bluuebunny/crossref_metadata_2025_split huggingface dataset:
Magnetic Resonance Imaging Data Phenotypes for the Parkinson’s Progression Markers Initiative
Authors: Avants Brian B , Fonville Leon , Hampton Olivia , Reardon Alexandra , Stenger Andrew , Wang Xue , Tustison Nicholas J , Stone James R , Cook Philip A , Marebwa Barbara , Chahine Lana M , Poston Kathleen L , Marek Kenneth , Becerra Lino , Gunn Roger ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: September 2024

AbstractThe Parkinson’s Progression Markers Initiative (PPMI) delivers multiple modality MRI (M3RI) and biomarker data for a comprehensive longitudinal study of Parkinson’s Disease (PD). These provide quantitative indices of deep brain and cortical structure (T1-weighted MRI), microstructural integrity of brain tissue (diffusion-weighted imaging) and resting brain function (resting state functional MRI). Integrating and uniformly analyzing M3RI alongside non-imaging biological and clinical data is challenging due to the distinct nature of each modality. This study systematically organizes these complex data into a structured format, provides a PD-focused evaluation of the methodologies and evidence for technical robustness of the approach. The cohort encompasses 841 idiopathic PD, 309 genetic PD, 1364 presymptomatic PD and 240 control subjects at baseline with followup at a mean of 1.83 years.
A decade of shifting cholera burden in Africa and its implications for control: a statistical mapping analysis
Authors: Perez-Saez Javier , Zheng Qulu , Kaminsky Joshua , Zou Kaiyue , Demby Maya N. , Alam Christina , Landau Daniel , DePencier Rachel , Langa Jose Paulo M. , Chilengi Roma , Okitayemba Placide Welo , Bwire Godfrey , Esso Linda , Ngomba Armelle Viviane , Mbarga Nicole Fouda , Okunga Emmanuel Wandera , Yennan Sebastian , Kapaya Fred , Ohize Stephen Ogirima , Seriki Adive Joseph , Hegde Sonia T. , Sikder Mustafa , Lessler Justin , Datta Abhirup , Azman Andrew S. , Lee Elizabeth C. 
Published: September 2024

AbstractBackgroundThe World Health Organization declared a global cholera emergency in 2023 due to an increase in cholera outbreaks, with most cholera-associated deaths reported in Africa. Characterizing large-scale burden patterns can help with monitoring progress in cholera control and targeting interventions.MethodsWe modeled the mean annual incidence of suspected cholera for 2011-2015 and 2016-2020 on a 20 km by 20 km grid across Africa using a global cholera database and spatial statistical models. We then examined how 2011-2020 incidence is associated with post-2020 cholera occurrence and investigated the potential reach of prospective interventions when prioritized by past incidence.FindingsAcross 43 African countries mean annual incidence rates remained steady at 11 cases per 100,000 population through both periods. Cholera incidence shifted from Western to Eastern Africa, and we estimated 125,701 cases annually (95% CrI: 124,737-126,717) in 2016-2020. There were 296 million (95% CrI: 282-312 million) people living in high-incidence second-level administrative (ADM2) units (≥ 10 cases per 100,000 per year) in 2020, of which 135 million experienced low incidence (<1 per 100,000) in 2011-2015. ADM2 units with sustained high incidence in Central and Eastern Africa from 2011-2020 were more likely to report cholera in 2022-2023, but cases were also reported in sustained low ADM2 units. Targeting the 100 million highest burden populations had potential to reach up to 63% of 2016-2020 mean annual cases but only 37% when targeting according to past 2011-2015 incidence.InterpretationBy revealing the changing spatial epidemiology of cholera in Africa, these 10-year subnational estimates may be used to project OCV demand, characterize the potential of targeting interventions based on past burden, and track progress towards disease control goals.
Understanding Embolus Transport And Source To Destination Mapping Of Thromboemboli In Hemodynamics Driven By Left Ventricular Assist Device
Authors: Majee Sreeparna , Sahni Akshita , Pal Jay D. , McIntyre Erin E. , Mukherjee Debanjan 
Published: September 2024

AbstractLeft Ventricular Assist Devices (LVADs) are a key treatment option for patients with advanced heart failure, but they carry a significant risk of thromboembolic complications. While improved LVAD design, and systemic anticoagulation regimen, have helped mitigate thromboembolic risks, ischemic stroke due to adverse thromboembolic events remains a major concern with current LVAD therapies. Improved understanding of embolic events, and embolus movement to the brain, is critical to develop techniques to minimize risks of occlusive embolic events such as a stroke after LVAD implantation. Here, we address this need, and devise a quantitativein silicoframework to characterize thromboembolus transport and distrbution in hemodynamics driven by an operating LVAD. We conduct systematic numerical experiments to quantify the source-to-destination transport patterns of thromboemboli as a function of: LVAD outflow graft anastomosis, LVAD operating pulse modulation, thromboembolus sizes, and origin locations of emboli. Additionally, we demonstrate how the resulting embolus distribution patterns compare and correlate with descriptors based solely on hemodynamic patterns such as helicity, vorticity, and wall shear stress. Using the concepts of size-dependent embolus-hemodynamics interactions, and two jet flow model for hemodynamics under LVAD operation as established in our prior works, we gain valuable insights on departure of thromboembolus distribution from flow distribution, and establish that ourin silicomodel can generate deep insights into embolus dynamics which is not otherwise available from standard of care imaging and clinical data.
Established Sulfopeptide Tandem Mass Spectrometry Behavior and Sulfotransferase Assays Refute Tyrosine Sulfation as a Histone Mark
Authors: Youssef Menatallah M. , Szot Carson W. , Ayad Miriam F. , Hussein Lobna A. , Abdel-Ghany Maha F. , Bailey Ryan C. , Mostafa Ahmed M. , Hakansson Kristina 
Published: September 2024

AbstractTyrosylprotein sulfotransferases (TPST1 and TPST2) are only known to exist in the Golgi1. Thus, Yu et al.’s findings that histone H3 sulfation occurs in the cytosol are surprising. Cytosolic sulfotransferase SULT1B1, which sulfates phenolic small molecules, was proposed to catalyze H3Y99 sulfation with 3′-phosphoadenosine 5′-phosphosulfate (PAPS) as SO3donor. Bottom-up liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomic analyses were key to this conclusion. Such experiments appear to have been mainly performed following standard protocols, including reduction (reagent unknown), alkylation with iodoacetamide (IAA), and proteolytic digestion prior to nanoflow LC (nanoLC) separation of proteolytic peptides and data-dependent higher energy collision dissociation (HCD) to generate sequence-informative peptide fragments. However, the published HCD MS/MS spectra do not match established sulfopeptide fragmentation behavior. We present reannotation of these spectra and additional experiments that found a lack of evidence to support H3Y99 sulfation.
Hippocampal representations of alternative possibilities are flexibly generated to meet cognitive demands
Authors: Comrie Alison E. , Monroe Emily J. , Kahn Ari E. , Denovellis Eric L. , Joshi Abhilasha , Guidera Jennifer A. , Krausz Timothy A. , Berke Joshua D. , Daw Nathaniel D. , Frank Loren M. 
Published: September 2024

AbstractThe cognitive ability to go beyond the present to consider alternative possibilities, including potential futures and counterfactual pasts, can support adaptive decision making. Complex and changing real-world environments, however, have many possible alternatives. Whether and how the brain can select among them to represent alternatives that meet current cognitive needs remains unknown. We therefore examined neural representations of alternative spatial locations in the rat hippocampus during navigation in a complex patch foraging environment with changing reward probabilities. We found representations of multiple alternatives along paths ahead and behind the animal, including in distant alternative patches. Critically, these representations were modulated in distinct patterns across successive trials: alternative paths were represented proportionate to their evolving relative value and predicted subsequent decisions, whereas distant alternatives were prevalent during value updating. These results demonstrate that the brain modulates the generation of alternative possibilities in patterns that meet changing cognitive needs for adaptive behavior.
Structural Basis for Antibody Neutralization of Pertussis Toxin
Authors: Goldsmith Jory A. , Nguyen Annalee W. , Wilen Rebecca E. , Wijagkanalan Wassana , McLellan Jason S. , Maynard Jennifer A. 
Published: September 2024

SUMMARY/ABSTRACTPertussis toxin (PT) is a key protective antigen in vaccine- and natural immunity-mediated protection fromBordetella pertussisinfection. Despite its importance, no PT-neutralizing epitopes have been characterized structurally. To define neutralizing epitopes and identify key structural elements to preserve during PT antigen design, we determined a 3.6 Å cryo-electron microscopy structure of genetically detoxified PT (PTg) bound to hu11E6 and hu1B7, two potently neutralizing anti-PT antibodies with complementary mechanisms: disruption of toxin adhesion to cells and intracellular activities, respectively. Hu11E6 bound the paralogous S2 and S3 subunits of PTg via a conserved epitope, but surprisingly did not span the sialic acid binding site implicated in toxin adhesion. High-throughput glycan array analysis showed that hu11E6 specifically prevents PTg binding to sialylated N-glycans, while a T cell activation assay showed that hu11E6 blocks PTg mitogenic activities to define the neutralizing mechanism. Hu1B7 bound a quaternary epitope spanning the S1 and S5 subunits, although functional studies of hu1B7 variants suggested that S5 binding is not involved in its PT neutralization mechanism. These results are the first to structurally define neutralizing epitopes on PT, improving our molecular understanding of immune protection fromB. pertussisand providing key information for the future development of PT immunogens.SIGNIFICANCEAntibodies neutralizing pertussis toxin (PT) prevent the severe clinical symptoms associated with infection byBordetella pertussis. However, the molecular basis of effective PT-targeted immunity is poorly understood. To gain insight into PT-inhibitory mechanisms, we determined the cryo-electron microscopy structure of genetically detoxified PT (PTg) with two potently neutralizing antibodies to precisely define their epitopes. Carbohydrate-binding studies show that the hu11E6-binding surface on PT interacts with N-linked glycans and that blocking these interactions prevents PT’s T cell mitogenic activities. Hu1B7 binds an epitope near the S1 active site that includes S5 contacts but these do not appear important for neutralization. This work identifies PT-neutralizing epitopes and supports inclusion of the hu1B7 and hu11E6 epitopes in next-generation vaccines and PT-based immunogens.
Temporal integration in human auditory cortex is predominantly yoked to absolute time, not structure duration
Authors: Norman-Haignere Sam V , Keshishian Menoua K. , Devinsky Orrin , Doyle Werner , McKhann Guy M. , Schevon Catherine A. , Flinker Adeen , Mesgarani Nima 
Published: September 2024

AbstractSound structures such as phonemes and words have highly variable durations. Thus, there is a fundamental difference between integrating across absolute time (e.g., 100 ms) vs. sound structure (e.g., phonemes). Auditory and cognitive models have traditionally cast neural integration in terms of time and structure, respectively, but the extent to which cortical computations reflect time or structure remains unknown. To answer this question, we rescaled the duration of all speech structures using time stretching/compression and measured integration windows in the human auditory cortex using a new experimental/computational method applied to spatiotemporally precise intracranial recordings. We observed significantly longer integration windows for stretched speech, but this lengthening was very small (∼5%) relative to the change in structure durations, even in non-primary regions strongly implicated in speech-specific processing. These findings demonstrate that time-yoked computations dominate throughout the human auditory cortex, placing important constraints on neurocomputational models of structure processing.
Elucidation of the glycan structure of the b-type flagellin ofPseudomonas aeruginosaPAO1
Authors: Hensbergen Paul J. , van Huijkelom Loes , van Angeren Jordy , de Ru Arnoud H. , Claushuis Bart , van Veelen Peter A. , Smits Wiep Klaas , Corver Jeroen 
Published: September 2024

AbstractFlagella are essential for motility and pathogenicity in many bacteria. The main component of the flagellar filament, flagellin, often undergoes post-translational modifications, with glycosylation being a common occurrence. InPseudomonas aeruginosaPAO1, the b-type flagellin isO-glycosylated with a structure that includes a rhamnose, a phospho-group and a previous unknown moiety. This structure resembles the well-characterized glycan (Type A) inClostridioides difficilestrain 630, which features anN-acetylglucosamine linked to anN-methylthreonine via a phosphodiester bond.This study aimed to characterize the b-type glycan structure inPseudomonas aeruginosaPAO1 using a set of mass spectrometry experiments. For this purpose, we used wildtypeP. aeruginosaPAO1 and several gene mutants from the b-type glycan biosynthetic cluster. Moreover, we compared the mass spectrometry characteristics of the b-type glycan with those ofin vitromodified Type A-peptides fromC. difficilestrain 630Δerm.Our results demonstrate that the thus far unknown moiety of the b-type glycan inP. aeruginosaconsists of anN,N-dimethylthreonine. These data allowed us to refine our model of the flagellin glycan biosynthetic pathway in bothP. aeruginosaPAO1 andC. difficilestrain 630.
Comparative proteomic analysis of the composition of decellularized extracellular matrix (dECM) and dECM-based inks as compared to the native tissue
Authors: Irastorza Ainhoa , Vázquez-Aristizabal Paula , Guerrero Pedro , de la Caba Koro , Izeta Ander 
Published: September 2024

AbstractRegenerative medicine and tissue engineering approaches based on the use of 3D-bioprinted decellularized extracellular matrix (dECM) present the advantage of a relatively biomolecule-rich matrix, which directs cell growth and differentiation in a tissue-specific manner. However, little is known about the composition changes that occur with standard processing of dECM-based inks. To characterize this process, six porcine tissues/tissue layers (artery, breast, dermis, epidermis, muscle and nerve) were independently decellularized via chemical, mechanical and enzymatic processes and the resulting dECMs formulated into biocompatible inks, to serve as source biomaterials for 3D printing. A comparative liquid chromatography–tandem mass spectrometry (LC–MS/MS)-based proteomic analysis was carried out for native tissue, decellularized and formulated ECMs, and the resulting complexity of the matrisome analyzed. A core matrisome was found to overlap in all decellularized tissues, as well as tissue-specific components that correlated with predicted functional (gene ontology-based) definitions. The proportion of collagens (mostly the α1 chains of collagen type I and III) increased in the final processing step (inks) as compared to the native ECM and dECM stages. Overall, a median of 55 matrisomal proteins (range 45-126) was detected in the dECM-derived inks. This complexity is far superior in terms of mimicking the composition of native tissue to non-dECM-based inks. Our results support the use of dECM-based inks and biomaterials in mimicking native tissue ECM complexity.
OPLS-based Multiclass Classification and Data-Driven Inter-Class Relationship Discovery
Authors: Forsgren Edvin , Björkblom Benny , Trygg Johan , Jonsson Pär 
Published: September 2024

AbstractMulticlass datasets and large-scale studies are increasingly common in omics sci-ences, drug discovery, and clinical research due to advancements in analytical platforms. Efficiently handling these datasets and discerning subtle differences across multiple classes remains a significant challenge.In metabolomics, two-class OPLS-DA (Orthogonal Projection to Latent Structures Discriminant Analysis) models are widely used due to their strong discrimination capa-bilities and ability to provide interpretable information on class differences. However, these models face challenges in multiclass settings. A common solution is to transform the multiclass comparison into multiple two-class comparisons, which, while more ef-fective than a global multiclass OPLS-DA model, unfortunately results in a manual, time-consuming model-building process with complicated interpretation.Here, we introduce an extension of OPLS-DA for data-driven multiclass classifi-cation: Orthogonal Partial Least Squares-Hierarchical Discriminant Analysis (OPLS-HDA). OPLS-HDA integrates Hierarchical Cluster Analysis (HCA) with the OPLS-DA framework to create a decision tree, addressing multiclass classification challenges and providing intuitive visualization of inter-class relationships. To avoid overfitting and ensure reliable predictions, we use cross-validation during model building. Benchmark results show that OPLS-HDA performs competitively across diverse datasets compared to eight established methods.This method represents a significant advancement, offering a powerful tool to dissect complex multiclass datasets. With its versatility, interpretability, and ease of use, OPLS-HDA is an efficient approach to multiclass data analysis applicable across various fields.
Low intensity pulsed ultrasound activates excitatory synaptic networks in cultured hippocampal neurons
Authors: Li Fenfang , Lin Jia Wei , Jiang Hao , Yong Yu , Augustine George J. 
Published: September 2024

AbstractUltrasound can non-invasively penetrate deep into brain for neuromodulation and has demonstrated good potential for clinical application. Excitation or inhibition of neurons by ultrasound has been reported, but the underlying mechanisms are largely unknown. So far most in vitro studies have focused on the activation of individual neurons by ultrasound with calcium imaging. As the focal region of ultrasound is typically millimeter or submillimeter size, it is important to investigate yet so far unclear how the mechanical effects of ultrasound would influence on the synaptic circuit activity of neurons.MethodsLow-intensity pulsed ultrasound (LIPUS) (25 MHz, 5% duty cycle, 5 Hz pulse repetition frequency, 0.4 – 1.6 W/cm2) was used to stimulate cultured hippocampal neurons. Action potentials and excitatory postsynaptic currents were recorded in individual cells with the whole-cell patch-clamp technique. We also simultaneously imaged intracellular calcium, along with neuronal electrical signals, to resolve neuronal network dynamics during LIPUS.ResultsExcitatory postsynaptic currents (EPSCs) were evoked by LIPUS in high-density neuronal cultures. Both the frequency and amplitude of EPSCs increased, indicating enhanced glutamatergic synaptic transmission. The probability of evoking responses, as well as the total charge of EPSCs evoked by ultrasound, increased with ultrasound intensity. Mechanistic analysis reveals that extracellular calcium influx, action potential (AP) firing and synaptic transmission are necessary for the responses to ultrasound in the high-density culture. In contrast, EPSCs were not enhanced in cultures with low densities of neurons. Simultaneous calcium imaging of neuronal network activity indicated that recurrent excitatory network activity is recruited during ultrasound stimulation in high-density cultures.ConclusionUltrasound can activate recurrent neuronal network activity, caused by excitatory synaptic transmission, over tens to hundreds of seconds. Our study provides insights into the mechanisms involved in the response of the brain to ultrasound and illuminates the potential to use ultrasound to regulate synaptic function in neurological disorders that involve synaptic dysfunction, such as Parkinson’s disease and Alzheimer’s disease.Graphical Abstract
Galvanin is an electric-field sensor for directed cell migration
Authors: Belliveau Nathan M. , Footer Matthew J. , Platenkamp Amy , Kim Heonsu , Eustis Tara E. , Theriot Julie A. 
Published: September 2024

AbstractDirected cell migration is critical for the rapid response of immune cells, such as neutrophils, following tissue injury or infection. Endogenous electric fields, generated by the disruption of the transepithelial potential across the skin, help to guide the movement of immune and skin cells toward the wound site. However, the mechanisms by which cells sense these physical cues remain largely unknown. Through a CRISPR-based screen, we identified Galvanin, a previously uncharacterized single-pass transmembrane protein that is required for human neutrophils to change their direction of migration in response to an applied electric field. Our results indicate that Galvanin rapidly relocalizes to the anodal side of a cell on exposure to an electric field, and that the net charge on its extracellular domain is necessary and sufficient to drive this relocalization. The spatial pattern of neutrophil protrusion and retraction changes immediately upon Galvanin relocalization, suggesting that it acts as a direct sensor of the electric field that then transduces spatial information about a cell’s electrical environment to the migratory apparatus. The apparent mechanism of cell steering by sensor relocalization represents a new paradigm for directed cell migration.
A toolbox for ablating excitatory and inhibitory synapses
Authors: Bareghamyan Aida , Deng Changfeng , Daoudi Sarah , Yadav Shubash C. , Lu Xiaocen , Zhang Wei , Campbell Robert E. , Kramer Richard H. , Chenoweth David M. , Arnold Don B. 
Published: September 2024

AbstractRecombinant optogenetic and chemogenetic proteins are potent tools for manipulating neuronal activity and controlling neural circuit function. However, there are few analogous tools for manipulating the structure of neural circuits. Here, we introduce three rationally designed genetically encoded tools that use E3 ligase-dependent mechanisms to trigger the degradation of synaptic scaffolding proteins, leading to functional ablation of synapses. First, we developed a constitutive excitatory synapse ablator, PFE3, analogous to the inhibitory synapse ablator GFE3. PFE3 targets the RING domain of the E3 ligase Mdm2 and the proteasome-interacting region of Protocadherin 10 to the scaffolding protein PSD-95, leading to efficient ablation of excitatory synapses. In addition, we developed a light-inducible version of GFE3, paGFE3, using a novel photoactivatable complex based on the photocleavable protein PhoCl2c. paGFE3 degrades Gephyrin and ablates inhibitory synapses in response to 400 nm light. Finally, we developed a chemically inducible version of GFE3, chGFE3, which degrades inhibitory synapses when combined with the bio-orthogonal dimerizer HaloTag ligand-trimethoprim. Each tool is specific, reversible, and capable of breaking neural circuits at precise locations.