bluuebunny/crossref_metadata_2025_split huggingface dataset:
Foundation Models Meet Imbalanced Single-Cell Data When Learning Cell Type Annotations
Authors: Alsabbagh Abdel Rahman , de Infante Alberto Maillo Ruiz , Gomez-Cabrero David , Kiani Narsis A. , Khan Sumeer Ahmad , Tegnér Jesper N. 
Published: October 2023

AbstractWith the emergence of single-cell foundation models, an important question arises: how do these models perform when trained on datasets having an imbalance in cell type distribution due to rare cell types or biased sampling? We benchmark three foundation models, scGPT, scBERT, and Geneformer, using skewed single-cell cell-type distribution for cell-type annotation. While all models had reduced performance when challenged with rare cell types, scGPT and scBERT, performed better than Geneformer. Notably, in contrast to scGPT and scBERT, Geneformer uses ordinal positions of the tokenized genes rather than actual raw gene expression values. To mitigate the effect of a skewed distribution, we find that random oversampling, but not random undersampling, improved the performance for all three foundation models. Finally, scGPT, using FlashAttention, has the fastest computational speed, whereas scBERT is more memory-efficient. We conclude that tokenization and data representation are essential areas of research, and new strategies are needed to mitigate the effects of imbalanced learning in single-cell foundation models. Code and data for reproducibility are available athttps://github.com/SabbaghCodes/ImbalancedLearningForSingleCellFoundationModels.
Repertoire-based mapping and time-tracking of helper T cell subsets in scRNA-Seq
Authors: Lukyanov D.K. , Kriukova V.V. , Ladell K. , Shagina I.A. , Staroverov D.B. , Minasian B.E. , Fedosova A.S. , Shelyakin P. , Suchalko O.N. , Komkov A.Y. , Blagodatskikh K.A. , Miners K.L. , Britanova O.V. , Franke A. , Price D.A. , Chudakov D.M. 
Published: October 2023

SummaryThe functional programs selected by CD4+ helper (Th) T cell clones fundamentally determine the architecture of the immune response to distinct challenges. Advances in scRNA-Seq have enhanced our understanding of the diversity of these programs, yet the correspondence between scRNA-Seq clusters and previously characterized Th subsets remains unclear. In this study, we use immune repertoires to position phenotypically sorted Th subsets within scRNA-Seq data from three healthy donors. This approach, termed TCR-Track, and accurately maps Th1, Th1-17, Th17, Th22, Th2a, Th2, Tfh, and Treg subsets, outperforming CITE-Seq-based mapping. Remarkably, the mapping is tightly focused on specific scRNA-Seq clusters despite a four-year interval between the sorting of subsets and the effector CD4+ scRNA-Seq experiment. Thus, while transient T cell plasticity is commonly observed in functionally active T cell populations, TCR-Track reveals high intrinsic program sustainability of Th clones circulating in peripheral blood. Repertoire overlap analysis at the scRNA-Seq level confirms that circulating Th1, Th2, Th2a, Th17, Th22, and Treg subsets are clonally independent. However, a prominent clonal overlap between corresponding clusters indicates that cytotoxic CD4+ T cells differentiate from Th1 clones. More specifically, we demonstrate that sorted CCR10+ Th cells correspond to a specific Th22 scRNA-Seq cluster, while CCR10-CCR6+CXCR3-CCR4+ cells, traditionally sorted as the Th17 subset, represent a mixture ofbona fideTh17 and clonally unrelated CCR10lowTh22 cells, which may have confounded investigators in previous studies. This clear distinction of Th17 and Th22 subsets should influence vaccine and T cell based therapies development. Additionally, we show that SARS-CoV-2 infection is associated with transient IFN type 1 activation of naive CD4+ T cells, and an increased proportion of effector IFN- induced Th cells is associated with a moderate course of the disease but remains low in critical COVID-19 cases. Using integrated scRNA-Seq, TCR-Track, and CITE-Seq data from 122 donors, we provide a comprehensive Th scRNA-Seq reference that should facilitate further investigation of Th subsets in fundamental and clinical studies.
Global transcription regulation revealed from dynamical correlations in time-resolved single-cell RNA-sequencing
Authors: Volteras Dimitris , Shahrezaei Vahid , Thomas Philipp 
Published: October 2023

AbstractSingle-cell transcriptomics reveals significant variations in the transcriptional activity across cells. Yet, it remains challenging to identify mechanisms of transcription dynamics from static snapshots. It is thus still unknown what drives global transcription dynamics in single cells. We present a stochastic model of gene expression with cell size- and cell cycle-dependent rates in growing and dividing cells that harnesses temporal dimensions of single-cell RNA-sequencing through metabolic labelling protocols and cell cycle reporters. We develop a parallel and highly scalable Approximate Bayesian Computation method that corrects for technical variation and accurately quantifies absolute burst frequency, burst size and degradation rate along the cell cycle at a transcriptome-wide scale. Using Bayesian model selection, we reveal scaling between transcription rates and cell size and unveil waves of gene regulation across the cell cycle-dependent transcriptome. Our study shows that stochastic modelling of dynamical correlations identifies global mechanisms of transcription regulation.
Divergent age-dependent conformational rearrangement within Aβ amyloid deposits in APP23, APPPS1, and AppNL-Fmice
Authors: Parvin Farjana , Haglund Samuel , Wegenast-Braun Bettina , Jucker Mathias , Saito Takashi , Saido Takaomi C , Nilsson K Peter R , Nilsson Per , Nyström Sofie , Hammarström Per 
Published: October 2023

AbstractAmyloid plaques composed of fibrils of misfolded Aβ peptides are pathological hallmarks of Alzheimer’s disease (AD). Aβ fibrils are polymorphic in their tertiary and quaternary molecular structures. This structural polymorphism may carry different pathologic potency and can putatively contribute to clinical phenotypes of AD. Therefore, mapping of structural polymorphism of Aβ fibrils is valuable to understand disease mechanisms. Here, we investigated how Aβ fibril morphologyin situdiffers in Aβ plaque of different mouse models expressing familial mutations in the AβPP gene. We used a combination of conformation-sensitive luminescent conjugated oligothiophene (LCO) ligands, Aβ-specific antibodies, and different fluorescence microscopy techniques. LCO fluorescence mapping revealed that mouse models APP23, APPPS1, andAppNL-Fhave different fibril structures depending on AβPP-processing genotype. Co-staining of Aβ-specific antibodies showed that individual plaques from APP23 mice, expressing Swedish mutations (NL) have two distinct fibril polymorph regions of core and corona. The plaque core is predominantly composed of compact Aβ40 fibrils and the corona region is dominated by diffusely packed Aβ40 fibrils. On the other hand, the APP knock-in mouseAppNL-F, expressing Iberian mutation (F) along with Swedish mutation has tiny, cored plaques consisting mainly of compact Aβ42 fibrils, vastly different from APP23 even at elevated age up to 21 months. Age dependent polymorph maturation of plaque cores observed for APP23 and APPPS1 mice >12 months, was minuscule inAppNL-F. These structural studies of amyloid plaquesin situcan map disease-relevant fibril polymorph distributions to guide the design of diagnostic and therapeutic molecules.SignificanceAlzheimer’s disease (AD) is associated with the formation of deposits in the brain known as Aβ-amyloid plaques. AD can emerge as a sporadic disease or due to familial mutations in genes encoding for Aβ precursor and processing proteins. The Aβ-amyloid found in plaques displays different structures in sporadic AD and in various types of familial AD. We hypothesize that understanding plaque morphology and development is crucial for understanding the initiation and progression of AD. We here compared amyloid structures in three of the most used mouse models of human Aβ-plaque formation. Our findings suggest significant differences in plaque morphologies and structural maturation processes during aging. Our results emphasize that strain-like differences of Aβ-amyloids develop as a function of Aβ precursor protein-processing genetics and age.
Pharmacological enhancement of dopamine neurotransmission does not affect illusory pattern perception
Authors: Smith Elke , Michalski Simon , Knauth Kilian , Tuzsus Deniz , Theis Hendrik , van Eimeren Thilo , Peters Jan 
Published: October 2023

AbstractPsychotic symptoms and delusional belief have been linked to dopamine transmission in both healthy and clinical samples and are assumed to result at least in part from perceiving illusory patterns in noise. However, the existing literature on the role of dopamine in detecting patterns in noise is inconclusive. To address this issue, we assessed the effect of manipulating dopaminergic neurotransmission on illusory pattern perception in healthy individuals (n= 48,n= 19 female) in a double-blind placebo-controlled within-subjects design (see preregistration athttps://osf.io/a4k9j/). We predicted individuals on vs. off L-DOPA to be more likely to perceive illusory patterns, specifically objects in images containing only noise. Using a signal detection model, however, we found no credible evidence that L-DOPA compared to placebo increased false alarm rates. Further, L-DOPA did not modulate measures of accuracy, discrimination sensitivity and response bias. In all cases, Bayesian statistics revealed strong evidence in favour of the null hypothesis Future studies should address possible dose-dependent effects and differential effects in healthy vs. clinical samples.
Spectral-based detection of chromatin loops in multiplexed super-resolution FISH data
Authors: Liefsoens Michaël , Földes Timothy , Barbi Maria 
Published: October 2023

AbstractInvolved in mitotic condensation, interaction of transcriptional regulatory elements or isolation of structural domains, understanding loop formation is becoming a paradigm in the deciphering of chromatin architecture and its functional role. Despite the emergence of increasingly powerful genome visualization techniques, the high variability in cell populations and the randomness of conformations still make loop detection a challenge. We introduce a new approach for determining the presence and frequency of loops in a collection of experimental conformations obtained by multiplexed super-resolution imaging. Based on a spectral approach, in conjunction with neural networks, this method offers a powerful tool to detect loops in large experimental data sets, both at the population and single cell level. The method’s performance is confirmed by applying it to recently published experimental data, where it provides a detailed and statistically quantified description of the global architecture of the chromosomal region under study.
PDB NextGen Archive: Centralising Access to Integrated Annotations and Enriched Structural Information by the Worldwide Protein Data Bank
Authors: Choudhary Preeti , Feng Zukang , Berrisford John , Chao Henry , Ikegawa Yasuyo , Peisach Ezra , Piehl Dennis W. , Smith James , Tanweer Ahsan , Varadi Mihaly , Westbrook John D. , Young Jasmine Y. , Patwardhan Ardan , Morris Kyle L. , Hoch Jeffrey C. , Kurisu Genji , Velankar Sameer , Burley Stephen K. 
Published: October 2023

AbstractThe Protein Data Bank (PDB) archive is the global repository for public-domain 3D biomolecular structural information. The archival nature of the PDB presents certain challenges pertaining to updating or adding associated annotations from trusted external biodata resources. While each Worldwide PDB (wwPDB) partner has made best efforts to provide up-to-date external annotations, accessing and integrating information from disparate wwPDB data centers can be an involved process. To address this issue, the wwPDB has established the PDB Next Generation or NextGen Archive, developed to centralize and streamline access to enriched structural annotations from wwPDB partners and trusted external sources. At present, the archive provides mappings between experimentally determined 3D structures of proteins and UniProt amino acid sequences, together with domain annotations from Pfam, SCOP2, and CATH databases, and intra-molecular connectivity information. Since launch, the PDB NextGen Archive has seen substantial user engagement with over 3.5 million data file downloads, ensuring researchers have access to accurate, up-to-date, and easily accessible structural annotations.Database URLhttp://www.wwpdb.org/ftp/pdb-nextgen-archive-site
Non-random polymorphisms near transposable elements facilitate evolution across the genome ofArabidopsis thaliana
Authors: De Kort H. , Ganseman Y. , Deforce D. , Van Nieuwerburgh F. 
Published: October 2023

AbstractEvolution is a key characteristic of all life on earth, and is achieved mainly through mutation and recombination. To facilitate evolutionary rates in the absence of recombination, increased mutagenesis could provide essential opportunities for evolution. Here, we harness the genomes of 973 wild accessions ofArabidopsis thaliana, a self-fertilizing species characterized by reduced recombination rates, to study the role of transposable elements (TEs) as mutagenic drivers of non-random genetic variation. We found that multiple TE superfamilies accumulate large numbers of genetic variants in gene-rich regions of the genome. Moreover, TEs were enriched in genes underpinning key molecular processes, including fertilization and mRNA cis-splicing, suggesting that TEs generate genetic variation that is fundamental to organismal functioning and reproduction. An excess of common genetic variants (maf>0.4) flanking TEs, despite the extreme degree of self-fertilization, further corroborates the notion that TEs can generate substantial evolutionary potential in the absence of outcrossing. Nevertheless, while other studies point to TE mobilization as a strategy to facilitate adaptive evolution, we find that only a fraction (4.8%) of TE families was linked to genetic variants involved in climate adaptation to a significantly larger extent than background genomic variation, possibly because the high mutation rates near TEs dilute adaptive signals. Overall, all TE superfamilies but one (Gypsy) were significantly associated with evolutionary processes through their association with genes, functional molecular processes, flanking common variants and/or climate adaptation. We conclude that non-random mutations flanking TEs provide substantial evolutionary potential in a self-fertilizing species.
Consistent higher emissions of carbon dioxide, nitrous oxide, and methane during the daytime in reservoirs
Authors: León-Palmero E. , Morales-Baquero R. , Reche I. 
Published: October 2023

AbstractGreenhouse gas (GHG) emissions from reservoirs are quantitatively relevant for atmospheric climatic forcing. These emissions have large temporal variability, with daily changes accounting for a substantial part of this variability. However, most estimations for GHG fluxes are based on the upscaling of discrete measurements performed during the daytime and, in general, they do not account for nighttime emissions. Here, we explored the daily patterns of CO2, N2O, and diffusive and ebullitive CH4fluxes in two eutrophic reservoirs with contrasted morphometries in two different years. We found a daily pattern for CO2, N2O, and diffusive CH4fluxes with consistent higher emissions during the daytime than during the nighttime, irrespectively of reservoir morphometry. These three diffusive fluxes showed evident daily synchrony suggesting a common driver. The emissions were coupled with the daily solar cycle, wind speed, and water temperature. The daily emissions of the CO2, N2O, and CH4were also positive and significantly related to oxygen saturation. In contrast, we did not find a consistent daily pattern for the ebullitive CH4fluxes, although they represented a significant fraction of the total CH4emitted in these reservoirs. Our study suggests that the daily variability in GHG emissions may be as relevant as the variability at spatial scale or inter-system variability. Therefore, daily ranges should be considered in future GHG budgets to refine temporal trends of GHG emissions from reservoirs.
Landscape structure drives eco-evolution in host-parasite systems
Authors: Deshpande Jhelam N. , Dakos Vasilis , Kaltz Oliver , Fronhofer Emanuel A. 
Published: October 2023

AbstractSpatial network structure of biological systems drives ecology and evolution by distributing organisms and their genes. The ubiquitous host-parasite systems are no exception. However, past work has largely ignored relevant spatial complexity, hampering the translation of theoretical predictions to real ecosystems. Thus, we develop an eco-evolutionary metapopulation model of host-parasite dynamics where hosts and parasites disperse through realistically complex spatial networks representing major biomes: riverine aquatic and terrestrial. We generate the testable prediction that parasite virulence, or how parasites harm their hosts, is unimodal with dispersal and can reach greater values in aquatic landscapes but saturates to lower values in terrestrial systems. Moreover, we show that kin selection drives virulence evolution. Spatial networks generate characteristic patterns of parasite relatedness which drive differential virulence evolution. Finally, we show that accounting for virulence evolution allows us to predict the distribution of key epidemiological variables (e.g., parasite extinction risks) within spatial networks.
Waveform-based classification of dentate spikes
Authors: Santiago Rodrigo M.M. , Lopes-dos-Santos Vítor , Jones Emily A. Aery , Huang Yadong , Dupret David , Tort Adriano B.L. 
Published: October 2023

AbstractSynchronous excitatory discharges from the entorhinal cortex (EC) to the dentate gyrus (DG) generate fast and prominent patterns in the hilar local field potential (LFP), called dentate spikes (DSs). As sharp-wave ripples in CA1, DSs are more likely to occur in quiet behavioral states, when memory consolidation is thought to take place. However, their functions in mnemonic processes are yet to be elucidated. The classification of DSs into types 1 or 2 is determined by their origin in the lateral or medial EC, as revealed by current source density (CSD) analysis, which requires recordings from linear probes with multiple electrodes spanning the DG layers. To allow the investigation of the functional role of each DS type in recordings obtained from single electrodes and tetrodes, which are abundant in the field, we developed an unsupervised method using Gaussian mixture models to classify such events based on their waveforms. Our classification approach achieved high accuracies (> 80%) when validated in 8 mice with DG laminar profiles. The average CSDs, waveforms, rates, and widths of the DS types obtained through our method closely resembled those derived from the CSD-based classification. As an example of application, we used the technique to analyze single-electrode LFPs from apolipoprotein (apo) E3 and apoE4 knock-in mice. We observed that the latter group, which is a model for Alzheimer’s disease, exhibited wider DSs of both types from a young age, with a larger effect size for DS type 2, likely reflecting early pathophysiological alterations in the EC-DG network, such as hyperactivity. In addition to the applicability of the method in expanding the study of DS types, our results show that their waveforms carry information about their origins, suggesting different underlying network dynamics and roles in memory processing.Author summaryThe entorhinal cortex and the dentate gyrus are regions of the brain’s hippocampal formation that play a crucial role in learning and memory. Their synchronous activation generates fast and high-amplitude electrophysiological patterns in the dentate gyrus, called dentate spikes (DSs). However, the functional role of DSs is still poorly understood. A technical limitation for the study of DSs is that their classification into types 1 and 2 is only possible through laminar profiles obtained by multicontact linear probes. In the present work, we propose a method to classify the different types of DSs through their waveforms, thus expanding the investigation of their significance in mnemonic processes by making possible their study in single-site recordings.
Viral protease NIa-Pro increases MEDIATOR SUBUNIT16 cleavage and plant susceptibility to turnip mosaic virus and its aphid vectorMyzus persicae
Authors: Ray Swayamjit , Murad Tyseen , Arena Gabriella D. , Arshad Kanza , Arendsee Zebulun , Herath Venura , Whitham Steven A. , Casteel Clare L. 
Published: October 2023

AbstractPlant viruses, such turnip mosaic virus (TuMV), both trigger and inhibit host plant defense responses, including defenses that target their insect vectors, such as aphids. TuMV infection and its protein, NIa-Pro (nuclear inclusion protease a), suppress aphid-induced plant defenses, however the mechanisms of this suppression are still largely unknown. In this study, we determined that NIa-Pro’s protease activity is required to increase aphid performance on host plants and that 40 transcripts with predicted NIa-Pro cleavage sequences are regulated in Arabidopsis plants challenged with aphids and/or virus compared to healthy controls. One of the candidates, MEDIATOR 16 (MED16), regulates the transcription of ethylene (ET)/jasmonic acid (JA)-dependent defense responses against necrotrophic pathogens. Using immunoblots, mutants, bioassays, and qRT-PCR, we show that a nuclear localization signal is cleaved from MED16 in virus-infected plants and in the presence of NIa-Pro along with the presence of aphids, suggesting MED16 functions in the nucleus may be impacted. Consistent with this, aphid induction of the MED16-dependent transcript ofPLANT DEFENSIN 1.2 (PDF1.2), was reduced in virus-infected plants and in plants expressing NIa-Pro compared to controls, and NIa-Pro’s protease activity was required for this reduction. Finally, we show performance of both the virus and the aphid vector was enhanced onmed16mutant Arabidopsis compared to controls. Overall, this study demonstrates MED16 regulates defense responses against both the virus and the aphid and provides insights into the mechanism by which TuMV suppresses anti-virus and anti-herbivore defenses.