bluuebunny/crossref_metadata_2025_split huggingface dataset:
ProtAlign-ARG: Antibiotic Resistance Gene Characterization Integrating Protein Language Models and Alignment-Based Scoring
Authors: Ahmed Shafayat , Emon Muhit Islam , Moumi Nazifa Ahmed , Huang Lifu , Zhou Dawei , Vikesland Peter , Pruden Amy , Zhang Liqing 
Published: March 2024

ABSTRACTThe evolution and spread of antibiotic resistance pose a global health challenge. Whole genome and metagenomic sequencing pose a promising approach to monitoring the spread, but typical alignment-based approaches for antibiotic resistance gene (ARG) detection are inherently limited in the ability to detect new variants. Large protein language models could present a powerful alternative but are limited by databases available for training. Here we introduce ProtAlign-ARG, a novel hybrid model combining a pre-trained protein language model and an alignment scoring-based model to expand the capacity for ARG detection from DNA sequencing data. ProtAlign-ARG learns from vast unannotated protein sequences, utilizing raw protein language model embeddings to improve the accuracy of ARG classification. In instances where the model lacks confidence, ProtAlign-ARG employs an alignment-based scoring method, incorporating bit scores and e-values to classify ARGs according to their corresponding classes of antibiotics. ProtAlign-ARG demonstrated remarkable accuracy in identifying and classifying ARGs, particularly excelling in recall compared to existing ARG identification and classification tools. We also extended ProtAlign-ARG to predict the functionality and mobility of ARGs, highlighting the model’s robustness in various predictive tasks. A comprehensive comparison of ProtAlign-ARG with both the alignment-based scoring model and the pre-trained protein language model demonstrated the superior performance of ProtAlign-ARG.
Retrieval of an ethanol-conditioned taste aversion promotes GABAergic plasticity in the insular cortex
Authors: Taxier Lisa R. , Flanigan Meghan E , Haun Harold L. , Kash Thomas L. 
Published: March 2024

AbstractBlunted sensitivity to ethanol’s aversive effects can increase motivation to consume ethanol; yet, the neurobiological circuits responsible for encoding these aversive properties are not fully understood. Plasticity in cells projecting from the insular cortex (IC) to the basolateral amygdala (BLA) is critical for taste aversion learning and retrieval, suggesting this circuit’s potential involvement in modulating the aversive properties of ethanol. Here, we tested the hypothesis that GABAergic activity onto IC-BLA projections would be facilitated following the retrieval of an ethanol-conditioned taste aversion (CTA). Consistent with this hypothesis, frequency of mIPSCs was increased following retrieval of an ethanol-CTA across cell layers in IC-BLA projection neurons. This increase in GABAergic plasticity occurred in both a circuit-specific and learning-dependent manner. Additionally, local inhibitory inputs onto layer 2/3 IC-BLA projection neurons were greater in number and strength following ethanol-CTA. Finally, DREADD-mediated inhibition of IC parvalbumin-expressing cells blunted the retrieval of ethanol-CTA in male, but not female, mice. Collectively, this work implicates a circuit-specific and learning-dependent increase in GABAergic tone following retrieval of an ethanol-CTA, thereby advancing our understanding of how the aversive effects of ethanol are encoded in the brain.Significance statementSensitivity to the aversive properties of ethanol contributes to motivation to consume alcohol. However, the plasticity-associated mechanisms through which ethanol’s aversive effects are represented within neural circuits are largely unidentified. In the present study, we used whole-cell patch clamp electrophysiology combined with synaptic input mapping to identify alterations in GABAergic plasticity within the insula, and within cells projecting from the insula to the basolateral amygdala. We demonstrate learning and circuit-specific alterations in GABAergic tone following retrieval of an ethanol-conditioned taste aversion, as well as a male-specific role for Parvalbumin-expressing interneurons in modulating the strength of an ethanol-conditioned taste aversion. Combined, these findings provide novel insights into how the aversive properties of ethanol are encoded within brain circuitry.
Rapid evolution of recombination landscapes during the divergence of cichlid ecotypes in Lake Masoko
Authors: Talbi Marion , Turner George F. , Malinsky Milan 
Published: March 2024

AbstractVariation of recombination rate along the genome is of crucial importance to rapid adaptation and organismal diversification. Many unknowns remain regarding how and why recombination landscapes evolve in nature. Here, we reconstruct recombination maps based on linkage disequilibrium and use subsampling and simulations to derive a new measure of recombination landscape evolution: the Population Recombination Divergence Index (PRDI). Using PRDI, we show that fine-scale recombination landscapes differ substantially between two cichlid fish ecotypes ofAstatotilapia callipterathat diverged only ∼2,500 generations ago. Perhaps surprisingly, recombination landscape differences are not driven by divergence in terms of allele frequency (FST) and nucleotide diversity (Δ(π)): although there is some association, we observe positive PRDI in regions whereFSTandΔ(π) are zero. We found a stronger association between evolution of recombination and 47 large haplotype blocks that are polymorphic in Lake Masoko, cover 21% of the genome, and appear to include multiple inversions. Among haplotype blocks, there is a strong and clear association between the degree of recombination divergence and differences between ecotypes in heterozygosity, consistent with recombination suppression in heterozygotes. Overall, our work provides a holistic view of changes in population recombination landscapes during early stages of speciation with gene flow.
Ecogeographic signals of local adaptation in a wild relative help to identify variants associated with improved wheat performance under drought stress
Authors: Nyine Moses , Davidson Dwight , Adhikari Elina , Clinesmith Marshall , Wang Huan , Akhunova Alina , Fritz Allan , Akhunov Eduard 
Published: March 2024

SummaryPrioritizing wild relative diversity for improving crop adaptation to emerging drought-prone environments is challenging. Here, we combined the genome-wide environmental scans (GWES) in wheat diploid ancestorAegilops tauschiiwith allele testing in the genetic backgrounds of adapted cultivars to identify new diversity for improving wheat adaptation to water-limiting conditions. Evaluation of adaptive allele effects was carried out inAe. tauschii-wheat introgression lines (ILs) phenotyped for multiple agronomic traits under irrigated and water-limiting conditions using both UAS-based imaging and conventional approaches. The GWES showed that climatic gradients alone explain most (57.8%) of genomic variation inAe. tauschii, with many alleles associated with climatic factors inAe. tauschiibeing linked with improved performance of ILs under water-limiting conditions. The most significant GWES SNP located on chromosome 4D and associated with temperature annual range was linked with reduced canopy temperature in ILs. Our results suggest that (i) introgression of climate-adaptive alleles fromAe. tauschiihave potential to improve wheat performance under water-limiting conditions, (ii) variants controlling physiological processes responsible for maintaining leaf temperature are likely among the targets of adaptive selection in a wild relative, and (iii) adaptive variation uncovered by GWES in wild relatives has potential to improve climate resilience of crop varieties.
The priming phosphorylation of KaiC is activated by the release of its autokinase autoinhibition
Authors: Furuike Yoshihiko , Onoue Yasuhiro , Saito Shinji , Mori Toshifumi , Akiyama Shuji 
Published: March 2024

AbstractKaiC, a cyanobacterial circadian clock protein with autokinase activity, catalyzes the dual phosphorylation of its own S431 and T432 residues in a circadian manner in the presence of KaiA and KaiB. Priming phosphorylation at T432 is a key step that promotes secondary phosphorylation at S431. Although KaiA binding is considered essential for KaiC phosphorylation, the mechanisms underlying the activation and inactivation of priming phosphorylation remain elusive. We found that the priming phosphorylation proceeds even in the absence of KaiA, but is autoinhibited within KaiC, which decreases the rate constant to 0.019 h-1. The autoinhibition of KaiC and the mechanism underlying the release from autoinhibition by KaiA were examined by KaiC structural analysis, and by classical molecular dynamics and quantum mechanics / molecular mechanics simulations. We found that the side chain of T432 adopts two rotamers in dephosphorylated KaiC, one of which places T432 in a position suitable for a nucleophilic attack on the terminal phosphate of adenosine triphosphate (ATP). However, the nucleophilicity of T432 was insufficient to overcome an energy barrier of approximately 22 kcal mol-1because the catalytic function of a nearby base, E318, was self-suppressed by hydrogen bonding to positively charged R385. Biochemical assays of KaiC mutants showed that the autoinhibition of KaiC autokinase activity is attenuated by conferring T432 high nucleophilicity through the KaiA-assisted release of R385 from E318 to E352. During the circadian cycle, R385 switches interacting partners to inactivate/activate the autokinase function and to ensure the unidirectionality of the KaiC phosphorylation cycle.Significance StatementKaiC, a central player in the circadian clock system of cyanobacteria, undergoes an ordered phosphorylation cycle in the presence of KaiA and KaiB. To elucidate the mechanism underlying the rhythmic regulation of the KaiC autokinase, we performed structural analyses, computational simulations, and biochemical assays of KaiC and its mutants. The results indicate that KaiC is essentially an autoinhibited autokinase, and the autoinhibition of primary phosphorylation at its T432 residue is attenuated by conferring it high nucleophilicity against the terminal phosphate of adenosine triphosphate. KaiA contributes to releasing the autoinhibition of KaiC in a morning phase by switching the interacting partners of R385 from a catalytic glutamate E318 to E352, as well as ensuring unidirectionality of the KaiC phosphorylation cycle.
Trace Amines are Essential Metabolites for the Autocrine Regulation ofβ-Cell Signaling and Insulin Secretion
Authors: Hauke Sebastian , Keutler Kaya , Laguerre Aurelien , Carbo Mireia A. , Rada Jona , Grandy David , Yushchenko Dmytro A. , Schultz Carsten 
Published: March 2024

ABSTRACTSecretion of insulin in response to extracellular stimuli, such as elevated glucose levels and small molecules that act on G-protein coupled receptors (GPCRs), is the hallmark ofβ-cell physiology. Trace amines (TAs) are small aromatic metabolites that were identified as low-abundant ligands of the trace amine-associated receptor 1 (TAAR1) in the central nervous system (CNS), a GPCR that is also expressed by pancreaticβ-cells. In the present work, we identify TAs as essential autocrine signaling factors forβ-cell activity and insulin secretion. We find thatβ-cells are producing TAs in significant amounts and that the modulation of endogenous TA levels by the selective inhibition of TA biosynthetic pathways directly translated into changes of oscillations of the intracellular Ca2+concentration ([Ca2+]ioscillations) and insulin secretion. Selective TAAR1 agonists or inhibitors of monoamine oxidases increased [Ca2+]ioscillations and insulin secretion. Opposite effects were mediated by selective TAAR1 antagonists, by recombinant monoamine oxidase action and by the inhibition of amino acid decarboxylase. As the modulation of TA biochemical pathways immediately translated into changes of [Ca2+]ioscillations, we inferred high metabolic turnover rates of TAs and autocrine feedback. We found that psychotropic drugs modulate [Ca2+]ioscillations and insulin secretion, either directly acting on TAAR1 or by altering endogenous TA levels. Our combined data support the hypothesis of TAs as essential autocrine signaling factors forβ-cell activity and insulin secretion as well as TAAR1 as an important mediator of amine-modulated insulin secretion.
Floral phenotypic divergence and genomic insights in anOphrysorchid: Unraveling early speciation processes
Authors: Gibert Anaïs , Schatz Bertrand , Buscail Roselyne , Nguyen Dominique , Baguette Michel , Barthes Nicolas , Bertrand Joris A.M. 
Published: March 2024

SummaryAdaptive radiation inOphrysorchids leads to complex floral phenotypes that vary in scent, color and shape.Using a novel pipeline to quantify these phenotypes, we investigated trait divergence at early stages of speciation in six populations ofOphrys aveyronensisexperiencing recent allopatry. By integrating different genetic/genomic techniques, we investigated: (i) variation and integration of floral components (scent, color and shape), (ii) phenotypes and genomic regions under divergent selection, and (iii) the genomic bases of trait variation.We identified a large genomic island of divergence, associated with phenotypic variation in particular in floral odor. We detected potential divergent selection on macular color, while convergent selection was suspected on floral morphology and for several volatile olfactive compounds. We also identify candidate genes involved in anthocyanin and in steroid biosynthesis pathways associated with standing genetic variation in color and odor.This study sheds light on early differentiation inOphrys, revealing patterns that often become invisible over time, i.e., the geographic mosaic of traits under selection and the early appearance of strong genomic divergence. It also supports a crucial genomic region for future investigation and highlights the value of a multifaceted approach in unraveling speciation within taxa with large genomes.
CD4+ T cells facilitate replication of primary HIV-1 strains in macrophages and formation of macrophage internal virus-containing compartments
Authors: Montero Sabina Victoria , Leyens Johanna , Meckes Lea Marie , Turk Gabriela , Schindler Michael 
Published: March 2024

ABSTRACTHIV-1 infects CD4+ T cells and macrophages. However, replication of HIV-1 in these cell types is highly variable and may depend on the use of CCR5 as a co-receptor. In addition, there is internal accumulation of infectious HIV-1 in so-called virus-containing compartments of macrophages (VCCs). VCCs are thought to represent a persistent viral reservoir that is shielded from the antiviral immune response. To date, VCC formation has only been studied in lab-adapted HIV-1 and it is unknown whether VCCs play a role in the replication of primary HIV-1 strains. Furthermore, although macrophages transmit HIV-1 from VCCs to CD4+ T cells, it is unknown whether T cells have an impact on VCC formation. We analyzed the ability of primary and lab-adapted HIV-1 to replicate in macrophages, the effect of coculture with non-infected CD4+ T cells and the extent of VCC formation. Although differentially, all HIV-1 strains replicated in CD4+ T cells, whereas only lab-adapted HIV-1 replicated in macrophages. Strikingly, replication of patient-derived HIV-1 in macrophages was enhanced by coculture with non-infected CD4+ T cells and correlated with VCC formation. In conclusion, non-infected CD4+ T cells facilitate the replication of primary HIV-1 strains in macrophages and the formation of VCCs appears to be a proxy for this phenotype. Our study suggests an essential role for VCCs in the replication of patient-derived HIV-1 in macrophages, which is fueled by non-infected CD4+ T cells. Furthermore, our findings call for strategies to specifically disrupt VCC formation in order to eliminate the HIV-1 reservoir in macrophages.IMPORTANCEHere we focus on the intimate interplay between HIV-1 infected macrophages and CD4+ T cells. Specifically, we analyzed whether primary HIV-1 strains induce virus-containing compartments (VCCs) within macrophages, which are thought to serve as viral sanctuaries and macrophage reservoirs. Notably, primary HIV-1 strains were unable to replicate in macrophages and induce VCCs unless they were cocultured with non-infected CD4+ T cells, leading to increased VCC formation and viral replication. This suggests an essential role for non-infected CD4+ T cells in facilitating primary HIV-1 replication in macrophages. Our data highlight the importance of not only targeting the latent HIV-1 T-cell reservoir, but also targeting VCC formation in macrophages to achieve the ultimate goal of functional HIV-1 cure.
In tissue spatial single-cell metabolomics by coupling mass spectrometry imaging and immunofluorescences
Authors: Blanc Landry , Grelard Florent , Tuck Michael , Dartois Véronique , Peixoto Antonio , Desbenoit Nicolas 
Published: March 2024

AbstractIn this work, we introduce a multimodal imaging workflow that integrates Matrix-assisted Laser Desorption Ionization Mass Spectrometry Imaging (MALDI-MSI) combined with Immunofluorescence (IF) microscopy to enhance in tissue spatial single-cell metabolomics. The workflow allows to correlate cell populations with associated small molecule distributions by conducting on the same tissue section MSI before IF staining, addressing tissue integrity challenges and joint image analysis.To process MSI data with IF guidance, we propose an original and advanced computational strategy utilizing Receiver Operating Characteristic (ROC) analysis, allowing to identify ions specific to targeted histological regions based on IF staining. Moreover, in a non-targeted strategy, we introduce a Spatial Coherence Measure (SCM) to distinguish genuine spatial patterns from noise within ion distributions, enhancing spatial metabolomics’ robustness. Then spatial clustering techniques are employed to group ions sharing similar spatial distribution to reveal histological structures, providing complementary insights into metabolite distributions. We validated our workflow mouse spleen section as this organ presents a spatially complex but well-detailed microenvironment.In conclusion, our multimodal and computational workflow opens new frontiers for diverse biomedical research applications by promoting precise spatial metabolomics in tissue sections.
LncRNASnhg3Aggravates Hepatic Steatosis via PPARγ Signaling
Authors: Xie Xianghong , Gao Mingyue , Zhao Wei , Li Chunmei , Zhang Weihong , Yang Jiahui , Zhang Yinliang , Chen Enhui , Guo Yanfang , Guo Zeyu , Zhang Minglong , Ngowi Ebenezeri Erasto , Wang Heping , Wang Xiaoman , Zhu Yinghan , Wang Yiting , Li Xiaolu , Yao Hong , Yan Li , Fang Fude , Li Meixia , Qiao Aijun , Liu Xiaojun 
Published: March 2024

AbstractLncRNAs are involved in modulating the individual risk and the severity of progression in metabolic dysfunction-associated fatty liver disease (MASLD), but their precise roles remain largely unknown. This study aimed to investigate the role of lncRNASnhg3in the development and progression of MASLD, along with the underlying mechanisms. The result showed thatSnhg3was significantly downregulated in the liver of high-fat diet-induced obesity (DIO) mice. Notably, palmitic acid promoted the expression ofSnhg3and overexpression ofSnhg3increased lipid accumulation in primary hepatocytes. Furthermore, hepatocyte-specificSnhg3deficiency decreased body and liver weight, alleviated hepatic steatosis and promoted hepatic fatty acid metabolism in DIO mice, whereas overexpression induced the opposite effect. Mechanistically,Snhg3promoted the expression, stability and nuclear localization of SND1 protein via interacting with SND1, thereby inducing K63-linked ubiquitination modification of SND1. Moreover,Snhg3decreased the H3K27me3 level and induced SND1-mediated chromatin loose remodeling, thus reducing H3K27me3 enrichment at thePparγ promoter and enhancingPparγ expression. The administration of PPARγ antagonist T0070907 improvedSnhg3-aggravated hepatic steatosis. Our study revealed a new signaling pathway,Snhg3/SND1/H3K27me3/PPARγ, responsible for MASLD and indicates that lncRNA-mediated epigenetic modification has a crucial role in the pathology of MASLD.
Deciphering the RNA-binding protein network during endosomal mRNA transport
Authors: Devan Senthil-Kumar , Shanmugasundaram Sainath , Müntjes Kira , Smits Sander HJ , Altegoer Florian , Feldbrügge Michael 
Published: March 2024

AbstractMicrotubule-dependent endosomal transport is crucial for polar growth, ensuring the precise distribution of cellular cargos such as proteins and mRNAs. However, the molecular mechanism linking mRNAs to the endosomal surface remains poorly understood. Here, we present a structural analysis of the key RNA-binding protein Rrm4 fromUstilago maydis. Our findings reveal a new type of MademoiseLLE domain featuring a seven-helical bundle that provides a distinct binding interface. A comparative analysis with the canonical MLLE domain of the poly(A)-binding protein Pab1 disclosed unique characteristics of both domains. Deciphering the MLLE binding code enabled prediction and verification of previously unknown Rrm4 interactors containing short linear motifs. Importantly, we demonstrated that the human MLLE domains, such as those of PABPC1 and UBR5, employed a similar principle to distinguish among interaction partners. Thus, our study provides unprecedented mechanistic insights into how structural variations in the widely distributed MLLE domain facilitates mRNA attachment during endosomal transport.SignificancePolar growing cells, such as fungal hyphae and neurons, utilize endosomes to transport mRNAs along their microtubules. But how do these mRNAs precisely attach to endosomes? Our study addresses this question by investing the key mRNA transporter, Rrm4, in a fungal model microorganism. We uncovered new features of a protein-protein interaction domain that recognizes specific short linear motifs in binding partners. While this domain resembles one found in the poly(A)-binding protein, it exhibits distinct motif recognition. Deciphering the underlying binding code unveiled new interaction partners for Rrm4. The recognition system is used to form a resilient network of RNA-binding proteins (RBPs) and their interaction partners during endosomal transport. This principle is applicable to humans, highlighting its fundamental importance.
Hepatitis E virus infection upregulates ING5 expression invitroandvivo
Authors: Zhao Wanqiu , Xia Yueping , Li Tengyuan , Liu Huichan , Zhong Guo , Chen Dongxue , Yu Wenhai , Li Yunlong , Huang Fen 
Published: March 2024

AbstractHepatitis E virus (HEV) is the major pathogen of viral hepatitis. Immunocompromised individual infected by HEV is prone to chronic hepatitis and increases the risk of hepato-cellular carcinoma (HCC). Inhibitor of growth family member 5 (ING5) is a tumor suppressor gene, is low expressed in cancer tumor or cells. However, the underlying relationship between ING5 and HEV infection is unclear. In the present study acute and chronic HEV animal models were employed to explore the interaction between ING5 and HEV. Notably, the expression of ING5 was significantly increased both in the liver of acute HEV infected BALB/c mice and chronic HEV infected rhesus macaques. In addition, the relationship between HEV infection and ING5 expression was further identified in human hepatoma (HepG-2) cells. In conclusion, HEV infection strongly upregulated ING5 expression invivoand invitro, bearing significant implications in further understanding the pathogenic mechanism of HEV infection.