bluuebunny/crossref_metadata_2025_split huggingface dataset:
B-OK: A Visual and Tactile Tool for HIV Treatment Adherence Support in a United States Urban Center
Authors: Richterman Aaron , Klaiman Tamar , Palma Daniel , Ryu Eric , Schmucker Laura , Villarin Katherine , Grosso Gabrielle , Brady Kathleen A , Thirumurthy Harsha , Buttenheim Alison 
Published: March 2024

AbstractLack of adherence to antiretroviral therapy (ART) and poor retention in care are significant barriers to ending HIV epidemics. Treatment adherence support (TAS) effectiveness may be constrained by limited awareness and understanding of the benefits of ART, particularly the concepts of treatment as prevention and Undetectable=Untransmittable (U=U), for which substantial knowledge gaps persist. We used mixed methods to evaluate a straightforward visual and tactile tool, the B-OK Bottles (“B-OK”), that incorporates human-centered design and behavioral economics principles and is designed to change and strengthen mental models about HIV disease progression and transmission. We enrolled 118 consenting adults living with HIV who were clients of medical case managers at one of four case management agencies in Philadelphia. All participants completed a pre-intervention survey, a B-OK intervention, and a post-intervention survey. A subset (N=52) also completed qualitative interviews before (N=20) or after (N=32) B-OK. Participants had a median age of 55 years (IQR 47-60), about two-thirds were male sex (N=77, 65%), nearly three-quarters identified as non-Hispanic Black (N=85, 72%), and almost all reported receiving ART (N=116, 98%). Exposure to B-OK was associated with improved awareness and understanding of HIV terminology, changes in attitudes about HIV treatment, and increased intention to rely on HIV treatment for transmission prevention. Insights from qualitative interviews aligned with the quantitative findings as respondents expressed a better understanding of U=U and felt that B-OK clearly explained concepts of HIV treatment and prevention. These findings provide a strong rationale to further evaluate the potential for B-OK to improve TAS for PLWH.
RFC1repeat expansion analysis from whole genome sequencing data simplifies screening and increases diagnostic rates
Authors: Sullivan Roisin , Chen Sai , Saunders Christopher T , Yau Wai Yan , Goh Yee Yen , O’Connor Emer , Dominik Natalia , Deforie Valentina Galassi , Morsy Heba , Cortese Andrea , Houlden Henry , Eberle Michael A. , Vandrovcova Jana 
Published: March 2024

AbstractBiallelic expansions and a motif change inRFC1are a common cause of cerebellar ataxia, neuropathy, and vestibular areflexia syndrome. Molecular diagnosis relies on a complicated combination of repeat primed PCR and Southern blotting. We developed a whole genome sequencing based method forRFC1repeat detection.The combination of sequence motifs and allele length analysis in 29,478 individuals showed that 92.5% of samples have no expanded allele or have expansions of known benign motifs on one allele. In total, 103 samples were classified as biallelic carriers of pathogenic expansions and the frequency of the most common pathogenic allele AAGGG was estimated as 3.9%. OurRFC1classification method was validated by molecular diagnostic methods achieving sensitivity and specificity of 100% and 97.4%, respectively. Additionally, we catalogued 8 rare repeat motifs, further elucidating the high sequence complexity within theRFC1locus.In this study we report a new method to identify patients carryingRFC1pathogenic repeat expansions from WGS data, reducing the need for the inefficient molecular workflow currently used for clinical diagnoses. This method correctly identifies recessive pathogenic repeat expansions inRFC1and allows screening of existing large scale WGS datasets of unsolved cases.
Laboratory validation of a clinical metagenomic next-generation sequencing assay for respiratory virus detection and discovery
Authors: Tan Jessica Karielle , Servellita Venice , Stryke Doug , Kelly Emily , Streithorst Jessica , Sumimoto Nanami , Foresythe Abiodun , Huh Hee Jae , Nguyen Jenny , Oseguera Miriam , Brazer Noah , Tang Jack , Ingebrigtsen Danielle , Fung Becky , Reyes Helen , Hillberg Melissa , Chen Alice , Guevara Hugo , Yagi Shigeo , Morales Christina , Wadford Debra A. , Mourani Peter M. , Langelier Charles R. , de Lorenzi-Tognon Mikael , Benoit Patrick , Chiu Charles Y. 
Published: March 2024

AbstractTools for rapid identification of novel and/or emerging viruses are urgently needed for clinical diagnosis of unexplained infections and pandemic preparedness. Here we developed and clinically validated a largely automated metagenomic next-generation sequencing (mNGS) assay for agnostic detection of respiratory viral pathogens from nasopharyngeal swab, bronchoalveolar lavage and tracheal aspirate samples in <24 hours. The mNGS assay achieved mean limits of detection of 543 copies/mL, viral load quantification with 100% linearity, and 93.6% sensitivity, 93.8% specificity, and 93.7% accuracy compared to gold-standard clinical multiplex RT-PCR. Performance increased to 97.9% overall predictive agreement after discrepancy testing and clinical adjudication, which was superior to that of RT-PCR (95.0% agreement). To enable discovery of novel, sequence-divergent human viruses with pandemic potential,de novoassembly and translated nucleotide algorithms were incorporated into the automated SURPI+ computational pipeline used by the mNGS assay for pathogen detection. Usingin silicoanalysis, we showed after removal of all human viral sequences from the reference database that 70 (100%) of 70 representative human viral pathogens could still be identified based on homology to related animal or plant viruses. Our assay, which was granted breakthrough device designation from the US Food and Drug Administration (FDA) in August of 2023, demonstrates the feasibility of routine mNGS testing in clinical and public health laboratories, thus enabling a robust and rapid response to the next viral respiratory pandemic.
Insight into the regulatory mechanism of the MFS transporter, SCO4121 by the MarR regulator, SCO4122
Authors: Nag Ankita , Sharma Shiksha , Rani Pittu Sandhya , Mehra Sarika 
Published: March 2024

AbstractMarR group of transcriptional regulators are ubiquitous in bacteria and found to be involved in regulation of efflux pumps that confer multidrug resistance phenotype. While most characterized MarR regulators act as transcriptional repressors, we earlier identified a MarR regulator SCO4122 inStreptomyces coelicolor, playing an essential role in transcriptional activation of the MFS transporter SCO4121 in response to multiple substrates of the latter, including streptomycin, ciprofloxacin and chloramphenicol. In this study, using Surface Plasmon Resonance, we demonstrate that SCO4122 interacts directly with the diverse substrates of SCO4121 with the highest affinity for streptomycin with a KD of 0.73 μM. Further, in-vitro and in-vivo studies reveal that SCO4122 also binds to the intergenic region betweensco4121andsco4122,where the interaction is dependent on the cooperative binding of SCO4122 to three motifs in this region. A conserved Methionine, M93, in SCO4122 is identified to be an integral amino acid residue that is involved in activation of SCO4121 in response to ciprofloxacin, streptomycin and EtBr but not chloramphenicol. Furthermore, our studies also indicate that upon binding to different substrates, the affinity of SCO4122 to thesco4121promoter increases 50-1000 fold, thereby leading to enhanced expression of the transporter, SCO4121. This study thus highlights that SCO4122 is a novel MarR regulator that functions as a strong transcriptional activator of an efflux pump, SCO4121, through intricate molecular mechanisms in presence of structurally dissimilar substrates.Graphical abstract
Spatial heterogeneity in collective electrotaxis: continuum modelling and applications to optimal control
Authors: Martina-Perez Simon F. , Breinyn Isaac B. , Cohen Daniel J. , Baker Ruth E. 
Published: March 2024

AbstractCollective electrotaxis is a phenomenon that occurs when a cellular collective, for example an epithelial monolayer, is subjected to an electric field. Biologically, it is well known that the velocity of migration during the collective electrotaxis of large epithelia exhibits significant spatial heterogeneity. In this work, we demonstrate that the heterogeneity of velocities in the electrotaxing epithelium can be accounted for by a continuum model of cue competition in different tissue regions. Having established a working model of competing migratory cues in the migrating epithelium, we develop and validate a reaction-convection-diffusion model that describes the movement of an epithelial monolayer as it undergoes electrotaxis. We use the model to predict how tissue size and geometry affect the collective migration of MDCK monolayers, and to propose several ways in which electric fields can be designed such that they give rise to a desired spatial pattern of collective migration. We conclude with two examples that demonstrate practical applications of the method in designing bespoke stimulation protocols.
RCE-IFE: Recursive Cluster Elimination with Intra-cluster Feature Elimination
Authors: Kuzudisli Cihan , Bakir-Gungor Burcu , Qaqish Bahjat , Yousef Malik 
Published: March 2024

AbstractThe computational and interpretational difficulties caused by the ever-increasing dimensionality of biological data generated by new technologies pose a major challenge. Feature selection (FS) methods aim to reduce the dimension, and feature grouping has emerged as a foundation for FS techniques that seek to detect strong correlations among features and the existence of irrelevant features. In this work, we develop Recursive Cluster Elimination with Intra-Cluster Feature Elimination (RCE-IFE), a method that iterates clustering and elimination steps in a supervised context. Recursively, feature clusters are formed, then scored, and less contributing clusters are eliminated. Next, low-scoring features in retained clusters are eliminated. Intra-cluster feature elimination aims to reduce noisy features while keeping a minimum number of predictive features. The performance of RCE-IFE is evaluated and compared to other FS techniques in several datasets. The results show that the proposed strategy effectively reduces the size of the feature set and also improves the model performance.
MultiMatch: Geometry-Informed Colocalization in Multi-Color Super-Resolution Microscopy
Authors: Naas Julia , Nies Giacomo , Li Housen , Stoldt Stefan , Schmitzer Bernhard , Jakobs Stefan , Munk Axel 
Published: March 2024

AbstractWith recent advances in multi-color super-resolution light microscopy it has become possible to simultaneously visualize multiple subunits within complex biological structures at nanometer resolution. To opti-mally evaluate and interpret spatial proximity of stainings on such an image, colocalization analysis tools have to be able to integrate prior knowledge on the local geometry of the recorded biological complex. Here, we presentMultiMatchto analyze the abundance and location of chain-like particle arrangements in multi-color microscopy based on multi-marginal optimal unbalanced transport methodology. Our object-based colocalization model statistically addresses the effect of incomplete labeling efficiencies enabling inference on existent, but not fully observ-able particle chains. We showcase that MultiMatch is able to consistently recover all existing chain structures in three-color STED images of DNA origami nanorulers and outperforms established geometry-uninformed triplet colocalization methods in this task in a simulation study. Further-more, MultiMatch also excels in the evaluation of simulated four-color STED images and generalizations to even more color channels can be immediately derived from our analysis. MultiMatch is provided as a user-friendly Python package comprising intuitive colocalization visual-izations and a computationally efficient network flow implementation.
PTM-Mamba: A PTM-Aware Protein Language Model with Bidirectional Gated Mamba Blocks
Authors: Peng Zhangzhi , Schussheim Benjamin , Chatterjee Pranam 
Published: March 2024

AbstractProteins serve as the workhorses of living organisms, orchestrating a wide array of vital functions. Post-translational modifications (PTMs) of their amino acids greatly influence the structural and functional diversity of different protein types and uphold proteostasis, allowing cells to swiftly respond to environmental changes and intricately regulate complex biological processes. To this point, efforts to model the complex features of proteins have involved the training of large and expressive protein language models (pLMs) such as ESM-2 and ProtT5, which accurately encode structural, functional, and physicochemical properties of input protein sequences. However, the over 200 million sequences that these pLMs were trained on merely scratch the surface of proteomic diversity, as they neither input nor account for the effects of PTMs. In this work, we fill this major gap in protein sequence modeling by introducing PTM tokens into the pLM training regime. We then leverage recent advancements in structured state space models (SSMs), specifically Mamba, which utilizes efficient hardware-aware primitives to overcome the quadratic time complexities of Transformers. After adding a comprehensive set of PTM tokens to the model vocabulary, we train bidirectional Mamba blocks whose outputs are fused with state-of-the-art ESM-2 embeddings via a novel gating mechanism. We demonstrate that our resultant PTM-aware pLM,PTM-Mamba, improves upon ESM-2’s performance on various PTM-specific tasks. PTM-Mamba is the first and only pLM that can uniquely input and represent both wild-type and PTM sequences, motivating downstream modeling and design applications specific to post-translationally modified proteins. To facilitate PTM-aware protein language modeling applications, we have made our model available at:https://huggingface.co/ChatterjeeLab/PTM-Mamba.
Structural basis ofFusobacterium nucleatumadhesin Fap2 interaction with receptors on cancer and immune cells
Authors: Schöpf Felix , Marongiu Gian L. , Milaj Klaudia , Sprink Thiemo , Kikhney Judith , Moter Annette , Roderer Daniel 
Published: March 2024

AbstractThe intestinal microbiome (IM) is decisive for the human host’s health. Numerous microbiota drive the progression of colorectal cancer (CRC), the third-most common cancer worldwide. The Gram-negativeFusobacterium nucleatum(Fn) is overrepresented in the IM of CRC patients and has been correlated with the emergence, progression, and metastasis of tumors. A key pathogenic factor of Fn is the adhesin Fap2, an autotransporter protein that facilitates association to cancer and immune cells via two receptors, the glycan Gal-GalNAc and the T-cell protein TIGIT, respectively. The latter interaction leads to deactivation of immune cells. Mechanistic details of the Fap2/TIGIT interaction remain elusive due to the lack of high-resolution structural data. Here, we report a system to recombinantly express functional Fap2 on theEscherichia colisurface, which interacts with Gal-GalNAc on cancer cells and with purified TIGIT with submicromolar affinity. Cryo-EM structures of Fap2, alone and in complex with TIGIT, show that the ∼50 nm long rod-shaped Fap2 extracellular region binds to TIGIT on its membrane-distal tip via an extension of a β-helix domain. Moreover, by combining structure predictions, cryo-EM, docking and MD simulations, we identified a binding pit for Gal-GalNAc on the tip of Fap2. Our data represent the first purification and high-resolution structural analysis of a Fn autotransporter adhesin and its receptor association.
Translation coupled mRNA-decay is a function of both structural and codon level characteristics
Authors: Basu Sudipto , Hait Suman , Kundu Sudip 
Published: March 2024

AbstractThe majority of mRNA degradation occurs co-translationally. Several works in the past elucidated the role of codon composition in regulating co-translational mRNA decay. Integration of mRNA sequence, structure and ribosomal density unravels common regulatory factors of translational and degradation and helps in understanding the intricate association between these two important processes. Co-translational degradation is a two-step process, involving translational stalling and mRNA release for degradation. Our findings highlight the role of Codon Adaptation Index, a sequence-level feature that serves as the primary determinant of translation rates facilitating transcript release from translational machinery upon stalling. Concurrently, cellular endonucleases targeting Internal Unstructured Segments, facilitating easy degradation of the stalled mRNA transcripts, influencing their half-lives across the genome and over evolutionary timescales.
Multimodal intrinsic activation of GPCRs in ultrastable plasma membrane nanodomains
Authors: Kockelkoren Gabriele , Carstensen Jens , Lauritsen Line , Kazepidou Eleftheria , Tonnesen Asger , Shuttle Christopher G. , Kaas Paulina S. , Gupta Ankur , Breuer Artù , Rasmussen Søren G. F. , Duffet Loïc , Warne Tony , Patriarchi Tommaso , Tate Christopher G. , Uline Mark , Stamou Dimitrios 
Published: March 2024

AbstractG protein-coupled receptors (GPCRs) mediate many physiological functions and are key targets in drug development1-3. A long-held tenet of molecular pharmacology is that GPCRs can spontaneously sample preexisting active conformations. This concept is pivotal to our understanding of ligand pharmacology4, however, direct evidence supporting it has only been obtained with reconstituted receptors5-12. Here, we introduce a method for quantitatively imaging the intrinsic activation probability of GPCRs directly at the plasma membrane of live cells, utilizing fluorescent conformational biosensors13,14. Our findings unveil a remarkable spatial multimodality in intrinsic activation probability, with a significant majority (up to 99%) of plasma membrane-expressed receptors showing negligible spontaneous activation. In contrast, the remaining minority of receptors exhibits spontaneous activation up to 22-fold higher than previously estimated. Experiments and theoretical calculations revealed that receptors diffuse into and out of ultralong-lived (∼5 minutes) nanodomains where the local membrane curvature allosterically enhances activation in the absence and presence of ligands. Extensive testing across five prototypic GPCRs indicates spatial nanoscale multimodality is ubiquitous, but varying in magnitude depending on the receptor and cell type. Upending conventional wisdom, this study reveals that drug efficacy is not a constant number but a spatiotemporal function ε(x, y, z, t)whose properties define and multiplex the signaling potency and efficacy of ternary complexes of GPCRs and likely other plasma membrane-receptors.Graphical AbstractGPCR spontaneous activation and intrinsic efficacy are not uniform across the plasma membrane but exhibit ultralong-lived spatial multimodality. Spatial variations in the curvature and composition of the plasma membrane, lead to the emergence of ultralong-lived nanodomains with contrasting physicochemical properties that allosterically regulate GPCR conformations. This results in a multimodal landscape of intrinsic efficacyϵ (x, y, z, t)that ultimately governs cell signaling. XY scalebar: 500 nm. Z-range: 100 nm.
Illuminating the functional landscape of the dark proteome across the Animal Tree of Life through natural language processing models
Authors: Martínez-Redondo Gemma I. , Barrios-Núñez Israel , Vázquez-Valls Marçal , Rojas Ana M. , Fernández Rosa 
Published: March 2024

AbstractBackgroundUnderstanding how coding genes and their functions evolve over time is a key aspect of evolutionary biology. Protein coding genes poorly understood or characterized at the functional level may be related to important evolutionary innovations, potentially leading to incomplete or inaccurate models of evolutionary change, and limiting the ability to identify conserved or lineage-specific features. Homology-based methodologies often fail to transfer functional annotations in a large fraction of the coding gene repertoire in non-model organisms. This is particularly relevant in animals, where a large number of their coding genes yield no functional annotation.ResultsHere, we leverage homology, deep learning, and protein language models to investigate functional annotation in the ‘dark proteome’ (defined as the unknown functional landscape’) of ca. 1,000 gene repertoires of virtually all animal phyla, totaling ca. 23.2 million coding genes. We then explored the ‘dark proteome’ of all animal phyla revealing an enrichment in functions related to immune response, viral infection, response to stimuli, development, or signaling, among others. Furthermore, we provide an open-source pipeline - FANTASIA - to implement and benchmark these methodologies in any dataset.ConclusionsOur results uncover the putative functions of poorly understood protein-coding genes across the Animal Tree of Life that were inaccessible before due to the limitations in homology inference, contributing to a more comprehensive understanding of the molecular basis of animal evolution, and providing a new tool for the functional annotation of protein-coding genes in newly generated genomes.
The Structure of ApoB100 from Human Low-density Lipoprotein
Authors: Berndsen Zachary T. , Cassidy C. Keith 
Published: March 2024

AbstractLow-density lipoprotein (LDL) plays a central role in lipid and cholesterol metabolism and is a key molecular agent involved in the development and progression of atherosclerosis, a leading cause of mortality worldwide. Apolipoprotein B100 (apoB100), one of the largest proteins in the genome, is the primary structural and functional component of LDL, yet its size and complex lipid associations have posed major challenges for structural studies. Here we overcome those challenges and present the first structure of apoB100 from human LDL using an integrative approach of cryo-electron microscopy, AlphaFold2, and molecular dynamics-based refinement. The structure consists of a large globular N-terminal domain that leads into a ∼58 nm long x 4 nm wide continuous amphipathic β-sheet that wraps completely around the circumference of the particle, holding it together like a belt. Distributed symmetrically across the two sides of the β-belt are 9 strategically located inserts that vary in size from ∼30-700 residues and appear to have diverse functions. The largest two form long flexible strings of paired amphipathic helices that extend across the lipid surface to provide additional structural support through specific long-range interactions. These results suggest a mechanism for how the various domains of apoB100 act in concert to maintain LDL shape and cohesion across a wide range of particle sizes. More generally, they advance our fundamental understanding of LDL form and function and will help accelerate the design of potential new therapeutics.