions (e.g., low light levels) and more divergent under other conditions. To resolve these possibilities, we examined how the spatiotemporal RF structure of six simultaneously measured RGC types in the rat retina change from rod-to cone-mediated light levels. While light adaptation altered the RF properties of all six RGC types, we found that the relative structure across different RGC types was largely preserved across light levels. However, in both the spatial and temporal domains, one of the six RGC types exhibited adaptation distinct from the other types, resulting in a partial reorganization of RF properties across RGC types. These measurements identify how parallel visual processing interacts with light adaptation and highlights the challenges to stably encode visual scenes across light levels.
Improved estimates of abortion rates in tsetse (Glossinaspp)
Authors: Hargrove J. W.
Published: September 2022

Abortion rates were assessed for 170, 846 tsetse (154,228G. pallidipesand 19,618G. m. morsitans) sampled in Zimbabwe in 1988 - 1999. Abortions were diagnosed for flies where the uterus was empty and the largest oocyte awaiting ovulation was <82% of the expected mature length. Of tsetse caught in odour-baited traps, 0.64% (95% ci: 0.59 - 0.69) ofG. pallidipesand 1.00% (0.76-1.29) ofG. m. morsitanswere diagnosed as having suffered a recent abortion. For flies from artificial refuges, abortion rates were higher, 2.03% (1.77 - 2.31) and 2.28% (1.85 - 2.79) for the two species, respectively. Abortion rates decreased with increasing wing fray and contrary to laboratory findings, did not increase in the oldest flies; they were highest in the hottest months and years, and increased with decreasing adult wing length. Percentages of tsetse with empty uteri, regardless of abortion status, were significantly higher than the estimated abortion percentages. For tsetse from traps, 4.01% (95% ci: 3.90 – 4.13) ofG. pallidipesand 2.52% (2.14-2.95) ofG. m. morsitanshad empty uteri; for flies from artificial refuges the percentage were 12.69% (12.07 – 13.34) and 14.90% (13.82 -16.02), respectively.
RECOMBINATION HOTSPOTS IN SOYBEAN [GLYCINE MAX (L.) MERR.]
Authors: McConaughy Samantha , Amundsen Keenan , Song Qijian , Pantalone Vince , Hyten David
Published: September 2022

Recombination allows for the exchange of genetic material between two parents which plant breeders exploit to make new and improved cultivars. This recombination is not distributed evenly across the chromosome. In crops, recombination mostly occurs in euchromatic regions of the genome and even then, recombination is focused into clusters of crossovers termed recombination hotspots. Understanding the distribution of these hotspots along with the sequence motifs associated with them may lead to methods that enable breeders to better exploit recombination in breeding. To map recombination hotspots and identify sequence motifs associated with hotspots in soybean [Glycine max (L.) Merr.], two bi-parental recombinant inbred lines (RILs) populations were genotyped with 50,000 SNP markers using the SoySNP50k Illumina Infinium assay. A total of 451 recombination hotspots were identified in the two populations. Despite being half-sib populations, only 18 hotspots were in common between the two populations. While pericentromeric regions did exhibit extreme suppression of recombination, twenty-seven percent of the detected hotspots were located in the pericentromic regions of the chromosomes. Two genomic motifs associated with hotspots are similar to human, dog, rice, wheat, drosophila, and arabidopsis. These motifs were a CCN repeat motif and a poly-A motif. Genomic regions spanning other hotspots were significantly enriched with the tourist family of mini-inverted-repeat transposable elements (MITEs) that resides in less than 0.34% of the soybean genome. The characterization of recombination hotspots in these two large soybean bi-parental populations demonstrates that hotspots do occur throughout the soybean genome and are enriched for specific motifs but their locations may not be conserved between different populations.
The influence of explicit local dynamics on range expansions driven by long-range dispersal
Authors: Villiger Nathan , Paulose Jayson
Published: September 2022

Range expansions are common in natural populations. They can take such forms as an invasive species spreading into a new habitat or a virus spreading from host to host during a pandemic. When the expanding species is capable of dispersing offspring over long distances, population growth is driven by rare but consequential long-range dispersal events that seed satellite colonies far from the densely occupied core of the population. These satellites accelerate growth by accessing unoccupied territory, and also act as reservoirs for maintaining neutral genetic variation present in the originating population, which would ordinarily be lost to drift. Prior theoretical studies of dispersal-driven expansions have shown that the sequential establishment of satellites causes initial genetic diversity to be either lost or maintained to a level determined by the breadth of the distribution of dispersal distances. If the tail of the distribution falls off faster than a critical threshold, diversity is steadily eroded over time; by contrast, broader distributions with a slower falloff allow some initial diversity to be maintained for arbitrarily long times. However, these studies used lattice-based models and assumed an instantaneous saturation of the local carrying capacity after the arrival of a founder. Real-world populations expand in continuous space with complex local dynamics, which potentially allow multiple pioneers to arrive and establish within the same local region. Here, we evaluate the impact of local dynamics on the population growth and the evolution of neutral diversity using a computational model of range expansions with long-range dispersal in continuous space, with explicit local dynamics that can be controlled by altering the mix of local and long-range dispersal events. We found that many qualitative features of population growth and neutral genetic diversity observed in lattice-based models are preserved under more complex local dynamics, but quantitative aspects such as the rate of population growth, the level of maintained diversity, and the rate of decay of diversity all depend strongly on the local dynamics. Besides identifying situations in which modeling the explicit local population dynamics becomes necessary to understand the population structure of jump-driven range expansions, our results show that local dynamics affects different features of the population in distinct ways, and can be more or less consequential depending on the degree and form of long-range dispersal as well as the scale at which the population structure is measured.
Fragile X Mental Retardation Protein (FMRP) expression in human nociceptor axons of the spinal dorsal horn— Implications for RNA targeting and localized translation
Authors: Mitchell Molly E. , Cook Lauren C. , Shiers Stephanie I. , Tavares-Ferreira Diana , Akopian Armen N , Dussor Gregory , Price Theodore J
Published: September 2022

Fragile X Mental Retardation Protein (FMRP) regulates activity-dependent RNA localization and local translation to modulate synaptic plasticity throughout the CNS. Mutations in theFMR1gene that hinder or ablate FMRP function cause Fragile X Syndrome (FXS), a disorder associated with sensory processing dysfunction. FXS pre-mutations are associated with increased FMRP expression and neurological impairments including sex dimorphic presentations of chronic pain. In mice, FMRP ablation causes dysregulated DRG neuron excitability and synaptic vesicle exocytosis, spinal circuit activity, and decreased translation-dependent nociceptive sensitization. Activity-dependent, local translation is a key mechanism for enhancing primary nociceptor excitability which promotes pain in animals and humans. These works indicate that FMRP likely regulates nociception and pain at the level of the primary nociceptor or spinal cord. Therefore, we sought to better understand FMRP expression in the human dorsal root ganglion (DRG) and spinal cord using immunostaining in organ donor tissues. We find that FMRP is highly expressed in DRG and spinal neuron subsets with substantia gelatinosa exhibiting the most abundant immunoreactivity in spinal synaptic fields. Here, it is expressed in nociceptor axons. FMRP puncta colocalized with Nav1.7 and TRPV1 receptor signals suggesting a pool of axoplasmic FMRP localizes to plasma membrane-associated loci in these branches. Interestingly, FMRP puncta exhibited notable colocalization with calcitonin gene-related peptide (CGRP) immunoreactivity selectively in female spinal cord. Our results support a regulatory role for FMRP in human nociceptor axons of the dorsal horn and implicate it in the sex dimorphic actions of CGRP signaling in nociceptive sensitization and chronic pain.
A large nuclear and mitochondrial sequence dataset for phylogenetic analysis of the hyperdiverse Asterophryinae frogs of the New Guinea region with data on lifestyle, GPS coordinates, elevation, and multispecies communities with accompanying code
Authors: Hill Ethan C. , Jarman Mary J. , Fraser Claire J. , Gao Diana F. , Henry Elizabeth R. , Fisher Allison R. , Iova Bulisa , Allison Allen , Butler Marguerite A.
Published: September 2022

The data provided here is related to the article “Resolving the Deep Phylogeny: Implications for Early Adaptive Radiation, Cryptic, and Present-day Ecological Diversity of Papuan Microhylid Frogs” [1]. The dataset is based on 233 tissue samples of the subfamily Asteroprhyinae, with representatives from all recognized genera, in addition to three outgroup taxa. The sequence dataset contains over 2400 characters per sample for five genes (three nuclear loci: BDNF, NXC-1, and SIA; and two mitochondrial loci: ND4 and CYTB) and is 99% complete. New primers were designed for all loci and accession numbers for the raw sequence data are provided. The sequences are used with geological time calibrations to produce time-calibrated Bayesian inference and Maximum Likelihood phylogenetic reconstructions using BEAST2 and IQTREE. Lifestyle data (arboreal, scansorial, terrestrial, fossorial, semi-aquatic) were collected from the literature and field notes and used to infer ancestral character states for each lineage. Collection location data (GPS and elevation data) were used to verify sites where multiple species or candidate species co-occur. All sequence data, alignments, and associated metadata (voucher specimen number, species identification, type locality status, GPS, elevation, site with species list, and lifestyle) as well as the code to produce all analyses and figures are provided.
Intermittent fasting has a diet-specific impact on the gut microbiota and colonic mucin O-glycosylation of mice
Authors: Gamage Hasinika K.A.H. , Sathili Abdulrahman M. M. , Nishtala Krishnatej , Chong Raymond W.W. , Packer Nicolle H. , Paulsen Ian T.
Published: September 2022

The colonic mucus layer and microbiota adhered to it are vital for mediating host metabolic, immune, and gut health. Yet, how intermittent fasting impacts these microbial communities and O-glycosylation of mucin proteins, the predominant component of the colonic mucus layer, remains largely unexplored. Here, using a C57BL/6J mouse model fed either a high-fat diet or normal chow, we examined the impact of a two-day a week fasting regimen on host physiology, faecal and colonic mucosal microbiota, and mucin O-glycosylation. Our results demonstrated distinct diet-specific impacts of intermittent fasting on host physiology; mice fed the high-fat diet had a lower body weight and improved glucose tolerance upon fasting, whilst there were no significant changes in mice fed the normal chow. This was observed despite the similar feed and energy intake between groups with and without fasting. There were significant changes in the faecal and colonic mucosal microbiota community structure and composition, and mucin O-glycosylation upon fasting in both dietary groups, but the specific nature of these alterations was diet-dependent. Correlation analysis revealed significant associations between fasting-mediated changes in the abundance of specific mucosal bacteria and O-glycan structures. While intermittent fasting is a popular means of extending healthy life expectancy, there is a lack of information on its impacts on the mucosal microbiota and colonic mucus layer, which are key determinants of gut health. Our study addresses this knowledge gap and serves as the first report on how intermittent fasting influences colonic mucin O-glycosylation and the associations between mucosal glycans and bacteria.