bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evolution of drug resistance drives progressive destabilizations in functionally conserved molecular dynamics of the flap region of the HIV-1 protease
Authors: Rajendran Madhusudan , Ferran Maureen C. , Mouli Leora , Everingham Eric , Babbitt Gregory A. , Lynch Miranda L. 
Published: November 2022

AbstractThe HIV-1 protease is one of several common key targets of combination drug therapies for human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS). During the progression of the disease, some individual patients acquire -drug resistance due to mutational hotspots on the viral proteins targeted by combination drug therapies. It has recently been discovered that drug-resistant mutations accumulate on the ‘flap region’ of the HIV-1 protease, which is a critical dynamic region involved in non-specific polypeptide binding during invasion and infection of the host cell. In this study, we utilize machine learning assisted comparative molecular dynamics, conducted at single amino acid site resolution, to investigate the dynamic changes that occur during functional dimerization and polypeptide binding of the main protease. We use a multi-agent machine learning model to identify conserved dynamics of the HIV-1 main protease that are preserved across simian and feline protease orthologs (SIV and FIV). We also investigate changes in dynamics due to common drug-resistant mutations in many patients. We find that a key functional site in the flap region, a solvent-exposed isoleucine (ILE50) and surrounding sites that control flap dynamics is often targeted by drug-resistance mutations, likely leading to malfunctional molecular dynamics affecting the overall flexibility of the flap region. We conclude that better long term patient outcomes may be achieved by designing drugs that target protease regions which are less dependent upon single sites with large functional binding effects.
Fatty acid elongases 1-3 have distinct roles in mitochondrial function, growth and lipid homeostasis inTrypanosoma cruzi
Authors: Pagura Lucas , Dumoulin Peter C. , Ellis Cameron C. , Estevao Igor L. , Mendes Maria T. , Almeida Igor C. , Burleigh Barbara A. 
Published: November 2022

AbstractTrypanosomatids are a diverse group of uniflagellate protozoa that include globally important pathogens such asTrypanosoma cruzi, the causative agent of Chagas disease. Trypanosomes lack the fatty acid synthase (FAS)-I system typically used forde novosynthesis of long chain fatty acids (LCFA) in other eukaryotes. Instead, these microbes have evolved a modular fatty acid elongase (ELO) system comprised of individual ELO enzymes that operate processively. The role of the ELO system in maintaining lipid homeostasis in trypanosomes has not been determined. Here we demonstrate that ELO2 and ELO3 are required for global lipidome maintenance in the insect stage ofT. cruziwhereas ELO1 is dispensable for this function. Instead, ELO1 activity is needed to sustain mitochondrial activity and normal growth. The cross-talk between microsomal ELO1 and the mitochondrion is a novel finding that merits examination of the trypanosomatid ELO pathway as critical for central metabolism.
Modulatory effect of non-invasive prefrontal brain stimulation on risk-taking behaviours in humans: preliminary insight on the influence of personality traits
Authors: de la Torre Ona Martin , Valero-Cabré Antoni , Gallardo-Pujol David , Redolar-Ripoll Diego 
Published: November 2022

AbstractWe investigated the modulatory effects of cathodal High-Definition transcranial Direct Current Stimulation (HD-tDCS) on the left dorsolateral prefrontal cortex (DLPFC) and the left ventrolateral prefrontal cortex (VLPFC) on risk-taking.MethodsThirty-four healthy adults underwent 3 independent cathodal HD-tDCS interventions (DLPFC, VLPFC, sham) delivered in counterbalanced order during the performance of the balloon analogue risk task (autoBART). Participants were clustered post-hoc in 3 separate personality profiles according to the HEXACO-60 and the Dark Triad dirty dozen and we reanalysed the data.ResultsDorsal prefrontal cathodal HD-tDCS significantly modulated autoBART performance rendering participants less prone to risk-taking (i.e., more conservative) under left DLPFC HD-tDCS compared to left VLPFC or sham stimulation. The re-analysis of the same dataset, taking into consideration personality traits, suggested specific effects in impulsive-disinhibited and normative participants for DLPFC and VLPFC stimulation, respectively. Specifically, we saw that participants classified as impulsive-disinhibited were more affected by HD-tDCS left DLPFC stimulation than other profiles.ConclusionsBoth, dorsal and ventral prefrontal active HD-tDCS decrease risk-taking behaviour compared to sham stimulation. Importantly, such effects are likely influenced by personality traits (impulsive disinhibited vs normative) exhibited by the participants.HighlightsWe investigated the effect of dorsal and ventral prefrontal HD-tDCS on risk-taking.We considered post-hoc, the influence of individual personality differences.Dorsal and ventral Prefrontal cathodal HD-tDCS decreased risk-taking behaviour.Left cathodal DLPFC HD-tDCS decreased risk propensity in impulsive-disinhibited participants.Left cathodal VLPFC HD-tDCS decreased risk propensity in normative personality participants.
A ubiquitination-mediated degradation system to target phospho-14-3-3-binding-motif embedded proteins
Authors: Li Zhaokai , Huang Xiaoqiang , Li Mohan , Sabry Ziad , Chen Y. Eugene , Wang Zhong , Liu Liu 
Published: November 2022

AbstractThe phosphorylation of 14-3-3 binding motif is involved in many cellular processes. A strategy that enables targeted degradation of phospho-14-3-3-binding-motif embedded (P-14-3-3-BME) proteins for studying their functions is highly desirable for basic research. Here, we report a phosphorylation-induced, ubiquitin-proteasome-system-mediated targeted protein degradation (TPD) strategy that allows specific degradation of P-14-3-3-BME proteins. Specifically, by ligating a modified von Hippel-Lindau E3-ligase with an engineered 14-3-3 bait, we generated a protein chimera referred to as Targeted Degradation of P-14-3-3-BME Protein (TDPP). TDPP can serve as a universal degrader for P-14-3-3-BME proteins based on the specific recognition of the phosphorylation in 14-3-3 binding motifs. TDPP shows high efficiency and specificity to a difopein-EGFP reporter, general and specific P-14-3-3-BME proteins. TDPP can also be applied for the validation of P-14-3-3-BME proteins. These results strongly support TDPP as a powerful tool for 14-3-3 related research.
Deficits in integrative NMDA receptors caused byGrin1disruption can be rescued in adulthood
Authors: Venkatesan S. , Binko M.A. , Mielnik C.A. , Ramsey A.J. , Lambe E.K. 
Published: November 2022

AbstractGlutamatergic NMDA receptors (NMDAR) are critical for cognitive function, and their reduced expression leads to intellectual disability. Since subpopulations of NMDARs exist in distinct subcellular environments, their functioning may be unevenly vulnerable to genetic disruption. Here, we investigate synaptic and extrasynaptic NMDARs on the major output neurons of the prefrontal cortex in mice deficient for the obligate NMDAR subunit encoded byGrin1and wild-type littermates. With whole-cell recording in brain slices, we find that single, low-intensity stimuli elicit surprisingly-similar glutamatergic synaptic currents in both genotypes. By contrast, clear genotype differences emerge with manipulations that recruit extrasynaptic NMDARs, including stronger, repetitive, or pharmacological stimulation. These results reveal a disproportionate functional deficit of extrasynaptic NMDARs compared to their synaptic counterparts. To probe the repercussions of this deficit, we examine an NMDAR-dependent phenomenon considered a building block of cognitive integration, basal dendrite plateau potentials. Since we find this phenomenon is readily evoked in wild-type but not inGrin1-deficient mice, we ask whether plateau potentials can be restored by an adult intervention to increaseGrin1expression. This genetic manipulation, previously shown to restore cognitive performance in adulthood, successfully rescues electrically-evoked basal dendrite plateau potentials after a lifetime of NMDAR compromise. Taken together, our work demonstrates NMDAR subpopulations are not uniformly vulnerable to the genetic disruption of their obligate subunit. Furthermore, the window for functional rescue of the more-sensitive integrative NMDARs remains open into adulthood.
Mutations in Complex I of the mitochondrial electron-transport chain sensitize the fruit fly (Drosophila melanogaster) to ether and non-ether volatile anesthetics
Authors: Borchardt Luke , Scharenbrock Amanda R. , Olufs Zachariah P. G. , Wassarman David A. , Perouansky Misha 
Published: November 2022

AbstractThe mitochondrial electron transport chain (mETC) contains molecular targets of volatile general anesthetics (VGAs), which places carriers of mutations at risk for anesthetic complications. TheND-2360114andmt:ND2del1lines of fruit flies (Drosophila melanogaster) that carry mutations in core subunits of Complex I of the mETC, replicate numerous characteristics of Leigh syndrome (LS) caused by orthologous mutations in mammals and serve as models of LS.ND-2360114flies are behaviorally hypersensitive to volatile anesthetic ethers and develop an age- and oxygen-dependent anesthetic-induced neurotoxicity (AiN) phenotype after exposure to isoflurane but not to the related anesthetic sevoflurane. The goal of this paper was to investigate whether the alkane volatile anesthetic halothane and other mutations in Complex I and in Complexes II-V of the mETC cause AiN. We found that (i)ND-2360114andmt:ND2del1were susceptible to toxicity from halothane; (ii) in wildtype flies halothane was toxic under anoxic conditions; (iii) alleles of accessory subunits of Complex I predisposed to AiN; and (iv) mutations in Complexes II-V did not result in an AiN phenotype. We conclude AiN is neither limited to ether anesthetics nor exclusive to mutations in core subunits of Complex I.Previous presentationsparts of the data were presented in abstract form at the 63rdAnnual Drosophila Research Conference in San Diego, March 2022.
Accuratede novodetection of somatic mutations in high-throughput single-cell profiling data sets
Authors: Muyas Francesc , Li Ruoyan , Rahbari Raheleh , Mitchell Thomas J. , Hormoz Sahand , Cortés-Ciriano Isidro 
Published: November 2022

AbstractCharacterization of somatic mutations at single-cell resolution is essential to study cancer evolution, clonal mosaicism, and cell plasticity. However, detection of mutations in single cells remains technically challenging. Here, we describe SComatic, an algorithm designed for the detection of somatic mutations in single-cell transcriptomic and ATAC-seq data sets without requiring matched bulk or single-cell DNA sequencing data. Using >1.5M single cells from 383 single-cell RNAseq and single-cell ATAC-seq data sets spanning cancer and non-neoplastic samples, we show that SComatic detects mutations in single cells, even in differentiated cells from polyclonal tissues not amenable to mutation detection using existing methods. In addition, SComatic permits the estimation of mutational burdens andde novomutational signature analysis at single-cell and cell-type resolution. Notably, using matched exome and single-cell RNAseq data, we show that SComatic achieves a 20 to 40-fold increase in precision as compared to existing algorithms for somatic SNV calling without compromising sensitivity. Overall, SComatic opens the possibility to study somatic mutagenesis at unprecedented scale and resolution using high-throughput single-cell profiling data sets.
A novel crosstalk between Nrf2 and Smad2/3 bridged by two nuanced Keap1 isoforms
Authors: Chen Feilong , Wang Qing , Xiao Mei , Lou Deshuai , Wufur Reziyamu , Hu Shaofan , Zhang Zhengwen , Wang Yeqi , Zhang Yiguo 
Published: November 2022

AbstractThe Keap1-Nrf2 signalling to transcriptionally regulate antioxidant response element (ARE)-driven target genes has been accepted as key redox-sensitive pathway governing a vast variety of cellular stresses during healthy survival and disease development. Herein, we identified two nuanced isoforms α and β of Keap1, arising from its first and another in-frame translation starting codons, respectively. In identifying those differential expression genes monitored by Keap1α and/or Keap1β, an unusual interaction of Keap1 with Smad2/3 was discovered by parsing transcriptome sequencing, Keap1-interacting protein profiling and relevant immunoprecipitation data. Further examination validated that Smad2/3 enable physical interaction with Keap1, as well as its isoforms α and β, by both EDGETSD and DLG motifs in the linker regions between their MH1 and MH2 domains, such that the stability of Smad2/3 and its transcriptional activity are enhanced with the prolonged half-lives and signalling responses from the cytoplasmic to nuclear compartments. The activation of Smad2/3 by Keap1, Keap1α or Keap1β was likely contributable to a coordinative or another competitive effect of Nrf2, particularly in distinct Keap1-based cellular responses to its cognate growth factor or redox stress. Overall, this discovery presents a novel functional bridge crossing both the Keap1-Nrf2 redox signalling and the TGF-β1-Smad2/3 pathways in healthy growth and development.
PilD mutant is a new cheater inPseudomonas aeruginosaquorum-sensing evolution
Authors: Qiu Huifang , Dai Weijun 
Published: November 2022

AbstractPathogen virulence is largely driven by the evolution and adaptation of the genome. LasR is a master regulator of quorum-sensing (QS) system. The QS-inactive LasR-null mutant regains QS activation in a laboratory evolution experiment through obtaining mutations inmexT, a gene encoding transcriptional regulator. How the QS-active LasR-MexT mutant continuously evolves is still unknown. Here we passaged the LasR-MexT mutant in casein broth and monitored its evolutionary trajectory. By examining the proteolytic phenotype of isolated single colonies, we found a protease-negative subpopulation arising from the parental population. The whole genome sequencing analysis revealed that these protease-negativ colonies bear mutations inpilDgene. In accordance with its role as a prepilin peptidase of type IV system, PilD mutants are defective in twitching motility. In conclusion, we identified a new PilD mutant cheater that evolved from the parental LasR-MexT mutant population. Our work demonstrates that population evolution is highly dynamics, with arising of distinct subpopulations containing different social behaviors.
OPUS-DSD: Deep Structural Disentanglement for cryo-EM Single Particle Analysis
Authors: Luo Zhenwei , Ni Fengyun , Wang Qinghua , Ma Jianpeng 
Published: November 2022

AbstractMany Cryo-EM datasets contain structural heterogeneity due to functional or nonfunctional dynamics that conventional reconstruction methods may fail to resolve. Here we propose a new method, OPUS-DSD (Deep Structural Disentanglement), which can reliably reconstruct the structural landscape of cryo-EM data by directly translating the 2D cryo-EM images into 3D structures. The method adopts a convolutional neural network and is regularized by a latent space prior that encourages the encoding of structural information. The performance of OPUS-DSD was systematically compared to a previously reported method, cryoDRGN, on synthetic and real cryo-EM data. It consistently outperformed existing methods, resolved large or small structural heterogeneity, and improved the final reconstructions of tested systems even on highly noisy cryo-EM data. The results have shown that OPUS-DSD should be particularly suitable for cases in which the high structural flexibilities cannot easily be represented by rigid-body movements. Therefore, OPUS-DSD represents a valuable tool that can not only recover functionally-important structural dynamics missed in a traditional cryo-EM refinement, but also improve the final reconstruction by increasing homogeneity in a dataset. OPUS-DSD is available athttps://github.com/alncat/opusDSD.
SARS-CoV-2 evolves increased infection elicited cell death and fusion in an immunosuppressed individual
Authors: Lustig Gila , Ganga Yashica , Rodel Hylton , Tegally Houriiyah , Jackson Laurelle , Cele Sandile , Khan Khadija , Jule Zesuliwe , Reedoy Kajal , Karim Farina , Bernstein Mallory , Moosa Mahomed-Yunus S. , Archary Derseree , de Oliveira Tulio , Lessells Richard , Abdool Karim Salim S. , Sigal Alex 
Published: November 2022

AbstractThe milder clinical manifestations of Omicron infection relative to pre-Omicron SARS-CoV-2 raises the possibility that extensive evolution results in reduced pathogenicity. To test this hypothesis, we quantified induction of cell fusion and cell death in SARS-CoV-2 evolved from ancestral virus during long-term infection. Both cell fusion and death were reduced in Omicron BA.1 infection relative to ancestral virus. Evolved virus was isolated at different times during a 6-month infection in an immunosuppressed individual with advanced HIV disease. The virus isolated 16 days post-reported symptom onset induced fusogenicity and cell death at levels similar to BA.1. However, fusogenicity was increased in virus isolated at 6 months post-symptoms to levels intermediate between BA.1 and ancestral SARS-CoV-2. Similarly, infected cell death showed a graded increase from earlier to later isolates. These results may indicate that, at least by the cellular measures used here, evolution in long-term infection does not necessarily attenuate the virus.
Reconstructing the formation of Hmong-Mien genetic fine-structure
Authors: Xia Zi-Yang , Chen Xingcai , Wang Chuan-Chao , Deng Qiongying 
Published: November 2022

AbstractThe linguistic, historical, and subsistent uniqueness of Hmong-Mien (HM) speakers offers a wonderful opportunity to investigate how these factors impact the genetic structure. Nevertheless, the genetic differentiation among HM-speaking populations and the formation process behind are far from well characterized in previous studies. Here, we generated genome-wide data from 67 Yao ethnicity samples and analyzed them together with published data, particularly by leveraging haplotype-based methods. We identify that the fine-scale genetic substructure of HM-speaking populations corresponds better to linguistic classification than to geography, while the parallel of serial founder events and language differentiations can be found in West Hmongic speakers. Multiple lines of evidence indicate that ~500-year-old GaoHuaHua individuals are most closely related to West Hmongic-speaking Bunu. The excessive level of the genetic bottleneck of HM speakers, especially Bunu, is in agreement with their long-term practice of slash-and-burn agriculture. The inferred admixture dates in most of the HM-speaking populations overlap the reign of the Ming dynasty (1368 – 1644 CE). Besides the common genetic origin of HM speakers, their external ancestry majorly comes from neighboring Han Chinese and Kra-Dai speakers in South China. Conclusively, our analysis reveals the recent isolation and admixture events that contribute to the fine-scale genetic formation of present-day HM-speaking populations underrepresented in previous studies.
AGO2a but not AGO2b mediates antiviral defense against the infection of wildtype Cucumber mosaic virus in tomato
Authors: Zhao Li-Ling , Chen Ying-Fang , Xiao Xing-Ming , Gao Hai-Ying , Cao Jia-Min , Zhang Zhong-Kai , Guo Zhongxin 
Published: November 2022

ABSTRACTEvolutionarily conserved antiviral RNA interference (RNAi) mediates a primary antiviral innate immunity preventing the infection of broad spectrum viruses in plants. However, the detailed mechanism in plants is still largely unknown, especially in important agricultural crops including tomato. On the other aspect, varieties of pathogenic viruses evolve to possess Viral Suppressor of RNA silencing (VSR) to suppress antiviral RNAi in host. Due to the prevalence of VSR, it is still skeptical that antiviral RNAi truly functions to prevent the invasion of natural wildtype viruses in plants and animals. In the research, it is for the first time we applied CRISPR-Cas9 to generateago2a, ago2borago2abmutants for two differentiatedSolanum lycopersicumAGO2, one key effector in antiviral RNAi. We found that AGO2a but not AGO2b was significantly induced to inhibit the propagation of not only VSR-deficient Cucumber mosaic virus (CMV) but also wildtype CMV-Fny in tomato, however, both AGO2a and AGO2b did not regulate disease induction after the infection of either virus. Our findings firstly reveal a prominent role of AGO2a in antiviral RNAi innate immunity in tomato and demonstrate that antiviral RNAi evolves to defend the infection of natural wildtype CMV-Fny in tomato, however AGO2a-mediated antiviral RNAi does not play major roles in promoting tolerance of tomato plants to CMV infection for maintaining health.
Pretrained language models and weight redistribution achieve precisekcatprediction
Authors: Yu Han , Luo Xiaozhou 
Published: November 2022

AbstractThe enzyme turnover number (kcat) is a meaningful and valuable kinetic parameter, reflecting the catalytic efficiency of an enzyme to a specific substrate, which determines the global proteome allocation, metabolic fluxes and cell growth. Here, we present a precisekcatprediction model (PreKcat) leveraging pretrained language models and a weight redistribution strategy. PreKcat significantly outperforms the previouskcatprediction method in terms of various evaluation metrics. We also confirmed the ability of PreKcat to discriminate enzymes of different metabolic contexts and different types. Additionally, the proposed weight redistribution strategies effectively reduce the prediction error of highkcatvalues and capture minor effects of amino acid substitutions on two crucial enzymes of the naringenin synthetic pathway, leading to obvious distinctions. Overall, the presentedkcatprediction model provides a valuable tool for deciphering the mechanisms of enzyme kinetics and enables novel insights into enzymology and biomedical applications.
Peptide-MHC Structure Prediction With Mixed Residue and Atom Graph Neural Network
Authors: Delaunay Antoine P. , Fu Yunguan , Bégué Alberto , McHardy Robert , Djermani Bachir A. , Rooney Michael , Tovchigrechko Andrey , Copoiu Liviu , Skwark Marcin J. , Carranza Nicolas Lopez , Lang Maren , Beguir Karim , Şahin Uğur 
Published: November 2022

AbstractNeoantigen-targeting vaccines have achieved breakthrough success in cancer immunotherapy by eliciting immune responses against neoantigens, which are proteins uniquely produced by cancer cells. During the immune response, the interactions between peptides and major histocompatibility complexes (MHC) play an important role as peptides must be bound and presented by MHC to be recognised by the immune system. However, only limited experimentally determined peptide-MHC (pMHC) structures are available, andin-silicostructure modelling is therefore used for studying their interactions. Current approaches mainly use Monte Carlo sampling and energy minimisation, and are often computationally expensive. On the other hand, the advent of large high-quality proteomic data sets has led to an unprecedented opportunity for deep learning-based methods with pMHC structure prediction becoming feasible with these trained protein folding models. In this work, we present a graph neural network-based model for pMHC structure prediction, which takes an amino acid-level pMHC graph and an atomic-level peptide graph as inputs and predicts the peptide backbone conformation. With a novel weighted reconstruction loss, the trained model achieved a similar accuracy to AlphaFold 2, requiring only 1.7M learnable parameters compared to 93M, representing a more than 98% reduction in the number of required parameters.