bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bacterial protein function prediction via multimodal deep learning
Authors: Muzio Giulia , Adamer Michael , Fernandez Leyden , Borgwardt Karsten , Avican Kemal 
Published: November 2024

AbstractBacterial proteins are specialized with extensive functional diversity for survival in diverse and stressful environments. A significant portion of these proteins remains functionally uncharacterized, limiting our understanding of bacterial survival mechanisms. Hence, we developed Deep Expression STructure (DeepEST), a multimodal deep learning framework designed to accurately predict protein function in bacteria by assigning Gene Ontology (GO) terms. DeepEST comprises two modules: a multi-layer perceptron that takes gene expression and location as input features, and a protein structure-based predictor. Within DeepEST, we integrated these modules through a learnable weighted linear combination and introduced a novel masked loss function to fine-tune the structure-based predictor for bacterial species. We showed that DeepEST strongly outperforms existing protein function prediction methods relying solely on amino acid sequence or protein structure. Moreover, DeepEST predicts GO terms for unclassified hypothetical proteins across 25 human bacterial pathogens, facilitating the design of experimental setups for characterization studies.
A Novel Cisplatin-Based Prodrug Inhibits Lysine Deacetylases, Suppresses Nucleotide Excision Repair, and Overcomes Resistance
Authors: Negev-Korem Ya’ara , Stern Esther , Golan-Berman Hadar , Heilbrun Elisheva , Karmakar Subhendu , Soroka Yoram , Frušić-Zlotkin Marina , Chen Ofer , Hassanain Hiba , Wald Ori , Gibson Dan , Kohen Ron , Adar Sheera 
Published: November 2024

AbstractCisplatin [cis-diamminedichloroplatinum(II)] is a widely used chemotherapeutic agent that induces cytotoxicity primarily through DNA damage, but drug resistance severely limits its efficacy and use. Cisplatin resistance is complex and multifactorial, involving DNA repair via nucleotide excision repair (NER), and overexpression of lysine deacetylases (KDACs), which reduce chromatin accessibility and alter transcription regulation. The combination of cisplatin and KDAC inhibitors has shown promise in improving treatment efficacy. This improved efficacy has been attributed to increased drug sensitivity due to higher chromatin accessibility, however, this hypothesis has not been validated. In this study, we synthesized a novel Pt(IV) derivative,cct-[Pt(NH3)2Cl2(VPA)(PhB)] (cPVP), which combines cisplatin and two KDAC inhibitors, phenyl butyrate and valproic acid. This triple-action prodrug enabled the simultaneous targeting of multiple cancer-related pathways. Compared to cisplatin, cPVP exhibited significantly enhanced damage formation and cytotoxicity. High-resolution mapping of cisplatin damage and repair, however, does not attribute the enhanced damage sensitivity to chromatin accessibility, but rather to increased drug uptake and inhibition of nucleotide excision repair. Moreover, cPVP treatment increased survival in a mouse mesothelioma model, and prevented the development of resistance to both cisplatin and itself in cancer cells. Our findings shed new light on the effect of KDAC inhibition on cisplatin treatment, and suggest that cPVP could serve as a promising alternative to cisplatin in the clinic.
Competition, precipitation and temperature shape deviations from scaling laws in the crown allometries of miombo woodlands
Authors: Yambayamba Arthur M. , Fischer Fabian J. , Jucker Tommaso 
Published: November 2024

AbstractScaling relationships between different axes of tree size, such as height, crown radius, crown depth and stem diameter, play a direct role in shaping forest structure and function. Theoretical models such as metabolic scaling theory postulate that they are optimized for biomechanical stability and hydraulic sap distribution. However, empirical data often show that such models are only good enough as first order approximations because they do not account for differences in species traits and environmental conditions where trees grow. Nevertheless, the vast majority of research has focused on temperate systems or tropical rainforests, so we continue to lack a full understanding of what factors shape allometries of trees in tropical dry forests. Here, we compile data on tree height, diameter, crown radius and depth from miombo woodlands across Zambia and use Bayesian hierarchical modelling framework to explore how allometric scaling relationships are shaped by climate and competition. Similar to previous studies, our results revealed that allometric scaling relationships deviate substantially from theoretical expectations. We found that competition, precipitation and temperature all affect crown allometric scaling relationships, with trees becoming more slender where neighbourhood competition was greater, while crowns were wider and deeper in warmer and wetter climates. Our study highlights how the structure and function of miombo woodlands is shaped by more than just water availability. Moreover, by developing improved crown allometric models for miombo woodlands, we provide new tools to aid the estimation of aboveground biomass and calibration of remote sensing products in these critically important dry forest ecosystems.
Evolutionary history and rhizosphere microbial community composition in domesticated hops (Humulus lupulus L.)
Authors: McElwee-Adame Alexandra , Esplin-Stout Raya , Mugoya Trevor , Vourlitis George , Welch Nautica , Afram Kayser , Jeshvaghane Maryam Ahmadi , Bingham Nathan , Dockter Alexis , Eslava Jacob , Gil Giovanni , Mergens Joshua , Mohamed Amran , Nguyen Tram , Noor Fatum , Salcedo Nathan , Sethuraman Arun 
Published: November 2024

AbstractHumulus lupulus L., commonly known as hops, is a perennial crop grown worldwide and is well known for its pharmacological, commercial, and most importantly brewing applications. For hundreds of years, hops have undergone intense artificial selection with over 250 cultivated varieties being developed worldwide, all displaying differences in key characteristics such as bitter acid concentrations, flavor and aroma profiles, changes in photoperiod, growth, and pathogen/pest resistances. Previous studies have individually explored differences between cultivars, aiming to identify markers that can quickly and cost-effectively differentiate between cultivars. However, little is known about their evolutionary history and the variability in their associated rhizospheric microbial communities. Coupling phenotypic, genomic, and soil metagenomic data, our study aims to explore the global population structure and domestication history of 98 hops cultivars. Additionally, we assessed differences in growth rates, rates of viral infection, usage of dissolvable nitrogen, and soil microbial community compositions between US and non-US based cultivars. Contrary to previous studies, our study revealed that worldwide hop cultivars cluster into four primary subpopulations; Central European, English, and American ancestry as previously reported, and one new group, the Nobles, revealing further substructure amongst Central European cultivars. Modeling the evolutionary history of domesticated hops reveals an early divergence of the common ancestors of modern US cultivars around 2800 ybp, and more recent divergences with gene flow across English, Central European, and Noble cultivars, reconciled with key events in human history and migrations. Furthermore, cultivars of US origin were shown to overall outperform non-US cultivars in both growth rates and usage of dissolvable nitrogen and display novel microbial composition.
Hypoxia induces extensive protein and proteolytic remodeling of the cell surface in pancreatic adenocarcinoma (PDAC) cell lines
Authors: Lui Irene , Schaefer Katie , Kirkemo Lisa L. , Zhou Jie , Perera Rushika M. , Leung Kevin K. , Wells James A. 
Published: November 2024

AbstractThe tumor microenvironment (TME) plays a crucial role in cancer progression. Hypoxia is a hallmark of the TME and induces a cascade of molecular events that affects cellular processes involved in metabolism, metastasis, and proteolysis. In pancreatic ductal adenocarcinoma (PDAC), tumor tissues are extremely hypoxic. Here, we leveraged mass spectrometry technologies to examine hypoxia-induced alterations in the abundance and proteolytic modifications to cell surface and secreted proteins. Across four PDAC cell lines, we discovered extensive proteolytic remodeling of cell surface proteins involved in cellular adhesion and motility. Looking outward at the surrounding secreted space, we identified hypoxia-regulated secreted and proteolytically-shed proteins that are responsible for regulating the humoral immune and inflammatory response and an upregulation of proteins involved in metabolic processing and tissue development. Combining cell surface N-terminomics and secretomics to evaluate the cellular response to hypoxia enabled us to identify significantly altered candidate proteins which may serve as potential biomarkers and therapeutic targets in PDAC. Furthermore, this approach provides a blue print for studying dysregulated extracellular proteolysis in other cancers and inflammatory diseases.
Synaptic cleft geometry modulates NMDAR opening probability by tuning neurotransmitter residence time
Authors: Mesa M. Hernández , McCabe K. J. , Rangamani P. 
Published: November 2024

1AbstractSynaptic morphology plays a critical role in modulating the dynamics of neurotransmitter diffusion and receptor activation in interneuron communication. In this study, we investigated how variations in synaptic geometry, including curvature of the synaptic cleft, distance between the presynaptic and postsynaptic membranes, and the surface area-to-volume ratio of the cleft, influence glutamate diffusion and N-Methyl-D-Aspartate receptor (NMDAR) opening probabilities. We developed a stochastic model for receptor activation using reconstructions from realistic synaptic geometries. Our simulations revealed a substantial variability in NMDAR activation, highlighting the significant impact of synaptic structure on receptor dynamics. By exploring the interplay between curvature and surface area-to-volume ratio, we found that increasing the curvature of the synaptic membranes could compensate for reduced NMDAR activation when the synaptic cleft distance was large. We also found that non-parallel membrane configurations, particularly convex presynapses or concave postsynaptic densities (PSDs), maximize NMDAR activation via increased surface area-to-volume ratio, leading to prolonged glutamate residence and reduced leakage. Finally, introducing NMDAR clustering within the PSD significantly enhanced receptor activation across different geometric conditions and mitigated the effects of synaptic morphology on NMDAR opening probabilities. Our findings underscore the complex interplay between synaptic geometry and receptor dynamics, providing insights into how structural modifications can influence synaptic efficacy and plasticity.2Significance statementThis study demonstrates that synaptic morphology profoundly shapes neurotransmitter diffusion and NMDA receptor activation, directly impacting synaptic efficacy. Our model shows that factors like synaptic cleft curvature, membrane spacing, and surface area-to-volume ratio significantly influence receptor dynamics. Given the dynamic nature of dendritic spines, which change shape and size during synaptic plasticity, our findings illustrate how purely morphological changes in cleft structure can modulate interneuronal communication and signal strength.
Causal Effects of Herpesvirus-Associated Antibodies on Autoimmune neuroinflammatory diseases: Mendelian Randomization Study
Authors: Sun Shujun , Wen Yiyong , Pan Tang , Fan Xie , Jun Wen , Xu Anding 
Published: November 2024

AbstractBackgroundHerpesvirus infections may trigger Autoimmune neuroinflammatory diseases (ANDs), but their causal role is uncertain. This study used Mendelian randomization (MR) to investigate the causal effects of herpesvirus antibodies on ANDs.MethodsWe assessed 22 herpesvirus antibodies and five ANDs—multiple sclerosis (MS), neuromyelitis optica (NMO), myasthenia gravis (MG), Guillain-Barr é syndrome (GBS), and chronic inflammatory demyelinating polyneuropathy (CIDP)—using five MR methods. MR-PRESSO, MR-Egger, and Cochran’s Q statistic identified pleiotropy and heterogeneity. Bonferroni correction set the significance threshold at P<4.545e-04. Validation used UK Biobank and FinnGen data, with meta-analysis for inconsistent results.ResultsSignificant positive causal effects were found for Epstein-Barr virus encoded nuclear antigen-1 (EBV EBNA-1) (OR=3.009), EBV viral capsid antigen (VCA) p18 (OR=8.700), and human herpesvirus 7(HHV7) U14 (OR=3.359) antibody levels on MS risk, and HHV7 U14 (OR=10.641), Varicella zoster virus glycoprotein E and glycoprotein I(VZV gE and gI) (OR=17.220) antibody levels on NMO risk. VZV gE and gI (OR=2.542) antibodies increased MG risk, while EBV ZEBRA (OR=0.592)reduced MS risk. Negative effects of EBV EA-D and ZEBRA antibodies on NMO were also noted. Validation confirmed the effects of EBV EBNA-1, EBV VCA p18 antibodies on MS, and VZV gE and gI on antibody MG, while EBV ZEBRA and HHV7 U14 antibodies effects on MS were not validated.ConclusionsThe study suggests a causal link between specific herpesvirus antibodies and the risk of MS, NMO, and MG.
PIPENN-EMB: ensemble net and protein embeddings generalise protein interface prediction beyond homology
Authors: Thomas David P. G. , Garcia Fernandez Carlos M. , Haydarlou Reza , Feenstra K. Anton 
Published: November 2024

ABSTRACTProtein interactions are crucial for understanding biological functions and disease mechanisms, but predicting these remains a complex task in computational biology. Increasingly, Deep Learning models are having success in interface prediction. This study presents PIPENN-EMB which explores the added value of using embeddings from theProtT5-XLprotein language model. Our results show substantial improvement over the previously published PIPENN model for protein interaction interface prediction, reaching an MCC of 0.313 vs. 0.249, and AUC-ROC 0.800 vs. 0.755 on theBIO_DL_TEtest set. We furthermore show that these embeddings cover a broad range of ‘hand-crafted’ protein features in ablation studies. PIPENN-EMB reaches state-of-the-art performance on theZK448dataset for protein-protein interface prediction. We showcase predictions on 25 resistance-related proteins fromMycobacterium tuberculosis. Furthermore, whereas other state-of-the-art sequence-based methods perform worse for proteins that have little recognisable homology in their training data, PIPENN-EMB generalises to remote homologs, yielding stable AUC-ROC across all three test sets with less than 30% sequence identity to the training dataset, and even to proteins with less than 15% sequence identity.AvailabilityWebserver, source code and datasets atwww.ibi.vu.nl/programs/pipennemb/
Dissociation of the nuclear basket triggers chromosome loss in aging yeast
Authors: Mirkovic Mihailo , McCarthy Jordan , Meinema Anne Cornelis , Parenteau Julie , Lee Sung Sik , Elela Sherif Abou , Barral Yves 
Published: November 2024

ABSTRACTIn many organisms, aging is a clear risk factor for increased rates of chromosome mis-segregation, the main source of aneuploidy. Here, we report that old yeast mother cells lose chromosomes by partitioning them asymmetrically to their daughter cells together with the pre-existing (old) Sindle Pole Body (centrosome equivalent in yeast). Strikingly, remodelling of the NPC and the displacement of its nuclear basket triggered these asymmetric segregation events. Concomitantly, basket displacement also caused unspliced pre-mRNAs to leak to the cytoplasm. We show that removing the introns of three genes involved in chromosome segregation was sufficient to fully suppress chromosome loss in old cells. Furthermore, promoting pre-mRNA leakage in young cells also caused asymmetric chromosome partition and loss through the same three introns. Therefore, we propose that basket displacement from NPCs and its ensuing effects on pre-mRNA quality control are a key trigger of aging phenotypes such as aneuploidy.
Subcellular plant carbohydrate metabolism under elevated temperature
Authors: Seydel Charlotte , Heß Martin , Schröder Laura , Klingl Andreas , Nägele Thomas 
Published: November 2024

AbstractIn many plant species, exposure to a changing environmental temperature regime induces an acclimation response which ultimately increases a plant’s thermotolerance. Under elevated temperature, membrane systems need remodelling to counteract de-stabilising thermodynamic effects. This also affects photosynthesis and carbohydrate metabolism due to heat affected protein functions, enzyme activities and transport processes across membrane systems. In the present study, a combination of electrolyte leakage assays and chlorophyll fluorescence measurements was applied to quantify heat tolerance before and after heat acclimation ofArabidopsis thalianaat different temperature regimes. Subcellular carbohydrate concentrations were determined in a combined approach of non-aqueous fractionation and 3D reconstruction of mesophyll cells and subcellular compartments using serial block-face scanning electron microscopy. Across temperature regimes between 32 °C and 38 °C, 7 days heat acclimation at 34 °C was found to most efficiently increase tissue heat tolerance. Under such conditions, cytosolic sucrose concentrations were stabilised by a shift of sucrose cleavage rates into the vacuolar compartment while invertase-driven cytosolic sucrose cleavage was found to be efficiently quenched by fructose and glucose acting as competitive and non-competitive inhibitors, respectively. Finally, this study provides strong evidence for a sucrose concentration gradient from the cytosol into the vacuole which might directly affect the physiological role and direction of proton gradient-driven sugar transport across the tonoplast.
Many transcription factor families have evolutionarily conserved binding motifs in plants
Authors: Zenker Sanja , Wulf Donat , Meierhenrich Anja , Viehöver Prisca , Becker Sarah , Eisenhut Marion , Stracke Ralf , Weisshaar Bernd , Bräutigam Andrea 
Published: November 2024

AbstractTranscription factors control gene expression during development and in response to a broad range of internal and external stimuli. They regulate promoter activity by directly bindingcis- regulatory elements in DNA. The angiospermArabidopsis thalianacontains more than 1,500 annotated transcription factors, each containing a DNA-binding domain that is used to define transcription factor families.Analyzing binding motifs of 686 and the binding sites of 335A. thalianatranscription factors as well as motifs of 92 transcription factors from other plants, we identified a constrained vocabulary of 74 conserved motifs spanning 50 families in plants. Among 21 transcription factor families, we found one core motif for all analyzed members and between 2 and 72% overlapping binding sites. Five families show conservation of the motif along phylogenetic clades. Five families including the C2H2 zinc finger family show high diversity among motifs in plants, suggesting potential for neofunctionalization of duplicated transcription factors based on the motif recognized. For conserved motifs we tested if they remained conserved since at least 450 million years ago by determining the binding motifs of 17 orthologous transcription factors from 11 families inM. polymorphausing amplified DNA affinity purification sequencing. We detected nearly identical binding motifs as predicted from the angiosperm data.Taken together, the results show a large repertoire of overlapping binding sites within a TF family and species and a high degree of binding motif conservation for at least 450 million years. The results indicate more potential for evolution incis-rather thantrans-regulatory elements.
The microbiome diversifiesN-acyl lipid pools - including short-chain fatty acid-derived compounds
Authors: Mannochio-Russo Helena , Charron-Lamoureux Vincent , van Faassen Martijn , Lamichhane Santosh , Gonçalves Nunes Wilhan D. , Deleray Victoria , Patan Abubaker , Vittali Kyle , Rajkumar Prajit , Abiead Yasin El , Zhao Haoqi Nina , Portal Gomes Paulo Wender , Mohanty Ipsita , Lee Carlynda , Sund Aidan , Sharma Meera , Liu Yuanhao , Pattynama David , Walker Gregory T. , Norton Grant J. , Khatib Lora , Andalibi Mohammadsobhan S. , Wang Crystal X. , Ellis Ronald J. , Moore David J. , Iudicello Jennifer E. , Franklin Donald , Letendre Scott , Chin Loryn , Walker Corinn , Renwick Simone , Zemlin Jasmine , Meehan Michael J. , Song Xinyang , Kasper Dennis , Burcham Zachary , Kim Jane J. , Kadakia Sejal , Raffatellu Manuela , Bode Lars , Zengler Karsten , Wang Mingxun , Siegel Dionicio , Knight Rob , Dorrestein Pieter C. 
Published: November 2024

AbstractN-acyl lipids are important mediators of several biological processes including immune function and stress response. To enhance the detection ofN-acyl lipids with untargeted mass spectrometry-based metabolomics, we created a reference spectral library retrievingN-acyl lipid patterns from 2,700 public datasets, identifying 851N-acyl lipids that were detected 356,542 times. 777 are not documented in lipid structural databases, with 18% of these derived from short-chain fatty acids and found in the digestive tract and other organs. Their levels varied with diet, microbial colonization, and in people living with diabetes. We used the library to link microbialN-acyl lipids, including histamine and polyamine conjugates, to HIV status and cognitive impairment. This resource will enhance the annotation of these compounds in future studies to further the understanding of their roles in health and disease and highlight the value of large-scale untargeted metabolomics data for metabolite discovery.
Histone variant H2BE controls activity-dependent gene expression and homeostatic scaling
Authors: Feierman Emily R. , Paranjapye Alekh , Su Steven , Qiu Qi , Wu Hao , Korb Erica 
Published: November 2024

SUMMARYA cell’s ability to respond and adapt to environmental stimuli relies in part on transcriptional programs controlled by histone proteins. Histones affect transcription through numerous mechanisms including through replacement with variant forms that carry out specific functions. We recently identified the first widely expressed H2B histone variant, H2BE and found that it promotes transcription and is critical for neuronal function and long-term memory. However, how H2BE is regulated by extracellular stimuli and whether it controls activity-dependent transcription and cellular plasticity remain unknown. We used CUT&Tag and RNA-sequencing of primary neurons, single-nucleus sequencing of cortical tissue, and multielectrode array recordings to interrogate the expression of H2BE in response to stimuli and the role of H2BE in activity-dependent gene expression and plasticity. We find that unlike Further, we show that neurons lacking H2BE are unable to mount proper long-term activity-dependent transcriptional responses both in cultured neurons and in animal models. Lastly, we demonstrate that H2BE knockout neurons fail to undergo the electrophysiological changes associated with homeostatic plasticity in neurons after long-term stimulation. In summary, these data demonstrate that H2BE expression is inversely correlated to activity and necessary for long-term activity-dependent responses, revealing the first instance of a histone variant involved in the homeostatic plasticity response in neurons.