bluuebunny/crossref_metadata_2025_split huggingface dataset:
Information is asymmetry: spatial relations were encoded by asymmetric mnemonic manifolds
Authors: Jiang Longsheng , Zhu Yanlin , Liu Jia 
Published: March 2024

AbstractSubstantial evidence suggests that working memory (WM) leverages relational representations to provide flexible support for cognitive functions, a capacity likely derived from the dynamic nature of neural codes in WM. However, how these dynamic codes represent and maintain relations remains unclear. Here, we examined the transformation of neural geometries in the dorsal prefrontal cortex of monkeys performing a visuospatial delayed-match/nonmatch task, where the monkeys were instructed to hold the spatial location of a white square in WM to match it with the spatial location of a subsequent square. We found that the sensory manifold during the square’s presence and the mnemonic manifold after the square’s offset both aligned with the stimulus manifold. However, significant differences emerged between the sensory and mnemonic manifolds, exhibiting little correlation in their neural geometries. Further analysis on the dynamic transformation from the sensory to mnemonic manifold revealed a process of expansion followed by flattening: the asymmetric sensory manifold first expanded into a symmetric neural geometry immediately after the square’s onset offset, which then gradually flattened along dimensions different from those initially expanded, culminating in an asymmetric mnemonic manifold. This dynamic process of reconstruction not only remained its faithfulness to the stimulus geometry but also gained the flexibility to meet task demands. In sum, this transformation from asymmetry to symmetry and back to asymmetry in neural geometry precisely illustrates the dynamics of memory reconstruction, shedding lights on the subjective nature of WM that generates both accurate and illusory representation of the world we lived in.
idh-1neomorphic mutation confers sensitivity to vitamin B12 via increased dependency on one-carbon metabolism inCaenorhabditis elegans
Authors: Ponomarova Olga , Starbard Alyxandra N. , Belfi Alexandra , Anderson Amanda V. , Sundaram Meera V. , Walhout Albertha J.M. 
Published: March 2024

AbstractThe isocitrate dehydrogenase neomorphic mutation (idh-1neo) generates increased levels of cellular D-2-hydroxyglutarate (D-2HG), a proposed oncometabolite. However, the physiological effects of increased D-2HG and whether additional metabolic changes occur in the presence of anidh-1neomutation are not well understood. We created aC. elegansmodel to study the effects of theidh-1neomutation in a whole animal. Comparing the phenotypes exhibited by theidh-1neotoΔdhgd-1(D-2HG dehydrogenase) mutant animals, which also accumulate D-2HG, we identified a specific vitamin B12 diet-dependent vulnerability inidh-1neomutant animals that leads to increased embryonic lethality. Through a genetic screen we found that impairment of the glycine cleavage system, which generates one-carbon donor units, exacerbates this phenotype. Additionally, supplementation with an alternate source of one-carbon donors suppresses the lethal phenotype. Our results indicate that theidh-1neomutation imposes a heightened dependency on the one-carbon pool and provides a further understanding how this oncogenic mutation rewires cellular metabolism.
Spotlight on 10x Visium: a multi-sample protocol comparison of spatial technologies
Authors: Du Mei R. M. , Wang Changqing , Law Charity W. , Amann-Zalcenstein Daniela , Anttila Casey J. A. , Ling Ling , Hickey Peter F. , Sargeant Callum J. , Chen Yunshun , Ioannidis Lisa J. , Rajasekhar Pradeep , Yip Raymond K. H. , Rogers Kelly L. , Hansen Diana S. , Bowden Rory , Ritchie Matthew E. 
Published: March 2024

BackgroundSpatial transcriptomics allows gene expression to be measured within complex tissue contexts. Among the array of spatial capture technologies available is 10x Genomics’ Visium platform, a popular method which enables transcriptomewide profiling of tissue sections. Visium offers a range of sample handling and library construction methods which introduces a need for benchmarking to compare data quality and assess how well the technology can recover expected tissue features and biological signatures.ResultsHere we presentSpatialBench, a unique reference dataset generated from spleen tissue of mice responding to malaria infection spanning several tissue preparation protocols (both fresh frozen and FFPE samples, with and without CytAssist tissue placement). We noted better quality control metrics in reference samples prepared using probe-based capture methods, particularly those processed with CytAssist, validating the improvement in data quality produced with the platform. Our analysis of replicate samples extends to explore spatially variable gene detection, the outcomes of clustering and cell deconvolution using matched single-cell RNA-sequencing data and publicly available reference data to identify cell types and tissue regions expected in the spleen. Multi-sample differential expression analysis recovered known gene signatures related to biological sex or gene knockout.ConclusionsWe framed a comprehensive multi-sample analysis workflow that allowed us to generate consistent results both within and between different subsets of replicate samples, enabling broader comparisons and interpretations to be made at the group-level. OurSpatialBenchdataset, analysis, and workflow can serve as a practical guide for Visium users and may prove valuable in other benchmarking studies.
Global Rearrangement of Degree Centrality Reflects Cognitive Impairment and Fatigue in Multiple Sclerosis
Authors: Hok Pavel , Thai Quang Thong , Rehák Bučková Barbora , Domin Martin , Řasová Kamila , Tintěra Jaroslav , Lotze Martin , Grothe Matthias , Hlinka Jaroslav 
Published: March 2024

AbstractBackground and ObjectivesThe aim of this secondary data analysis was to determine whether multiple sclerosis (MS) is associated with changes in global degree rank order disruption index (kD), a graph theory-based functional connectivity measure representing shift in overall distribution of nodal degree centrality. Additionally, we tested the relationship betweenkDand MS symptoms (cognitive and motor impairment, fatigue, and global disability).MethodsGlobalkDwas computed in a pre-existing cross-sectional fMRI dataset and compared between patients with MS (PwMS) and healthy controls (HCs). Group differentiation was tested against other known biomarkers in MS (regional degree centrality, structural MRI with volumetry, diffusion-weighted imaging, lesion mapping) using receiver operating characteristic and logistic regression analysis. Associations betweenkDand cognitive processing speed (Symbol Digit Modalities Test), fatigue (Fatigue Scale for Motor and Cognitive Functions), gait (Timed Up and Go Test), and disability (Expanded Disability Status Scale [EDSS]) were evaluated using Spearman correlation coefficient and ordinal regression adjusted for structural imaging, age, sex, and disease duration.ResultsAnalysis included 56 PwMS and 58 HCs (35/27 women, median age 45.1/40.5 years). GlobalkDwas lower in PwMS (median −0.30, inter-quartile range [IQR] 0.55) than in HCs (median −0.06, IQR 0.54;p= 0.009, Mann-Whitney U test).kDyielded acceptable differentiation between groups (area under curve 0.64), but did not improve such differentiation on top of structural imaging. BothkDand regional degree in medial prefrontal cortex (MPFC) were correlated with cognitive decline (kD: Spearman’sρ= 0.32,p= 0.019; MPFC:ρ= −0.45,p= 0.001,n= 55), whilekDwas also correlated with fatigue (ρ= −0.34,p= 0.010,n= 56), but not with EDSS (ρ= −0.06, p = 0.674,n= 56) or gait (ρ= −0.18,p= 0.211,n= 52).kDsignificantly explained cognitive impairment (χ2= 4.49,p= 0.034) and fatigue (χ2= 7.18,p= 0.007).DiscussionOur data provide evidence thatkDis a potential biomarker of cognitive decline and fatigue. Further cross-validations are required to assess its generalizability.
Role of non-coding RNA hsa_circ_0001495 in 16HBE cellular inflammation induced by PM2.5and O3combined exposure
Authors: Wang HongJie , Tan Yi , Li CaiXia , Jin WenJia , Yu Ying , Mu Xuan , Peng XiaoWu 
Published: March 2024

AbstractBackgroundPM2.5and O3are the main air pollutants in China, and inflammation of the respiratory system is one of their main toxic effects. Cyclic RNAs are involved in many pathophysiological processes, but their relationship to the combined exposure to PM2.5and O3has not yet been investigated.ObjectiveTo elucidate the biological function played by hsa_circ_0001495 in the induction of 16HBE cellular inflammation by combined exposure to PM2.5and O3.MethodDetection of cell survival after 24h exposure of 16HBE cells to a combination of PM2.5and O3by CCK8. RT-qPCR and ELISA were used to detect inflammatory factors in 16HBE cells after co-exposing to PM2.5and O3. CircRNA was screened using high throughput sequencing and bioinformatics analysis approaches. RNaseR experiments were carried out to verify the circular RNA properties of the circRNAs. Cytoplasmic-nuclear subcellular localisation assays and fish assays were used to verify the distribution of circRNAs in the nucleus versus the cytoplasm of the cell. To validate functions related with circRNA,RT-qPCR and ELISA were employed.ResultCombined exposure to PM2.5and O3resulted in decreased cell viability.Combined exposure to PM2.5and O3resulted in 16HBE inflammation. High throughput sequencing and RT-qPCR results showed that the expression of hsa_circ_0001495 was significantly downregulated in 16HBE exposed to PM2.5and O3in combination. Hsa_circ_0001495 is not easily digested by RNaseR enzymes and has the properties of a circular RNA. Hsa_circ_0001495 is expressed in the cytoplasm as well as in the nucleus, but its distribution is predominantly in the cytoplasm.ConclusionIn 16HBE cells, combined exposure to PM2.5and O3can induce an inflammatory response.hsa_circ_0001495 plays an inhibitory role in the inflammatory response of 16HBE cells that can be induced by combined exposure to PM2.5and O3.
Open-Source Tools to Analyze Temporal and Spatial Properties of Local Field Potentials
Authors: Barrett Geoffrey M. , Vajram Srujan , Shetler Oliver , Aoun Andrew , Hussaini S. Abid 
Published: March 2024

AbstractAnalysis of local field potentials (LFPs) is important for understanding how ensemble neurons function as a network in a specific region of the brain. Despite the availability of tools for analyzing LFP data, there are some missing features such as analysis of high frequency oscillations (HFOs) and spatial properties. In addition, accessibility of most tools is restricted due to closed source code and/or high costs. To overcome these issues, we have developed two freely available tools that make temporal and spatial analysis of LFP data easily accessible. The first tool, hfoGUI (High Frequency Oscillation Graphical User Interface), allows temporal analysis of LFP data and scoring of HFOs such as ripples and fast ripples which are important in understanding memory function and neurological disorders. To complement the temporal analysis tool, a second tool, SSM (Spatial Spectral Mapper), focuses on the spatial analysis of LFP data. The SSM tool maps the spectral power of LFPs as a function of subject’s position in a given environment allowing investigation of spatial properties of LFP signal. Both hfoGUI and SSM are open-source tools that have unique features not offered by any currently available tools, and allow visualization and spatio-temporal analysis of LFP data.
Transcriptomic and epigenomic consequences of heterozygous loss of function mutations inAKAP11, the first large-effect shared risk gene for bipolar disorder and schizophrenia
Authors: Farhangdoost Nargess , Liao Calwing , Liu Yumin , Alda Martin , Dion Patrick A. , Rouleau Guy A. , Khayachi Anouar , Chaumette Boris 
Published: March 2024

AbstractThe gene A-kinase anchoring protein 11 (AKAP11) recently emerged as a shared risk factor between bipolar disorder and schizophrenia, driven by large-effect loss-of-function (LoF) variants. Recent research has uncovered the neurophysiological characteristics and synapse proteomics profile ofAkap11-mutant mouse models. Considering the role of AKAP11 in binding cAMP-dependent protein kinase A (PKA) and mediating phosphorylation of numerous substrates, such as transcription factors and epigenetic regulators, and given that chromatin alterations have been implicated in the brains of patients with bipolar disorder and schizophrenia, it is crucial to uncover the transcriptomic and chromatin dysregulations following the heterozygous knockout ofAKAP11, particularly in human neurons. In this study, we use genome-wide approaches to investigate such aberrations in human induced pluripotent stem cell (iPSC)-derived neurons. We show the impact of heterozygousAKAP11LoF mutations on the gene expression landscape and profile the methylomic and acetylomic modifications. Altogether we highlight the involvement of aberrant activity of intergenic and intronic enhancers, which are enriched in PBX homeobox 2 (PBX2) and Nuclear Factor-1 (NF1) known binding motifs, respectively, in transcription dysregulations of genes functioning as DNA-binding transcription factors, actin and cytoskeleton regulators, and cytokine receptors, as well as genes involved in G-protein-coupled receptors (GPCRs) binding and signaling. A better understanding of the dysregulations resulting from haploinsufficiency inAKAP11improves our knowledge of the biological roots and pathophysiology of BD and SCZ, paving the way for better therapeutic approaches.
Polymorphic positions 349 and 725 of the autoimmunity-protective allotype 10 of ER aminopeptidase 1 are key in determining its unique enzymatic properties
Authors: Georgaki Galateia , Mpakali Anastasia , Trakada Myrto , Papakyriakou Athanasios , Stratikos Efstratios 
Published: March 2024

ABSTRACTER aminopeptidase 1 (ERAP1) is a polymorphic intracellular aminopeptidase with key roles in antigen presentation and adaptive immune responses. ERAP1 allotype 10 is highly protective towards developing some forms of autoimmunity and displays unusual functional properties, including very low activity versus some substrates. To understand the molecular mechanisms that underlie the biology of allotype 10 we studied its enzymatic and biophysical properties focusing on its unique polymorphisms V349M and Q725R. Compared to ancestral allotype 1, allotype 10 is much less effective in trimming small substrates but presents allosteric kinetics that ameliorate activity differences at high substrate concentrations. Furthermore, it is inhibited by a transition-state analogue via a non-competitive mechanism and is much less responsive to an allosteric small-molecule modulator. It also presents opposite enthalpy, entropy and heat capacity of activation compared to allotype 1 and its catalytic rate is highly dependent on viscosity. Polymorphisms V349M and Q725R significantly contribute to the lower enzymatic activity of allotype 10 for small substrates, especially at high substrate concentrations, influence the cooperation between the regulatory and active sites and regulate viscosity dependence, likely by limiting product release. Overall, our results suggest that allotype 10 is not just an inactive variant of ERAP1 but rather carries distinct enzymatic properties that largely stem from changes at positions 349 and 725. These changes affect kinetic and thermodynamic parameters that likely control rate-limiting steps in the catalytic cycle, resulting in an enzyme optimized for sparing small substrates and contributing to the homeostasis of antigenic epitopes in the ER.
Amyloid Beta Oligomers Accelerate ATP-Dependent Phase Separation of miRNA-Bound Ago2 to RNA Processing Bodiesin vitro
Authors: Ray Sritama , Roychowdhury Sumangal , Chakraborty Yogaditya , Banerjee Saikat , Chattopadhyay Krishnananda , Mukherjee Kamalika , Bhattacharyya Suvendra N. 
Published: March 2024

AbstractPhase separation to insoluble membrane-less organelles is a major way of activity regulation of specific proteins in eukaryotic cells. miRNA-repressed mRNAs and Ago proteins are known to be localized to RNA-processing bodies, the subcellular structures which are formed due to assembly of several RNA binding and regulatory proteins in eukaryotic cells. Ago2 is the most important miRNA binding protein that by forming complex with miRNA binds to mRNAs having cognate miRNA binding sites and represses protein synthesis in mammalian cells. Factors which control compartmentalization of Ago2 and miRNA-repressed mRNAs to RNA processing bodies are largely unknown. We have adopted a detergent permeabilized cell-based assay system to follow the phase separation of exogenously added Ago2 to RNA processing bodiesin vitro. The Ago2 phase separation process is ATP dependent and is influenced by osmolarity and salt concentration of the reaction buffer. miRNA binding of Ago2 is essential for its targeting to RNA processing bodies and the compartmentalization process gets retarded by miRNA binding “sponge” protein HuR. This assay system found to be useful in identification of amyloid beta oligomers as miRNA-activity modulators which repress miRNA activity by enhancing Ago2-miRNP targeting to RNA processing bodies.Graphical AbstractmiRNA bound Ago2 gets phase separatedin vitroto RNA processing bodies (PBs) in detergent permeabilized mammalian cells.Phase separation of Ago2 to PBs is controlled by presence of ATP and RNA.Amyloid beta oligomers retard dynamics of Ago2 bodies to inhibit miRNA function and enhance PB targeting of Ago2 miRNPs.microRNA binding protein HuR can rescue Ago2 miRNP from PBs and inverse the effect of amyloid beta oligomers.
The T4bSS ofLegionellafeatures a two-step secretion pathway with an inner membrane intermediate for secretion of transmembrane effectors
Authors: Malmsheimer Silke , Grin Iwan , Bohn Erwin , Franz-Wachtel Mirita , Macek Boris , Sahr Tobias , Smollich Fabian , Chetrit David , Meir Amit , Roy Craig , Buchrieser Carmen , Wagner Samuel 
Published: March 2024

AbstractTo promote intracellular survival and infection,Legionella spp.translocate hundreds of effector proteins into eukaryotic host cells using a type IV b protein secretion system (T4bSS). T4bSS are well known to translocate soluble as well as transmembrane domain-containing effector proteins (TMD-effectors) but the mechanisms of secretion are still poorly understood. Herein we investigated the secretion of hydrophobic TMD-effectors, of which about 80 were previously reported to be encoded byL. pneumophila. A proteomic analysis of fractionated membranes revealed that TMD-effectors are targeted to and inserted into the bacterial inner membranes ofL. pneumophilaindependent of the presence of a functional T4bSS. While the T4bSS chaperones IcmS and IcmW were critical for secretion of all tested TMD-effectors, they did not influence inner membrane targeting of these proteins. As for soluble effector proteins, translocation of TMD-effectors into host cells depended on a C-terminal secretion signal and this signal needed to be presented towards the cytoplasmic side of the inner membrane. A different secretion behavior of TMD- and soluble effectors and the need for small periplasmic loops within TMD-effectors provided strong evidence that TMD-effectors are secreted in a two-step secretion process: Initially, an inner membrane intermediate is formed, that is extracted towards the cytoplasmic side, possibly by the help of the type IV coupling protein complex and subsequently secreted into eukaryotic host cells by the T4bSS core complex. Overall, our study highlights the amazing versatility of T4bSS to secrete soluble and TMD-effectors from different subcellular locations of the bacterial cell.
Neurogenomic diversity enhances collective antipredator performance inDrosophila
Authors: Sato Daiki X. , Takahashi Yuma 
Published: March 2024

AbstractCollective behavior is a unique social behavior that plays crucial roles in detecting and avoiding predators. Despite a long history of research on the ecological significance, its neural and genetic underpinnings remain elusive. Here we focus on the mesmerizing nature that visual cues from surrounding conspecifics alleviate the fear response to threatening stimuli inDrosophila melanogaster. A large-scale behavioral experiment and genome-wide association analysis utilizing 104 strains with known genomes uncovered the genetic foundation of the emergent behavioral properties of flies. We found genes involved in visual neuron development associated with visual response to conspecifics, and the functional assay confirmed the regulatory significance of lamina neurons. Furthermore, behavioral synchronization combined with interindividual heterogeneity in freezing drove nonadditive, synergistic changes in group performance for predatory avoidance. Our novel approach termed genome-wide higher-level association study (GHAS) identified loci whose within-group genetic diversity potentially contributes to such an emergent effect. Population genetic analysis revealed that selective pressure may favor increased responsiveness to conspecifics, indicating that by-productive genomic diversity within the group leads to a collective phenomenon. This work opens up a new avenue to understand the genomics underpinning the group-level phenotypes and offers an evolutionary perspective on the mechanism of collective behavior.
Distributed encoding of hippocampal information in mossy cells
Authors: Ouchi Ayako , Toyoizumi Taro , Ikegaya Yuji 
Published: March 2024

AbstractIn neural information processing, the nervous system transmits neuronal activity across layers of neural circuits, occasionally passing through small layers composed only of sparse neurons. Hippocampal hilar mossy cells (MCs) constitute such a typical bottleneck layer.In vivo/vitropatch-clamp recordings revealed that MCs were reliably depolarized in response to sharp-wave ripples (SWRs), synchronous neuronal events transmitted from the CA3 region to the dentate gyrus via the MC layer. Machine-learning algorithms predicted the waveforms of SWRs in the CA3 region, based on the MC depolarization waveforms, suggesting that CA3 neural information is indeed transmitted to the MC layer. However, the prediction accuracy varied;i.e., a particular MC showed a more robust association with a particular SWR cluster, and the SWR cluster associated with one MC rarely overlapped with the SWR clusters associated with other MCs. Thus, CA3 network activity is distributed across MC ensembles with pseudo-orthogonal neural representations, allowing the small MC layer to effectively compress hippocampal information.