bluuebunny/crossref_metadata_2025_split huggingface dataset:
Psychosocial and behavioral problems of children and adolescents in the early stage of reopening schools after the COVID-19 pandemic: a national cross-sectional study in China
Authors: Wang Lin , Zhang Yiwen , Chen Li , Wang Jianhong , Jia Feiyong , Li Fei , Froehlich Tanya E. , Hou Yan , Hao Yan , Shi Yuan , Deng Hongzhu , Zhang Jie , Huang Linjuan , Xie Xianghui , Fang Shuanfeng , Xu Liang , Xu Qi , Guan Hongyan , Wang Weijie , Shen Jianna , Qian Ying , Wang Xi , Shan Ling , Tan Chuanxue , Yu Yabin , Wang Xiaoyan , Chen Fangfang , Zhang Lili , Li Xiaomeng , Shi Xinmiao , Ke Xiaoyan , Li Tingyu 
Published: June 2021

AbstractThis study aims to explore the psychosocial and behavioral problems of children and adolescents in the early stage of reopening schools. In this national cross-sectional study, a total of 11072 students from China were naturally divided into two groups based on their schooling status: reopened schools (RS) and home schooling (HS) group. The psychosocial and behavioral functioning were measured by Achenbach Child Behaviour Checklist (CBCL) and compared in these two groups. Multivariable logistic regression analyses were conducted to explore the independent predictors associated with the psychosocial and behavioral problems. Our results showed that the students in the RS group had more adverse behaviors than that of HS group. The RS group had the higher rates of parent-offspring conflict, prolonged homework time, increased sedentary time and sleep problems (all p < 0.001). When separate analyses were conducted in boys and girls, the RS group had the higher scores for (1) overall behavioral problems (p = 0.02 and p = 0.01), internalizing (p = 0.02 and p = 0.02) and externalizing (p = 0.02 and p = 0.004) behaviors in the 6–11 age group; (2) externalizing (p = 0.049 and p = 0.006) behaviors in the 12–16 age group. Multivariable regression showed parent-offspring conflict and increased sedentary time were the most common risk factors, while physical activity and number of close friends were protective factors for behavior problems in RS students (p < 0.01 or 0.05). The present study revealed that students’ psychosocial and behavioral problems increased in the early stage of schools reopened unexpectedly. These findings suggest that close attention must be paid and holistic strategies employed in the school reopening process of post-COVID-19 period.
Oxytocin receptor induces mammary tumorigenesis through prolactin/p-STAT5 pathway
Authors: Li Dan , San Mingjun , Zhang Jing , Yang Anlan , Xie Wanhua , Chen Yang , Lu Xiaodan , Zhang Yuntao , Zhao Mingyue , Feng Xuechao , Zheng Yaowu 
Published: June 2021

AbstractOxytocin receptor (OXTR) is involved in social behaviors, thermoregulation, and milk ejection, yet little is known about its role in breast cancer. To investigate the role of OXTR in mammary gland development and tumorigenesis, a transgenic mouse model of OXTR overexpression (++Oxtr) was used. Overexpression of OXTR-induced progressive mammary hyperplasia, unexpected milk production, and tumorigenesis in females. OXTR-induced mammary tumors showed ERBB2 upregulation and mixed histological subtypes with predomination of papillary and medullary carcinomas. OXTR overexpression led to an activation of prolactin (PRL)/p-STAT5 pathway and created a microenvironment that promotes mammary-specific tumorigenesis. PRL inhibitor bromocriptine (Br) could mitigate OXTR-driven mammary tumor growth. The study demonstrates Oxtr is an oncogene and a potential drug target for HER2-type breast cancer.
Reduced hyaluronan cross-linking induces breast cancer malignancy in a CAF-dependent manner
Authors: Zhang Guoliang , He Yiqing , Liu Yiwen , Du Yan , Yang Cuixia , Gao Feng 
Published: June 2021

AbstractHyaluronan (HA) cross-linking is a conformational state of HA, a covalent complex between HA and heavy chains (HCs) from inter-α-trypsin inhibitor (I-α-I) mediated by tumor necrosis factor-induced protein 6 (TSG6). Cross-linked HA has been identified as a protective factor in physiological and inflammatory conditions. However, the state of HA cross-linking in tumor microenvironment has not been fully elucidated. As a major constituent of the extracellular matrix (ECM), HA is mainly synthesized by cancer-associated fibroblasts (CAFs). Our study aimed to clarify the role of HA cross-linking in breast cancer malignancy. Compared to normal mammary gland tissues, cross-linked HA levels were significantly decreased in breast cancer and associated with tumor malignancy. When NFbs were activated into CAFs, the levels of cross-linked HA and TSG6 were both suppressed. Through upregulating TSG6, CAFs restored the high level of cross-linked HA and significantly inhibited breast cancer malignancy, whereas NFbs promoted the malignancy when the cross-linked HA level was reduced. Furthermore, the inhibitory role of HA cross-linking in tumor malignancy was directly verified using the synthesized HA-HC complex. Collectively, our study found that the deficiency of cross-linked HA induced breast cancer malignancy in a CAF-dependent manner, suggesting that recovering HA cross-linking may be a potential therapeutic strategy.
Leveraging supervised learning for functionally informed fine-mapping of cis-eQTLs identifies an additional 20,913 putative causal eQTLs
Authors: Wang Qingbo S. , Kelley David R. , Ulirsch Jacob , Kanai Masahiro , Sadhuka Shuvom , Cui Ran , Albors Carlos , Cheng Nathan , Okada Yukinori ,   The Biobank Japan Project, Matsuda Koichi , Yamanashi Yuji , Furukawa Yoichi , Morisaki Takayuki , Murakami Yoshinori , Kamatani Yoichiro , Muto Kaori , Nagai Akiko , Obara Wataru , Yamaji Ken , Takahashi Kazuhisa , Asai Satoshi , Takahashi Yasuo , Suzuki Takao , Sinozaki Nobuaki , Yamaguchi Hiroki , Minami Shiro , Murayama Shigeo , Yoshimori Kozo , Nagayama Satoshi , Obata Daisuke , Higashiyama Masahiko , Masumoto Akihide , Koretsune Yukihiro , Aguet Francois , Ardlie Kristin G. , MacArthur Daniel G. , Finucane Hilary K. 
Published: June 2021

AbstractThe large majority of variants identified by GWAS are non-coding, motivating detailed characterization of the function of non-coding variants. Experimental methods to assess variants’ effect on gene expressions in native chromatin context via direct perturbation are low-throughput. Existing high-throughput computational predictors thus have lacked large gold standard sets of regulatory variants for training and validation. Here, we leverage a set of 14,807 putative causal eQTLs in humans obtained through statistical fine-mapping, and we use 6121 features to directly train a predictor of whether a variant modifies nearby gene expression. We call the resulting prediction the expression modifier score (EMS). We validate EMS by comparing its ability to prioritize functional variants with other major scores. We then use EMS as a prior for statistical fine-mapping of eQTLs to identify an additional 20,913 putatively causal eQTLs, and we incorporate EMS into co-localization analysis to identify 310 additional candidate genes across UK Biobank phenotypes.
Crowdsourced mapping of unexplored target space of kinase inhibitors
Authors: Cichońska Anna , Ravikumar Balaguru , Allaway Robert J. , Wan Fangping , Park Sungjoon , Isayev Olexandr , Li Shuya , Mason Michael , Lamb Andrew , Tanoli Ziaurrehman , Jeon Minji , Kim Sunkyu , Popova Mariya , Capuzzi Stephen , Zeng Jianyang , Dang Kristen , Koytiger Gregory , Kang Jaewoo , Wells Carrow I. , Willson Timothy M. ,   The IDG-DREAM Drug-Kinase Binding Prediction Challenge Consortium,   User oselot, Tan Mehmet ,   Team N121, Huang Chih-Han , Shih Edward S. C. , Chen Tsai-Min , Wu Chih-Hsun , Fang Wei-Quan , Chen Jhih-Yu , Hwang Ming-Jing ,   Team Let_Data_Talk, Wang Xiaokang , Ben Guebila Marouen , Shamsaei Behrouz , Singh Sourav ,   User thinng, Nguyen Thin ,   Team KKT, Karimi Mostafa , Wu Di , Wang Zhangyang , Shen Yang ,   Team Boun, Öztürk Hakime , Ozkirimli Elif , Özgür Arzucan ,   Team KinaseHunter, Lim Hansaim , Xie Lei ,   Team AmsterdamUMC-KU-team, Kanev Georgi K. , Kooistra Albert J. , Westerman Bart A. ,   Team DruginaseLearning, Terzopoulos Panagiotis , Ntagiantas Konstantinos , Fotis Christos , Alexopoulos Leonidas ,   Team KERMIT-LAB - Ghent University, Boeckaerts Dimitri , Stock Michiel , De Baets Bernard , Briers Yves ,   Team QED, Luo Yunan , Hu Hailin , Peng Jian ,   Team METU_EMBLEBI_CROssBAR, Dogan Tunca , Rifaioglu Ahmet S. , Atas Heval , Atalay Rengul Cetin , Atalay Volkan , Martin Maria J. ,   Team DMIS_DK, Jeon Minji , Lee Junhyun , Yun Seongjun , Kim Bumsoo , Chang Buru ,   Team AI Winter is Coming,   Team hulab, Turu Gábor , Misák Ádám , Szalai Bence , Hunyady László ,   Team ML-Med, Lienhard Matthias , Prasse Paul , Bachmann Ivo , Ganzlin Julia , Barel Gal , Herwig Ralf ,   Team Prospectors, Oršolić Davor , Lučić Bono , Stepanić Višnja , Šmuc Tomislav ,   Challenge organizers, Oprea Tudor I. , Schlessinger Avner , Drewry David H. , Stolovitzky Gustavo , Wennerberg Krister , Guinney Justin , Aittokallio Tero 
Published: June 2021

AbstractDespite decades of intensive search for compounds that modulate the activity of particular protein targets, a large proportion of the human kinome remains as yet undrugged. Effective approaches are therefore required to map the massive space of unexplored compound–kinase interactions for novel and potent activities. Here, we carry out a crowdsourced benchmarking of predictive algorithms for kinase inhibitor potencies across multiple kinase families tested on unpublished bioactivity data. We find the top-performing predictions are based on various models, including kernel learning, gradient boosting and deep learning, and their ensemble leads to a predictive accuracy exceeding that of single-dose kinase activity assays. We design experiments based on the model predictions and identify unexpected activities even for under-studied kinases, thereby accelerating experimental mapping efforts. The open-source prediction algorithms together with the bioactivities between 95 compounds and 295 kinases provide a resource for benchmarking prediction algorithms and for extending the druggable kinome.
miR-802 regulates Paneth cell function and enterocyte differentiation in the mouse small intestine
Authors: Goga Algera , Yagabasan Büsra , Herrmanns Karolin , Godbersen Svenja , Silva Pamuditha N. , Denzler Remy , Zünd Mirjam , Furter Markus , Schwank Gerald , Sunagawa Shinichi , Hardt Wolf-Dietrich , Stoffel Markus 
Published: June 2021

AbstractThe intestinal epithelium is a complex structure that integrates digestive, immunological, neuroendocrine, and regenerative functions. Epithelial homeostasis is maintained by a coordinated cross-talk of different epithelial cell types. Loss of integrity of the intestinal epithelium plays a key role in inflammatory diseases and gastrointestinal infection. Here we show that the intestine-enriched miR-802 is a central regulator of intestinal epithelial cell proliferation, Paneth cell function, and enterocyte differentiation. Genetic ablation of mir-802 in the small intestine of mice leads to decreased glucose uptake, impaired enterocyte differentiation, increased Paneth cell function and intestinal epithelial proliferation. These effects are mediated in part through derepression of the miR-802 target Tmed9, a modulator of Wnt and lysozyme/defensin secretion in Paneth cells, and the downstream Wnt signaling components Fzd5 and Tcf4. Mutant Tmed9 mice harboring mutations in miR-802 binding sites partially recapitulate the augmented Paneth cell function of mice lacking miR-802. Our study demonstrates a broad miR-802 network that is important for the integration of signaling pathways of different cell types controlling epithelial homeostasis in the small intestine.
Laboratory measurements of the physics of auroral electron acceleration by Alfvén waves
Authors: Schroeder J. W. R. , Howes G. G. , Kletzing C. A. , Skiff F. , Carter T. A. , Vincena S. , Dorfman S. 
Published: June 2021

AbstractWhile the aurora has attracted attention for millennia, important questions remain unanswered. Foremost is how auroral electrons are accelerated before colliding with the ionosphere and producing auroral light. Powerful Alfvén waves are often found traveling Earthward above auroras with sufficient energy to generate auroras, but there has been no direct measurement of the processes by which Alfvén waves transfer their energy to auroral electrons. Here, we show laboratory measurements of the resonant transfer of energy from Alfvén waves to electrons under conditions relevant to the auroral zone. Experiments are performed by launching Alfvén waves and simultaneously recording the electron velocity distribution. Numerical simulations and analytical theory support that the measured energy transfer process produces accelerated electrons capable of reaching auroral energies. The experiments, theory, and simulations demonstrate a clear causal relationship between Alfvén waves and accelerated electrons that directly cause auroras.
Chemodivergent manganese-catalyzed C–H activation: modular synthesis of fluorogenic probes
Authors: Kaplaneris Nikolaos , Son Jongwoo , Mendive-Tapia Lorena , Kopp Adelina , Barth Nicole D. , Maksso Isaac , Vendrell Marc , Ackermann Lutz 
Published: June 2021

AbstractBioorthogonal late-stage diversification of amino acids and peptides bears enormous potential for drug discovery and molecular imaging. Despite major accomplishments, these strategies largely rely on traditional, lengthy prefunctionalization methods, heavily involving precious transition-metal catalysis. Herein, we report on a resource-economical manganese(I)-catalyzed C–H fluorescent labeling of structurally complex peptides ensured by direct alkynylation and alkenylation manifolds. This modular strategy sets the stage for unraveling structure-activity relationships between structurally discrete fluorophores towards the rational design of BODIPY fluorogenic probes for real-time analysis of immune cell function.
Ubiquitylation of MLKL at lysine 219 positively regulates necroptosis-induced tissue injury and pathogen clearance
Authors: Garcia Laura Ramos , Tenev Tencho , Newman Richard , Haich Rachel O. , Liccardi Gianmaria , John Sidonie Wicky , Annibaldi Alessandro , Yu Lu , Pardo Mercedes , Young Samuel N. , Fitzgibbon Cheree , Fernando Winnie , Guppy Naomi , Kim Hyojin , Liang Lung-Yu , Lucet Isabelle S. , Kueh Andrew , Roxanis Ioannis , Gazinska Patrycja , Sims Martin , Smyth Tomoko , Ward George , Bertin John , Beal Allison M. , Geddes Brad , Choudhary Jyoti S. , Murphy James M. , Aurelia Ball K. , Upton Jason W. , Meier Pascal 
Published: June 2021

AbstractNecroptosis is a lytic, inflammatory form of cell death that not only contributes to pathogen clearance but can also lead to disease pathogenesis. Necroptosis is triggered by RIPK3-mediated phosphorylation of MLKL, which is thought to initiate MLKL oligomerisation, membrane translocation and membrane rupture, although the precise mechanism is incompletely understood. Here, we show that K63-linked ubiquitin chains are attached to MLKL during necroptosis and that ubiquitylation of MLKL at K219 significantly contributes to the cytotoxic potential of phosphorylated MLKL. The K219R MLKL mutation protects animals from necroptosis-induced skin damage and renders cells resistant to pathogen-induced necroptosis. Mechanistically, we show that ubiquitylation of MLKL at K219 is required for higher-order assembly of MLKL at membranes, facilitating its rupture and necroptosis. We demonstrate that K219 ubiquitylation licenses MLKL activity to induce lytic cell death, suggesting that necroptotic clearance of pathogens as well as MLKL-dependent pathologies are influenced by the ubiquitin-signalling system.
SARS-CoV-2 RNAemia and proteomic trajectories inform prognostication in COVID-19 patients admitted to intensive care
Authors: Gutmann Clemens , Takov Kaloyan , Burnap Sean A. , Singh Bhawana , Ali Hashim , Theofilatos Konstantinos , Reed Ella , Hasman Maria , Nabeebaccus Adam , Fish Matthew , McPhail Mark JW. , O’Gallagher Kevin , Schmidt Lukas E. , Cassel Christian , Rienks Marieke , Yin Xiaoke , Auzinger Georg , Napoli Salvatore , Mujib Salma F. , Trovato Francesca , Sanderson Barnaby , Merrick Blair , Niazi Umar , Saqi Mansoor , Dimitrakopoulou Konstantina , Fernández-Leiro Rafael , Braun Silke , Kronstein-Wiedemann Romy , Doores Katie J. , Edgeworth Jonathan D. , Shah Ajay M. , Bornstein Stefan R. , Tonn Torsten , Hayday Adrian C. , Giacca Mauro , Shankar-Hari Manu , Mayr Manuel 
Published: June 2021

AbstractPrognostic characteristics inform risk stratification in intensive care unit (ICU) patients with coronavirus disease 2019 (COVID-19). We obtained blood samples (n = 474) from hospitalized COVID-19 patients (n = 123), non-COVID-19 ICU sepsis patients (n = 25) and healthy controls (n = 30). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA was detected in plasma or serum (RNAemia) of COVID-19 ICU patients when neutralizing antibody response was low. RNAemia is associated with higher 28-day ICU mortality (hazard ratio [HR], 1.84 [95% CI, 1.22–2.77] adjusted for age and sex). RNAemia is comparable in performance to the best protein predictors. Mannose binding lectin 2 and pentraxin-3 (PTX3), two activators of the complement pathway of the innate immune system, are positively associated with mortality. Machine learning identified ‘Age, RNAemia’ and ‘Age, PTX3’ as the best binary signatures associated with 28-day ICU mortality. In longitudinal comparisons, COVID-19 ICU patients have a distinct proteomic trajectory associated with mortality, with recovery of many liver-derived proteins indicating survival. Finally, proteins of the complement system and galectin-3-binding protein (LGALS3BP) are identified as interaction partners of SARS-CoV-2 spike glycoprotein. LGALS3BP overexpression inhibits spike-pseudoparticle uptake and spike-induced cell-cell fusion in vitro.
Chemical combinations potentiate human pluripotent stem cell-derived 3D pancreatic progenitor clusters toward functional β cells
Authors: Liu Haisong , Li Ronghui , Liao Hsin-Kai , Min Zheying , Wang Chao , Yu Yang , Shi Lei , Dan Jiameng , Hayek Alberto , Martinez Martinez Llanos , Nuñez Delicado Estrella , Izpisua Belmonte Juan Carlos 
Published: June 2021

AbstractHuman pluripotent stem cell (hPSC)-derived pancreatic β cells are an attractive cell source for treating diabetes. However, current derivation methods remain inefficient, heterogeneous, and cell line dependent. To address these issues, we first devised a strategy to efficiently cluster hPSC-derived pancreatic progenitors into 3D structures. Through a systematic study, we discovered 10 chemicals that not only retain the pancreatic progenitors in 3D clusters but also enhance their potentiality towards NKX6.1+/INS+ β cells. We further systematically screened signaling pathway modulators in the three steps from pancreatic progenitors toward β cells. The implementation of all these strategies and chemical combinations resulted in generating β cells from different sources of hPSCs with high efficiency. The derived β cells are functional and can reverse hyperglycemia in mice within two weeks. Our protocol provides a robust platform for studying human β cells and developing hPSC-derived β cells for cell replacement therapy.
Cis-regulatory evolution spotlights species differences in the adaptive potential of gene expression plasticity
Authors: He F. , Steige K. A. , Kovacova V. , Göbel U. , Bouzid M. , Keightley P. D. , Beyer A. , de Meaux J. 
Published: June 2021

AbstractPhenotypic plasticity is the variation in phenotype that a single genotype can produce in different environments and, as such, is an important component of individual fitness. However, whether the effect of new mutations, and hence evolution, depends on the direction of plasticity remains controversial. Here, we identify the cis-acting modifications that have reshaped gene expression in response to dehydration stress in three Arabidopsis species. Our study shows that the direction of effects of most cis-regulatory variants differentiating the response betweenA. thalianaand the sister speciesA. lyrataandA. halleridepends on the direction of pre-existing plasticity in gene expression. A comparison of the rate of cis-acting variant accumulation in each lineage indicates that the selective forces driving adaptive evolution in gene expression favors regulatory changes that magnify the stress response inA. lyrata. The evolutionary constraints measured on the amino-acid sequence of these genes support this interpretation. In contrast, regulatory changes that mitigate the plastic response to stress evolved more frequently inA. halleri. Our results demonstrate that pre-existing plasticity may be a stepping stone for adaptation, but its selective remodeling differs between lineages.
Smart-watch-programmed green-light-operated percutaneous control of therapeutic transgenes
Authors: Mansouri Maysam , Hussherr Marie-Didiée , Strittmatter Tobias , Buchmann Peter , Xue Shuai , Camenisch Gieri , Fussenegger Martin 
Published: June 2021

AbstractWearable smart electronic devices, such as smart watches, are generally equipped with green-light-emitting diodes, which are used for photoplethysmography to monitor a panoply of physical health parameters. Here, we present a traceless, green-light-operated, smart-watch-controlled mammalian gene switch (Glow Control), composed of an engineered membrane-tethered green-light-sensitive cobalamin-binding domain of Thermus thermophilus (TtCBD) CarH protein in combination with a synthetic cytosolic TtCBD-transactivator fusion protein, which manage translocation of TtCBD-transactivator into the nucleus to trigger expression of transgenes upon illumination. We show that Apple-Watch-programmed percutaneous remote control of implanted Glow-controlled engineered human cells can effectively treat experimental type-2 diabetes by producing and releasing human glucagon-like peptide-1 on demand. Directly interfacing wearable smart electronic devices with therapeutic gene expression will advance next-generation personalized therapies by linking biopharmaceutical interventions to the internet of things.
Tumor suppressor p53 regulates intestinal type 2 immunity
Authors: Chang Chun-Yuan , Wang Jianming , Zhao Yuhan , Liu Juan , Yang Xue , Yue Xuetian , Wang Huaying , Zhou Fan , Inclan-Rico Juan M. , Ponessa John J. , Xie Ping , Zhang Lanjing , Siracusa Mark C. , Feng Zhaohui , Hu Wenwei 
Published: June 2021

AbstractThe role of p53 in tumor suppression has been extensively studied and well-established. However, the role of p53 in parasitic infections and the intestinal type 2 immunity is unclear. Here, we report that p53 is crucial for intestinal type 2 immunity in response to the infection of parasites, such asTritrichomonas murisandNippostrongylus brasiliensis. Mechanistically, p53 plays a critical role in the activation of the tuft cell-IL-25-type 2 innate lymphoid cell circuit, partly via transcriptional regulation of Lrmp in tuft cells. Lrmp modulates Ca2+influx and IL-25 release, which are critical triggers of type 2 innate lymphoid cell response. Our results thus reveal a previously unrecognized function of p53 in regulating intestinal type 2 immunity to protect against parasitic infections, highlighting the role of p53 as a guardian of immune integrity.