bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hidradenitis Suppurativa Patients Exhibit a Distinctive and Highly Individualized Skin Virome
Authors: Jansen Daan , Bens Lene , Wagemans Jeroen , Green Sabrina I. , Hillary Tom , Vanhoutvin Tine , Laethem An Van , Vermeire Séverine , Sabino João , Lavigne Rob , Matthijnssens Jelle 
Published: November 2023

ABSTRACTHidradenitis suppurativa (HS) is a chronic inflammatory disease characterized by recurring painful skin lesions. Despite ongoing research, the exact cause underlying the initiation and progression of disease remains unknown. While prior research has linked the skin microbiota to HS pathology, the role of viruses has remained unexplored. To investigate the skin virota, metagenomic sequencing of viral particles was performed on 144 skin samples from 57 individuals (39 HS patients and 18 controls). It was found that the virome is not only linked to BMI, but also to the presence and severity of HS, marking a diverging viral profile in the progression of disease. Despite no differences in alpha-diversity, HS patients exhibited a significantly higher beta-diversity compared to healthy controls, indicating a more personalized virome with reduced viral sharing among patients. We identified distinct groups of commonly shared phages, referred to as the core phageome, associated with either healthy controls or patients. Healthy controls displayed a higher abundance of two coreCaudoviricetesphages predicted to infectCorynebacteriumandStaphylococcus, comprising normal skin commensals. In contrast, HS patients carried previously uncharacterized phages that were more prevalent in advanced stages of the disease, which likely infectPeptoniphilusandFinegoldia, known HS-associated pathogens. Interestingly, genes involved in superinfection exclusion and antibiotic resistance could be found in phage genomes of healthy controls and HS patients, respectively. In conclusion, we report the existence of distinct core phages that may have clinical relevance in HS pathology by influencing skin bacteria through mechanisms such as superinfection exclusion and antibiotic resistance.
Precision-Cut Liver Slices as anex vivomodel to evaluate antifibrotic therapies for liver fibrosis and cirrhosis
Authors: Wang Yongtao , Leaker Ben , Qiao Guoliang , Sojoodi Mozhdeh , Eissa Ibrahim Ragab , Epstein Eliana T. , Eddy Jonathan , Dimowo Oizoshimoshiofu , Lauer Georg M. , Chung Raymond T. , Qadan Motaz , Lanuti Michael , Fuchs Bryan C. , Tanabe Kenneth K. 
Published: November 2023

AbstractBackgroundPrecision-Cut Liver Slices (PCLS) are anex vivoculture model developed to study hepatic drug metabolism. One of the main benefits of this model is that it retains the structure and cellular composition of the native liver. PCLS also represents a potential model system to study liver fibrosis in a setting that more closely approximatesin vivopathology thanin vitromethods. The aim of this study was to assess whether responses to antifibrotic interventions can be detected and quantified with PCLS.MethodsPCLS of 250 μm thickness were prepared from four different murine fibrotic liver models: choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD), thioacetamide (TAA), diethylnitrosamine (DEN), and carbon tetrachloride (CCl4). PCLS were treated with 5 μM Erlotinib for 72 hours. Histology and gene expression were then compared within vivomurine experiments and TGF-β1 activated hepatic stellate cells (HSCs). These types of PCLS characterization were also evaluated in PCLS from human cirrhotic liver.ResultsPCLS viability in culture was stable for 72 hours. Treatment of erlotinib, an EGFR inhibitor significantly inhibited the expression of profibrogenic genesIl6,Col1a1andTimp1in PCLS from CDAHFD-induced cirrhotic mice, andIl6,Col1a1andTgfb1in PCLS from TAA-induced cirrhotic rats. Erlotinib treatment of PCLS from DEN-induced cirrhotic rats inhibited the expression ofCol1a1,Timp1,Tgfb1andIl6, which was consistent with the impact of erlotinib onCol1a1andTgfb1expression inin vivoDEN-induced cirrhosis. Erlotinib treatment of PCLS from CCl4-induced cirrhosis caused reduced expression ofTimp1,Col1a1andTgfb1, which was consistent with the effect of erlotinib inin vivoCCl4-induced cirrhosis. In addition, in HSCs at PCLS from normal mice, TGF-β1 treatment upregulatedActa2(αSMA), while treatment with erlotinib inhibited the expression ofActa2. Similar expression results were observed in TGF-β1 treatedin vitroHSCs. Expression of MMPs and TIMPs, key regulators of fibrosis progression and regression, were also significantly altered under erlotinib treatment in PCLS. Expression changes under erlotinib treatment were also corroborated with PCLS from human cirrhosis samples.ConclusionThe responses to antifibrotic interventions can be detected and quantified with PCLS at the gene expression level. The antifibrotic effects of erlotinib are consistent between PCLS models of murine cirrhosis and those observedin vivoandin vitro. Similar effects were also reproduced in PCLS derived from patients with cirrhosis. PCLS is an excellent model to assess antifibrotic therapies that is aligned with the principles of Replacement, Reduction and Refinement (3Rs).
High Frequency Oscillations (>250Hz) Outnumber Interictal Spikes in Preclinical Studies of Alzheimer’s Disease
Authors: Lisgaras Christos Panagiotis , Scharfman Helen E. 
Published: November 2023

ABSTRACTInterictal spikes (IIS) and seizures are well-documented in Alzheimer’s disease (AD). IIS typically outnumber seizures, supporting their role as a prominent EEG biomarker in AD. In preclinical models, we showed that high frequency oscillations (HFOs>250Hz) also occur, but it is currently unknown how HFOs compare to IIS. Therefore, we asked whether the incidence of HFOs and IIS differed and if they are differentially affected by behavioral state.We used three mouse lines that simulate aspects of AD: Tg2576, presenilin 2 knockout, and Ts65Dn mice. We recorded and quantified HFOs and IIS in the hippocampus during wakefulness, slow-wave sleep, and rapid eye movement sleep.In all three mouse lines, HFOs were more frequent than IIS. High numbers of HFOs correlated with fewer IIS, suggesting for the first time possible competing dynamics among them in AD. Notably, HFOs occurred in more behavioral states than IIS.In summary, HFOs were the most abundant EEG abnormality when compared to IIS, and occurred in all behavioral states, suggesting they are a better biomarker than IIS. These findings pertained to three mouse lines, which is important because they simulate different aspects of AD. We also show that HFOs may inhibit IIS.SHORT SUMMARYInterictal spikes (IIS) and seizures are common in Alzheimer’s disease (AD). IIS are more frequent than seizures and occur during earlier disease stages. In preclinical models, we showed that high frequency oscillations (HFOs>250Hz) occur, but a comparison between IIS and HFOs is lacking. Here we used 3 mouse lines with AD features and local field potential recordings to quantify IIS and HFOs. We found that HFOs outnumbered IIS and that their total numbers were inversely correlated with IIS. HFOs occurred during more behavioral states than IIS. Therefore, HFOs were the most abundant EEG abnormality, and this was generalizable across 3 types of preclinical AD.
Lightway access to AlphaMissense data that demonstrates a balanced performance of this missense mutation predictor
Authors: Tordai H. , Torres O. , Csepi M. , Padányi R. , Lukács G. L. , Hegedűs T. 
Published: November 2023

AbstractSingle amino acid substitutions can profoundly affect protein folding, dynamics, and function, leading to potential pathological consequences. The ability to discern between benign and pathogenic substitutions is pivotal for therapeutic interventions and research directions. Given the limitations in experimental examination of these variants, AlphaMissense has emerged as a promising predictor of the pathogenicity of single nucleotide polymorphism variants. In our study, we assessed the efficacy of AlphaMissense across several protein groups, such as mitochondrial, housekeeping, transmembrane proteins, and specific proteins like CFTR, using ClinVar data for validation. Our comprehensive evaluation showed that AlphaMissense delivers outstanding performance, with MCC scores predominantly between 0.6 and 0.74. We observed low performance on the CFTR and disordered, membrane-interacting MemMoRF datasets. However, an enhanced performance with CFTR was shown when benchmarked against the CFTR2 database. Our results also emphasize that quality of AlphaFold’s predictions can seriously influence AlphaMissense predictions. Most importantly, AlphaMissense’s consistent capability in predicting pathogenicity across diverse protein groups, spanning both transmembrane and soluble domains was found. Moreover, the prediction of likely-pathogenic labels for IBS and CFTR coupling helix residues emphasizes AlphaMissense’s potential as a tool for pinpointing functionally significant sites. Additionally, to make AlphaMissense predictions more accessible, we have introduced a user-friendly web resource (https://alphamissense.hegelab.org) to enhance the utility of this valuable tool. Our insights into AlphaMissense’s capability, along with this online resource, underscore its potential to significantly aid both research and clinical applications.
Characterization of alternative splicing in high-risk Wilms’ tumors
Authors: Trink Yaron , Urbach Achia , Dekel Benjamin , Hohenstein Peter , Goldberger Jacob , Kalisky Tomer 
Published: November 2023

ABSTRACTThe significant heterogeneity of Wilms’ tumors between different patients is thought to arise from genetic and epigenetic distortions that occur during various stages of fetal kidney development in a way that is poorly understood. To address this, we characterized the heterogeneity of alternative mRNA splicing in Wilms’ tumors using a publicly available RNAseq dataset of high-risk Wilms’ tumors and normal kidney samples. Through Pareto task inference and cell deconvolution, we found that the tumors and normal kidney samples are organized according to progressive stages of kidney development within a triangle-shaped region in latent space, whose vertices, or “archetypes,” resemble the cap mesenchyme, the nephrogenic stroma, and epithelial tubular structures of the fetal kidney. We identified a set of genes that are alternatively spliced between tumors located in different regions of latent space and found that many of these genes are associated with the Epithelial to Mesenchymal Transition (EMT) and muscle development. Using motif enrichment analysis, we identified putative splicing regulators, some of which are associated with kidney development. Our findings provide new insights into the etiology of Wilms’ tumors and suggest that specific splicing mechanisms in early stages of development may contribute to tumor development in different patients.
Local Delivery of SBRT and IL12 by mRNA Technology Overcomes Immunosuppressive Barriers to Eliminate Pancreatic Cancer
Authors: Hughson Angela L. , Hannon Gary , Salama Noah A. , Vrooman Tara G. , Stockwell Caroline A. , Mills Bradley N. , Garrett-Larsen Jesse , Qiu Haoming , Katerji Roula , Benoodt Lauren , Johnston Carl J. , Murphy Joseph D. , Kruger Emma , Ye Jian , Gavras Nicholas W. , Keeley David C. , Qin Shuyang S. , Lesch Maggie L. , Muhitch Jason B. , Love Tanzy M.T. , Calvi Laura M. , Lord Edith M. , Luheshi Nadia , Elyes Jim , Linehan David C. , Gerber Scott A. 
Published: November 2023

AbstractThe immunosuppressive milieu in pancreatic cancer (PC) is a significant hurdle to treatments, resulting in survival statistics that have barely changed in 5 decades. Here we present a combination treatment consisting of stereotactic body radiation therapy (SBRT) and IL-12 mRNA lipid nanoparticles delivered directly to pancreatic murine tumors. This treatment was effective against primary and metastatic models, achieving cures in both settings. IL-12 protein concentrations were transient and localized primarily to the tumor. Depleting CD4 and CD8 T cells abrogated treatment efficacy, confirming they were essential to treatment response. Single cell RNA sequencing from SBRT/IL-12 mRNA treated tumors demonstrated not only a complete loss of T cell exhaustion, but also an abundance of highly proliferative and effector T cell subtypes. SBRT elicited T cell receptor clonal expansion, whereas IL-12 licensed these cells with effector function. This is the first report demonstrating the utility of SBRT and IL-12 mRNA in PC.Statement of significanceThis study demonstrates the use of a novel combination treatment consisting of radiation and immunotherapy in murine pancreatic tumors. This treatment could effectively treat local and metastatic disease, suggesting it may have the potential to treat a cancer that has not seen a meaningful increase in survival in 5 decades.
Hsp90 shapes adaptation by controlling the fitness consequences of regulatory variation
Authors: Jakobson Christopher M. , Aguilar-Rodríguez José , Jarosz Daniel F. 
Published: November 2023

ABSTRACTThe essential stress-responsive chaperone Hsp90 impacts development and adaptation from microbes to humans. Yet despite evidence of its role in evolution, pathogenesis, and oncogenic transformation, the molecular mechanisms by which Hsp90 alters the consequences of mutations remain vigorously debated. Here we exploit the power of nucleotide-resolution genetic mapping inSaccharomyces cerevisiaeto uncover more than 1,000 natural variant-to-phenotype associations governed by this molecular chaperone. Strikingly, Hsp90 more frequently modified the phenotypic effects ofcis-regulatory variation than variants that altered protein sequence. Moreover, these interactions made the largest contribution to Hsp90-dependent heredity. Nearly all interacting variants—both regulatory and protein-coding—fell within clients of Hsp90 or targets of its direct binding partners. Hsp90 activity affected mutations in evolutionarily young genes, segmental deletions, and heterozygotes, highlighting its influence on variation central to evolutionary novelty. Reconciling the diverse epistatic effects of this chaperone, synthetic transcriptional regulation and reconstructions of natural alleles by genome editing revealed a central role for Hsp90 in regulating the fundamental relationship between activity and phenotype. Our findings establish that non-coding variation is a core driver of Hsp90’s influence on heredity, offering a mechanistic explanation for the chaperone’s strong effects on evolution and development across species.
Critical role of CD206+ macrophages in promoting a cDC1-NK-CD8 T cell anti-tumor immune axis
Authors: Ray Arja , Hu Kenneth H. , Kersten Kelly , Courau Tristan , Kuhn Nicholas F. , Zaleta-Linares Itzia , Samad Bushra , Combes Alexis J. , Krummel Matthew F. 
Published: November 2023

AbstractTumor-associated macrophages (TAMs) are frequently categorized as being ‘M1’ or ‘M2’ polarized, even as substantial data challenges this binary modeling of macrophage cell state. One molecule consistently referenced as a delineator of a putative immunosuppressive ‘M2’ state is the surface protein CD206. We thus made a novel conditional CD206 (Mrc1) knock-in mouse to specifically visualize and/or deplete CD206+ ‘M2-like’ TAMs and assess their correspondence with pro-tumoral immunity. Early, but not late depletion of CD206+ macrophages and monocytes (here, ‘Mono/Macs’) led to an indirect loss of a key anti-tumor network of NK cells, conventional type I dendritic cells (cDC1) and CD8 T cells. Among myeloid cells, we found that the CD206+ TAMs are the primary producers of CXCL9, and able to differentially attract activated CD8 T cells. In contrast, a population of stress-responsive TAMs (“Hypoxic” orSpp1+) and immature monocytes, which lack CD206 expression and become prominent following early depletion, expressed markedly diminished levels of CXCL9. Those NK and CD8 T cells which enter CD206- depleted tumors express vastly reduced levels of the corresponding receptorCxcr3,the cDC1- attracting chemokineXcl1and cDC1 growth factorFlt3ltranscripts. Consistent with the loss of this critical network, early CD206+ TAM depletion decreased tumor control by antigen specific CD8 T cells in mice. Likewise, in humans, the CD206Replete, but not the CD206DepletedMono/Mac gene signature correlated robustly with CD8 T cell, NK cell and stimulatory cDC1 gene signatures and transcriptomic signatures skewed towards CD206RepleteMono/Macs associated with better survival. Together, these findings negate the unqualified classification of CD206+ ‘M2-like’ macrophages as immunosuppressive by illuminating contexts for their role in organizing a critical tumor-reactive archetype of immunity.
A proteogenomic pipeline for the analysis of protein biosynthesis errors in the human pathogenCandida albicans
Authors: Correia Inês , Oliveira Carla , Reis Andreia , Guimarães Ana Rita , Aveiro Susana , Domingues Pedro , Bezerra Ana Rita , Vitorino Rui , Moura Gabriela , Santos Manuel A. S. 
Published: November 2023

AbstractCandida albicansis a diploid pathogen known for its ability to live as a commensal fungus in healthy individuals, but causing both superficial infections and disseminated candidiasis in immunocompromised patients where it is associated with high morbidity and mortality. Its success in colonizing the human host is attributed to a wide range of virulence traits that modulate interactions between the host and the pathogen, such as optimal growth rate at 37°C, the ability to switch between yeast and hyphal forms and a remarkable genomic and phenotypic plasticity. A fascinating aspect of its biology is a prominent heterogeneous proteome that arises from frequent genomic rearrangements, high allelic variation, and high levels of amino acid misincorporations in proteins. The latter leads to increased morphological and physiological phenotypic diversity of high adaptive potential, but the scope of such protein mistranslation is poorly understood due to technical difficulties in detecting and quantifying amino acid misincorporation events in complex proteomic samples.To address this question, we have developed and optimized mass spectrometry and bioinformatics pipelines capable of identifying low-level amino acid misincorporation events at the proteome level. We have also analysed the proteomic profile of an engineeredC. albicansstrain that exhibits high level of leucine misincorporation at protein CUG sites and employed anin vivoquantitative gain-of-function fluorescence reporter system to validate our MS/MS data. The data show thatC. albicansmisincorporates amino acids above the background level at protein sites of diverse codons, particularly at CUG sites, confirming our previous data on the quantification of leucine incorporation at single CUG sites of recombinant reporter proteins. The study also demonstrates that increasing misincorporation of Leucine at CUG sites does not alter the translational fidelity of the other codons. These findings advance existing knowledge on amino acid misincorporations inC. albicansand add a new dimension to the remarkable capacity of this fungus to diversify its proteome.
Anticipatory smooth pursuit eye movements scale with the probability of visual motion: the role of target speed and acceleration
Authors: Morita Vanessa Carneiro , Souto David , Masson Guillaume S. , Montagnini Anna 
Published: November 2023

AbstractSensory-motor systems can extract statistical regularities in dynamic uncertain environments, enabling quicker responses and anticipatory behavior for expected events. Anticipatory smooth pursuit eye movements (aSP) have been observed in primates when the temporal and kinematic properties of a forthcoming visual moving target are fully or partially predictable. To investigate the nature of the internal model of target kinematics underlying aSP, we tested the effect of varying the target kinematics and its predictability. Participants tracked a small visual target in a constant direction with either constant, accelerating or decelerating speed. Across experimental blocks, we manipulated the probability of each kinematic condition varying either speed or acceleration across trials; with either one kinematic condition (providing certainty) or with a mixture of conditions with a fixed probability within a block. We show that aSP is robustly modulated by target kinematics. With constant-velocity targets, aSP velocity scales linearly with target velocity in blocked sessions, and matches the probability-weighted average in the mixture sessions. Predictable target acceleration does also have an influence on aSP, suggesting that the internal model of motion which drives anticipation contains some information about the changing target kinematics, beyond the initial target speed. However, there is a large variability across participants in the precision and consistency with which this information is taken into account in order to control anticipatory behavior.
Decreased fucosylation impacts epithelial integrity and increases risk for COPD
Authors: Swaby Carter , Yeung-Luk Bonnie , Thapa Shreeti , Nishida Kristine , Wally Arabelis , Ghosh Baishakhi , Niederkofler Austin , Luk Sean , Girgis Mirit , Keller Allison , Cortez Cecilia , Ramaswamy Sahana , Wilmsen Kai , Bouché Laura , Dell Anne , Drummond M. Bradley , Putcha Nirupama , Haslam Stuart M. , Mathias Rasika , Hansel Nadia N. , Sheng Jian , Sidhaye Venkataramana 
Published: November 2023

AbstractCOPD causes significant morbidity and mortality worldwide. Epithelial damage is fundamental to disease pathogenesis, although the mechanisms driving disease remain undefined. Published evidence from a COPD cohort (SPIROMICS) and confirmed in a second cohort (COPDgene) demonstrate a polymorphism inFucosyltransferese-2 (FUT2)is a trans-pQTL for E-cadherin, which is critical in COPD pathogenesis. We found by MALDI-TOF analysis thatFUT2increased terminal fucosylation of E-cadherin. Using atomic force microscopy, we found that FUT2-dependent fucosylation enhanced E-cadherin-E-cadherin bond strength, mediating the improvement in monolayer integrity. Tracheal epithelial cells fromFut2-/-mice have reduced epithelial integrity, which is recovered with reconstitution ofFut2. Overexpression ofFUT2in COPD derived epithelia rescues barrier function.Fut2-/-mice show increased susceptibility in an elastase model of disease developing both emphysema and fibrosis. We propose this is due to the role ofFUT2in proliferation and cell differentiation. Overexpression of FUT2 significantly increased proliferation. Loss ofFut2results in accumulation of Spc+ cells suggesting a failure of alveolar type 2 cells to undergo transdifferentiation to alveolar type 1. Using a combination of population data, genetically manipulated mouse models, and patient-derived cells, we present a novel mechanism by which post-translational modifications modulate tissue pathology and serve as a proof of concept for the development of a disease-modifying target in COPD.