bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Homology Guide for Pacific Salmon Genus Oncorhynchus resolves patterns of Duplicate Retention, Rediploidization and Local Adaptation Following the Salmonid Specific Whole Genome Duplication Event
Authors: Dimos Bradford , Phelps Michael 
Published: October 2022

AbstractSalmonid fishes have emerged as a tractable model to study whole genome duplications (WGD) as this group has undergone four rounds of WGD, with a significant proportion of the genome yet to rediploidize. The fact that much of modern salmonid genomes retain duplicates from the most recent WGD while other regions have rediploidized creates complications for genetic studies by obscuring homology relationships and the necessity of filtering duplicate regions from many analyses. The difficulty this creates is particularly prominent in Pacific salmonids genus Oncorhynchus who are the focus of intense genetics-based conservation and management efforts owing to the important ecological and cultural role these fish play. To address this gap, we generated a homology guide for six species of Oncorhynchus with available genomes and used this guide to describe patterns of duplicate retention and rediploidization. Overall, we find that retained duplicates comprise over half of modern gene repertoires and that retained duplicate genes are enriched for genes involved in nuclear stability, while rediploidized genes which represent a smaller proportion of genes are heavily enriched in dosage sensitive processes such as mitochondria. Additionally, by reanalyzing published expression data from locally adapted strains of O. mykiss we demonstrate that retained duplicates are more likely to be associated with adaptive divergence than rediploidized genes, highlighting the potential of WGDs to promote adaptation. Finally, we demonstrate the utility of our homology guide by investigating the evolutionary relationship among genes highlighted as playing a role in salmonid life history traits or gene editing targets.
A bacterial microbiome is dispensable for the induction of CD8 T cell exhaustion
Authors: Kuhlmann Miriam , Kolland Daphne Del Carmen , Almeida Gustavo Pereira de , Hoffmann Christian , von Hoesslin Madlaina , Berner Jacqueline , Wurmser Christine , Ohnmacht Caspar , Zehn Dietmar 
Published: October 2022

ABSTRACTProlonged antigen exposure in chronic viral infections reduces the effector capacity of cytotoxic T cells - a phenomenon known as T cell exhaustion. Development of T cell exhaustion is driven by high viral titers, strong TCR stimulation, and high antigen concentrations associated with strong inflammatory signals. A largely unexplored factor has been the influence of the microbiome in these processes. Here, we report that T cell exhaustion progresses independently of the presence or absence of a microbiome in chronic lymphocytic choriomeningitis virus (LCMV) infections. Virus-specific CD8 T cells in germ-free mice showed high expression of the inhibitory receptor PD-1 and decreased cytokine production. Moreover, their global gene expression patterns, as determined by single-cell sequencing, were similar to those of cells in specific pathogen-free mice. In line with this, we observed similar pathogen loads with and without a microbiome. Thus, our study demonstrates that the microbiome is dispensable for the induction of T cell exhaustion and for the limited virus control seen in chronic LCMV infections.
KMT2D Regulates thymic Egress by Modulating Maturation and integrin Expression
Authors: Potter Sarah J , Zhang Li , Kotliar Michael , Wu Yuehong , Schafer Caitlin , Stefan Kurtis , Boukas Leandros , Qu’d Dima , Bodamer Olaf , Simpson Brittany N , Barski Artem , Lindsley Andrew W , Bjornsson Hans T 
Published: October 2022

AbstractObjectiveThere is a clinical need to understand how dysregulated thymocyte development, caused by pathogenic variants in the gene encoding the histone-modifying enzyme, lysine methyltransferase 2D (KMT2D), contributes to immune dysfunction, including immune deficiency, autoimmunity, and lymphoproliferative sequela, and immune-driven mortality in individuals with Kabuki syndrome type 1 (KS1).MethodsWe studied peripheral T cells and thymocytes in both individuals with KS1 and murine constitutive and conditional targeted Kmt2d in T cells and hematopoietic lineages. KMT2D target genes, identified by RNA-sequencing of murine Kmt2d-knockout single-positive thymocytes, were validated with H3K4me3 ChIP-PCR and flow cytometry.ResultsRecent thymic emigrant (RTE) and naïve T cells were reduced, and memory and double-negative (DN)-T cells were expanded in human KS1 and murine models. Kmt2d loss led to Mature 1 CD8+-single positive (SP) thymocyte accumulation and a decrease in SP thymocyte egress licensing expression (normally associated with the Mature 2 phenotype). Splenomegaly is associated with hematopoietic-driven Kmt2d loss and brings to light potential overlapping phenotypes with lymphoproliferative syndromes. Finally, we identified a KMT2D-regulated cluster of integrins which likely mediates aspects of the T cell egression.ConclusionsSingle-positive thymocyte populations deficient in Kmt2d display less integrin, less maturation, and less egress licensing gene expression; thereby, altering the downstream peripheral T cell composition that contribute to the observed KS1-associated immune deficiency. T cell intrinsic Kmt2d loss increases the percentage of peripheral DNT cells potentially through dysregulated apoptotic signaling, while hematopoietic-driven Kmt2d loss predisposes to splenomegaly; therefore, loss of Kmt2d recapitulates several distinct features of lymphoproliferative syndromes.
Early development of electrophysiological activity: contribution of periodic and aperiodic components of the EEG signal
Authors: Rico-Picó Josué , Moyano Sebastián , Conejero Ángela , Hoyo Ángela , Ballesteros-Duperón M. Ángeles , Rueda M. Rosario 
Published: October 2022

AbstractBrain function rapidly changes in the first two years of life. In the last decades, resting-state EEG has been widely used to explore those changes. Previous studies have focused on the relative power of the signal in canonical frequency bands (i.e., theta, alpha, beta, gamma). However, EEG power is a mixture of a 1/f-like background power (aperiodic) in combination with narrow peaks that appear over that curve (periodic activity; e.g., alpha peak). Therefore, the relative power may capture both, aperiodic and periodic brain activity, misleading actual periodic changes in infancy. For this reason, we explored the early developmental trajectory of the relative power in the canonical frequency bands from infancy to toddlerhood and compared it to changes in periodic activity in a longitudinal study with three waves of data collection at ages 6, 9, and 16 to 18 months. Finally, we analyzed whether the periodic activity and/or aperiodic components of the EEG contributed to explaining age changes in relative power. We found that relative power and periodic activity trajectories differed in this period in all the frequency bands but alpha, and we replicated an increment of alpha peak frequency. We found that age changes in aperiodic parameters (exponent and offset) depend on the frequency range. More importantly, only alpha relative power was directly related to periodic activity but other frequency bands were predicted also by aperiodic components. This suggests that relative power is capturing the developmental changes of the aperiodic brain activity and, therefore, more fine-grained measures are needed.
A possible origin of the inverted vertebrate retina revealed by physical modeling
Authors: Oomens Jan M.M. 
Published: October 2022

AbstractThere is no established explanation for the evolution of the inverted retina in the vertebrate camera-type eye. This report shows that the inverted retina may have evolved in the light-sensitive organ of the predecessor of the vertebrates. A patch of light-sensitive epithelium with light-facing photoreceptors developed through evagination into a transparent spherical organ covered in photoreceptors. Photons can activate a photoreceptor either directly or indirectly through the transparent interior of the organ. Models for photoreceptor distribution and spatial resolution show how the inverted retina may have evolved with minimal morphological changes, assuming that natural selection driven optimization of the maximum detectable spatial resolution played a major role.
Distorted neural signal dynamics create hypersensitivity to background noise after hearing loss
Authors: Sabesan Shievanie , Fragner Andreas , Lesica Nicholas A. 
Published: October 2022

AbstractListeners with hearing loss often struggle to understand speech in noise, even with a hearing aid. To better understand the auditory processing deficits that underlie this problem, we made large-scale brain recordings from gerbils, a common animal model for human hearing, while presenting a large database of speech and noise sounds. We first used manifold learning to identify the neural subspace in which speech is encoded and found that it is low-dimensional and that the dynamics within it are profoundly distorted by hearing loss. We then trained a deep neural network (DNN) to replicate the neural coding of speech with and without hearing loss and analyzed the underlying network dynamics. We found that hearing loss primarily impacts spectral processing, creating nonlinear distortions in cross-frequency interactions that result in a hypersensitivity to background noise that persists even after amplification with a hearing aid. Our results identify a new focus for efforts to design improved hearing aids and demonstrate the power of DNNs as a tool for the study of central brain structures.
Host transcriptome and microbiome interactions in Holstein cattle under heat stress condition
Authors: Czech Bartosz , Wang Yachun , Wang Kai , Luo Hanpeng , Hu Lirong , Szyda Joanna 
Published: October 2022

ABSTRACTClimate changes affects animal physiology. In particular, rising ambient temperatures reduce animal vitality due to heat stress and this can be observed at various levels which included genome, transcriptome, and microbiome. In a previous study, microbiota highly associated with changes in cattle physiology were identified under heat stress conditions which included rectal temperature, drooling score, and respiratory score. In the present study, genes differentially expressed between individuals were selected representing different additive genetic effects towards the heat stress response in cattle in their production condition. Moreover, a correlation network analysis was performed to identify interactions between the transcriptome and microbiome for 71 Chinese Holstein cows sequenced for mRNA from blood samples and for 16S rRNA genes from fecal samples. Bioinformatics analysis was performed comprising: i) clustering and classification of 16S rRNA sequence reads, ii) mapping cows’ transcripts to the reference genome and their expression quantification, and iii) statistical analysis of both data types – including differential gene expression analysis and gene set enrichment analysis. A weighted co-expression network analysis was carried out to assess changes in the association between gene expression and microbiota abundance as well as to find hub genes/microbiota responsible for the regulation of gene expression under heat stress. Results showed 1,851 differentially expressed genes were found that were shared by three heat stress phenotypes. These genes were predominantly associated with the cytokine-cytokine receptor interaction pathway. The interaction analysis revealed three modules of genes and microbiota associated with rectal temperature with which two hubs of those modules were bacterial species, demonstrating the importance of the microbiome in the regulation of gene expression during heat stress. Genes and microbiota from the significant modules can be used as biomarkers of heat stress in cattle.
Sexually dimorphic neural encoding of threat discrimination in nucleus accumbens afferents drives suppression of reward behavior
Authors: Muir J , Tse YC , Iyer E , Sorensen J , Eid R , Cvetkovska V , Wassef K , Gostlin S , Spencer NJ , Bagot RC 
Published: October 2022

AbstractLearning to predict threat is essential but equally important yet often overlooked is learning about the absence of threat. Interrogating neural activity in two nucleus accumbens afferents in male and female mice during aversive and neutral cues reveals sex-specific encoding of cue discrimination and cuemediated suppression of reward behavior. Sexual dimorphisms in neural bases of threat discrimination may reflect sex differences in behavioral strategy relevant to differential psychiatric risk.
Dynamic switching between distinct oscillatory rhythms in prefrontal-amygdala circuits for dimorphic defensive behaviors under natural threats
Authors: Han Hio-Been , Shin Hee-Sup , Jeong Yong , Kim Jisoo , Choi Jee Hyun 
Published: October 2022

SummaryThe medial prefrontal cortex (mPFC) and basolateral amygdala (BLA) are involved in the regulation of defensive behavior under threat, but their engagement in flexible behavior shifts remains unclear. Here, we report the oscillatory activities of mPFC-BLA circuit in reaction to a naturalistic threat, created by a predatory robot in mice. Specifically, we found dynamic frequency tuning among two different theta rhythms (∼5 or ∼10 Hz) was accompanied by agile changes of two different defensive behaviors (freeze or flight). By analyzing flight trajectories, we also found that high beta (∼30 Hz) is engaged in the top-down process for goal-directed flights and accompanied by a reduction in fast gamma (60–120 Hz, peak near 70 Hz). The elevated beta nested the fast gamma activity by its phase more strongly. Our results suggest that the mPFC-BLA circuit has a potential role in oscillatory gear shifting allowing flexible information routing for behavior switches.HighlightsWhen threatened, mice take quick defensive behaviors such as freeze or flight.mPFC-BLA theta tunes its frequency at 5 or 10 Hz for freeze or flight, respectively.Low and high theta rhythms in mPFC-BLA emerge in a mutually exclusive way.mPFC-driven beta emerges during goal-directed flights, coordinating fast gamma in BLA.eTOC BlurbHan et al. presents neural dynamics of mPFC-BLA network for freeze-or-flight defensive behaviors under naturalistic threats. Tuning the theta frequency in the mPFC-BLA network is for fast and agile actions under a naturalistic threat, and mPFC-driven beta oscillatory burst is for strategic action.
Rapid ex vivo reverse genetics identifies the essential determinants of prion protein toxicity
Authors: Reimann Regina R. , Puzio Martina , Rosati Antonella , Emmenegger Marc , Schneider Bernard L , Valdés Pamela , Huang Danzhi , Caflisch Amedeo , Aguzzi Adriano 
Published: October 2022

AbstractThe cellular prion protein PrPC mediates the neurotoxicity of prions and other protein aggregates through poorly understood mechanisms. Antibody-derived ligands against the globular domain of PrPC (GDL) can also initiate neurotoxicity by inducing an intramolecular R208-H140 hydrogen bond (“H-latch”) between the α2-α3 and β2-α2 loops of PrPC. Importantly, GDL that suppress the H-latch prolong the life of prion-infected mice, suggesting that GDL toxicity and prion infections exploit convergent pathways. To define the structural underpinnings of these phenomena, we transduced nineteen individual PrPC variants to PrPC-deficient cerebellar organotypic cultured slices using adenovirus-associated viral vectors (AAV). We report that GDL toxicity requires a single N-proximal cationic residue (K27 or R27) within PrPC. Alanine substitution of K27 also prevented the toxicity of PrPC mutants that induce Shmerling syndrome, a neurodegenerative disease that is suppressed by co-expression of wild-type PrPC. K27 may represent an actionable target for compounds aimed at preventing prion-related neurodegeneration.
Whole brain evaluation of cortical micro-connectomes
Authors: Matsuda Kouki , Shirakami Arata , Nakajima Ryota , Akutsu Tatsuya , Shimono Masanori 
Published: October 2022

AbstractThe brain is an organ that functions as a network of many elements connected in a non-uniform manner. Especially, the cortex is evolutionarily newest, and is thought to be primarily responsible for the high intelligence of mammals. In the mature mammalian brain, all cortical regions are expected to have some degree of homology, but have some variations of local circuits to achieve specific functions enrolled by individual regions. However, few cellular-level studies have examined how the networks within different cortical regions differ. This study aimed to find rules for systematic changes of connectivity (microconnectomes) across 16 different cortical region groups. We also observed unknown trends in basic parameters in vitro such as firing rate and layer thickness across brain regions. The results revealed that the frontal group shows unique characteristics such as dense active neurons, thick cortex and strong connections with deeper layers. This suggests the frontal side of the cortex is inherently capable of driving, even in isolation.This may suggest that deep layers of frontal node provide the driving force generating a global pattern of spontaneous synchronous activity, such as the Default Mode Network. This finding may explain why disruption in this region causes a large impact on mental health.
Identifying good practices for detecting inter-regional linear functional connectivity from EEG
Authors: Pellegrini Franziska , Delorme Arnaud , Nikulin Vadim , Haufe Stefan 
Published: October 2022

AbstractAggregating voxel-level statistical dependencies between multivariate time series is an important intermediate step when characterising functional connectivity (FC) between larger brain regions. However, there are numerous ways in which voxel-level data can be aggregated into inter-regional FC, and the advantages of each of these approaches are currently unclear.In this study we generate ground-truth data and compare the performances of various pipelines that estimate directed and undirected linear phase-to-phase FC between regions. We test the ability of several existing and novel FC analysis pipelines to identify the true regions within which connectivity was simulated. We test various inverse modelling algorithms, strategies to aggregate time series within regions, and connectivity metrics. Furthermore, we investigate the influence of the number of interactions, the signal-to-noise ratio, the noise mix, the interaction time delay, and the number of active sources per region on the ability of detecting phase-to-phase FC.Throughout all simulated scenarios, lowest performance is obtained with pipelines involving the absolute value of coherency. Further, the combination of dynamic imaging of coherent sources (DICS) beamforming with directed FC metrics that aggregate information across multiple frequencies leads to unsatisfactory results. Pipeline that show promising results with our simulated pseudo-EEG data involve the following steps: (1) Source projection using the linearly-constrained minimum variance (LCMV) beamformer. (2) Principal component analysis (PCA) using the same fixed number of components within every region. (3) Calculation of the multivariate interaction measure (MIM) for every region pair to assess undirected phase-to-phase FC, or calculation of time-reversed Granger Causality (TRGC) to assess directed phase-to-phase FC. We formulate recommendations based on these results that may increase the validity of future experimental connectivity studies.We further introduce the free ROIconnect plugin for the EEGLAB toolbox that includes the recommended methods and pipelines that are presented here. We show an exemplary application of the best performing pipeline to the analysis EEG data recorded during motor imagery.
Umbilical cord blood-derived cell therapy for perinatal brain injury: A systematic review & meta-analysis of preclinical studies - Part A
Authors: Nguyen Timothy , Purcell Elisha , Smith Madeleine , Penny Tayla , Paton Madison CB , Zhou Lindsay , Jenkin Graham , Miller Suzanne L , McDonald Courtney A , Malhotra Atul 
Published: October 2022

ABSTRACTIntroductionPerinatal brain injury is a major contributor to long-term adverse neurodevelopment. There is mounting preclinical evidence for use of umbilical cord blood (UCB)-derived cell therapy as potential treatment.ObjectivesTo systematically review and analyse effects of UCB-derived cell therapy on brain outcomes in preclinical models of perinatal brain injury.MethodsMEDLINE and Embase databases were searched for relevant studies. Brain injury outcomes were extracted for meta-analysis to calculate standard mean difference (SMD) with 95% confidence interval (CI), using an inverse variance, random effects model. Outcomes were separated based on grey matter (GM) and white matter (WM) regions where applicable. Risk of bias was assessed using SYRCLE, and GRADE was used to summarise certainty of evidence.ResultsFifty-five eligible studies were included (7 large, 48 small animal models). UCB-derived cell therapy significantly improved outcomes across multiple domains, including decreased infarct size (SMD 0.53; 95%CI (0.32, 0.74), P<0.00001), apoptosis (WM, SMD 1.59; 95%CI (0.86, 2.32), P<0.0001), astrogliosis (GM, SMD 0.56; 95%CI (0.12, 1.01), P=0.01), microglial activation (WM, SMD 1.03; 95%CI (0.40, 1.66), P=0.001), neuroinflammation (TNF-α, SMD 0.84; 95%CI (0.44, 1.25), P<0.0001); as well as improved neuron number (SMD 0.86; 95%CI (0.39, 1.33), P=0.0003), oligodendrocyte number (GM, SMD 3.35; 95%CI (1.00, 5.69), P=0.005) and motor function (cylinder test, SMD 0.49; 95%CI (0.23, 0.76), P=0.0003). Risk of bias was determined as serious, and overall certainty of evidence was low.ConclusionsUCB-derived cell therapy is an efficacious treatment in pre-clinical models of perinatal brain injury, however findings are limited by low certainty of evidence.SIGNIFICANCE STATEMENTPerinatal brain injury can lead to significant long-term neurodevelopmental deficits. There are limited treatment options available, and new interventions are urgently required. Through assessment of preclinical studies, this systematic review and meta-analysis shows that umbilical cord blood-derived cell therapy is an efficacious treatment for perinatal brain injury across a wide range of neuropathological and functional domains, albeit with low certainty of evidence. It also identified knowledge gaps, including that future studies should focus on non-hypoxic ischemic models, preterm models, large animal models and should explore the heterogeneity that exists in treatment protocols.