bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combining protein sequences and structures with transformers and equivariant graph neural networks to predict protein function
Authors: Boadu Frimpong , Cao Hongyuan , Cheng Jianlin 
Published: January 2023

AbstractMotivationMillions of protein sequences have been generated by numerous genome and transcriptome sequencing projects. However, experimentally determining the function of the proteins is still a time consuming, low-throughput, and expensive process, leading to a large protein sequence-function gap. Therefore, it is important to develop computational methods to accurately predict protein function to fill the gap. Even though many methods have been developed to use protein sequences as input to predict function, much fewer methods leverage protein structures in protein function prediction because there was lack of accurate protein structures for most proteins until recently.ResultsWe developed TransFun - a method using a transformer-based protein language model and 3D-equivariant graph neural networks to distill information from both protein sequences and structures to predict protein function. It extracts feature embeddings from protein sequences using a pre-trained protein language model (ESM) via transfer learning and combines them with 3D structures of proteins predicted by AlphaFold2 through equivariant graph neural networks. Benchmarked on the CAFA3 test dataset and a new test dataset, TransFun outperforms several state-of-the-art methods, indicating the language model and 3D-equivariant graph neural networks are effective methods to leverage protein sequences and structures to improve protein function prediction. Combining TransFun predictions and sequence similarity-based predictions can further increase prediction accuracy.AvailabilityThe source code of TransFun is available athttps://github.com/jianlin-cheng/TransFunContactchengji@missouri.edu
Dating in the Dark: Elevated Substitution Rates in Cave Cockroaches (Blattodea: Nocticolidae) Have Negative Impacts on Molecular Date Estimates
Authors: Kovacs Toby G. L. , Walker James , Hellemans Simon , Bourguignon Thomas , Tatarnic Nikolai J. , Mcrae Jane M. , Ho Simon Y. W. , Lo Nathan 
Published: January 2023

AbstractRates of nucleotide substitution vary substantially across the Tree of Life, with potentially confounding effects on phylogenetic and evolutionary analyses. A large acceleration in mitochondrial substitution rate occurs in the cockroach family Nocticolidae, which predominantly inhabit subterranean environments. To evaluate the impacts of this among-lineage rate heterogeneity on estimates of phylogenetic relationships and evolutionary timescales, we analysed nuclear ultraconserved elements (UCEs) and mitochondrial genomes from nocticolids and other cockroaches. Substitution rates were substantially elevated in nocticolid lineages compared with other cockroaches, especially in mitochondrial protein-coding genes. This disparity in evolutionary rates is likely to have led to different evolutionary relationships being supported by phylogenetic analyses of mitochondrial genomes and UCE loci. Furthermore, Bayesian dating analyses using relaxed-clock models inferred much deeper divergence times compared with a flexible local clock. Our phylogenetic analysis of UCEs, which is the first genome-scale study to include all ten major cockroach families, unites Corydiidae and Nocticolidae and places Anaplectidae as the sister lineage to the rest of Blattoidea. We uncover an extraordinary level of genetic divergence in Nocticolidae, including two highly distinct clades that separated ∼115 million years ago despite both containing representatives of the genusNocticola. The results of our study highlight the potential impacts of high among-lineage rate variation on estimates of phylogenetic relationships and evolutionary timescales.
Implantable flexible multielectrode arrays for multi-site sensing of serotonin tonic levels
Authors: Castagnola Elisa , Robbins Elaine M. , Krahe Daniela , Wu Bingchen , Pwint May Yoon , Cao Qun , Cui Xinyan Tracy 
Published: January 2023

AbstractReal-time multi-channel measurements of tonic serotonin (5-hydroxytryptamine, 5-HT) concentrations across different brain regions are of utmost importance to the understanding of 5-HT’s role in anxiety, depression, and impulse control disorders, which will improve the diagnosis and treatment of these neuropsychiatric illnesses. Chronic sampling of 5-HT is critical in tracking disease development as well as the time course of pharmacological treatments. Despite their value,in vivochronic multi-site measurements of 5-HT have not been reported.To fill this technological gap, we batch fabricated implantable glassy carbon (GC) microelectrode arrays (MEAs) on a flexible SU-8 substrate to provide an electrochemically stable and biocompatible device/tissue interface. Then, to achieve multi-site detection of tonic 5-HT concentrations, we incorporated the poly(3,4-ethylenedioxythiophene)/functionalized carbon nanotube (PEDOT/CNT) coating on the GC microelectrodes in combination with a new square wave voltammetry (SWV) approach, optimized for selective 5-HT measurement.In vitro, the PEDOT/CNT coated GC microelectrodes achieved high sensitivity towards 5-HT, good fouling resistance in the presence of 5-HT, and excellent selectivity towards the most common neurochemical interferents.In vivo, our PEDOT/CNT-coated GC MEAs were able to successfully detect basal 5-HT concentrations at different locations of the CA2 hippocampal region of mice in both anesthetized and awake head-fixed conditions. Furthermore, the implanted PEDOT/CNT-coated MEA achieved stable detection of tonic 5-HT concentrations for one week. Finally, histology data in the hippocampus shows reduced tissue damage and inflammatory responses compared to stiff silicon probes. To the best of our knowledge, this PEDOT/CNT-coated GC MEA is the first implantable flexible multisite sensor capable of chronicin vivomulti-site sensing of tonic 5-HT. This implantable MEA can be custom-designed according to specific brain region of interests and research questions, with the potential to combine electrophysiology recording and multiple analyte sensing to maximize our understanding of neurochemistry.HighlightsPEDOT/CNT-coated GC microelectrodes enabled sensitive and selective tonic detection of serotonin (5-HT) using a new square wave voltammetry (SWV) approachPEDOT/CNT-coated GC MEAs achieved multi-sitein vivo5-HT tonic detection for one week.Flexible MEAs lead to reduced tissue damage and inflammation compared to stiff silicon probes.
Long COVID brain fog and muscle pain are associated with longer time to clearance of SARS-CoV-2 RNA from the upper respiratory tract during acute infection
Authors: Antar Annukka A. R. , Yu Tong , Demko Zoe O , Hu Chen , Tornheim Jeffrey A. , Blair Paul W. , Thomas David L. , Manabe Yukari C. ,   OutSMART Study Group
Published: January 2023

AbstractThe incidence of long COVID is substantial, even in people who did not require hospitalization for acute COVID-19. The pathobiological mechanisms of long COVID and the role of early viral kinetics in its development are largely unknown. Seventy-three non-hospitalized adult participants were enrolled within approximately 48 hours of their first positive SARS-CoV-2 RT-PCR test, and mid-turbinate nasal and saliva samples were collected up to 9 times within the first 45 days after enrollment. Samples were assayed for SARS-CoV-2 using RT-PCR and additional test results were abstracted from the clinical record. Each participant indicated the presence and severity of 49 long- COVID symptoms at 1-, 3-, 6-, 12-, and 18-months post-COVID-19 diagnosis. Time from acute COVID-19 illness onset to SARS-CoV-2 RNA clearance greater or less than 28 days was tested for association with the presence or absence of each of 49 long COVID symptoms at 90+ days from acute COVID-19 symptom onset. Brain fog and muscle pain at 90+ days after acute COVID-19 onset were negatively associated with viral RNA clearance within 28 days of acute COVID-19 onset with adjustment for age, sex, BMI ≥ 25, and COVID vaccination status prior to COVID-19 (brain fog: aRR 0.46, 95% CI 0.22-0.95; muscle pain: aRR 0.28, 95% CI 0.08-0.94). This work indicates that at least two long COVID symptoms - brain fog and muscle pain – at 90+ days from acute COVID-19 onset are specifically associated with longer time to clearance of SARS-CoV-2 RNA from the upper respiratory tract.
Effect of soilless media on small-scale propagation ofPinguicula gigantea
Authors: Tarner Kevin , Jones Hakon , Ingwers Mile , Gaya Heather , McNair Mason 
Published: January 2023

AbstractBecause of their large size, colorful flowers, and insectivorous habit, butterworts (genusPinguicula)are desirable ornamental plants among hobbyists and botanical conservatories. Propagation via leaves is a popular propagation method for the genus, especially for tropical species.P. gigantea, a species found approximately 700m above sea level in Oaxaca, Mexico, was selected to evaluate its preference for various blends of soilless media. This study found that number of leaves produced by plantlets is significantly impacted by soil type. However, there was no significant difference in biomass, plantlet diameter or average number of plantlets produced between soil treatments. These results suggest that soils with high nitrogen content may promote increased leaf number, but do not significantly affect plant biomass.
Proteomics of the astrocyte secretome reveals changes in their response to soluble oligomeric Aß
Authors: Matafora Vittoria , Gorb Alena , Noble Wendy , Bachi Angela , Perez-Nievas Beatriz Gomez , Jimenez-Sanchez Maria 
Published: January 2023

ABSTRACTAstrocytes associate with amyloid plaques in Alzheimer’s disease (AD). Astrocytes react to changes in the brain environment, including to increasing concentrations of amyloid-ß (Aß). However, the precise response of astrocytes to soluble small Aß oligomers at concentrations similar to those present in the human brain has not been addressed. In this study, we exposed astrocytes to neuronal media containing soluble human Aß oligomers and used proteomics to investigate changes in the astrocyte secretome. Our data shows dysregulated secretion of astrocytic proteins involved in the extracellular matrix and cytoskeletal organization and increase secretion of proteins involved in oxidative stress responses and those with chaperone activity. Several of these proteins have been identified in previous transcriptomic and proteomic studies using brain tissue from human AD and cerebrospinal fluid (CSF). Our work highlights the relevance of studying astrocyte secretion to understand the brain response to AD pathology and the potential use of these proteins as biomarkers for the disease.
Lineage tracing identifies heterogeneous hepatoblast contribution to cell lineages and postembryonic organ growth dynamics
Authors: Unterweger Iris. A. , Klepstad Julie , Hannezo Edouard , Lundegaard Pia R. , Trusina Ala , Ober Elke A. 
Published: January 2023

AbstractTo meet the physiological demands of the body, organs need to establish a functional tissue architecture and adequate size as the embryo develops to adulthood. In the liver, uni- and bipotent progenitor differentiation into hepatocytes and biliary epithelial cells (BECs), and their relative proportions comprise the functional architecture. Yet, the contribution of individual liver progenitors at the organ level to both fates, and their specific proportion is unresolved. Combining mathematical modelling with organ-wide, multispectral FRaeppli-NLS lineage tracing in zebrafish, we demonstrate that a precise BEC to hepatocyte ratio is established (i) fast, (ii) solely by heterogeneous lineage decisions from uni- and bipotent progenitors, and (iii) independent of subsequent cell type-specific proliferation. Extending lineage tracing to adulthood determined that embryonic cells undergo spatially heterogeneous three-dimensional growth associated with distinct environments. Strikingly, giant clusters comprising almost half a ventral lobe suggest lobe-specific dominant-like growth behaviours. We show substantial hepatocyte polyploidy in juveniles representing another hallmark of postembryonic liver growth. Our findings uncover heterogeneous progenitor contributions to tissue architecture-defining cell type proportions and postembryonic organ growth as key mechanisms forming the adult liver.
Mll1 pioneers histone H3K4me3 deposition and promotes formation of CD8+T stem cell memory
Authors: Getzler Adam J. , Frederick Megan A. , Milner Justin J. , Venables Thomas , Diao Huitian , Toma Clara , Nagaraja Shashank D. , Albao Dominic S. , Bélanger Simon , Tsuda Shanel M. , Kim Jihye , Crotty Shane , Goldrath Ananda W. , Pipkin Matthew E. 
Published: January 2023

AbstractCD8+T cells with stem cell-like properties (TSCM) sustain adaptive immunity to intracellular pathogens and tumors. However, the developmental origins and chromatin regulatory factors (CRFs) that establish their differentiation are unclear. Using an RNA interference screen of all CRFs we discovered the histone methylase Mll1 was required during T cell receptor (TCR) stimulation for development of a TSCMprecursor state and mature memory (TMEM) cells, but not short-lived or transitory effector cell-like states, in response to viral infections and tumors. Mll1 was essential for widespreadde novodeposition of histone H3 lysine 4 trimethylation (H3K4me3) upon TCR stimulation, which accounted for 70% of all activation-induced sites in mature TMEMcells. Mll1 promoted both H3K4me3 deposition and reduced TCR-induced Pol II pausing at genes whose single-cell transcriptional dynamics explained trajectories into nascent TSCMprecursor states during viral infection. Our results suggest Mll1-dependent control of Pol II elongation and H3K4me3 establishes and maintains differentiation of CD8+TSCMcell states.
Immune-mediated tumor control in the 5TGM1 transfer model of multiple myeloma
Authors: Kellermayer Zoltán , Tahri Sabrin , de Jong Madelon M. E. , Papazian Natalie , Fokkema Cathelijne , Hoogenboezem Remco , Sanders Mathijs A. , Boon Louis , Hollander Chelsea Den , Broijl Annemiek , Sonneveld Pieter , Cupedo Tom 
Published: January 2023

AbstractMultiple myeloma is a disease of malignant plasma cells residing in the bone marrow, where interactions with local immune cells are thought to contribute to disease pathobiology. However, since a multiple myeloma diagnosis is virtually always preceded by an asymptomatic precursor phase, identifying early alterations in the bone marrow micro-environment following occupation by multiple myeloma cells remains challenging. Here we used the 5TGM1 transfer model of murine myeloma in combination with myeloma-permissive KaLwRij mice and myeloma-resistant C57Bl/6 mice and hypothesized that differential sensitivity to myeloma in these HLA-identical mouse strains has an immunological basis and might allow for dissection of early immune responses to myeloma cells.Using flow cytometry and single-cell RNA sequencing we show that C57Bl/6 mice can restrain tumor growth for prolonged periods, associated with activation of cytotoxic immune responses that were absent from KaLwRij mice. Transcriptional analysis of immune cells and stromal cells identified a central role for IFN-signaling in tumor containment, and antibody-mediated neutralization of IFNγ increased both incidence and outgrowth of multiple myeloma in C57Bl/6 mice. Together these findings highlight the ability of a fully functional immune system to control multiple myeloma progression in an IFNγ−dependent manner and suggest that transfer of 5TGM1 cells into parental C57Bl/6 mice can serve as a faithful model to track anti-myeloma immune responses in immune competent and genetically modifiable mice.
Postinspiratory complex acts as a gating mechanism regulating swallow-breathing coordination and other laryngeal behaviors
Authors: Huff Alyssa , Karlen-Amarante Marlusa , Oliveira Luiz Marcelo , Ramirez Jan Marino 
Published: January 2023

AbstractBreathing needs to be tightly coordinated with upper airway behaviors, such as swallowing. Discoordination leads to aspiration pneumonia, the leading cause of death in neurodegenerative diseases. Here we study the role of the postinspiratory complex, (PiCo) in coordinating breathing and swallowing. Using optogenetic approaches in freely breathing-anesthetized ChATcre, Vglut2cre and co-transmission of ChATcre/Vglut2FlpO mice reveals this small brainstem microcircuit acts as a central gating mechanism for airway protective behaviors. Activation of PiCo during inspiration or the beginning of postinspiration triggers swallow behavior, while there is a higher probability for stimulating laryngeal activation when activated further into expiration, suggesting PiCo’s role in swallow-breathing coordination. PiCo triggers consistent swallow behavior and preserves physiologic swallow motor sequence, while stimulates laryngeal activation variable to stimulation duration. Sufficient bilateral PiCo activation is necessary for gating function since activation of only a few PiCo neurons or unilateral activation leads to blurred behavioral response. Viral tracing experiments reveal projections from the caudal nucleus of the solitary tract (cNTS), the presumed swallow pattern generator (SPG), to PiCo and vice versa. However, PiCo does not directly connect to laryngeal muscles. Investigating PiCo’s role in swallow and laryngeal coordination will aid in understanding discoordination in breathing and neurological diseases.
Single-cell RNA sequencing reveals aortic cellular heterogeneity in MSC_ITGB3-treated ApoE-/- mice on a high-fat diet
Authors: Hu Haijuan , Liu Demin , Geng Xue , Han Mei , Cui Wei 
Published: January 2023

AbstractThe aorta contains various cell types that are involved in the development of vascular inflammation and atherosclerosis. However, the cellular atlas of heterogeneous aorta cells, cellular responses, and intercellular communication has not been investigated in the background of a high-fat diet (HFD) and treatment with integrin beta 3-modified mesenchymal stem cells (MSC_ITGB3). In this study, 33,782 individual cells from mouse aortas under HFD with or without MSC_ITGB3 treatment were subjected to single-cell RNA sequencing as an unbiased analysis strategy. We generated a compendium of 30 different clusters, mainly smooth muscle cells (SMCs), endothelial cells, and immune cells. The proportion of the different cell types was considerably influenced by HFD and MSC_ITGB3. In the HFD group, genes associated with proliferation, migration, and collagen were highly expressed in the major SMC subpopulations. However, the expression of contraction-related genes in SMC subpopulations was significantly higher in the MSC_ITGB3 group than in the HFD group. After HFD consumption, subpopulations of ECs with active PI3K-Akt signaling pathway, ECM-receptor interaction, and contraction-related genes were significantly enriched. In the MSC_ITGB3 group, the number of dendritic cells (DCs), which are positively correlated with atherosclerotic lesion progression and contribute to lipid accumulation, and levels of inflammatory factors notably decreased. Our findings provide data on the composition, signaling pathways, and cellular communication of the aorta cells following stem cell treatment as well as on the evolution and progression of atherosclerotic disease. The findings may help in improving the treatment of atherosclerosis.
Sas3-mediated histone acetylation regulates effector gene activation in a fungal plant pathogen
Authors: Suarez-Fernandez Marta , Álvarez-Aragón Rocío , Pastor-Mediavilla Ana , Maestre-Guillén Alejandro , del Olmo Ivan , De Francesco Agustina , Meile Lukas , Sánchez-Vallet Andrea 
Published: January 2023

ABSTRACTEffector proteins are secreted by plant pathogens to enable host colonization. Typically, effector genes are tightly regulated, have very low expression levels in axenic conditions, and are strongly induced during host colonization. Chromatin remodeling contributes to the activation of effector genesin plantaby still poorly known mechanisms. In this work we investigated the role of histone acetylation in effector gene derepression in plant pathogens. We usedZymoseptoria tritici, a major pathogen of wheat, as a model to determine the role of lysine acetyltransferases (KATs) in plant infection. We showed that effector gene activation is associated with chromatin remodeling, featuring increased acetylation levels of histone H3 lysine 9 (H3K9) and 14 (H3K14) in effector loci. We functionally characterized the role ofZ. triticiKATs and demonstrated their distinct contributions to growth, development, and infection. Sas3 is required for host colonization and pycnidia production, while Gcn5 has a major role in pycnidia production. Furthermore, we demonstrated that Sas3 is involved in acetylation of H3K9 and H3K14 in effector loci and in effector gene activation during plant infection. We propose that Sas3-mediated histone acetylation is required for spatiotemporal activation of effector genes and virulence ofZ. tritici.IMPORTANCEPathogen infections require the production of effectors that enable host colonization. Effectors have diverse functions and are only expressed at certain stages of the infection cycle. Thus, effector genes are tightly regulated by several mechanisms, including chromatin remodeling. Here, we investigate the role of histone acetylation in effector gene activation in the fungal wheat pathogenZymoseptoria tritici. We demonstrated that lysine acetyltransferases (KATs) are essential for the spatiotemporal regulation of effector genes. We show that two KATs, Sas3 and Gcn5, are involved in leaf symptom development and pycnidia formation. Importantly, our results indicated that Sas3 controls histone acetylation of effector loci and is a regulator of effector gene activation during stomatal penetration. Overall, our work demonstrates the key role of histone acetylation in regulating gene expression associated with plant infection.
Cracking the black box of deep sequence-based protein-protein interaction prediction
Authors: Bernett Judith , Blumenthal David B. , List Markus 
Published: January 2023

AbstractIdentifying protein-protein interactions (PPIs) is crucial for deciphering biological pathways. Numerous prediction methods have been developed as cheap alternatives to biological experiments, reporting surprisingly high accuracy estimates. We systematically investigated how much reproducible deep learning models depend on data leakage, sequence similarities, and node degree information, and compared them to basic machine learning models. We found that overlaps between training and test sets resulting from random splitting lead to strongly overestimated performances. In this setting, models learn solely from sequence similarities and node degrees. When data leakage is avoided by minimizing sequence similarities between training and test set, performances become random. Moreover, baseline models directly leveraging sequence similarity and network topology show good performances at a fraction of the computational cost. Thus, we advocate that any improvements should be reported relative to baseline methods in the future. Our findings suggest that predicting protein-protein interactions remains an unsolved task for proteins showing little sequence similarity to previously studied proteins, highlighting that further experimental research into the “dark” protein interactome and better computational methods are needed.