bluuebunny/crossref_metadata_2025_split huggingface dataset:
moPPIt:De NovoGeneration of Motif-Specific Binders with Protein Language Models
Authors: Chen Tong , Zhang Yinuo , Chatterjee Pranam 
Published: August 2024

AbstractThe ability to precisely target specific motifs on disease-related proteins, whether conserved epitopes on viral proteins, intrinsically disordered regions within transcription factors, or breakpoint junctions in fusion oncoproteins, is essential for modulating their function while minimizing off-target effects. Current methods struggle to achieve this specificity without reliable structural information. In this work, we introduce amotif-specificPPI targeting algorithm,moPPIt, forde novogeneration of motif-specific peptide binders from the target protein sequence alone. At the core of moPPIt is BindEvaluator, a transformer-based model that interpolates protein language model embeddings of two proteins via a series of multi-headed self-attention blocks, with a key focus on local motif features. Trained on over 510,000 annotated PPIs, BindEvaluator accurately predicts target binding sites given protein-protein sequence pairs with a test AUC > 0.94, improving to AUC > 0.96 when fine-tuned on peptide-protein pairs. By combining BindEvaluator with our PepMLM peptide generator and genetic algorithm-based optimization, moPPIt generates peptides that bind specifically to user-defined residues on target proteins. We demonstrate moPPIt’s efficacy in computationally designing binders to specific motifs, first on targets with known binding peptides and then extending to structured and disordered targets with no known binders. In total, moPPIt serves as a powerful tool for developing highly specific peptide therapeutics without relying on target structure or structure-dependent latent spaces.
Vanadium-dependent haloperoxidases from diverse microbes halogenate exogenous alkyl quinolone quorum sensing signals
Authors: Baumgartner Jackson T. , McCaughey Catherine S. , Fleming Hanna S. , Lentz Adam R. , Sanchez Laura M. , McKinnie Shaun M. K. 
Published: August 2024

AbstractSite-selective vanadium-dependent haloperoxidases (VHPOs) are a unique enzyme family that catalyze selective halogenation reactions previously characterized within bacterial natural product biosynthetic pathways. However, the broader chemical roles and biological distribution of these halogenases remains to be explored. Using bioinformatic methods, we have defined a VHPO subfamily that regioselectively brominates alkyl quinolone (AQ) quorum sensing molecules.In vitroAQ halogenation activity was demonstrated from phylogenetically distinct bacteria lacking established AQ biosynthetic pathways and sourced from diverse environments. AQ-VHPOs show high sequence and biochemical similarities with negligible genomic synteny or biosynthetic gene cluster co-localization. Exposure of VHPO-containing microbes to synthetic AQs or established bacterial producers identifies the chemical and spatial response to subvert their bacteriostatic effects. The characterization of novel homologs from bacterial taxa without previously demonstrated vanadium enzymology suggests VHPO-mediated AQ bromination is a niche to manipulate the chemical ecology of microbial communities.Table of Contents GraphicSynopsisA broadly distributed subfamily of bacterial site-selective VHPOs provides protection against exogenously encountered bacteriostatic alkyl quinolone quorum sensing signals.
An Automated Pipeline for the Identification of Liver Tissue in Ultrasound Video
Authors: Ockenden Eloise , Mpooya Simon , Noble J. Alison , Chami Goylette F. 
Published: August 2024

AbstractLiver diseases are a leading cause of death worldwide, with an estimated 2 million deaths each year. Causes of liver disease are difficult to ascertain, especially in sub-Saharan Africa where there is a high prevalence of infectious diseases such as hepatitis B and schistosomiasis, along with alcohol use. Point-of-care ultrasound often is used in low-resource settings for diagnosis of liver disease due to its portability and low cost. For classification models that can automatically stage liver disease from ultrasound video, the region of interest is liver tissue. A fully-automated pipeline for liver tissue identification in ultrasound video is presented. Ultrasound video data was collected using a low-cost, portable ultrasound machine in rural areas of Uganda. The pipeline first detects the diaphragm in each ultrasound video frame, then segments the diaphragm to ultimately use this segmentation to infer the position of liver tissue in each frame. This pipeline outperforms directly segmenting liver tissue with an intersection over union of 0.83 compared to 0.62. This pipeline also shows improved results with respect to the ease of clinical interpretation and anticipated clinical utility.
A novel two-hit insomnia and inflammation rodent model of depressive-like behaviors
Authors: Mei Junhua , Song Xinhua , Wang Ying , Lyu Honggang , Wang Guang , Chen Chao , Zhang Honghan , Wang Chao , Xie Xin-hui , Chen Guohua , Liu Zhongchun 
Published: August 2024

ABSTRACTBackgroundSystemic inflammation and insomnia often co-occur in patients with depression. However, there is no suitable animal model to investigate the relationship between inflammation, sleep deprivation (SD), and depression.MethodsTo model interactions between insomnia, inflammation, and depression, we developed a novel “two-hit” rodent model of depressive-like behaviors using continuous SD followed by daily lipopolysaccharide (LPS) treatment. Control groups received SD, LPS, or sterile phosphate-buffered salinealone. The model’s validity was assessed at the cellular and molecular levels, with fluoxetine rescue applied to confirm model validity.ResultsThe model group demonstrated significant depressive-like behaviors that were rescued by fluoxetine treatment. Transcriptomic analysis revealed alterations in neuroinflammation and synaptic plasticity pathways within the hippocampus and prefrontal cortex (PFC) of model rats. Western blotting validated alterations in key protein markers related to both processes, and immunofluorescence confirmed microglia and astrocyte activation, indicative of neuroinflammation. Additionally, transmission electron microscopy and Golgi-Cox staining revealed reduced synapse and dendritic spine density in the model group. Fluoxetine treatment reversed these structural changes. Sixteen genes associated with neuroinflammation and synaptic function were validated in human genetic studies by transcriptome-wide association analysis.ConclusionThis reliable two-hit model will be useful for investigating the roles of insomnia and inflammation in depression.
Model-informed optimal allocation of limited resources to mitigate infectious disease outbreaks in societies at war
Authors: Srivastava Vaibhava , Sarkar Drik , Kadelka Claus 
Published: August 2024

Infectious diseases thrive in war-torn societies. The recent sharp increase in human conflict and war thus requires the development of disease mitigation tools that account for the specifics of war, such as scarcity of important public health resources. Differential equation-based compartmental models constitute the standard tool for forecasting disease dynamics and evaluating intervention strategies. We developed a compartmental disease model that considers key social, war, and disease mechanisms, such as gender homophily and the replacement of soldiers. This model enables the identification of optimal allocation strategies that, given limited resources required for treating infected individuals, minimize disease burden, assessed by total mortality and final epidemic size. A comprehensive model analysis reveals that the level of resource scarcity fundamentally affects the optimal allocation. Desynchronization of the epidemic peaks among several population subgroups emerges as a desirable principle since it reduces disease spread between different sub-groups. Further, the level of preferential mixing among people of the same gender, gender homophily, proves to strongly affect disease dynamics and optimal treatment allocation strategies, highlighting the importance of accurately accounting for heterogeneous mixing patterns. Altogether, the findings help answer a timely question: how can infectious diseases be best controlled in societies at war? The developed model can be easily extended to specific diseases, countries, and interventions.Significance statementSocieties at war are particularly affected by infectious disease outbreaks, necessitating the development of mathematical models tailored to the intricacies of war and disease dynamics as valuable tools for policy-makers. The frequently limited availability of public health resources, such as drugs or medical personnel, yields a fundamental optimal allocation problem. This study frames this problem in a generic, modifiable context and proposes model-informed solutions by identifying allocation strategies that minimize disease burden, measured by total deaths or infections. The desynchronization of epidemic peaks among a heterogeneous population emerges as a general disease mitigation strategy. Moreover, the level of contact heterogeneity proves to substantially affect disease spread and optimal control.
Multiple Protein Structure Alignment at Scale with FoldMason
Authors: Gilchrist Cameron L.M. , Mirdita Milot , Steinegger Martin 
Published: August 2024

AbstractProtein structure is conserved beyond sequence, making multiple structural alignment (MSTA) essential for analyzing distantly related proteins. Computational prediction methods have vastly extended our repository of available proteins structures, requiring fast and accurate MSTA methods. Here, we introduce FoldMason, a progressive MSTA method that leverages the structural alphabet from Foldseek, a pairwise structural aligner, for multiple alignment of hundreds of thousands of protein structures, exceeding alignment quality of state-of-the-art methods, while two orders of magnitudes faster than other MSTA methods. FoldMason computes confidence scores, offers interactive visualizations, and provides essential speed and accuracy for large-scale protein structure analysis in the era of accurate structure prediction. Using Flaviviridae glycoproteins, we demonstrate how FoldMason’s MSTAs support phylogenetic analysis below the twilight zone. FoldMason is free open-source software:foldmason.foldseek.comand webserver:search.foldseek.com/foldmason.
Structure-based mechanism of RyR channel operation by calcium and magnesium ions
Authors: Zahradníková Alexandra , Pavelková Jana , Sabo Miroslav , Baday Sefer , Zahradník Ivan 
Published: August 2024

AbstractRyanodine receptors (RyRs) serve for excitation-contraction coupling in skeletal and cardiac muscle cells in a noticeably different way, not fully understood at the molecular level. We addressed the structure of skeletal (RyR1) and cardiac (RyR2) isoforms relevant to gating by Ca2+and Mg2+ions (M2+). Bioinformatics analysis of RyR structures ascertained the EF-hand loops as the M2+binding inhibition site and revealed its allosteric coupling to the channel gate. The intra-monomeric inactivation pathway interacts with the Ca2+-activation pathway in both RyR isoforms, and the inter-monomeric pathway, stronger in RyR1, couples to the gate through the S23*-loop of the neighbor monomer. These structural findings were implemented in the model of RyR operation based on statistical mechanics and the Monod-Wyman-Changeux theorem. The model, which defines closed, open, and inactivated macrostates allosterically coupled to M2+-binding activation and inhibition sites, approximated the open probability data for both RyR1 and RyR2 channels at a broad range of M2+concentrations. The proposed mechanism of RyR operation provides a new interpretation of the structural and functional data of mammalian RyR channels on common grounds. This may provide a new platform for designing pharmacological interventions in the relevant diseases of skeletal and cardiac muscles. The synthetic approach developed in this work may find general use in deciphering mechanisms of ion channel functions.
The RND efflux pump EefABC is highly conserved within lineages ofE. colicommonly associated with infection
Authors: Pugh Hannah L. , Darby Elizabeth M. , Burgess Leah , Colclough Abigail L. , Meosa John Asti-Rochelle , Dunn Steven , Connor Christopher , Perry Eoughin A. , McNally Alan , Bavro Vassiliy N. , Blair Jessica M. A. 
Published: August 2024

AbstractTripartite resistance-nodulation-division (RND) efflux pumps confer multidrug resistance (MDR) in Gram-negative bacteria and are critical for many physiological functions including virulence and biofilm formation. The common laboratory strain ofE. coli,K-12 MG1655 has six recognised RND transporters participating in tripartite pump formation (AcrB, AcrD, AcrF, CusA, MdtBC, and MdtF). However, by studying >20,000E. coligenomes we show thatE. colibelonging to phylogroups B2, D, E, F and G, which are commonly associated with infection, possess an additional, seventh RND transporter, EefB. It is found in a five gene operon,eefRABCD,which also encodes a TetR family transcription factor, a periplasmic adapter protein, an outer membrane factor and major facilitator superfamily pump. In contrast,E. colifrom phylogroups A, B1 and C, generally containing environmental and commensal strains, do not encode the operon and instead encode an uncharacterised ORF,ycjD. In phylogroups where theeefRABCDoperon is present it was very highly conserved. In fact, conservation levels were comparable to that of the majorE. coliRND efflux system AcrAB-TolC, suggesting a critical biological function. Protein modelling shows that this pump is highly divergent from endogenousE. coliRND systems with unique structural features, while showing similarities to efflux systems found inPseudomonas aeruginosa. However, unlike other major RND efflux systems, EefABC does not appear to transport antimicrobials and instead may be important for infection or survival in the host environment.ImportanceEfflux pumps are molecular machines that export molecules out of bacterial cells. The efflux pumps belonging to the RND family are particularly important as they export antibiotics out of Gram-negative bacterial cells, contributing to antibiotic resistance. The important human pathogen,E. coli, has been previously reported to have six RND pumps. However, we show that phylogroups ofE. colicommonly associated with infection encode a seventh RND pump, EefABC which is highly conserved, suggesting an important biological function. While the function of EefABC inE. coliremains to be resolved, it does not seem to transport antimicrobial compounds. These findings are important because they reveal a new RND pump, potentially involved in virulence and survival in the host, that could represent a new therapeutic target. Additionally, it again shows that laboratory type strains of common bacterial pathogens are not representative of those that are infection causing.
Plasmids encode and can mobilize onion pathogenicity inPantoea agglomerans
Authors: Shin Gi Yoon , Asselin Jo Ann , Smith Amy , Aegerter Brenna , Coutinho Teresa , Zhao Mei , Dutta Bhabesh , Mazzone Jennie , Neupane Ram , Gugino Beth , Hoepting Christy , Khanal Manzeal , Malla Subas , Nischwitz Claudia , Sidhu Jaspreet , Burke Antoinette Machado , Davey Jane , Uchanski Mark , Derie Michael L. , Toit Lindsey J. du , Stresow Stephen , Bonasera Jean M. , Stodghill Paul , Kvitko Brian 
Published: August 2024

AbstractPantoea agglomeransis one of fourPantoeaspecies for which strains have been reported in the United States to cause bacterial rot of onion bulbs. However, not allP. agglomeransstrains are pathogenic to onion. We characterized onion-associated strains ofP. agglomeransto elucidate the genetic and genomic signatures of onion-pathogenicP. agglomerans. We collected >300P. agglomeransstrains associated with symptomatic onion plants and bulbs from public culture collections, research laboratories, and a multi-year survey in 11 states in the USA. Genome assemblies were generated for 87P. agglomeransstrains that showed a range in onion virulence phenotypes. Combining the 87 genome assemblies with 100 high-quality, publicP. agglomeransgenome assemblies identified two well-represented and well-supportedP. agglomeransphylogroups. Strains causing severe symptoms on onion leaves and bulbs were only identified in Phylogroup II and encoded the HiVir biosynthetic cluster for the phytotoxin pantaphos, supporting the role of HiVir as a crucial pathogenicity factor. Using a MASH-based plasmid classification system, theP. agglomeransHiVir cluster was determined to be encoded in two distinct plasmid contexts: 1) as an accessory gene cluster on a conservedP. agglomeransplasmid (pAggl), or 2) on a mosaic cluster of plasmids common among onion strains (pOnion). Analysis of closed genomes ofP. agglomeransrevealed that the pOnion plasmids harboredaltgenes responsible for encoding tolerance to the thiosulfinate defensive chemistry inAlliumspp. Additionally, many of these pOnion plasmids harboredcopgene clusters, which confer resistance to copper. However, the pOnion plasmids encoded the HiVir cluster less frequently. We demonstrated that the pOnion plasmid pCB1C, encoding HiVir andaltclusters as well as an intact conjugative type IV secretion system (T4SS), can act as a natively mobilizable pathogenicity plasmid that transformsP. agglomeransPhylogroup I strains, including environmental strains, into virulent pathogens of onion. This work indicates a central role for plasmids and plasmid ecology in mediatingP. agglomeransinteractions with onion plants, with potential implications for onion bacterial disease management.
Cellular N-myristoyl transferases Are Required for Mammarenavirus Multiplication
Authors: Witwit Haydar , Betancourt Carlos , Cubitt Beatrice , Khafaji Roaa , Kowalski Heinrich , Jackson Nathaniel , Ye Chengjin , Martinez-Sobrido Luis , de la Torre Juan C. 
Published: August 2024

ABSTRACTThe mammarenavirus matrix Z protein plays critical roles in virus assembly and cell egress, whereas heterotrimer complexes of a stable signal peptide (SSP) together with glycoprotein subunits GP1 and GP2, generated via co-and post-translational processing of the surface glycoprotein precursor GPC, form the spikes that decorate the virion surface and mediate virus cell entry via receptor-mediated endocytosis. The Z protein and SSP undergo N-terminal myristoylation by host cell N-myristoyltransferases (NMT1 and NMT2), and G2A mutations that prevent myristoylation of Z or SSP have been shown to affect Z mediated virus budding and GP2 mediated fusion activity required to complete the virus cell entry process. In the present work, we present evidence that the validated on-target specific pan NMT inhibitor DDD85464 exerts a potent antiviral activity against the prototypic mammarenavirus lymphocytic choriomeningitis virus (LCMV) that correlated with reduced Z budding activity and GP2 mediated fusion activity, as well as proteasome mediated degradation of the Z protein. The potent anti-mammarenaviral activity of DDD85646 was also observed with the hemorrhagic fever causing mammarenaviruses Junin (JUNV) and Lassa (LASV) viruses. Our results support exploration of NMT inhibition as a broad-spectrum antiviral against human pathogenic mammarenaviruses.
Prediction of Threonine-Tyrosine Kinase Receptor-Ligand Unbinding Kinetics with Multiscale Milestoning and Metadynamics
Authors: Votapka Lane W. , Ojha Anupam Anand , Asada Naoya , Amaro Rommie E. 
Published: August 2024

AbstractAccurately describing protein-ligand binding and unbinding kinetics remains challenging. Computational calculations are difficult and costly, while experimental measurements often lack molecular detail and can be unobtainable. Here we extend our multiscale milestoning method, Simulation-Enabled Estimation of Kinetics Rates (SEEKR), with metadynamics molecular dynamics simulations to yield accurate small molecule drug residence times. Using the pharmaceutically relevant threonine-tyrosine kinase (TTK) and eight long-residence-time (tens of seconds to hours) inhibitors, we demonstrate accurate prediction of absolute and rank-ordered ligand residence times and free energies of binding.TOC Graphic
FourierMIL: Fourier filtering-based multiple instance learning for whole slide image analysis
Authors: Zheng Yi , Sharma Harsh , Betke Margrit , Beane Jennifer E. , Kolachalama Vijaya B. 
Published: August 2024

AbstractRecent advancements in computer vision, driven by convolutional neural network, multilayer perceptron and transformer architectures, have significantly improved the analysis on natural images. Despite their potential, the application of these architectures in digital pathology, specifically for analyzing gigapixel-resolution whole-slide images (WSIs), remains challenging due to the extensive and variable sizes of these images. Here we present a multiple instance learning framework that leverages the discrete Fourier transform and learns from WSIs. Dubbed as FourierMIL, our framework is designed to capture both global and local dependencies within WSIs. To validate the efficacy of our model, we conducted extensive experiments on a prevalent computational pathology challenge: tumor classification. Our results demonstrate that FourierMIL outperforms existing state-of-the-art methods, marking a significant advancement in the field of digital pathology and highlighting the potential of attention-free architectures in managing the complexities related to WSI analysis. The code will be released for public access upon the manuscript’s acceptance.
The triad interaction of ULK1, ATG13, and FIP200 is required for ULK complex formation and autophagy
Authors: Hama Yutaro , Fujioka Yuko , Yamamoto Hayashi , Mizushima Noboru , Noda Nobuo N. 
Published: August 2024

AbstractIn mammals, autophagosome formation, a central event in autophagy, is initiated by the ULK complex comprising ULK1/2, FIP200, ATG13, and ATG101. However, the structural basis and mechanism of the ULK complex formation remain poorly understood. Here, we predicted the core interactions organizing the ULK complex using AlphaFold, which proposed that the intrinsically disordered region of ATG13 binds to the base of the two UBL domains in the FIP200 dimer using two phenylalanines and to the tandem MIT domain of ULK1, allowing for the 1:1:2 stoichiometry of the ULK1–ATG13–FIP200 complex. We confirmed the predicted interactions by point mutations and revealed the existence of direct triad interactions among ULK1, ATG13, and FIP200 in vitro and in cells, in which each interaction was additively important for autophagic flux. These results indicate that the ULK1–ATG13–FIP200 triadic interaction is crucial for autophagosome formation and provide a structural basis and insights into the regulation mechanism of autophagy initiation in mammals.