bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early hippocampal high-amplitude rhythmic spikes predict post-traumatic epilepsy in mice
Authors: Shannon Tyler , Levine Noah , Dirickson Rina , Shen Yiyun , Cotter Christopher , Yi Yoon-Jae , Rajjoub Noora , de Villena Fernando Pardo-Manuel , Kokiko-Cochran Olga , Gu Bin 
Published: April 2024

ABSTRACTOscillations, a highly conserved brain function across mammalian species, are pivotal in brain physiology and pathology. Traumatic brain injury (TBI) often leads to subacute and chronic brain oscillatory alterations associated with complications like post-traumatic epilepsy (PTE) in patients and animal models. Our recent work longitudinally recorded local field potential from the contralateral hippocampus of 12 strains of recombinant inbred Collaborative Cross (CC) mice alongside classical laboratory inbred C57BL/6J mice after lateral fluid percussion injury. In this study, we profiled the acute (<12 hr post-injury) and subacute (12-48 hr post-injury) hippocampal oscillatory responses to TBI and evaluated their predictive value for PTE. We found dynamic high-amplitude rhythmic spikes with elevated power density and reduced entropy that prevailed during the acute phase in CC031 mice who later developed PTE. This characteristic early brain oscillatory alteration is absent in CC031 sham controls or other CC and reference C57BL/6J strains that did not develop PTE after TBI. Our work provides quantitative measures linking early brain oscillation to PTE at a population level in mice under controlled experimental conditions. These findings will offer insights into circuit mechanisms and potential targets for neuromodulatory intervention.
Brilacidin, a host defense peptide mimetic, potentiates ibrexafungerp antifungal activity against the human pathogenic fungusAspergillus fumigatus
Authors: dos Reis Thaila Fernanda , Diehl Camila , Pinzan Camila Figueiredo , de Castro Patrícia Alves , Goldman Gustavo H. 
Published: April 2024

AbstractAspergillus fumigatusis the primary etiological agent of aspergillosis. Here, we show that the host defense peptide mimetic, brilacidin (BRI) can potentiate ibrexafungerp (IBX) against clinical isolates ofA. fumigatus. CAS-resistant strains with mutations infks1that encodes the 1,3-β-D-glucan synthase are not IBX-resistant and BRI+IBX can inhibit their growth. The combination of BRI+IBX plays a fungicidal role, increases the fungal cell permeability and decreases the fungal survival in the presence of A549 epithelial cells.
Sinorhizobium melilotiBR-bodies promote fitness during host colonization
Authors: Mallikaarachchi Kaveendya S. , Huang Jason L. , Madras Shanmukha , Cuellar Rodrigo A. , Huang Zhenzhong , Gega Alisa , Rathnayaka-Mudiyanselage Imalka W. , Al-Husini Nadra , Saldaña-Rivera Natalie , Ma Loi H. , Ng Eric , Chen Joseph C. , Schrader Jared M. 
Published: April 2024

AbstractBiomolecular condensates, such as the nucleoli or P-bodies, are non-membrane-bound assemblies of proteins and nucleic acids that facilitate specific cellular processes. Like eukaryotic P-bodies, the recently discovered bacterial ribonucleoprotein bodies (BR-bodies) organize the mRNA decay machinery, yet the similarities in molecular and cellular functions across species have been poorly explored. Here, we examine the functions of BR-bodies in the nitrogen-fixing endosymbiontSinorhizobium meliloti, which colonizes the roots of compatible legume plants. Assembly of BR-bodies into visible foci inS. meliloticells requires the C-terminal intrinsically disordered region (IDR) of RNase E, and foci fusion is readily observedin vivo, suggesting they are liquid-like condensates that form via mRNA sequestration. Using Rif-seq to measure mRNA lifetimes, we found a global slowdown in mRNA decay in a mutant deficient in BR-bodies, indicating that compartmentalization of the degradation machinery promotes efficient mRNA turnover. While BR-bodies are constitutively present during exponential growth, the abundance of BR-bodies increases upon cell stress, whereby they promote stress resistance. Finally, usingMedicago truncatulaas host, we show that BR-bodies enhance competitiveness during colonization and appear to be required for effective symbiosis, as mutants without BR-bodies failed to stimulate plant growth. These results suggest that BR-bodies provide a fitness advantage for bacteria during infection, perhaps by enabling better resistance against the host immune response.SignificanceWhile eukaryotes often organize their biochemical pathways in membrane-bound organelles, bacteria generally lack such subcellular structures. Instead, membraneless compartments called biomolecular condensates have recently been found in bacteria to enhance biochemical activities. Bacterial ribonucleoprotein bodies (BR-bodies), as one of the most widespread biomolecular condensates identified to date, assemble the mRNA decay machinery via the intrinsically disordered regions (IDRs) of proteins. However, the implications of such assemblies are unclear. Using a plant-associated symbiont, we show that the IDR of its mRNA degradation protein is necessary for condensate formation. Absence of BR-bodies results in slower mRNA decay and ineffective symbiosis, suggesting that BR-bodies play critical roles in regulating biochemical pathways and promoting fitness during host colonization.
Elasmobranchs Exhibit Species-Specific Epidermal Microbiomes Guided by Denticle Topography
Authors: Goodman Asha Z. , Papudeshi Bhavya , Mora Maria , Kerr Emma N. , Torres Melissa , Moffatt Jennifer Nero , Lima Laís F.O. , Niesman Ingrid R. , Moreno Isabel Y. , Doane Michael P. , Dinsdale Elizabeth A. 
Published: April 2024

AbstractElasmobranch epidermal microbiomes are species-specific, yet microbial assembly and retainment drivers are mainly unknown. The contribution of host-derived factors in recruiting an associated microbiome is essential for understanding host-microbe interactions. Here, we focus on the physical aspect of the host skin in structuring microbial communities. Each species of elasmobranch exhibits unique denticle morphology, and we investigate whether microbial communities and functional pathways are correlated with the morphological features or follow the phylogeny of the three species. We extracted and sequenced the DNA from the epidermal microbial communities of three captive shark species: Horn (Heterodontus francisci), Leopard (Triakis semifasciata), and Swell shark (Cephaloscyllium ventriosum) and use electron microscopy to measure the dermal denticle features of each species. Our results outline species-specific microbial communities, as microbiome compositions vary at the phyla level;C. ventriosumhosted a higher relative abundance of Pseudomonadota and Bacillota, whileH. francisciwere associated with a higher prevalence of Euryarchaeota and Aquificae, and Bacteroidota and Crenarchaeota were ubiquitous withT. semifasciata. Functional pathways performed by each species’ respective microbiome were species-specific metabolic. Microbial genes associated with aminosugars and electron-accepting reactions were correlated with the distance between dermal denticles, whereas desiccation stress genes were only present when the dermal denticle overlapped. Microbial genes associated with Pyrimidines, chemotaxis and virulence followed the phylogeny of the sharks. Several microbial genera display associations that resemble host evolutionary lineage, while others had linear relationships with interdenticle distance. Therefore, denticle morphology was a selective influence for some microbes and functions in the microbiome contributing to the phylosymbiosis.ImportanceMicrobial communities form species-specific relationships with vertebrate hosts, but the drivers of these relationships remain an outstanding question. We explore the relationship between a physical feature of the host and the microbial community. A distinguishing feature of the subclass Elasmobranchii (sharks, rays, and skates), is the presence of dermal denticles on the skin. These structures protrude through the epidermis providing increased swimming efficiency for the host and an artificial model skin affect microbial recruitment and establishment of cultured microbes but has not been tested on natural microbiomes. Here, we show some naturally occurring microbial genera and functional attributes were correlated with dermal denticle features, suggesting they are one, but not only contributing factor in microbiome structure on benthic sharks.
Requirements for efficient endosomal escape by designed mini-proteins
Authors: Giudice Jonathan , Brauer Daniel D. , Zoltek Madeline , Vázquez Maldonado Angel L. , Kelly Mark , Schepartz Alanna 
Published: April 2024

AbstractZF5.3 is a compact, rationally designed mini-protein that escapes efficiently from the endosomes of multiple cell types. Despite its small size (27 amino acids), ZF5.3 can be isolated intact from the cytosol of treated cells and guides multiple classes of proteins into the cytosol and/or nucleus. In the best cases, delivery efficiencies reach or exceed 50% to establish nuclear or cytosolic concentrations of 500 nM or higher. But other than the requirement for unfoldable cargo and an intact HOPS complex, there is little known about how ZF5.3 traverses the limiting endocytic membrane. Here we delineate the attributes of ZF5.3 that enable efficient endosomal escape. We confirm that ZF5.3 is stable at pH values between 5.5 and 7.5, with no evidence of unfolding even at temperatures as high as 95 °C. The high-resolution NMR structure of ZF5.3 at pH 5.5, also reported here, shows a canonical p zinc-finger fold with the penta-arg motif integrated seamlessly into the C-terminal ⍺-helix. At lower pH, ZF5.3 unfolds cooperatively as judged by both circular dichroism and high-resolution NMR. Unfolding occurs upon protonation of a single Zn(II)-binding His side chain whose pKacorresponds almost exactly to that of the late endosomal lumen. pH-induced unfolding is essential for endosomal escape, as a ZF5.3 analog that remains folded at pH 4.5 fails to efficiently reach the cytosol, despite high overall uptake. Finally, using reconstituted liposomes, we identify a high-affinity interaction of ZF5.3 with a specific lipid–BMP–that is selectively enriched in the inner leaflet of late endosomal membranes. This interaction is 10-fold stronger at low pH than neutral pH, providing a molecular picture for why escape occurs preferentially and in a HOPS-dependent manner from late endosomal compartments. The requirements for programmed endosomal escape identified here should aid and inform the design of proteins, peptidomimetics, and other macromolecules that reach cytosolic or nuclear targets intact and at therapeutically relevant concentrations.
Structural basis for CCR6 modulation by allosteric antagonists
Authors: Wasilko David Jonathan , Gerstenberger Brian S. , Farley Kathleen A. , Li Wei , Alley Jennifer , Schnute Mark E. , Unwalla Ray J. , Victorino Jorge , Crouse Kimberly K. , Ding Ru , Sahasrabudhe Parag V. , Vincent Fabien , Frisbie Richard K. , Dermenci Alpay , Flick Andrew , Choi Chulho , Chinigo Gary , Mousseau James J. , Trujillo John I. , Nuhant Philippe , Mondal Prolay , Lombardo Vincent , Lamb Daniel , Hogan Barbara J. , Minhas Gurdeep Singh , Segala Elena , Oswald Christine , Windsor Ian W. , Han Seungil , Rappas Mathieu , Cooke Robert M. , Calabrese Matthew F. , Berstein Gabriel , Thorarensen Atli , Wu Huixian 
Published: April 2024

AbstractThe CC chemokine receptor 6 (CCR6) is a potential target for chronic inflammatory diseases such as psoriasis and inflammatory bowel disease. Previously, we reported an active CCR6 structure in complex with its cognate chemokine CCL20, revealing the molecular basis of CCR6 activation mediated by CCL20. Here, we present two inactive CCR6 structures determined by cryo-EM in ternary complexes with different allosteric antagonists, CCR6/SQA1/OXM1 and CCR6/SQA1/OXM2. OXM1 and OXM2 are oxomorpholine (OXM) analogues which are highly selective for CCR6 and disrupt the molecular network critical for receptor activation by binding to an extracellular allosteric pocket within the transmembrane domain. A U-shaped conformation stabilized by intramolecular interactions was revealed by structural and NMR studies of active OXM analogues. SQA1 is a squaramide (SQA) derivative with close-in analogues that were previously reported to be antagonists of CCR6 and other chemokine receptors. Our structures reveal an intracellular pocket occupied by SQA1 that overlaps with the G protein binding site. In addition, SQA1 stabilizes a closed conformation of the intracellular pocket, a hallmark of the inactive state of GPCRs. Minimal communication was found between the two allosteric pockets. Overall, our work provides new evidence of the versatility of GPCR antagonism by small molecules, complementing previous knowledge on CCR6 activation, and sheds light on drug discovery approaches to target CCR6 for autoimmune disorders.
Antigenic cartography using hamster sera identifies SARS-CoV-2 JN.1 evasion seen in human XBB.1.5 booster sera
Authors: Wang Wei , Bhushan Gitanjali L. , Paz Stephanie , Stauft Charles B. , Selvaraj Prabhu , Goguet Emilie , Bishop-Lilly Kimberly A. , Subramanian Rahul , Vassell Russell , Lusvarghi Sabrina , Cong Yu , Agan Brian , Richard Stephanie A. , Epsi Nusrat J. , Fries Anthony , Fung Christian K. , Conte Matthew A. , Holbrook Michael R. , Wang Tony T. , Burgess Timothy H. , Mitre Edward , Pollett Simon D. , Katzelnick Leah C. , Weiss Carol D. 
Published: April 2024

AbstractAntigenic assessments of SARS-CoV-2 variants inform decisions to update COVID-19 vaccines. Primary infection sera are often used for assessments, but such sera are rare due to population immunity from SARS-CoV-2 infections and COVID-19 vaccinations. Here, we show that neutralization titers and breadth of matched human and hamster pre-Omicron variant primary infection sera correlate well and generate similar antigenic maps. The hamster antigenic map shows modest antigenic drift among XBB sub-lineage variants, with JN.1 and BA.4/BA.5 variants within the XBB cluster, but with five to six-fold antigenic differences between these variants and XBB.1.5. Compared to sera following only ancestral or bivalent COVID-19 vaccinations, or with post-vaccination infections, XBB.1.5 booster sera had the broadest neutralization against XBB sub-lineage variants, although a five-fold titer difference was still observed between JN.1 and XBB.1.5 variants. These findings suggest that antibody coverage of antigenically divergent JN.1 could be improved with a matched vaccine antigen.
Landscape-scale endophytic community analyses in replicated grapevine stands reveal that dieback disease is not caused by specific fungal communities
Authors: Monod Vinciane , Hofstetter Valérie , Viret Olivier , Zufferey Vivian , Gindro Katia , Croll Daniel 
Published: April 2024

AbstractTree diebacks are complex and multi-factorial diseases with suspected biotic and abiotic components. Microbiome effects on plant health are challenging to assess due to the complexity of fungal and bacterial communities. Grapevine wood dieback is the main threat to sustainable production worldwide and no causality with microbial species has been established. Here, we aimed to test the hypothesis that grapevine esca disease progression has reproducible drivers in the fungal species community. For this, we analyzed a set of 21 vineyards planted simultaneously with a single susceptible cultivar to provide replication at the landscape scale. We sampled a total of 496 plants across vineyards in two different years to perform deep amplicon sequencing analyses of the fungal communities inhabiting grapevine trunks. The communities were highly diverse with a total of 4,129 amplified sequence variants assigned to 697 distinct species. Individual plants varied in fungal community composition depending on the year of sampling, vineyard location, and disease status. However, we detect no specific fungal species driving symptom development across the vineyards contrary to long-standing expectations. Our study shows how landscape-scale replicated field surveys allow for powerful hypothesis-testing for complex dieback disease drivers and prioritize future research towards additional factors.
Test-retest repeatability of intravoxel incoherent motion (IVIM) measurements in the cervical cord
Authors: Lebret Anna , Lévy Simon , Freund Patrick , Callot Virginie , Seif Maryam 
Published: April 2024

AbstractThis work aimed at assessing the reliability of intravoxel incoherent motion (IVIM) parameters sensitive to perfusion changes in the cervical cord by determining the test-retest variability across subjects and different post-processing fitting algorithms. IVIM test-retest scans were acquired in the cervical cord (C1-C3) of 10 healthy subjects on a 3T MRI scanner, with a 15-minute break in-between. IVIM parameters, including microvascular volume fraction (F), pseudo-diffusion coefficient (D*), blood flow-related coefficient (F·D*), and diffusion coefficient (D), were derived using voxel-wise and region of interest (ROI)-wise fits. The reliability of each IVIM parameter was determined with coefficients of variation (CV), intraclass correlation coefficients (ICC), Bland-Altman analysis and linear regression. To assess the effects of the different fitting approaches, a two-way repeated-measures analysis of variance (ANOVA) was conducted on the CVs calculated across fitting algorithms. Mean CVs of IVIM parameters calculated across subjects using the voxel-wise fit was lower in the white matter (WM) and grey matter (GM) (2.6% to 15.6%; 2.2% to 16.4%, respectively) compared with those calculated using the ROI-wise fit approach (WM: 4.5%-32.2%; GM: 3.4%-53.4%). The voxel-wise fit in the WM yielded higher ICC values (good-to-excellent, 0.71 – 0.97) compared to the ROI-wise fit approach (0.49 – 0.90). IVIM parameters, derived using the voxel-wise fitting approach, demonstrated a high reliability in the cervical cord. Robust IVIM metrics, observed across scans and subjects, can facilitate studies targeting perfusion impairment and pave the way to future clinical trials assessing perfusion impairment as a potential quantitative biomarker.
Leveraging large-scale biobank EHRs to enhance pharmacogenetics of cardiometabolic disease medications
Authors: Sadler Marie C. , Apostolov Alexander , Cevallos Caterina , Ribeiro Diogo M. , Altman Russ B. , Kutalik Zoltán 
Published: April 2024

AbstractElectronic health records (EHRs) coupled with large-scale biobanks offer great promises to unravel the genetic underpinnings of treatment efficacy. However, medication-induced biomarker trajectories stemming from such records remain poorly studied. Here, we extract clinical and medication prescription data from EHRs and conduct GWAS and rare variant burden tests in the UK Biobank (discovery) and the All of Us program (replication) on ten cardiometabolic drug response outcomes including lipid response to statins, HbA1c response to metformin and blood pressure response to antihypertensives (N = 740-26,669). Our findings at genome-wide significance level recover previously reported pharmacogenetic signals and also include novel associations for lipid response to statins (N = 26,669) nearLDLRandZNF800. Importantly, these associations are treatment-specific and not associated with biomarker progression in medication-naive individuals. Furthermore, we demonstrate that individuals with higher genetically determined low-density and total cholesterol baseline levels experience increased absolute, albeit lower relative biomarker reduction following statin treatment. In summary, we systematically investigated the common and rare pharmacogenetic contribution to cardiometabolic drug response phenotypes in over 50,000 UK Biobank and All of Us participants with EHR and identified clinically relevant genetic predictors for improved personalized treatment strategies.
BPP43_05035 is aBrachyspira pilosicolicell surface adhesin that weakens the integrity of the epithelial barrier during infection
Authors: Rajan Anandi , Gallego Pablo , Dolan Brendan , Patel Piyush , Dwibedi Chinmay , Luis Ana S. , Trillo-Muyo Sergio , Arike Liisa , van der Post Sjoerd , Simrén Magnus , Pelaseyed Thaher 
Published: April 2024

AbstractThe anaerobic spirocheteBrachyspiracauses intestinal spirochetosis, characterized by the intimate attachment of bacterial cells to the colonic mucosa, potentially leading to symptoms such as diarrhea, abdominal pain, and weight loss. Despite the clinical significance ofBrachyspirainfections, the mechanism behind the interaction betweenBrachyspiraand the colonic epithelium is not known. In this study, we characterized the molecular mechanism ofB. pilosicoli-epithelium interaction and its impact on the epithelial barrier during infection. Through a proteomics approach, we identified BPP43_05035 as a candidateB. pilosicoliadhesion protein that mediates bacterial attachment to cultured human colonic epithelial cells. The crystal structure of BPP43_05035 revealed a globular lipoprotein with a six-bladed beta-propeller domain. Blocking the native BPP43_05035 onB. pilosicoli, either with a specific antibody or via competitive inhibition, abrogated its binding to epithelial cells. Furthermore, the binding of BPP43_05035 to epithelial cells required surface-exposed hostN-glycans. Proximity labeling and interaction assays revealed that BPP43_05035 bound to tight junctions, thereby increasing the permeability of the epithelial monolayer. Extending our investigation to human patients, we identified a downregulation of tight junction and brush border genes inB. pilosicoli-infected patients carrying detectible levels of epithelium-bound BPP43_05035. Collectively, our findings identify BPP43_05035 as aB. pilosicoliadhesin that weakens the colonic epithelial barrier during infection.
Genome-wide profiling of the hierarchical control of autophagy dynamics using deep learning
Authors: Chica Nathalia , Andersen Aram N. , Orellana-Muñoz Sara , Garcia Ignacio , Nguéa P Aurélie , Ayuda-Durán Pilar , Håkensbakken Linda , Rødningen Eline , Putnam Christopher D. , Zucknick Manuela , Rusten Tor Erik , Enserink Jorrit M. 
Published: April 2024

AbstractRecycling of nutrients through autophagy is a crucial mechanism for cells to sustain internal stability in a fluctuating environment. Dysregulation of the process has been associated with a range of human disorders, and the core components of autophagy have been comprehensively outlined. However, limited insight into its systems-wide dynamical control has hampered predictive modeling and effectivein vivomanipulation. Here, we mapped yeast genomic influences on autophagy dynamics in response to changes in nitrogen levels. Using time-resolved high-content imaging coupled with deep learning, we examined the kinetics of autophagy activation and inactivation in 5919 gene deletion mutants, and classified their profiles based on temporal responsiveness and activation potential, as well as their contribution to autophagosome formation and clearance. By integrating these profiles with functional and genetic network data, we unveiled a hierarchical and multi-layered control of autophagy dynamics and exposed novel regulatory features of the core components and well-established nutrient-sensing pathways. Furthermore, by leveraging multi-omics resources and explainable machine learning to model genetic perturbation effects, we identified the retrograde pathway as a central time-varying transcriptional modulator of autophagy execution. These findings offer valuable insights into the systems-wide tuning of autophagy, and advance our understanding of the dynamical control by providing genome-wide quantitative data under concurrent genetic and environmental interventions. We further anticipate that our study can serve as a blueprint for high-content, deep learning-driven exploration of complex dynamical processes in any organism.