bluuebunny/crossref_metadata_2025_split huggingface dataset:
racoon_clip – a complete pipeline for single-nucleotide analyses of iCLIP and eCLIP data
Authors: Klostermann Melina , Zarnack Kathi 
Published: March 2024

AbstractSummaryHere, we introduceracoon_clip, a sustainable and fully automated pipeline for the complete processing of iCLIP and eCLIP data to extract RNA binding signal at single-nucleotide resolution.racoon_clipis easy to install and execute, with multiple pre-settings and fully customizable parameters, and outputs a conclusive summary report with visualizations and statistics for all analysis steps.Availability and Implementationracoon_clipis implemented as a snakemake-powered command line tool (snakemake version ≥ 7.22, Python version ≥ 3.9). The latest release can be downloaded from GitHub (https://github.com/ZarnackGroup/racoon_clip/tree/main) and installed via pip. A detailed documentation, including installation, usage and customization, can be found athttps://racoon-clip.readthedocs.io/en/latest/.The example datasets can be downloaded from the Short Read Archive (SRA; iCLIP: SRR5646576, SRR5646577, SRR5646578) or the ENCODE Project (eCLIP: ENCSR202BFN).ContactKathi Zarnack,kathi.zarnack@bmls.deIssue SectionGenome analysis
A Silicon Diode based Optoelectronic Interface for Bidirectional Neural Modulation
Authors: Fu Xin , Hu Zhengwei , Li Wenjun , Ma Liang , Chen Junyu , Liu Muyang , Liu Jie , Hu Shuhan , Wang Huachun , Huang Yunxiang , Tang Guo , Zhang Bozhen , Cai Xue , Wang Yuqi , Li Lizhu , Ma Jian , Shi Song-Hai , Yin Lan , Zhang Hao , Li Xiaojian , Sheng Xing 
Published: March 2024

AbstractThe development of advanced neural modulation techniques is crucial to neuroscience research and neuroengineering applications. Recently, optical-based, non-genetic modulation approaches have been actively investigated to remotely interrogate the nervous system with high precision. Here, we show that a thin-film, silicon (Si)-based diode device is capable to bidirectionally regulate in vitro and in vivo neural activities upon adjusted illumination. When exposed to high-power and short-pulsed light, the Si diode generates photothermal effects, evoking neuron depolarization and enhancing intracellular calcium dynamics. Conversely, low-power and long-pulsed light on the Si diode hyperpolarizes neurons and reduces calcium activities. Furthermore, the Si diode film mounted on the brain of living mice can activate or suppress cortical activities under varied irradiation conditions. The presented material and device strategies reveal an innovated optoelectronic interface for precise neural modulations.TeaserA thin-film, silicon (Si)-based diode device is capable to bidirectionally regulate in vitro and in vivo neural activities.
Chitosan induces salicylic acid local and systemically in banana plants and reduces colonization by the pathogenFusarium oxysporumf. sp. cubense TR4
Authors: Lopez-Moya Federico , Zorrilla-Fontanesi Jassmin , Lozano-Soria Ana , de Larrinoa Ganado Naia Fernandez , Moreno González Celia Mei , Hernández Arnau , Torres Ariadna , Gonzalez-Silvera Daniel , Gunsé Benet , Lopez Jimenez Jose Angel , Lopez-Llorca Luis V. 
Published: March 2024

AbstractBanana (Musaspp.) is essential for food security. For its clonality is highly susceptible to pests and diseases. The wilt fungusFusarium oxysporumf. sp.cubenseTropical Race 4 (FocTR4) threatens banana production worldwide. We notice that chitosan protects banana from biotic stress. Chitosan, a plant defence elicitor with antimicrobial activity, triggers salicylic acid (SA) and methyl salicylate biosynthesis and induces systemic acquired resistance (SAR) genes, mainly flavin-dependent monooxygenase 1 (FMO1), in banana. Chitosan promotes root exudation of SA and emission of methyl salicylate (MeSA). Banana germplasm,Petit Naine,Gros Michel,Enzirabahima,Yangambi Km5andFoconahbanana differ in their response to chitosan. Chitosan induces, in Foc resistantYangambi Km5, ca. 7-fold FMO1. Preventive chitosan treatments together with the endophytic biocontrol fungusPochonia chlamydosporiastrain 123 reduce (ca. 4-fold) colonization of banana roots by FocTR4. Therefore, chitosan and beneficial endophytes can help to manage sustainably FocTR4 in banana.
Khdc3 Regulates Metabolism Across Generations in a DNA-Independent Manner
Authors: Senaldi Liana , Hassan Nora , Cullen Sean , Balaji Uthra , Trigg Natalie , Gu Jinghua , Finkelstein Hailey , Phillips Kathryn , Conine Colin , Smith-Raska Matthew 
Published: March 2024

AbstractGenetic variants can alter the profile of heritable molecules such as small RNAs in sperm and oocytes, and in this manner ancestral genetic variants can have a significant effect on offspring phenotypes even if they are not themselves inherited. Here we show that wild type female mice descended from ancestors with a mutation in the mammalian germ cell geneKhdc3have hepatic metabolic defects that persist over multiple generations. We find that genetically wild type females descended fromKhdc3mutants have transcriptional dysregulation of critical hepatic metabolic genes, which persist over multiple generations and pass through both female and male lineages. This was associated with dysregulation of hepatically-metabolized molecules in the blood of these wild type mice with mutational ancestry. The oocytes ofKhdc3-null females, as well as their wild type descendants, had dysregulation of multiple small RNAs, suggesting that these epigenetic changes in the gametes transmit the phenotype between generations. Our results demonstrate that ancestral mutation inKhdc3can produce transgenerational inherited phenotypes, potentially indefinitely.
Endothelial features along the pulmonary vascular tree in chronic thromboembolic pulmonary hypertension: distinctive or shared facets?
Authors: Verhaegen Janne , Willems Lynn , Wagenaar Allard , Spreuwers Ruben , Dahdah Nessrine , Aversa Lucia , Verbelen Tom , Delcroix Marion , Quarck Rozenn 
Published: March 2024

ABSTRACTChronic thromboembolic pulmonary hypertension (CTEPH) is a rare complication of pulmonary embolism, characterized by the presence of organized fibro-thrombotic material that partially or fully obstructs the lumen of large pulmonary arteries, microvasculopathy, and enlargement of the bronchial systemic vessels. The precise mechanisms underlying CTEPH remain unclear. However, defective angiogenesis and altered pulmonary arterial endothelial cell (PAEC) function may contribute to disease progression. Despite the observation of differences in histological features, shear stress and ischemia along the pulmonary vascular tree, the potential contribution of PAEC phenotype and function to these disparate aspects remains unexplored. Based on these observations, we postulated that angiogenic capacities and endothelial barrier function may contribute to disparities in histological features observed along the pulmonary vascular tree.We thus explored the histological characteristics of the pulmonary vascular tree using pulmonary arterial lesions obtained during pulmonary endarterectomy (PEA). We focused on the angiogenic vascular endothelial growth factor (VEGF)-A/VEGF receptor-2 (VEGFR2) axis and collagen 15A1 (COL15A1), a potential marker of endothelial cells of the systemic circulation. Concurrently, we examinedin vitroangiogenic properties and barrier function of PAECs derived from large and (sub)-segmental pulmonary arterial lesions. (Sub)-segmental pulmonary arterial lesions were abundantly recanalized by neovessels, paralleled by an enriched expression of VEGFR2. VEGF-A expression was more pronounced in large pulmonary arterial lesions. Nevertheless, no significant difference was discerned inin vitroangiogenic capacities and barrier integrity of PAECs isolated from large and (sub)- segmental pulmonary arterial lesions. Importantly, our findings revealed the presence of endothelial cells (CD31+) expressing COL15A1, as well as CD31+cells that did not express COL15A1. This suggests that endothelial cells from both systemic and pulmonary circulation contribute to lesion recanalization.Despite disparatein situangiogenic cues in VEGF-A/VEGFR2 axis between large and (sub)- segmental pulmonary arterial lesions in CTEPH,in vitroangiogenic capacities and barrier function remain unaltered.
Subcellular thermal profiling enables the deep functional exploration of the mitochondrial proteome
Authors: Rivera-Mejías Pablo , Le Sueur Cécile , Kurzawa Nils , Becher Isabelle , Savitski Mikhail M 
Published: March 2024

AbstractMitochondria are membrane-bound organelle hubs of cellular metabolism and signaling. The dysregulation of mitochondria is related to the genesis of several highly prevalent diseases, including cancer and cardiovascular disorders, urging the development of novel technologies to systematically study this organelle and its dynamics. Thermal proteome profiling (TPP) allows the unbiased study of the interactions of proteins with drugs, metabolites, and other proteins, providing a unique understanding of the state of the proteome. Here, we develop and introduce an optimized TPP workflow, mito-TPP, for the direct and extensive study of this organelle. We demonstrate that our approach detects both direct mitochondrial small molecule-protein and metabolite-protein interactions, as well as indirect downstream effects. We also show that mito-TPP preserves features from whole-cell systems, such as the coaggregation of interacting proteins. Finally, we explore the mitochondrial proteoform map, detecting more than 180 proteins with multiple proteoform groups. Overall, we demonstrate that mito-TPP is a powerful new tool for the functional study of the mitochondrial proteome.
Functional overlap between the mammalianSar1aandSar1bparalogs in vivo
Authors: Tang Vi T. , Xiang Jie , Chen Zhimin , McCormick Joseph , Abbineni Prabhodh S. , Chen Xiao-Wei , Hoenerhoff Mark , Emmer Brian T. , Khoriaty Rami , Lin Jiandie D. , Ginsburg David 
Published: March 2024

AbstractProteins carrying a signal peptide and/or a transmembrane domain enter the intracellular secretory pathway at the endoplasmic reticulum (ER) and are transported to the Golgi apparatus via COPII vesicles or tubules. SAR1 initiates COPII coat assembly by recruiting other coat proteins to the ER membrane. Mammalian genomes encode twoSAR1paralogs,SAR1AandSAR1B. While these paralogs exhibit ∼90% amino acid sequence identity, it is unknown whether they perform distinct or overlapping functions in vivo. We now report that genetic inactivation ofSar1ain mice results in lethality during mid-embryogenesis. We also confirm previous reports that complete deficiency of murineSar1bresults in perinatal lethality. In contrast, we demonstrate that deletion ofSar1brestricted to hepatocytes is compatible with survival, though resulting in hypocholesterolemia that can be rescued by adenovirus-mediated overexpression of either SAR1A or SAR1B. To further examine the in vivo function of these 2 paralogs, we genetically engineered mice with theSar1acoding sequence replacing that ofSar1bat the endogenousSar1blocus. Mice homozygous for this allele survive to adulthood and are phenotypically normal, demonstrating complete or near-complete overlap in function between the two SAR1 protein paralogs in mice. These data also suggest upregulation ofSAR1Agene expression as a potential approach for the treatment of SAR1B deficiency (chylomicron retention disease) in humans.
Dual agonism of sodium iodide symporter functionin vivo
Authors: Brookes Katie , Thornton Caitlin M. , Zha Ling , Kim Jana , Small Benjamin , Manivannan Selvambigai , Nieto Hannah R. , Adcock Holly , Bottegoni Giovanni , Cox Liam R. , Kannappan Vinodh , Wang Weiguang , Gorvin Caroline M. , Jhiang Sissy , Ringel Matthew D. , Campbell Moray J. , Sunassee Kavitha , Blower Philip J. , Boelaert Kristien , Smith Vicki E. , Read Martin L. , McCabe Christopher J. 
Published: March 2024

AbstractNew approaches are urgently needed to enhance the radioiodide (RAI) ablation of aggressive and metastatic thyroid cancer. We recently discovered that valosin-containing protein inhibitors (VCPi) such as clotrimazole and disulfiram transiently block sodium iodide symporter (NIS) proteasomal degradation, hence promoting RAI uptake. However, poor bioavailability diminishes their potential impactin vivo. Following 3D modelling and iterative drug design we appraised 26 novel analogues of clotrimazole, as well as albumin nano-encapsulated copper-diethyldithiocarbamate [Cu(DDC)2-alb] – a stabilised reformulation of a disulfiram metabolite. While several clotrimazole analogues specifically increased RAI uptake, the greatest impact was observed with Cu(DDC)2-alb in thyroid cancer cells as well as human primary thyrocytes from patients with thyroid hyperplasia. NanoBRET assays revealed that Cu(DDC)2enhanced the plasma membrane accumulation of NIS in living cells. In BALB/c mice, both intraperitoneal and intravenous administration of Cu(DDC)2-alb significantly enhanced thyroidal99mTc-uptake. RNA-Seq revealed the surprising observation that Cu(DDC)2-alb induced key thyroid transcription factors. Accordingly, expression of PAX8 and NKX2.1 was upregulated in thyroid glands from drug treated mice, with NIS levels correlating closely to99mTc-uptake. As Cu(DDC)2inhibits the VCP cofactor NPL4, with VCP being critical to the proteostatic processing of NIS protein, we identify a new dual agonist of RAI uptakein vivo, with the potential to directly impact RAI therapy for patients with aggressive thyroid cancer.
Genome-wide association study reveals multiple loci for nociception and opioid consumption behaviors associated with heroin vulnerability in outbred rats
Authors: Kuhn Brittany N. , Cannella Nazzareno , Chitre Apurva S. , Nguyen Khai-Minh H. , Cohen Katarina , Chen Denghui , Peng Beverly , Ziegler Kendra S. , Lin Bonnie , Johnson Benjamin B. , Missfeldt Sanches Thiago , Crow Ayteria D. , Lunerti Veronica , Gupta Arkobrato , Dereschewitz Eric , Soverchia Laura , Hopkins Jordan L. , Roberts Analyse T. , Ubaldi Massimo , Abdulmalek Sarah , Kinen Analia , Hardiman Gary , Chung Dongjun , Polesskaya Oksana , Solberg Woods Leah C. , Ciccocioppo Roberto , Kalivas Peter W. , Palmer Abraham A. 
Published: March 2024

AbstractThe increased prevalence of opioid use disorder (OUD) makes it imperative to disentangle the biological mechanisms contributing to individual differences in OUD vulnerability. OUD shows strong heritability, however genetic variants contributing to vulnerability remain poorly defined. We performed a genome-wide association study using over 850 male and female heterogeneous stock (HS) rats to identify genes underlying behaviors associated with OUD such as nociception, as well as heroin-taking, extinction and seeking behaviors. By using an animal model of OUD, we were able to identify genetic variants associated with distinct OUD behaviors while maintaining a uniform environment, an experimental design not easily achieved in humans. Furthermore, we used a novel non-linear network-based clustering approach to characterize rats based on OUD vulnerability to assess genetic variants associated with OUD susceptibility. Our findings confirm the heritability of several OUD-like behaviors, including OUD susceptibility. Additionally, several genetic variants associated with nociceptive threshold prior to heroin experience, heroin consumption, escalation of intake, and motivation to obtain heroin were identified.Tom1, a microglial component, was implicated for nociception. Several genes involved in dopaminergic signaling, neuroplasticity and substance use disorders, includingBrwd1,Pcp4, Phb1l2andMmp15were implicated for the heroin traits. Additionally, an OUD vulnerable phenotype was associated with genetic variants for consumption and break point, suggesting a specific genetic contribution for OUD-like traits contributing to vulnerability. Together, these findings identify novel genetic markers related to the susceptibility to OUD-relevant behaviors in HS rats.
Epigenetic programming of host lipid metabolism associates with resistance to TST/IGRA conversion after exposure toMycobacterium tuberculosis
Authors: Dill-McFarland Kimberly A , Simmons Jason D , Peterson Glenna J , Nguyen Felicia K , Campo Monica , Benchek Penelope , Stein Catherine M , Vaisar Tomas , Mayanja-Kizza Harriet , Boom W Henry , Hawn Thomas R 
Published: March 2024

ABSTRACTMycobacterium tuberculosis(Mtb) exposure leads to a range of outcomes including clearance, latent TB infection (LTBI), and pulmonary tuberculosis (TB). Some heavily exposed individuals resist tuberculin skin test (TST) and interferon gamma release assay (IGRA) conversion (RSTR), which suggests that they employ IFNγ-independent mechanisms of Mtb control. Here, we compare monocyte epigenetic profiles of RSTR and LTBI from a Ugandan household contact cohort. Chromatin accessibility did not differ between uninfected RSTR and LTBI monocytes. In contrast, methylation significantly differed at 174 CpG sites and across 63 genomic regions. Consistent with previous transcriptional findings in this cohort, differential methylation was enriched in lipid and cholesterol associated pathways including in the genes APOC3, KCNQ1, and PLA2G3. In addition, methylation was enriched in Hippo signaling, which is associated with cholesterol homeostasis and includes CIT and SHANK2. Lipid export and Hippo signaling pathways were also associated with gene expression in response to Mtb in RSTR as well as IFN stimulation in monocyte-derived macrophages (MDMs) from an independent healthy donor cohort. Moreover, serum-derived HDL from RSTR had elevated ABCA1-mediated cholesterol efflux capacity (CEC) compared to LTBI. Our findings suggest that resistance to TST/IGRA conversion is linked to regulation of lipid accumulation in monocytes, which could facilitate early Mtb clearance among RSTR subjects through IFNγ-independent mechanisms.IMPORTANCETuberculosis (TB) remains an enduring global health challenge with millions of deaths and new cases each year. Despite recent advances in TB treatment, we lack an effective vaccine or a durable cure. While heavy exposure toMycobacterium tuberculosisoften results in latent TB latent infection (LTBI), subpopulations exist who are either resistant to infection or contain Mtb with IFNγ-independent mechanisms not indicative of LTBI. These resisters provide an opportunity to investigate mechanisms of TB disease and discover novel therapeutic targets. Here, we compare monocyte epigenetic profiles of RSTR and LTBI from a Ugandan household contact cohort. We identify methylation signatures in host lipid and cholesterol pathways with potential relevance to early TB clearance before the sustained IFN responses indicative of LTBI. This adds to a growing body of literature linking TB disease outcomes to host lipids.
Virus-derived Synthetic Riboswitches for Real-time Coronaviruses Sensing in Live Cells
Authors: Zeng Leiping , Qi Lei S. 
Published: March 2024

AbstractReal-time sensing of viral infection in live cells are crucial for virology research and antiviral development. However, existing methods face challenges of low signal sensitivity and the necessity for viral manipulation and cell fixation. Here, we develop aviralriboswitch (vRibo) approach that employs the viral replicase to induce transgene expression upon viral infection. The vRibo is designed to detect viral real-time transcription and replication in live cells, which in response triggers the translation of reporter and therapeutic genes. By integrating a viral packaging sequence, vRibo can be transmitted to neighboring cells through progeny virions, effectively acting as a ‘Trojan Horse’. The negative-strand vRibo elements demonstrated effective detection of several coronaviruses, including 229E and OC43, due to the conservation of cis-acting RNA structures across coronaviruses. Notably, vRibo functions as a dual-purpose system, acting both as an infection detector and inducible antiviral system. vRibo has the potential for basic virology research applications and can be adopted in improving the inducible expression of mRNA medicines for future coronaviruses.
Evaluating the impacts of tiered restrictions introduced in England in December 2020 on covid-19 hospitalisations: a synthetic control study
Authors: Zhang Xingna , Hungerford Daniel , Green Mark A. , García-Fiñana Marta , Buchan Iain E. , Barr Ben 
Published: March 2024

ABSTRACTObjectivesTo assess the impact of Tier 3 covid-19 restrictions implemented in December 2020 in England on covid-19 hospital admissions compared to Tier 2 restrictions, and its potential variations by neighbourhood deprivation levels and the prevalence of the Alpha variant (B.1.1.7).DesignObservational study utilising a synthetic control approach. Comparison of changes in weekly hospitalisation rates in Tier 3 areas to a synthetic control group derived from Tier 2 areas.SettingEngland between 4thOctober 2020 and 21stFebruary 2021.Participants23 million people under Tier 3 restrictions, compared to a synthetic control group derived from 29 million people under Tier 2 restrictions.InterventionsImplementation of Tier 3 covid-19 restrictions in designated areas on 7thDecember 2020, with additional constraints on indoor and outdoor meetings and the hospitality sector compared to less stringent Tier 2 restrictions.Main Outcome MeasuresWeekly covid-19 related hospital admissions for neighbourhoods in England over a 12-week period following the interventions.ResultsThe introduction of Tier 3 restrictions was associated with a 17% average reduction in hospital admissions compared to Tier 2 areas (95% CI 13% to 21%; 8158 (6286 to 9981) in total)). The effects were similar across different levels of neighbourhood deprivation and prevalence of the Alpha variant (B.1.1.7).ConclusionsRegionally targeted Tier 3 restrictions in England had a moderate but significant effect on reducing hospitalisations. The impact did not exacerbate socioeconomic inequalities during the pandemic. Our findings suggest that regionally targeted restrictions can be effective in managing infectious diseases.SUMMARY BOXESWhat is already known on this topic— Previous studies of localised non-pharmaceutical interventions (NPIs) found that they could be effective in reducing covid-19 transmissions.— covid-19 hospitalisation was a key indicator of healthcare resource dynamics, encompassing supply, demand, burden, and allocation, during the pandemic.— There is a need for a detailed examination of the impact of specific localised restrictions in the UK, such as Tier 3 measures, on hospital admissions to inform targeted public health strategies.What this study adds— This study found that additional localised restrictions on outdoor gatherings and in the hospitality sector were effective in mitigating hospital admissions during the pandemic.How this study might affect research, practice or policy— This study provides evidence for future public health policies and preparedness strategies supporting the use of differential regional restrictions during pandemics.