bluuebunny/crossref_metadata_2025_split huggingface dataset:
Kinematics of Cenozoic Shortening of the Hotan Anticline Along the Northwestern Margin of the Tibetan Plateau (Western Kunlun, China)
Authors: Baby Guillaume , Simoes Martine , Barrier Laurie , Guilbaud Christelle , Li Haibing , Van der Woerd Jérôme 
Published: May 2022

AbstractKinematic constraints on the Cenozoic deformation along the northwestern edge of the Tibetan Plateau remain limited. Combining surface geological data and seismic profiles, we document the structural geometry and kinematics of the large‐scale east‐west striking Hotan anticline, along the foothills of the Western Kunlun Range. Four new balanced cross sections are constructed, and the temporal evolution of deformation is deciphered from the exceptionally well‐imaged growth strata at the front of the fold. This anticline results from a broad fault‐bend fold, subsequently deformed by a footwall duplex. The total shortening across the whole structure is relatively constant along strike, from ∼40 to ∼35 km. However, the shortening accommodated by the duplex varies laterally from ∼50–40% to 0% of the total shortening. Two distinct successive patterns of growth strata are recognized and are interpreted to be representative of deformation on the ramp anticline, followed by deformation on the duplex. The onset of deformation initiated by ∼16 Ma. Deformation of the underlying duplex began at ∼12 Ma to the west and subsequently propagated eastward. From these results, we determine a shortening rate of ∼5 mm/yr from ∼16 to ∼8–9 Ma across the Hotan thrust system, followed by a significant decrease in shortening rate, possibly down to <0.5 mm/yr. We explore the significance of this deceleration of deformation at the scale of the Western Kunlun foothills and at a broader regional scale as it may point to a regional kinematic reorganization by the late Miocene.
Cord blood metabolites and rapid postnatal growth as multiple mediators in the prenatal propensity to childhood overweight
Authors: Alfano Rossella , Plusquin Michelle , Robinson Oliver , Brescianini Sonia , Chatzi Lida , Keski-Rahkonen Pekka , Handakas Evangelos , Maitre Lea , Nawrot Tim , Robinot Nivonirina , Roumeliotaki Theano , Sassi Franco , Scalbert Augustin , Vrijheid Martine , Vineis Paolo , Richiardi Lorenzo , Zugna Daniela 
Published: May 2022

AbstractBackgroundThe mechanisms underlying childhood overweight and obesity are poorly known. Here, we investigated the direct and indirect effects of different prenatal exposures on offspring rapid postnatal growth and overweight in childhood, mediated through cord blood metabolites. Additionally, rapid postnatal growth was considered a potential mediator on childhood overweight, alone and sequentially to each metabolite.MethodsWithin four European birth-cohorts (N = 375 mother-child dyads), information on seven prenatal exposures (maternal education, pre-pregnancy BMI, weight gain and tobacco smoke during pregnancy, age at delivery, parity, and child gestational age), selected as obesogenic according to a-priori knowledge, was collected. Cord blood levels of 31 metabolites, associated with rapid postnatal growth and/or childhood overweight in a previous study, were measured via liquid-chromatography-quadrupole-time-of-flight-mass-spectrometry. Rapid growth at 12 months and childhood overweight (including obesity) between four and eight years were defined with reference to WHO growth charts. Single mediation analysis was performed using the imputation approach and multiple mediation analysis using the extended-imputation approach.ResultsSingle mediation suggested that the effect of maternal education, pregnancy weight gain, parity, and gestational age on rapid postnatal growth but not on childhood overweight was partly mediated by seven metabolites, including cholestenone, decenoylcarnitine(C10:1), phosphatidylcholine(C34:3), progesterone and three unidentified metabolites; and the effect of gestational age on childhood overweight was mainly mediated by rapid postnatal growth. Multiple mediation suggested that the effect of gestational age on childhood overweight was mainly mediated by rapid postnatal growth and that the mediating role of the metabolites was marginal.ConclusionOur findings provide evidence of the involvement of in utero metabolism in the propensity to rapid postnatal growth and of rapid postnatal growth in the propensity to childhood overweight. We did not find evidence supporting a mediating role of the studied metabolites alone between the studied prenatal exposures and the propensity to childhood overweight.
A game changer for bipolar disorder diagnosis using RNA editing-based biomarkers
Authors: Salvetat Nicolas , Checa-Robles Francisco Jesus , Patel Vipul , Cayzac Christopher , Dubuc Benjamin , Chimienti Fabrice , Abraham Jean-Daniel , Dupré Pierrick , Vetter Diana , Méreuze Sandie , Lang Jean-Philippe , Kupfer David J. , Courtet Philippe , Weissmann Dinah 
Published: May 2022

AbstractIn clinical practice, differentiating Bipolar Disorder (BD) from unipolar depression is a challenge due to the depressive symptoms, which are the core presentations of both disorders. This misdiagnosis during depressive episodes results in a delay in proper treatment and a poor management of their condition. In a first step, using A-to-I RNA editome analysis, we discovered 646 variants (366 genes) differentially edited between depressed patients and healthy volunteers in a discovery cohort of 57 participants. After using stringent criteria and biological pathway analysis, candidate biomarkers from 8 genes were singled out and tested in a validation cohort of 410 participants. Combining the selected biomarkers with a machine learning approach achieved to discriminate depressed patients (n = 267) versus controls (n = 143) with an AUC of 0.930 (CI 95% [0.879–0.982]), a sensitivity of 84.0% and a specificity of 87.1%. In a second step by selecting among the depressed patients those with unipolar depression (n = 160) or BD (n = 95), we identified a combination of 6 biomarkers which allowed a differential diagnosis of bipolar disorder with an AUC of 0.935 and high specificity (Sp = 84.6%) and sensitivity (Se = 90.9%). The association of RNA editing variants modifications with depression subtypes and the use of artificial intelligence allowed developing a new tool to identify, among depressed patients, those suffering from BD. This test will help to reduce the misdiagnosis delay of bipolar patients, leading to an earlier implementation of a proper treatment.
SP1-mediated up-regulation of lncRNA TUG1 underlines an oncogenic property in colorectal cancer
Authors: Liu Wei , Meng Jin , Su Rongjun , Shen Changjun , Zhang Shuai , Zhao Yantao , Liu Wenqi , Du Jiang , Zhu Shuai , Li Pan , Wang Zhigang , Li Xiaoxia 
Published: May 2022

AbstractThe long non-coding RNA (lncRNA) taurine up-regulated gene 1 (TUG1) acts as tumor-promoting factor in colorectal cancer (CRC). We aimed to elucidate the mechanism by which the transcription factor specificity protein 1 (SP1) regulates TUG1 and microRNAs (miRs)/mRNAs in the context of CRC, which has not been fully studied before. Expression patterns of TUG1 and SP1 were determined in clinical CRC samples and cells, followed by identification of their interaction. Next, the functional significance of TUG1 in CRC was investigated. An in vivo CRC model was established to validate the effect of TUG1. The results demonstrated that TUG1 and SP1 were highly-expressed in CRC, wherein SP1 bound to the TUG1 promoter and consequently, positively regulated its expression. Silencing of TUG1 caused suppression of CRC cell growth and promotion of cell apoptosis. TUG1 could bind to miR-421 to increase KDM2A expression, a target gene of miR-421. TUG1 could activate the ERK pathway by impairing miR-421-targeted inhibition of KDM2A. Additionally, SP1 could facilitate the tumorigenesis of CRC cells in vivo by regulating the TUG1/miR-421/KDM2A/ERK axis. Altogether, the current study emphasizes the oncogenic role of TUG1 in CRC, and illustrates its interactions with the upstream transcription factor SP1 and the downstream modulatory axis miR-421/KDM2A/ERK, thus offering novel insights into the cancerogenic mechanism in CRC.
KLF4 regulates TERT expression in alveolar epithelial cells in pulmonary fibrosis
Authors: Wang Hui , Xu Hongyang , Lyu Wenting , Xu Qinghua , Fan Shiwen , Chen Haoran , Wang Dongjin , Chen Jingyu , Dai Jinghong 
Published: May 2022

AbstractIdiopathic pulmonary fibrosis (IPF) was considered as a telomere-mediated disease. TERT and TERC correlated with telomere length. Although telomerase gene mutations were associated with IPF, majority patients did not carry mutations. The mechanism by which telomerase expression was regulated in IPF are still unclear. In this study, we aimed to delineate the mechanisms that how TERT protein expression were regulated in alveolar epithelial cells (AECs) in pulmonary fibrosis. Here, we found that P16, P21 and fibrosis markers (αSMA and Collagen-I) were prominently increased in lung tissues of IPF patients and bleomycin-induced mouse models, while the expression of KLF4 and TERT were decreased in AECs. In vivo experiments, AAV-6 vectors mediated KLF4 over-expression with specific SP-C promoter was constructed. Over-expression of KLF4 in AECs could protect TERT expression and suppress the development of pulmonary fibrosis in bleomycin-induced mouse models. In the mechanism exploration of TERT regulation, KLF4 and TERT were both down-regulated in bleomycin-induced senescent MLE-12 and BEAS-2B cells. Compared with control group, small-interfering RNA targeting KLF4 significantly reduced the TERT expression and telomerase activity, while overexpression of KLF4 can increased the expression of TERT and telomerase activity in senescent AECs. Furthermore, ChIP showed that KLF4 protein could bind to the TERT promoter region in MLE-12 cells, suggesting that KLF4 could implicate in pathogenesis of lung fibrosis through regulating TERT transcription in AECs. Taken together, this study identified that KLF4 might be a promising potential target for further understanding the mechanism and developing novel strategy for the treatment of lung fibrosis in IPF.
Changes in 12-month outcomes over time for age-related macular degeneration, diabetic macular oedema and retinal vein occlusion
Authors: Bhandari Sanjeeb , Nguyen Vuong , Hunt Adrian , Gabrielle Pierre-Henry , Viola Francesco , Mehta Hemal , Manning Les , Squirrell David , Arnold Jennifer , McAllister Ian L. , Barthelmes Daniel , Gillies Mark 
Published: May 2022

AbstractObjectivesTo identify whether the outcomes of neovascular age-related macular degeneration (nAMD), diabetic macular oedema (DMO) and retinal vein occlusion (RVO) in routine clinical practice have changed over time.MethodsWe analysed 12-month outcomes in treatment-naïve eyes that started aflibercept or ranibizumab for nAMD (3802 eyes), DMO (975 eyes), Branch RVO (BRVO, 357 eyes), Central RVO (CRVO, 371 eyes) and Hemi-RVO (HRVO, 54 eyes) from 2015 and 2019 tracked in the prospectively designed observational Fight Retinal Blindness! Registry.ResultsThe mean VA change at 12-month for each year between 2015 and 2019 remained stable or otherwise showed no discernible trends over time in eyes with nAMD (+3.3 to +6 letters), DMO (+3.6 to +6.7 letters) and RVO (+10.3 to +11.7 letters for BRVO, +5.9 to +17.7 letters for CRVO and 10.2 to 20.7 letters for HRVO). The median number of VEGF-inhibitor injections in eyes that completed 12-month follow-up also remained stable at 8–9 for nAMD, 6–7 for DMO, 7–9 for RVO. Fewer eyes (<one-fourth) that started treatment between 2015 and 2018 and more eyes starting in 2019 did not complete 12-month’s follow-up visit. The mean VA in non-completers at their last visit was higher than that of their baseline visit.ConclusionsTreatment patterns and outcomes for nAMD, DMO and RVO in routine clinical practice have stabilised over the past 5 years at levels inferior to those reported by the pivotal phase 3 studies. A conscious effort to treat these conditions more intensively, or with longer lasting agents, would likely improve outcomes further in our patients.
Elucidating Human Milk Oligosaccharide biosynthetic genes through network-based multi-omics integration
Authors: Kellman Benjamin P. , Richelle Anne , Yang Jeong-Yeh , Chapla Digantkumar , Chiang Austin W. T. , Najera Julia A. , Liang Chenguang , Fürst Annalee , Bao Bokan , Koga Natalia , Mohammad Mahmoud A. , Bruntse Anders Bech , Haymond Morey W. , Moremen Kelley W. , Bode Lars , Lewis Nathan E. 
Published: May 2022

AbstractHuman Milk Oligosaccharides (HMOs) are abundant carbohydrates fundamental to infant health and development. Although these oligosaccharides were discovered more than half a century ago, their biosynthesis in the mammary gland remains largely uncharacterized. Here, we use a systems biology framework that integrates glycan and RNA expression data to construct an HMO biosynthetic network and predict glycosyltransferases involved. To accomplish this, we construct models describing the most likely pathways for the synthesis of the oligosaccharides accounting for >95% of the HMO content in human milk. Through our models, we propose candidate genes for elongation, branching, fucosylation, and sialylation of HMOs. Our model aggregation approach recovers 2 of 2 previously known gene-enzyme relations and 2 of 3 empirically confirmed gene-enzyme relations. The top genes we propose for the remaining 5 linkage reactions are consistent with previously published literature. These results provide the molecular basis of HMO biosynthesis necessary to guide progress in HMO research and application with the goal of understanding and improving infant health and development.
Enhancer RNAs stimulate Pol II pause release by harnessing multivalent interactions to NELF
Authors: Gorbovytska Vladyslava , Kim Seung-Kyoon , Kuybu Filiz , Götze Michael , Um Dahun , Kang Keunsoo , Pittroff Andreas , Brennecke Theresia , Schneider Lisa-Marie , Leitner Alexander , Kim Tae-Kyung , Kuhn Claus-D. 
Published: May 2022

AbstractEnhancer RNAs (eRNAs) are long non-coding RNAs that originate from enhancers. Although eRNA transcription is a canonical feature of activated enhancers, the molecular features required for eRNA function and the mechanism of how eRNAs impinge on target gene transcription have not been established. Thus, using eRNA-dependent RNA polymerase II (Pol II) pause release as a model, we here investigate the requirement of sequence, structure and length of eRNAs for their ability to stimulate Pol II pause release by detaching NELF from paused Pol II. We find eRNAs not to exert their function through common structural or sequence motifs. Instead, eRNAs that exhibit a length >200 nucleotides and that contain unpaired guanosines make multiple, allosteric contacts with NELF subunits -A and -E to trigger efficient NELF release. By revealing the molecular determinants of eRNA function, our study establishes eRNAs as an important player in Pol II pause release, and it provides new insight into the regulation of metazoan transcription.
E(3)-equivariant graph neural networks for data-efficient and accurate interatomic potentials
Authors: Batzner Simon , Musaelian Albert , Sun Lixin , Geiger Mario , Mailoa Jonathan P. , Kornbluth Mordechai , Molinari Nicola , Smidt Tess E. , Kozinsky Boris 
Published: May 2022

AbstractThis work presents Neural Equivariant Interatomic Potentials (NequIP), an E(3)-equivariant neural network approach for learning interatomic potentials from ab-initio calculations for molecular dynamics simulations. While most contemporary symmetry-aware models use invariant convolutions and only act on scalars, NequIP employs E(3)-equivariant convolutions for interactions of geometric tensors, resulting in a more information-rich and faithful representation of atomic environments. The method achieves state-of-the-art accuracy on a challenging and diverse set of molecules and materials while exhibiting remarkable data efficiency. NequIP outperforms existing models with up to three orders of magnitude fewer training data, challenging the widely held belief that deep neural networks require massive training sets. The high data efficiency of the method allows for the construction of accurate potentials using high-order quantum chemical level of theory as reference and enables high-fidelity molecular dynamics simulations over long time scales.
Versican promotes T helper 17 cytotoxic inflammation and impedes oligodendrocyte precursor cell remyelination
Authors: Ghorbani Samira , Jelinek Emily , Jain Rajiv , Buehner Benjamin , Li Cenxiao , Lozinski Brian M. , Sarkar Susobhan , Kaushik Deepak K. , Dong Yifei , Wight Thomas N. , Karimi-Abdolrezaee Soheila , Schenk Geert J. , Strijbis Eva M. , Geurts Jeroen , Zhang Ping , Ling Chang-Chun , Yong V. Wee 
Published: May 2022

AbstractRemyelination failure in multiple sclerosis (MS) contributes to progression of disability. The deficient repair results from neuroinflammation and deposition of inhibitors including chondroitin sulfate proteoglycans (CSPGs). Which CSPG member is repair-inhibitory or alters local inflammation to exacerbate injury is unknown. Here, we correlate high versican-V1 expression in MS lesions with deficient premyelinating oligodendrocytes, and highlight its selective upregulation amongst CSPG members in experimental autoimmune encephalomyelitis (EAE) lesions modeling MS. In culture, purified versican-V1 inhibits oligodendrocyte precursor cells (OPCs) and promotes T helper 17 (Th17) polarization. Versican-V1-exposed Th17 cells are particularly toxic to OPCs. In NG2CreER:MAPTmGFP mice illuminating newly formed GFP+ oligodendrocytes/myelin, difluorosamine (peracetylated,4,4-difluoro-N-acetylglucosamine) treatment from peak EAE reduces lesional versican-V1 and Th17 frequency, while enhancing GFP+ profiles. We suggest that lesion-elevated versican-V1 directly impedes OPCs while it indirectly inhibits remyelination through elevating local Th17 cytotoxic neuroinflammation. We propose CSPG-lowering drugs as potential dual pronged repair and immunomodulatory therapeutics for MS.
Using sero-epidemiology to monitor disparities in vaccination and infection with SARS-CoV-2
Authors: Routledge Isobel , Takahashi Saki , Epstein Adrienne , Hakim Jill , Janson Owen , Turcios Keirstinne , Vinden Jo , Risos John Tomas , Baniqued Margaret Rose , Pham Lori , Di Germanio Clara , Busch Michael , Kushel Margot , Greenhouse Bryan , Rodríguez-Barraquer Isabel 
Published: May 2022

AbstractAs SARS-CoV-2 continues to spread and vaccines are rolled-out, the “double burden” of disparities in exposure and vaccination intersect to determine patterns of infection, immunity, and mortality. Serology provides a unique opportunity to measure prior infection and vaccination simultaneously. Leveraging algorithmically-selected residual sera from two hospital networks in the city of San Francisco, cross-sectional samples from 1,014 individuals from February 4–17, 2021 were each tested on two assays (Ortho Clinical Diagnostics VITROS Anti-SARS-CoV-2 and Roche Elecsys Anti-SARS-CoV-2), capturing the first year of the epidemic and early roll-out of vaccination. We estimated, using Bayesian estimation of infection and vaccination, that infection risk of Hispanic/Latinx residents was five times greater than of White residents aged 18–64 (95% Credible Interval (CrI): 3.2–10.3), and that White residents over 65 were twice as likely to be vaccinated as Black/African American residents (95% CrI: 1.1–4.6). We found that socioeconomically-deprived zipcodes had higher infection probabilities and lower vaccination coverage than wealthier zipcodes. While vaccination has created a ‘light at the end of the tunnel’ for this pandemic, ongoing challenges in achieving and maintaining equity must also be considered.
Understanding the rheology of nanocontacts
Authors: Khosravi Ali , Lainé Antoine , Vanossi Andrea , Wang Jin , Siria Alessandro , Tosatti Erio 
Published: May 2022

AbstractMechanical stiffness, as opposed to softness, is a fundamental property of solids. Its persistence or rheological evolution in vibrating solid-solid nanocontacts is important in physics, materials science and technology. A puzzling apparent liquefaction under oscillatory strain, totally unexpected at room temperature, was suggested by recent experiments on solid gold nano-junctions. Here we show theoretically that realistically simulated nanocontacts actually remain crystalline even under large oscillatory strains. Tensile and compressive slips, respectively of “necking” and “bellying” types, do take place, but recover reversibly even during fast oscillatory cycles. We also show that, counterintuitively, the residual stress remains tensile after both slips, driving the averaged stiffness from positive to negative, thus superficially mimicking a liquid’s. Unlike a liquid, however, rheological softening occurs by stick-slip, predicting largely frequency independent stiffness with violent noise in stress and conductance, properties compatible with experiments. The baffling large amplitude rheology of gold nanocontacts and its consequences should apply, with different parameters, to many other metals.
Liver-directed lentiviral gene therapy corrects hemophilia A mice and achieves normal-range factor VIII activity in non-human primates
Authors: Milani Michela , Canepari Cesare , Liu Tongyao , Biffi Mauro , Russo Fabio , Plati Tiziana , Curto Rosalia , Patarroyo-White Susannah , Drager Douglas , Visigalli Ilaria , Brombin Chiara , Albertini Paola , Follenzi Antonia , Ayuso Eduard , Mueller Christian , Annoni Andrea , Naldini Luigi , Cantore Alessio 
Published: May 2022

AbstractLiver gene therapy with adeno-associated viral (AAV) vectors delivering clotting factor transgenes into hepatocytes has shown multiyear therapeutic benefit in adults with hemophilia. However, the mostly episomal nature of AAV vectors challenges their application to young pediatric patients. We developed lentiviral vectors, which integrate in the host cell genome, that achieve efficient liver gene transfer in mice, dogs and non-human primates, by intravenous delivery. Here we first compare engineered coagulation factor VIII transgenes and show that codon-usage optimization improved expression 10-20-fold in hemophilia A mice and that inclusion of an unstructured XTEN peptide, known to increase the half-life of the payload protein, provided an additional >10-fold increase in overall factor VIII output in mice and non-human primates. Stable nearly life-long normal and above-normal factor VIII activity was achieved in hemophilia A mouse models. Overall, we show long-term factor VIII activity and restoration of hemostasis, by lentiviral gene therapy to hemophilia A mice and normal-range factor VIII activity in non-human primate, paving the way for potential clinical application.