bluuebunny/crossref_metadata_2025_split huggingface dataset:
H3K4me3 methyltransferase KMT2F promotes pre-initiation complex formation by RNA Polymerase I to regulate ribosomal RNA transcription
Authors: Lone Kaisar Ahmad , Karole Amit Mahendra , Ravindran Geethanjali , Tyagi Shweta 
Published: November 2024

AbstractTrimethylation of histone 3 lysine 4 (H3K4me3) is mark of active transcription and its regulatory role in RNA polymerase II-mediated transcription has been well-studied. However, if and how this mark regulates RNA polymerase I (RNA Pol I) is not known. Here we used customized genome assemblies for rDNA to demonstrate that KMT2A and KMT2F bind to entire rDNA loci. The binding of these enzymes were mirrored by the binding of H3K4me2 and H3K4me3 marks. Using biochemical assays, we demonstrate the interaction of KMT2-specific subunits with RNA Pol I transcriptional machinery. Our findings reveal KMT2F as the primary KMT depositing the H3K4me3 on rDNA. Loss of H3K4me3 adversely affects the epigenetic landscape and promotes heterochromatization of rDNA locus. Mechanistically, we show that KMT2F promotes pre-initiation complex formation of RNA Pol I. Our findings highlights the thus far undiscovered role of H3K4me3 in the transcriptional initiation of rDNA genes.
Antagonism as a foraging strategy in microbial communities
Authors: Stubbusch Astrid K.M. , Peaudecerf François J. , Soo Lee Kang , Paoli Lucas , Schwartzman Julia , Stocker Roman , Basler Marek , Schubert Olga T. , Ackermann Martin , Magnabosco Cara , D’Souza Glen G. 
Published: November 2024

AbstractIn natural habitats, nutrient availability limits bacterial growth. We discovered that bacteria can overcome this limitation by acquiring nutrients through lysing neighboring cells via contact-dependent antagonism. Using single-cell live imaging and isotopic markers, we found that during starvation the type VI secretion system, which transfers toxins into neighboring cells, increases growth by enabling the uptake of nutrients from lysing cells. In a spatially structured environment, the gradual lysis of just a few target cells allows for the growth of a new antagonist cell. Genomic adaptations in antagonists, characterized by a reduced metabolic gene repertoire, and the prevalence of the type VI secretion system in natural environments, such as global oceans and soils, suggest that bacterial antagonism has the potential to substantially contribute to nutrient transfer within microbial communities across various ecosystems.
Targeting the energy metabolism of melanoma cells: FX-11 acts as a mitochondrial uncoupler
Authors: Preis Jasmin Renate , Rolvering Catherine , Kirchmeyer Mélanie , Behrmann Iris , Haan Claude 
Published: November 2024

AbstractIn a compound screen on melanoma cells, which included different microenvironmental contexts aiming at better representing the environmental and growth characteristics of tumours, we identified several drugs efficiently suppressing cell viability. Here we focus on results obtained with FX-11, reported to be an inhibitor of lactate dehydrogenase (LDH). FX-11 dose-dependently inhibited growth of 624Mel and Wm3248 melanoma cells grown in a modular physiologic medium (MPM). Importantly, FX-11 was able to reduce the growth of the corresponding drug-resistant melanoma sublines equipotently.When testing the on-target activity of FX-11, the results were unexpected: in contrast to other LDH inhibitors (used as positive controls), FX-11 did not decrease the NAD+/NADH ratio, the glucose uptake, or the lactate secretion of melanoma cells. However, in seahorse assays, FX-11 increased the oxygen consumption rate as well as the extracellular acidification rate of cells, behaving like the mitochondrial uncouplers FCCP and Bam15. Treatment with FX-11, FCCP, or Bam15 induced an increase in acetyl-CoA carboxylase phosphorylation and a decrease in serine 65 phosphorylation of the eukaryotic initiation factor 4E-binding protein 1, indicative of AMPK activation by a decreased ATP/ADP ratio. Importantly, FX-11 and Bam15 drastically decreased the mitochondrial membrane potential in contrast to the LDH inhibitors LDH-IN-I and GNE-140.Taken together, we provide evidence that FX-11 effectively inhibits the growth of melanoma cells, including drug-resistant ones. FX-11 profoundly affects their energy metabolism, although it does not seem to act as other LDH inhibitors, but as a mitochondrial uncoupler.
Spatiotemporal transcriptomic niches of complement pathway and serine protease inhibitor activation in aging and infection
Authors: Kern Fabian , Wagner Viktoria , Wahl Vanessa , Ludwig Nicole , Graf Simon , Amand Jeremy , Foltz Aulden , Atkins Micaiah , Kedir Blen , Hadjilaou Alexandros , Flotho Matthias , Grandke Friederike , Wartenberg Philipp , Hollenhorst Monika I. , Lotter Hanna , Müller Rolf , Boehm Ulrich , Hahn Oliver , Jacobs Thomas , Krasteva-Christ Gabriela , Wyss-Coray Tony , Keller Andreas 
Published: November 2024

AbstractAging is a multifactorial and complex physiological process, affecting every organ with characteristic manifestations. Understanding the molecular mechanisms that drive aging processes is crucial to targeting age-related disorders. Recent reports suggest that severe post-infection syndromes can partially accelerate aging. However, the underlying gene-encoded regulatory interplay, whether being shared or distinct between aging and infection biology are poorly understood. Here, we employed spatial transcriptomics to establish a multi-organ atlas (brain, heart, kidney, liver, lung, and spleen) across the mouse lifespan (4, 17, and 26 months). Dissecting high-quality fresh-frozen tissue samples at unbiased molecular resolution, we found both organ-specific and cross-organ gene dysregulation upon aging. We identified age-related trajectories in gene expression and cell state, some only detectable within their spatial context, and provide validation at subcellular resolution. The most prominent effect was organ-wide immune system activation with spatially variable severity. We therefore evaluated how aging mimics the expression signatures observed in systemic infection, using spatial transcriptomics slices from young mice infected with Plasmodium berghei ANKA. While on the gene level the effect sizes caused by the infection outweighed those of aging, we reveal a shared activation of the early complement pathway (C4b) and serine protease inhibitors (Serpin gene family) within by phenotype distinct spatial niches. We show that this common RNA signature is driven by tissue-specific cell types and eventually affects protein levels in the aged brain, rendering them a target for future mechanistic and drug discovery studies. Taken together, our study provides a coherent in-depth and cross-organ transcriptomics atlas to systematically study aging and infection in the mouse at spatiotemporal resolution.Key highlightsLarge-scale and high-resolution atlas of spatial transcriptomics from six organs to study aging and systemic infection across two mouse cohorts.Strong transcriptional alterations found in distinct organ-specific niches for aging and acute malaria, with organ- and cell type-associated immune responses.Dysregulation of early complement proteases (C4b) and serine protease inhibitors (Serpina3n) as common theme across central nervous system and peripheral organs.
Systematic effects of retinotopic biases and category selectivity across human occipitotemporal cortex
Authors: Silson Edward H , Groen Iris I A , Baker Chris I 
Published: November 2024

AbstractThe organization of human visual cortex has traditionally been studied using two different methods: retinotopic mapping and category-selectivity mapping. Retinotopic mapping has identified a large number of systematic maps of the visual field, while category-selectivity mapping has identified clusters of neural populations that reliably respond more strongly to specific image categories such as objects, faces, scenes and body parts compared to other categories. While early investigations seemed to suggest that these two organizing principles were largely separated in the brain, with retinotopic maps in posterior visual cortex and category-selective regions in anterior visual cortex, recent work shows that category-selective regions overlap with retinotopic maps, giving rise to spatial visual field biases within these regions.Here, we collected fMRI responses whilst performing both retinotopic and category mapping within the same participants, allowing detailed comparison of neural tuning for space and category at the single voxel level. We use these data to evaluate two previous proposals of how retinotopic biases relate to category-selectivity: 1) complementary quadrant biases (upper vs. lower contralateral visual field) inherited from early visual cortex explain the presence of paired regions selective for thesame categoryacross lateral and ventral occipitotemporal cortex (lOTC, vOTC); and 2) eccentricity biases (center vs. periphery of the visual field) explain the presence of selectivity fordifferent categories, specifically differentiating face-versus scene-selectivity within the ventral surface.Confirming and extending previous findings for a comprehensive set of face-, scene-, object, and place-selective regions of interest, we provide robust evidence that category-selective regions do not sample visual space uniformly, exhibiting systematic biases towards either the upper or lower field (all category regions) and center vs. periphery (face vs. place regions). Consistent with 1), we find that quadrant biases differ systematically between lateral and ventral OTC, with lateral regions showing systematic lower field biases and ventral regions showing upper field biases, differentiating regions selective for the same category in terms of their spatial bias. However, contrary to 2), we find that eccentricity tuning does not strongly predict the strength of face-or scene category-selectivity in a given voxel. Specifically, highly face-selective voxels are not solely confined to the fovea, and while most scene-selective voxels show peripheral tuning, highly scene-selective voxels actually show strong foveal tuning, particularly in anterior medial-ventral cortex.Collectively, these results demonstrate that spatial biases in category-selective cortex are widespread and robust, whilst also suggesting there is no simple relation between spatial tuning and category-selectivity.
Using phage display for rational engineering of a higher affinity humanized 3’phosphohistidine-specific antibody
Authors: Martyn Gregory D. , Kalagiri Rajasree , Veggiani Gianluca , Stanfield Robyn L. , Choudhuri Indrani , Sala Margaux , Meisenhelder Jill , Chen Chao , Biswas Avik , Levy Ronald M. , Lyumkis Dmitry , Wilson Ian A. , Hunter Tony , Sidhu Sachdev S. 
Published: November 2024

AbstractHistidine phosphorylation (pHis) is a non-canonical post-translational modification (PTM) that is historically understudied due to a lack of robust reagents that are required for its investigation, such as high affinity pHis-specific antibodies. Engineering pHis-specific antibodies is very challenging due to the labile nature of the phosphoramidate (P-N) bond and the stringent requirements for selective recognition of the two isoforms, 1-phosphohistidine (1-pHis) and 3-phosphohistidine (3-pHis). Here, we present a strategy forin vitroengineering of antibodies for detection of native 3-pHis targets. Specifically, we humanized the rabbit SC44-8 anti-3-pTza (a stable 3-pHis mimetic) mAb into a scaffold (herein referred to as hSC44) that was suitable for phage display. We then constructed six unique Fab phage-displayed libraries using the hSC44 scaffold and selected high affinity 3-pHis binders. Our selection strategy was carefully designed to enrich antibodies that bound 3-pHis with high affinity and had specificity for 3-pHis versus 3-pTza. hSC44.20N32FL, the best engineered antibody, has an ∼10-fold higher affinity for 3-pHis than the parental hSC44. Eleven new Fab structures, including the first reported antibody-pHis peptide structures were solved by X-ray crystallography. Structural and quantum mechanical calculations provided molecular insights into 3-pHis and 3-pTza discrimination by different hSC44 variants and their affinity increase obtained throughin vitroengineering. Furthermore, we demonstrate the utility of these newly developed high-affinity 3-pHis-specific antibodies for recognition of pHis proteins in mammalian cells by immunoblotting and immunofluorescence staining. Overall, our work describes a general method for engineering PTM-specific antibodies and provides a set of novel antibodies for further investigations of the role of 3-pHis in cell biology.Significance StatementHistidine phosphorylation is an elusive PTM whose role in mammalian cell biology is largely unknown due to the lack of robust tools and methods for its analysis. Here we report the development of antibodies with unprecedented affinity and specificity towards 3-pHis and present the first crystal structures of a pHis peptide in complex with an antibody. Finally, we show how these antibodies can be used in standard molecular biology workflows to investigate pHis-dependent biology.
Predicted meta-omics: a potential solution to multi-omics data scarcity in microbiome studies
Authors: Cosma Bianca-Maria , Pillay Stephanie , Calderón-Franco David , Abeel Thomas 
Published: November 2024

AbstractImbalances in the gut microbiome have been linked to conditions such as inflammatory bowel disease, diabetes, and cancer. While metagenomics and amplicon sequencing are commonly used to study the microbiome, they do not capture all layers of microbial functions. Other meta-omics data can provide more insights, but these are more costly and laborious to procure. The growing availability of paired meta-omics data offers an opportunity to develop machine learning models that can infer connections between metagenomics data and other forms of meta-omics data, enabling the prediction of these other forms of meta-omics data from metagenomics. We evaluated several machine learning models for predicting meta-omics features from various meta-omics inputs. Simpler architectures such as elastic net regression and random forests generated reliable predictions of transcript and metabolite abundances, with correlations of up to 0.77 and 0.74, respectively, but predicting protein profiles was more challenging. We also identified a core set of well-predicted features for each meta-omics output type, and showed that multi-output regression neural networks performed similarly when trained using fewer output features. Lastly, our experiments demonstrated that predicted features can be used for the downstream task of inflammatory bowel disease classification, with performance comparable to that of experimental data.
Flow parsing as causal source separation: A computational model for concurrent retrieval of object and self-motion information from optic flow
Authors: Scherff Malte , Lappe Markus 
Published: November 2024

AbstractOptic flow, the retinal pattern of motion that is experience during self-motion contains information about one’s direction of heading. If the visual scene contains other moving objects optic flow becomes a combination of self-motion and independent object motion. The global pattern due to self-motion is locally confounded, and the locally restricted object flow is the sum of components due to these different causal sources of motion. Nonetheless, humans are able to retrieve information from such flow accurately, including the direction of heading and the scene-relative motion of an object.One way to handle such complex flow is flow parsing, a process speculated to allow the brain’s sensitivity to optic flow to separate the causal sources of retinal motion in information due to self-motion and information due to object motion. In a computational model that retrieves object and self-motion information from optic flow, we implemented such a process of causal separation based on heading likelihood maps, whose distributions indicate the consistency of parts of the flow with self-motion alone. The flow parsing allows for concurrent estimation of heading, the detection and localization of and independently moving object, and the estimation of scene-relative motion of that object.We developed a paradigm that allows the model to perform all the different estimations while system-atically varying how the object contributes to the flow field. Simulations of that paradigm showed that the model replicates many aspects of human performance, including the dependence of heading estimation on object speed and how different object movements bias that estimation. Regarding object detection and motion estimation, the model’s results fit human behavioral data, the latter even for flow of reduced quality.
Genome-wide mapping of RPA1 and RAD9 reveals the management of polycistronic transcription, replication initiation, and responses to replication stress inLeishmania
Authors: Black J.A. , Virgilio S. , Bastos M.S. , Silva G.L.A. , Damasceno J.D. , Lapsley C. , McCulloch R. , Tosi L.R.O. 
Published: November 2024

AbstractWhen exposed single-stranded DNA accumulates at stalled or collapsed replication forks, the replication stress response is triggered to prevent genome instability.Leishmaniaare parasitic eukaryotes where gene expression is universally polycistronic and whose plastic genomes facilitate rapid adaptations in response to stress, with evidence implicating intrinsic replication stress as a source. Little is known about theLeishmaniareplication stress response. In this study, we reveal the global dynamics of the replication stress response inL. majorpromastigotes by performing ChIP-seq on three key replication stress response proteins, γH2A, RPA1 and RAD9, in the absence and presence of replication stress. We show that common ‘hotspots’ of replication stress correlate with DNA replication initiation and transcription termination inLeishmania. When DNA replication is stalled, replication stress response factors accumulate at early S-phase origins, with a signal pattern reminiscent of bidirectional replication fork progression. Under conditions of chronic replication stress, increased accumulation of replication stress response factors emerges at wider sites of transcription initiation, suggestingLeishmaniamay possess compensatory strategies to limit the effects of replication stress and ensure DNA replication can complete under these conditions. In contrast, chronic replication stress enhances RSR factor accumulation at transcription termination sites, highlighting these regions as key replication stress ‘hotspots’ inLeishmania. Lastly, variations in RPA dynamics in ATR-deficient cells uncover crucial roles of this protein kinase in managing polycistronic transcription and DNA replication, particularly under replication stress, inLeishmania.SummaryStrict controls operate to precisely copy an organism’s DNA. However, cells need ways to rapidly adapt and respond to stimuli. In some cases, these beneficial adaptations come from problems during replication.Leishmaniaparasites cause serious neglected infections in humans and animals across the world’s tropics and sub-tropics. Remarkably, recent evidence suggests thatLeishmaniaDNA experiences enhanced stress during replication that can drive its ability to rapidly adapt in response to stress. How Leishmaniarespond to DNA replication stress is still poorly understood. Here, using a genome-wide approach to map the locations of key proteins that manage DNA replication stress and maintain genome integrity, we show ‘hotspots’ of DNA replication stress coincide with start sites of DNA replication and regions of transcription termination.
Brain-wide population activity during reaching integrates action-mediated goal expectation
Authors: Peng Yangfan , Lindersson Carl , Tinelli Sasha , Stedehouder Jeffrey , Shah Rahul S , Lak Armin , Stagg Charlotte J , Sharott Andrew 
Published: November 2024

SummaryLarge scale recordings have revealed that neurons encoding motor and non-motor variables are highly distributed across the brain. While these neurons generate population level dynamics during spontaneous behavior, it remains unclear how these latent subspaces relate to the simultaneous motor and cognitive demands during ongoing goal-directed behavior. Here, we show that continuously anticipated action outcome, in addition to movement, drives ubiquitous latent dynamics during goal-directed movements. We used multiple Neuropixels probes to simultaneously record spiking activity from cortical and subcortical regions during a reaching task in head-fixed mice. Task-related population dynamics covaried within a common latent subspace across regions and was conserved across recording days and animals. These latent dynamics preceded movement onset and were modulated by reach distance and reward availability. Furthermore, their temporal progression continuously scaled with the timing of reward consumption and their activity decreased afterwards, despite ongoing stereotypical re-reaches. Our findings thus provide evidence for a brain-wide latent subspace for continuous representation of action-mediated proximity to goal, which could provide the basis for ubiquitous temporal difference learning based on predicted action outcome.
SeedMatExplorer: The transcriptome atlas of Arabidopsis seed maturation
Authors: Artur Mariana A. S. , Koetsier Robert A. , Willems Leo A. J. , Bakermans Lars L. , van Driel Annabel D. , Dongus Joram A. , Dekkers Bas J. W. , Marques Alexandre C. S. S. , Sami Asif Ahmed , Nijveen Harm , Bentsink Leónie , Hilhorst Henk , Teixeira Renake Nogueira 
Published: November 2024

AbstractSeed maturation is a critical developmental phase during which seeds acquire essential traits for nutritional value and desiccation survival. Abscisic acid (ABA) signalling has long been recognized as a key positive regulator of this process, coordinating the expression of genes that drive the acquisition of vital seed quality traits (SQTs) crucial for survival, resilience, and storage. However, the precise molecular regulation of many SQTs remains elusive. To address this gap, we conducted an extensive transcriptome analysis of seed maturation inArabidopsis thaliana, focusing on Col-0 wild-type and ten mutant lines affecting ABA biosynthesis, signaling, and catabolism from 12 days after pollination up to the dry seed stage. Our study employed Weighted Gene Co-Expression Network Analysis (WGCNA) and module-trait correlation to uncover specific gene groups linked to the regulation of multiple SQTs. We identifiedLate Embryogenesis Abundant(LEA) genes uniquely associated with desiccation tolerance and threeDREB AND EAR MOTIF PROTEIN(DEAR) transcription factors involved in seed longevity regulation. The value of our dataset lies not only in its depth and detail, but also in its integration into SeedMatExplorer, a web tool specifically designed to advance seed maturation research. SeedMatExplorer serves as a unique resource, enabling researchers to explore, visualize, and generate new hypotheses about gene expression regulation during seed maturation and the intricate control of SQTs. This physiological and transcriptomic atlas offers unprecedented insights into the complex, coordinated gene expression that drives SQT acquisition in Arabidopsis seeds, making it an invaluable asset for the scientific community.