bluuebunny/crossref_metadata_2025_split huggingface dataset:
Denoising complex-valued diffusion MR images using a two-step non-local principal component analysis approach
Authors: Ye Xinyu , Ma Xiaodong , Pan Ziyi , Zhang Zhe , Guo Hua , Uğurbil Kâmil , Wu Xiaoping 
Published: October 2024

AbstractPurposeto propose a two-step non-local principal component analysis (PCA) method and demonstrate its utility for denoising diffusion tensor MRI (DTI) with a few diffusion directions.MethodsA two-step denoising pipeline was implemented to ensure accurate patch selection even with high noise levels and was coupled with data preprocessing for g-factor normalization and phase stabilization before data denoising with a non-local PCA algorithm. At the heart of our proposed pipeline was the use of a data-driven optimal shrinkage algorithm to manipulate the singular values in a way that would optimally estimate the noise-free signal. Our approach’s denoising performances were evaluated using simulation and in-vivo human data experiments. The results were compared to those obtained with existing local-PCA-based methods.ResultsIn both simulation and human data experiments, our approach substantially enhanced image quality relative to the noisy counterpart, yielding improved performances for estimation of relevant DTI metrics. It also outperformed existing local-PCA-based methods in reducing noise while preserving anatomic details. It also led to improved whole-brain tractography relative to the noisy counterpart.ConclusionThe proposed denoising method has the utility for improving image quality for DTI with reduced diffusion directions and is believed to benefit many applications especially those aiming to achieve quality parametric mapping using only a few image volumes.
Modeling Protein Conformations by Guiding AlphaFold2 with Distance Distributions. Application to Double Electron Electron Resonance (DEER) Spectroscopy
Authors: Wu Tianqi , Stein Richard A. , Kao Te-Yu , Brown Benjamin , Mchaourab Hassane S. 
Published: November 2024

AbstractWe describe a modified version of AlphaFold2 that incorporates experiential distance distributions into the network architecture for protein structure prediction. Harnessing the OpenFold platform, we fine-tuned AlphaFold2 on a small number of structurally dissimilar proteins to explicitly model distance distributions between spin labels determined from Double Electron-Electron Resonance (DEER) spectroscopy. We demonstrate the performance of the modified AlphaFold2, referred to as DEERFold, in switching the predicted conformations guided by experimental or simulated distance distributions. Remarkably, the intrinsic performance of AlphaFold2 substantially reduces the number and the accuracy of the widths of the distributions needed to drive conformational selection thereby increasing the experimental throughput. The blueprint of DEERFold can be generalized to other experimental methods where distance constraints can be represented by distributions.
Genome-wide investigation of outer membrane protein families under mosaic evolution inEscherichia coli
Authors: Cao Xin , Cao Cuihua , Chen Zefan , Li Jialin , Zheng Yidong , Wu Jinjin , Li Zeling , Hu Yueming , Hao Gaofeng , Zhu Guoqiang , Köster Wolfgang , White Aaron P. , Wang Yejun 
Published: November 2024

AbstractSeveral genes in Gram-negative bacteria encoding outer membrane proteins (OMPs) have been reported to show patterns of mosaic evolution featured by mixture of negative selection and local recombination. Here, we proposed a strategy, and applied it to screen OMPs under mosaic evolution inEscherichia coliin the genome level. In total, 21 OMP families, including 16 new ones, were detected with the typical patterns of mosaic evolution. An abosolute majority of the protein families are conserved inE. colifor the composition, genomic loci and the overall structures. Highly Variable Regions (HVRs) can be recognized, which are frequently located extracellularly within the protruding loops. There are only limited number of major HVR sequence types, within which positively selected sites can be detected ocassionally. Based on the simulated results of multiple models, the OMPs under mosaic evolution are often with good antigenicity, with HVRs of various sequence types coinciding with the B-cell epitopes of the strongest immunogenicity. The study futher broadened our understanding of the characteristics of mosaic evolution and the functions of OMPs in Gram-negative bacteria, laying an important foundation for their potential translational applications.ImportanceIt is important to understand the evolutionary mechanisms of bacterial OMP-encoding genes, which would facilitate the development of anti-bacterial reagents. This study made the first genome-wide screening of bacterial OMPs under mosaic evolution, and increased the list of candidate OMP families by 3 folds inE. coli, far more than we expected. The study further confirmed the hypothesis about the evolutionary, micro-evolutionary and structural features of these OMPs, and facilitated the functional theory of mosaic evolution. Moreover, the findings of limited HVR sequence types and strong immunogenicity of HVRs paved important foundation for application of these OMPs and their HVRs in development of antibodies or other anti-bacterial treatment.
Structural and Functional Relevance of Charge Based Transient Interactions inside Intrinsically Disordered Proteins
Authors: Wohl Samuel , Gilron Yishai , Zheng Wenwei 
Published: November 2024

AbstractIntrinsically disordered proteins (IDPs) perform a wide range of biological functions without adopting stable, well-defined, three-dimensional structures. Instead, IDPs exist as dynamic ensembles of flexible conformations, traditionally thought to be governed by weak, nonspecific interactions, which are well described by homopolymer theory. However, recent research highlights the presence of transient, specific interactions in several IDPs, suggesting that factors beyond overall size influence their conformational behavior. In this study, we investigate how the spatial arrangement of charged amino acids within IDP sequences shapes the prevalence of transient, specific interactions. Through a series of model peptides, we establish a quantitative empirical relationship between the fraction of transient interactions and a novel sequence metric, termed effective charged patch length, which characterizes the ability of charged patches to drive these interactions. By examining IDP ensembles with varying levels of transient interactions, we further explore their heteropolymeric structural behavior in phase-separated condensates, where we observe the formation of a condensate-spanning network structure. Additionally, we perform a proteome-wide scan for charge-based transient interactions within disordered regions of the human proteome, revealing that approximately 10% of these regions exhibit such charge-driven transient interactions, leading to heteropolymeric behaviors in their conformational ensembles. Finally, we examine how these charge-based transient interactions correlate with molecular functions, identifying specific biological roles in which these interactions are enriched.
Practice beyond performance stabilization increases the use of online adjustments to unpredictable perturbations in an interceptive task
Authors: Couto Crislaine Rangel , Leite Cláudio Manoel Ferreira , Campos Carlos Eduardo , Portes Leonardo Luiz , Matos Cíntia de Oliveira , Santos Suziane Peixoto , Ambrósio Natália Fontes Alves , Yehia Hani Camille , Ugrinowitsch Herbert 
Published: November 2024

AbstractIn recent decades, research has focused on motor adjustments in interception tasks within predictable environments. However, emerging studies suggest that continued practice beyond performance stabilization enhances the ability to adapt to unpredictable events. The objective of this study was to investigate the effects of practicing until performance stabilization versus extended practice through superstabilization on the ability to adjust to unpredictable perturbations in intercepting a moving target. We hypothesized superstabilization would better facilitate motor adjustments in response to unpredictable perturbations. Forty participants engaged in an interception task until they achieved either performance stabilization or superstabilization. Subsequently, both stabilization and superstabilization groups were tested in an unpredictable environment, where, in certain trials, the target’s velocity unexpectedly changed after the onset of the movement. The findings revealed that the superstabilization group made more adjustments in response to these perturbations than the stabilization group, attributed to their developed capacity to use online feedback as a control mechanism more efficiently. In contrast, the practice until performance stabilization did not foster this adaptive mechanism. These results support the notion that learning is a dynamic process that extends beyond the point of performance stabilization, emphasizing the benefits of continued practice for mastering complex motor tasks in variable contexts.
Antigenic imprinting dominates humoral responses to new variants of SARS-CoV-2 in a hamster model of COVID-19
Authors: Degryse Joran , Maas Elke , Lassaunière Ria , Geerts Katrien , Kumpanenko Yana , Weynand Birgit , Maes Piet , Neyts Johan , Thibaut Hendrik Jan , Alpizar Yeranddy A. , Dallmeier Kai 
Published: November 2024

AbstractThe emergence of SARS-CoV-2 variants escaping immunity challenges the efficacy of current vaccines. Here, we investigated humoral recall responses and vaccine-mediated protection in Syrian hamsters immunized with the third-generation Comirnaty® Omicron XBB.1.5-adapted COVID-19 mRNA vaccine, followed by infection with either antigenically closely (EG.5.1) or distantly related (JN.1) Omicron subvariants. Vaccination with YF17D vector encoding a modified Gamma spike (YF-S0*) served as a control for pre-Omicron SARS-CoV-2 immunity. Our results show that both Comirnaty® XBB.1.5 and YF-S0* induce robust, however, poorly cross-reactive, neutralizing antibody (nAb) responses. In either case, total antibody and nAb levels increased following infection. Intriguingly, the specificity of these boosted nAbs did not match the respective challenge virus but was skewed towards the primary antigen used for immunization, suggesting a marked impact of antigenic imprinting; confirmed by antigenic cartography. Furthermore, limited cross-reactivity and rapid decline of nAbs induced by Comirnaty® XBB.1.5 with EG.5.1 and, more concerning, JN.1. raises doubts about sustained vaccine efficacy against recent circulating Omicron subvariants. Future vaccine design may have to address two major issues: (i) to overcome original antigenic sin that limits the breadth of a protective response towards emerging variants, and (ii) to achieve sustained immunity that lasts for at least one season.
A designed Zn2+sensor domain transmits binding information to transmembrane histidine kinases
Authors: Hatstat A. Katherine , Kormos Rian , Xu Vee , DeGrado William F. 
Published: November 2024

AbstractGenerating stimulus-responsive, allosteric signalingde novois a significant challenge in protein design. In natural systems like bacterial histidine kinases (HKs), signal transduction occurs when ligand binding initiates a signal that is amplified across biological membranes over long distances to induce large-scale rearrangements and phosphorylation relays. Here, we ask whether our understanding of protein design and multi-domain, intramolecular signaling has progressed sufficiently to enable engineering of a HK with tunablede novocomponents. We generatedde novometal-binding sensor domains and substituted them for the native sensor domain of a transmembrane HK, affording chimeras that transduce signals initiated from ade novosensor. Signaling depended on the designed sensor’s stability and the interdomain linker’s phase and length. These results show the usefulness ofde novodesign to elucidate biochemical mechanisms and principles for design of new signaling systems.
Multiscale Quantification of Hemispheric Asymmetry in Cortical Maps Using Geometric Eigenmodes
Authors: Milloz Alicia , Vogel Jacob , Olsen Anders , Pang James C , Strandberg Olof , Anijärv Toomas Erik , Stomrud Erik , Palmqvist Sebastian , Spotorno Nicola , Ossenkoppele Rik , Van De Ville Dimitri , Hansson Oskar , Behjat Hamid 
Published: October 2024

ABSTRACTHemispheric asymmetry is a universal property of brain organization with wide implications into brain function and structure, and diseases. This study presents a laterality index for characterizing hemispheric asymmetries that underlie cortical maps using geometric eigenmodes derived from human cortical surfaces.We develop a generalized design to quantify asymmetries across various cortical spatial scales. While the design is individual-specific, we implement normalization steps to enable unbiased comparisons across individuals. As a proof of concept, we validated the method on cortical maps of 545 subjects across two datasets, using fMRI maps of healthy individuals and tau-PET maps of patients across the Alzheimer’s disease continuum. Our results reveal that cortical regions in different canonical functional networks have connectivity patterns that entail different degrees of hemispheric asymmetry. Moreover, aggregates of the pathological tau protein manifest subtle asymmetries at varying spatial scales along the disease continuum.
Phage-encoded small RNA hijacks host replication machinery to support the phage lytic cycle
Authors: Silverman Aviezer , Nashef Raneem , Bruner Reut , Noy Tamar , Melamed Sahar 
Published: November 2024

ABSTRACTBacteriophages (phages) significantly influence bacterial populations in their natural environment. However, one aspect that has not been thoroughly explored in the context of phage-bacteria interactions is the post-transcriptional regulation of gene expression, despite growing recognition of its importance in bacterial physiology over the past two decades. Important players in this process are small RNAs (sRNAs) that regulate target mRNAs via base-pairing, typically using RNA chaperones like Hfq to facilitate this regulation. Here, we apply RIL-seq to mapin-vivothe sRNA-RNA network inEscherichia coliupon lambda phage infection. We highlight changes in the bacterial transcriptome and sRNA interactome while uncovering a novel phage-encoded sRNA that regulates key genes inE. coli. We decipher the molecular mechanism of the sRNA-mediated regulation and illustrate how the sRNA hijacks the host replication machinery and helps the infection cycle. Overall, we uncover an RNA-level regulatory layer that shapes theE. coli- lambda interactions.
A potently neutralizing and protective human antibody targeting antigenic site V on RSV and hMPV fusion glycoprotein
Authors: Abu-Shmais Alexandra A. , Guo Luqiang , Khalil Ahmed Magady , Miller Rose J. , Janke Alexis K. , Vukovich Matthew J. , Bass Lindsay E. , Suresh Yukthi P. , Rush Scott A. , Wolters Rachael M. , Kose Nurgun , Carnahan Robert H. , Crowe James E. , Bonami Rachel H. , Mousa Jarrod J. , McLellan Jason S. , Georgiev Ivelin S. 
Published: November 2024

ABSTRACTHuman respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) are frequent drivers of morbidity and mortality in susceptible populations, most often infantile, older adults, and immunocompromised. The primary target of neutralizing antibodies is the fusion (F) glycoprotein on the surface of the RSV and hMPV virion. As a result of the structural conservation between RSV and hMPV F, three antigenic regions are known to induce cross-neutralizing responses: sites III, IV, and V. Leveraging LIBRA-seq, we identify five RSV/hMPV cross-reactive human antibodies. One antibody, 5-1, potently neutralizes all tested viruses from the major subgroups of RSV and hMPV and provides protection against RSV and hMPV in a mouse challenge model. Structural analysis reveals that 5-1 utilizes an uncommon genetic signature to bind an epitope that spans sites Ø, II and V, defining a new mode of antibody cross-reactivity between RSV and hMPV F. These findings highlight the molecular and structural elements influencing RSV and hMPV cross-reactivity as well as the potential of antibody 5-1 for translational development.
Awakening of the RuMP cycle for partial methylotrophy in the thermophileParageobacillus thermoglucosidasius
Authors: Paredes-Barrada Miguel , Mathissen Annemieke , van der Molen Roland A. , Jiménez-Huesa Pablo J. , Polano Machiel Eduardo , Donati Stefano , Abele Miriam , Ludwig Christina , van Kranenburg Richard , Claassens Nico J. 
Published: November 2024

AbstractGiven sustainability and scalability concerns of using sugar feedstocks for microbial bioproduction of bulk chemicals, widening the feedstock range for microbial cell factories is of high interest. Methanol is a one-carbon alcohol that stands out as an alternative feedstock for the bioproduction of chemicals, as it is electron-rich, water-miscible and can be produced from several renewable resources. Bioconversion of methanol into products under thermophilic conditions (>50°C) could be highly advantageous for industrial biotechnology. Although progress is being made with natural, thermophilic methylotrophic microorganisms, they are not yet optimal for bioproduction and establishing alternative thermophilic methylotrophic bioproduction platforms can widen possibilities. Hence, we set out to implement synthetic methanol assimilation in the emerging thermophilic model organismParageobacillus thermoglucosidasius.We engineeredP. thermoglucosidasiusto be strictly dependent for its growth on methanol assimilation via the core of the highly efficient ribulose monophosphate (RuMP) cycle, while co-assimilating ribose. Surprisingly, this did not require heterologous expression of RuMP enzymes. Instead, by laboratory evolution we awakened latent, native enzyme activities to form the core of the RuMP cycle. We obtained fast methylotrophic growth in which ∼17% of biomass was strictly obtained from methanol. This work lays the foundation for developing a versatile thermophilic bioproduction platform based on renewable methanol.
Chromatin-associated lncRNA-splicing factor condensates regulate hypoxia responsive RNA processing of genes pre-positioned near nuclear speckles
Authors: Song You Jin , Shinn Min Kyung , Bangru Sushant , Wang Yu , Sun Qinyu , Hao Qinyu , Chaturvedi Pankaj , Freier Susan M. , Perez-Pinera Pablo , Nelson Erik R. , Belmont Andrew S. , Guttman Mitchell , Prasanth Supriya G. , Kalsotra Auinash , Pappu Rohit V. , Prasanth Kannanganattu V. 
Published: November 2024

AbstractHypoxia-induced alternative splicing (AS) regulates tumor progression and metastasis. Little is known about how such AS is controlled and whether higher-order genome and nuclear domain (ND) organizations dictate these processes. We observe that hypoxia-responsive alternatively spliced genes position near nuclear speckle (NS), the ND that enhances splicing efficiency. NS-resident MALAT1 long noncoding RNA, induced in response to hypoxia, regulates hypoxia-responsive AS. MALAT1 achieves this by organizing the SR-family of splicing factor, SRSF1, near NS and regulating the binding of SRSF1 to pre-mRNAs. Mechanistically, MALAT1 enhances the recruitment of SRSF1 to elongating RNA polymerase II (pol II) by promoting the formation of phase-separated condensates of SRSF1, which are preferentially recognized by pol II. During hypoxia, MALAT1 regulates spatially organized AS by establishing a threshold SRSF1 concentration near NSs, potentially by forming condensates, critical for pol II-mediated recruitment of SRSF1 to pre-mRNAs.
Genome-wide analysis of fitness determinants ofStaphylococcus aureusduring growth in milk
Authors: Mårli Marita Torrissen , Nordraak Anne Olsdatter Ohren , de Bakker Vincent , Winther Anja Ruud , Liu Xue , Veening Jan-Willem , Porcellato Davide , Kjos Morten 
Published: November 2024

AbstractStaphylococcus aureusis a major concern in the dairy industry due to its significance as a pathogen causing bovine mastitis as well as a source of food poisoning. The nutrient-rich milk environment supports bacterial growth, but the specific genetic determinants that facilitateS. aureusproliferation and persistence in milk are poorly understood. In this study, we conducted a genome-wide CRISPR interference sequencing (CRISPRi-seq) screen to identify fitness determinants essential forS. aureusgrowth and survival in milk. We identified 282 milk-essential genes, including those with key roles in DNA replication, protein synthesis, and metabolism. Comparative analysis with brain heart infusion (BHI) as growth medium, revealed 79 genes with differential fitness, highlighting specific adaptations required for growth in milk. Notably, we found that purine biosynthesis, folate cycle pathways, and metal acquisition were particularly important in this environment. Based on this, we further demonstrate thatS. aureusis more sensitive to the folate inhibitors trimethoprim-sulfamethoxazole (TMP-SMX) in milk and identify several genes whose knockdown results in hypersensitivity to TMP-SMX in milk. Additionally, our analysis showed a relatively reduced importance of cell wall components, such as teichoic acids, forS. aureusfitness in milk, which is also reflected in reduced efficiency of antimicrobials targeting teichoic acids. Together, these findings provide new insights into the genetic basis ofS. aureusfitness and antibiotic susceptibility in milk, offering directions for novel treatment strategies against bovine mastitis.
Influenza A Virus H7 nanobody recognizes a conserved immunodominant epitope on hemagglutinin head and confers heterosubtypic protection
Authors: Chen Zhao-Shan , Huang Hsiang-Chi , Wang Xiangkun , Schön Karin , Jia Yane , Lebens Michael , Besavilla Danica F. , Murti Janarthan R. , Ji Yanhong , Sarshad Aishe A. , Deng Guohua , Zhu Qiyun , Angeletti Davide 
Published: November 2024

AbstractInfluenza remains a persistent global health challenge, largely due to the virus’ continuous antigenic drift and shift, which impede the development of a universal vaccine. To address this, the identification of broadly neutralizing antibodies and their epitopes is crucial. Nanobodies, with their unique characteristics and binding capacity, offer a promising avenue to identify such epitopes. Here, we isolated and purified a hemagglutinin (HA)-specific nanobody that recognizes an H7 subtype of influenza A virus. Notably, the nanobody, named E10, exhibited broad-spectrum binding, cross-group neutralization andin vivoprotection across various influenza A subtypes. Through phage display andin vitrocharacterization, we demonstrated that E10 specifically targets an epitope on HA head. This epitope is part of the conserved lateral patch of HA head and proved to be highly immunodominant upon H7 infection. Importantly, immunization with a peptide including the E10 epitope elicited cross-reactive antibodies and mediated partial protection from lethal viral challenge. Our data highlight the potential of E10 and its associated epitope as a candidate for future influenza prevention strategies.