bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sex-specific DNA methylation differences in Amyotrophic lateral sclerosis
Authors: Grant Olivia A. , Iacoangeli Alfredo , Zwamborn Ramona A. J. , van Rheenen Wouter , Byrne Ross , Van Eijk Kristel R. , Kenna Kevin , van Vugt Joke J.F.A. , Cooper-Knock Johnathan , Kenna Brendan , Vural Atay , Topp Simon , Campos Yolanda , Weber Markus , Smith Bradley , Dobson Richard , van Es Michael A. , Vourc’h Patrick , Corcia Philippe , de Carvalho Mamede , Gotkine Marc , Panades Monica P. , Mora Jesus S. , Mill Jonathan , Garton Fleur , McRae Allan , Wray Naomi R. , Shaw Pamela J. , Landers John E. , Glass Jonathan D. , Shaw Christopher E. , Basak Nazli , Hardiman Orla , Van Damme Philip , McLaughlin Russell L. , van den Berg Leonard H. , Veldink Jan H. , Al-Chalabi Ammar , Al Khleifat Ahmad 
Published: November 2024

ABSTRACTSex is an important covariate in all genetic and epigenetic research due to its role in the incidence, progression and outcome of many phenotypic characteristics and human diseases. Amyotrophic lateral sclerosis (ALS) is a motor neuron disease with a sex bias towards higher incidence in males. Here, we report for the first time a blood-based epigenome-wide association study meta-analysis in 9274 individuals after stringent quality control (5529 males and 3975 females). We identified a total of 226 ALS saDMPs (sex-associated DMPs) annotated to a total of 159 unique genes. These ALS saDMPs were depleted at transposable elements yet significantly enriched at enhancers and slightly enriched at 3’UTRs. These ALS saDMPs were enriched for transcription factor motifs such as ESR1 and REST. Moreover, we identified an additional 10 genes associated with ALS saDMPs through chromatin loop interactions, suggesting a potential regulatory role for these saDMPs on distant genes. Furthermore, we investigated the relationship between DNA methylation at specific CpG sites and overall survival in ALS using Cox proportional hazards models. We identified two ALS saDMPs, cg14380013 and cg06729676, that showed significant associations with survival. Overall, our study reports a reliable catalogue of sex-associated ALS saDMPs in ALS and elucidates several characteristics of these sites using a large-scale dataset. This resource will benefit future studies aiming to investigate the role of sex in the incidence, progression and risk for ALS.
Frequency-dependent and capacitive tissue electrical properties in spinal cord stimulation models
Authors: Khadka Niranjan , Wang Boshuo , Bikson Marom 
Published: November 2024

AbstractBackgroundModels of spinal cord stimulation (SCS) simulate the electric fields (E-fields) generated in targeted tissues, which in turn can predict physiological and then behavioral outcomes. Notwithstanding increasing sophistication and use in optimizing therapy, SCS models typically calculate E-fields using the quasi-static approximation (QSA). QSA, as implemented in neuromodulation models, neglects the frequency dispersion of tissue conductivity, as well as propagation, capacitive, and inductive effects on the E-field. The reliability of QSA specifically for SCS has not been considered in detail, especially for higher-frequency SCS.MethodsWe implemented a frequency-dependent finite element method (FEM) and solved a high- resolution RADO-SCS model with voltage-controlled (VC) and current-controlled (CC) stimulation to assess the impact of frequency-dependent conductivity (dispersion) and permittivity of spinal tissues on E-fields generated at three different spinal column locations (epidural space, spinal cord, and root) for frequencies spanning from 1 Hz to 10 MHz. Results were compared with predictions of QSA method, with varied conductivity values of purely resistive tissues. We further assessed the impact of frequency-dependent and capacitive tissue properties on spinal heating and distortion of the E-field waveform.ResultsTissue-specific electric properties around the energized leads and mode of stimulation-control impacted the magnitude of E-fields. In the spinal cord, the VC-SCS E-field generated with the frequency-dependent and capacitive properties was comparable to the QSA with 2X epidural fat conductivity, whereas the CC-SCS generated E-field was minimally impacted by frequency- dependent and capacitive properties up to 10 kHz. Spinal cord heating predicted by frequency- dependent and capacitive tissue properties was comparable to the QSA conditions with VC-SCS, whereas with CC-SCS, there was no impact of the frequency-dependent and capacitive tissue properties in spinal cord heating. E-field waveform distortion in the spinal cord, with CC-SCS at 1 kHz-specific electrical properties, was significant when fat capacitance (permittivity) was increased by 10X, whereas with VC-SCS, there was no effect of tissue capacitance.ConclusionRegardless of the mode of SCS, QSA was still valid in predicting SCS-induced E-field and heating at the spinal tissues- acrossαandβdispersion region of spinal tissue’s dielectric spectrum for VC-SCS and up to 10 kHz for CC-SCS.
Novel Immunological Markers of Intestinal Impairment Indicative of HIV-1 Status and/or Subclinical Atherosclerosis
Authors: Moreira Gabriel Etiene , Dias Jonathan , Caballero Ramon Edwin , Salinas Tomas Wiche , Nayrac Manon , Filali-Mouhim Abdelali , Chartrand-Lefebvre Carl , Routy Jean-Pierre , Durand Madeleine , El-Far Mohamed , Tremblay Cécile , Ancuta Petronela 
Published: November 2024

ABSTRACTAntiretroviral therapy (ART) controls HIV-1 replication in people with HIV-1 (PWH), but immunological restauration at mucosal barrier surfaces is not achieved. This fuels microbial translocation, chronic immune activation, and increased comorbidities, including cardiovascular disease (CVD). Here, we sought to identify novel markers of mucosal barrier impairment in the blood to predict the HIV and/or CVD status. Flow cytometry was used to characterize CD326/EpCAM+intestinal epithelial cells (IEC); CD4+T-cells; CD8+and CD4+intraepithelial lymphocytes (IELs); and subsets of CD4+T-cells expressing Th17 (CCR6) and gut-homing (Itgβ7) markers. To this aim, we collected peripheral blood mononuclear cells (PBMCs) from 42 ART-treated PWH (HIV+) and 40 uninfected participants (HIV-) from the Canadian HIV and Aging Cohort Study (CHACS). Both groups were categorized based on the presence of coronary atherosclerotic plaques measured by CT scan angiography as total plaque volume (TPV, mm3). Our findings associate the HIV-1 status with increased frequencies of circulating CD326+IEC; CD326+CD4+T-cells with activated (CD69+HLA-DR+) and gut-homing (ItgαE+CCR6+CCR9+) phenotypes, CCR6+Itgβ7-CD4+T-cells; and decreased frequencies of CD8+IELs. Logistic regression analyses confirmed the predictive capacity of the above cellular markers regarding HIV status. Spearman correlation revealed a positive correlation between TPV and CCR6+Itgβ7-and CCR6+Itgβ7+CD4+T-cell frequencies.Together, these results highlighted significant immune dysregulation and persistent mucosal barrier alterations despite effective viral suppression by ART and linked the abundance of CCR6+Itgβ7+and CCR6+Itgβ7-CD4+T-cells to increased atherosclerotic plaque burden. Thus, strategies targeting the gut-immune axis restoration may reduce CVD onset and improve long-term health outcomes in PWH.
Repression of the Wnt pathway effector TCF7L2 reverses lethal cachexia in mice with intestinal cancers
Authors: Leong Mei Ling , Ruedl Christiane , Karjalainen Klaus 
Published: November 2024

AbstractHyper-activation of the canonical Wnt signaling pathway drives small intestine and colon tumors. As the major Wnt pathway effector in healthy intestines, TCF7L2 is a suspected oncogene in both cancer types. However, this has been challenging to verify becauseTcf7l2knockout is lethal. To circumvent lethality, we generated a novel transgenic mouse that allows dose-dependent, systemic, inducible and reversible repression of endogenousTcf7l2expression. Using this mouse, we demonstrate that TCF7L2 is essential for early adenoma development in the small intestine (ApcMin/+mouse model) but not colon (DSS-treatedApcMin/+mouse model). Once established however, neither small intestine nor colon adenomas require TCF7L2 for maintenance. Despite this,Tcf7l2repression rescues both types of cancer mice from lethal cachexia—a prevalent cancer comorbidity characterized by debilitating weight loss and skeletal muscle atrophy. In colon cancer cachexia, elevated TCF7L2 in the gastrocnemius muscle induces atrophy by activating the transcription of multiple atrophy genes within the ubiquitin-proteasome and autophagy-lysosome systems. Hence, repressingTcf7l2normalizes atrophy gene expression back to non-cachectic expression levels and restores muscle mass. The cachexia recovery mechanism in small intestine cancer remains undefined but is independent of the gastrocnemius. This study shows that systemic and partialTcf7l2repression is both well-tolerated and effective in rescuing moribund cancer mice from cachexia-induced death. Hence this is a promising treatment strategy for cancer patients suffering from cachexia. Additionally, our transgenic mouse is a valuable tool to study muscle atrophy across other conditions including aging, diabetes and neuromuscular disease.
Fluorescence based live cell imaging identifies exon 14 skipped hepatocyte growth factor receptor (MET) degraders
Authors: Mallareddy Jayapal Reddy , Yang Lin , Lin Wan-Hsin , Feathers Ryan , Ayers-Ringler Jennifer , Tolosa Ezequiel , Kizhake Amritha G. , Kizhake Smitha , Kubica Sydney P. , Boghean Lidia , Alvarez Sophie , Naldrett Michael J. , Singh Sarbjit , Rana Sandeep , Zahid Muhammad , Schaefer-Klein Janet , Roden Anja , Kosari Farhad , Anastasiadis Panos Z. , Borad Mitesh , Natarajan Amarnath , Mansfield Aaron S. 
Published: November 2024

AbstractDespite ongoing efforts to employ structure-based methods to discover targeted protein degraders (TPD), the prevailing strategy continues to be the synthesis of a focused set of heterobifunctional compounds and screen them for target protein degradation. Here we used a fluorescence based live cell imaging screen to identify degraders that target exon 14 skipped hepatocyte growth factor receptor (MET). MET is a known oncogenic driver. MET exon 14 skipping mutations (METex14Δ) are found in lung cancers and result in the loss of a degron that is required for E3-ligase recognition and subsequent ubiquitination, prolonging the half-life and oncogenicity of MET. Since proteolysis targeting chimeras (PROTACs) are heterobifunctional molecules that promote target degradation by the proteosome, we sought to restore degradation of MET lost with METex14Δ using a MET-targeting PROTAC. We generated a library of sixty PROTACs of which 37 used the MET inhibitor capmatinib as the protein of interest targeting ligand. We screened this PROTAC library for targeted degradation of METex14Δ-GFP using live cell imaging. We benchmarked out MET-targeting PROTACs to that of a previously reported MET-targeting PROTAC, SJF8240. Curve fitting live cell imaging data affords determination of time required to degrade 50% of the target protein (DT50), which was used in determining structure activity relationships. A promising candidate, 48-284, identified from the screen, exhibited classic PROTAC characteristics, was > 15-fold more potent than SJF8240, had fewer off targets compared to SJF8240, and degraded MET in multiple cell lines.
Cells transit through a quiescent-like state to convert to neurons at high rates
Authors: Beitz A , Teves JMY , Oakes C , Johnstone C , Wang N , Brickman JM , Galloway KE 
Published: November 2024

AbstractWhile transcription factors (TFs) provide essential cues for directing and redirecting cell fate, TFs alone are insufficient to drive cells to adopt alternative fates. Rather, transcription factors rely on receptive cell states to induce novel identities. Cell state emerges from and is shaped by cellular history and the activity of diverse processes. Here, we define the cellular and molecular properties of a highly receptive state amenable to transcription factor-mediated direct conversion from fibroblasts to induced motor neurons. Using a well-defined model of direct conversion to a post-mitotic fate, we identify the highly proliferative, receptive state that transiently emerges during conversion. Through examining chromatin accessibility, histone marks, and nuclear features, we find that cells reprogram from a state characterized by global reductions in nuclear size and transcriptional activity. Supported by globally increased levels of H3K27me3, cells enter a quiescent-like state of reduced RNA metabolism and elevated expression of REST and p27, markers of quiescent neural stem cells. From this transient state, cells convert to neurons at high rates. Inhibition of Ezh2, the catalytic subunit of PRC2 that deposits H3K27me3, abolishes conversion. Our work offers a roadmap to identify global changes in cellular processes that define cells with different conversion potentials that may generalize to other cell-fate transitions.HighlightsProliferation drives cells to a compact nuclear state that is receptive to TF-mediated conversion.Increased receptivity to TFs corresponds to reduced nuclear volumes.Reprogrammable cells display global, genome-wide increases in H3K27me3.High levels of H3K27me3 support cells’ transits through a state of altered RNA metabolism.Inhibition of Ezh2 increases nuclear size, reduces the expression of the quiescence marker p27.Acute inhibition of Ezh2 abolishes motor neuron conversion.One Sentence SummaryCells transit through a quiescent-like state characterized by global reductions in nuclear size and transcriptional activity to convert to neurons at high rates.Graphical Abstract
On the robustness to gene tree rooting (or lack thereof) of triplet-based species tree estimation methods
Authors: Zaman Tanjeem Azwad , Jahin Rabib , Bayzid Md. Shamsuzzoha 
Published: November 2024

AbstractSpecies tree estimation is frequently based on phylogenomic approaches that use multiple genes from throughout the genome. This process becomes particularly challenging due to gene tree heterogeneity (discordance), often resulting from Incomplete Lineage Sorting (ILS). Triplet- and quartet-based approaches for species tree estimation have gained substantial attention as they are provably statistically consistent in the presence of ILS. However, unlike quartet-based methods, the limitation of rooted triplet-based methods in handling unrooted gene trees has restricted their adoption in the systematics community. Furthermore, since the induced triplet distribution in a gene tree depends on the placement of the root, the accuracy of triplet-based methods depends on the accuracy of gene tree rooting. Despite progress in developing methods for rooting unrooted gene trees, greatly understudied is the choice of rooting technique and downstream effects on species tree inference under realistic model conditions. This study involves rigorous empirical testing with different gene tree rooting approaches to establish a nuanced understanding of the impact of rooting on species tree accuracy. Moreover, we aim to investigate the conditions under which triplet-based methods provide more accurate species tree estimations than the widely-used quartet-based methods such as ASTRAL.
Oxidative Injury to Lung Mitochondrial DNA is a Key Contributor for the Development of Chemical Lung Injury
Authors: Dubey Shubham , Yu Zhihong , Stephens Emily Morgan , Lazrak Ahmed , Ahmad Israr , Aggarwal Saurabh , Andrabi Shaida , Hossain M. Iqbal , Jilling Tamas , Fernadez Solana R. , Bartels Jennifer L. , Lapi Suzanne E. , Mobley James , Pastukh Viktor M. , Gillespie Mark , Matalon Sadis 
Published: November 2024

AbstractThe mechanisms and extent to which inhalation of oxidant gases damage the mitochondrial genome contributing to the development of acute and chronic lung injury have not been investigated. C57BL/6 mice exposed to chlorine (Cl2) gas and returned to room air, developed progressive loss of lung DNA glycosylase OGG1, significant oxidative injury to mtDNA, decreased intact lung mitochondrial (mt) DNA, generation of inflammatory pathway by DAMPs causing airway and alveolar injury with significant mortality. Global proteomics identified over 1400 lung proteins with alteration of key mitochondrial proteins at 24 h post Cl2exposure. Intranasal instillation of a recombinant protein containing mitochondrial targeted OGG1 (mitoOGG1) post exposure, decreased oxidative injury to mtDNA, lung mitochondrial proteome, severity of the acute and chronic lung injury and increased survival. These data show that injury to the mt-genome is a key contributor to the development of acute and chronic lung injury.
Bacterial lipoate protein ligases rescue lipoylation and respiration deficiency in mammals
Authors: Hu Zhijuan , Yu Junru , Liu Ziwei , Jiang Min , Zeng An-Ping 
Published: November 2024

SummaryHuman lipoylation pathway deficiencies caused by LIPT2/LIAS/LIPT1 gene mutations lead to inherited metabolic disorders characterized by severe defects of mitochondrial energy and amino acids metabolism. Patients with such mutations suffer from hyperlactic acidemia, encephalopathy, hypotonia and early death. So far there is no effective treatment. Here we introduced the bacteria salvage lipoylation pathway, which is absent in eukaryotes, into lipoylation defective human cells and mouse models. BothE. coli-derived LplA andB. subtilis-derived LplJ restored the phenotypes of LIPT2/LIAS/LIPT1 gene knockout cells to those of wildtype cells with lipoic acid supplementation. Biochemical and isotope tracing analysis demonstrated LplA and LplJ function through direct lipoylation of the H protein of glycine cleavage system and the E2 subunits of 2-oxoacid dehydrogenases, thereby reactivating the short-circuited TCA cycle and amino acids metabolism. This strategy is further extended to treat lipoyl precursor supply defects caused by MECR and FDX1 mutations and its efficacy and safety are validated inLipt1-/-andLplAOE/+mouse models. This study provides systematic characterization of lipoylation deficiency and paves the way to gene therapy for treatment of lipoylation-deficient patients.
An estrogen receptor signaling transcriptional program linked to immune evasion in human hormone receptor-positive breast cancer
Authors: Shimada Kenichi , Michaud Daniel E. , Cui Yvonne Xiaoyong , Zheng Kelly , Goldberg Jonathan , Ju Zhenlin , Schnitt Stuart J. , Pastorello Ricardo , Kania Lukas D. , Hoffer John , Muhlich Jeremy L. , Hyun Nhan , Krueger Robert , Gottlieb Alexander , Nelson Adam , Wanderley Carlos W. , Antonellis Gabriella , McAllister Sandra S. , Tolaney Sara M. , Waks Adrienne G. , Jeselsohn Rinath , Sorger Peter K. , Agudo Judith , Mittendorf Elizabeth A. , Guerriero Jennifer L. 
Published: November 2024

AbstractT cells are generally sparse in hormone receptor-positive (HR+) breast cancer, potentially due to limited antigen presentation, but the driving mechanisms of low T cell abundance remains unclear. Therefore, we defined and investigated programs (‘gene modules’), related to estrogen receptor signaling (ERS) and immune signaling using bulk and single-cell transcriptome and multiplexed immunofluorescence of breast cancer tissues from multiple clinical sources and human cell lines. The ERS gene module, dominantly expressed in cancer cells, was negatively associated with immune-related gene modules TNFα/NF-κB signaling and type-I interferon (IFN-I) response, which were expressed in distinct stromal and immune cell types, but also, in part, expressed and preserved as a cancer cell-intrinsic mechanisms. Spatial analysis revealed that ERS strongly correlated with reduced T cell infiltration, potentially due to its association with suppression of TNFα/NF-κB-induced angiogenesis and IFN-I-induced HLA expression in macrophages. Preoperative endocrine therapy in ER+/HER2-breast cancer patients produced better responses in ERS-high patients, with TNFα/NF-κB expression associated with reduced ERS. Targeting these pathways may enhance T cell infiltration in HR+ breast cancer patients.Statement of SignificanceThis study elucidates the immunosuppressive role of ER signaling in breast cancer, highlighting a complex interplay between cancer, stromal, and immune cells and reveals potential approaches to enhance immunogenicity in HR+ breast cancer. These findings offer crucial insights into immune evasion in breast cancer and identify strategies to enhance T cell abundance.
Comparative transcriptomics ofLathyrus sativusreveals accession-specific resistance responses againstErysiphe pisi
Authors: Marques Rita Maravilha , Fernandes Telma , Barros Pedro M. , Leitão Susana Trindade , Rubiales Diego , Vaz Patto Maria Carlota , Santos Carmen 
Published: November 2024

AbstractLathyrus sativus(grass pea) is a valuable crop for sustainable agriculture, offering both dietary benefits and desirable agronomic traits. However, its yield stability is limited by different diseases such as powdery mildew caused byErysiphe pisi. Frequent fungal resistance to pesticides and growing environmental concerns highlight the need for research investment to develop resistant crop varieties. FourL. sativusaccessions, exhibiting varying levels of resistance toE. pisi(resistant, partially resistant, partially susceptible, and susceptible), were analysed using dual RNA-seq to identify key defence mechanisms and effector genes involved in this plant-pathogen interaction. The dual transcriptomic analysis highlighted a host biphasic response, characterised by an initial burst of gene expression, followed by a quiescent phase, and a second wave of intense gene expression at 72 hours after inoculation. CommonL. sativusdefence mechanisms, including antifungal protein expression, cell wall reinforcement, reactive oxygen species-mediated defence were activated by all accessions compared to susceptible accession. Unique responses in the resistant accession integrate early reinforcement of structural barriers with sustained chemical defences and stress responses. Overall, the partially resistant accession exhibited a front-loaded defence response, focused on biotic stimuli and interspecies interactions at early infection stages. In contrast, partial susceptible accessions exhibited a weaker baseline defence system, with a slower and less robust response specifically targeting pathogen infection. We identified potentialE. pisieffectors, including genes involved in cell wall hydrolysis, nutrient acquisition, and virulence, with a higher diversity of effectors identified in the susceptible accession. This study identifies novel targets within the complex defence mechanisms of theLathyrus sativus-Erysiphe pisiinteraction that will support to future breeding programs aimed at enhancing resistance toE. pisiinL. sativusand other related species.