bluuebunny/crossref_metadata_2025_split huggingface dataset:
c-MYC-induced long noncoding RNA MEG3 aggravates kidney ischemia–reperfusion injury through activating mitophagy by upregulation of RTKN to trigger the Wnt/β-catenin pathway
Authors: Liu Dajun , Liu Ying , Zheng Xiaotong , Liu Naiquan 
Published: February 2021

AbstractIschemia–reperfusion injury (IRI)-induced acute kidney injury (AKI) is a life-threatening disease. The activation of mitophagy was previously identified to play an important role in IRI. Maternally expressed 3 (MEG3) can promote cerebral IRI and hepatic IRI. The present study was designed to study the role of MEG3 in renal IRI. Renal IRI mice models were established, and HK-2 cells were used to construct the in vitro models of IRI. Hematoxylin–eosin staining assay was applied to reveal IRI-triggered tubular injury. MitoTracker Green FM staining and an ALP kit were employed for detection of mitophagy. TdT-mediated dUTP-biotin nick-end labeling assay was used to reveal cell apoptosis. The results showed that renal cortex of IRI mice contained higher expression of MEG3 than that of sham mice. MEG3 expression was also elevated in HK-2 cells following IRI, suggesting that MEG3 might participate in the development of IRI. Moreover, downregulation of MEG3 inhibited the apoptosis of HK-2 cells after IRI. Mitophagy was activated by IRI, and the inhibition of MEG3 can restore mitophagy activity in IRI-treated HK-2 cells. Mechanistically, we found that MEG3 can bind with miR-145-5p in IRI-treated cells. In addition, rhotekin (RTKN) was verified to serve as a target of miR-145-5p. MEG3 upregulated RTKN expression by binding with miR-145-5p. Further, MEG3 activated the Wnt/β-catenin pathway by upregulation of RTKN. The downstream effector of Wnt/β-catenin pathway, c-MYC, served as the transcription factor to activate MEG3. In conclusion, the positive feedback loop of MEG3/miR-145-5p/RTKN/Wnt/β-catenin/c-MYC promotes renal IRI by activating mitophagy and inducing apoptosis, which might offer a new insight into the therapeutic methods for renal IRI in the future.
Syngeneic leukemia models using lentiviral transgenics
Authors: Keinan Nurit , Scharff Ye’ela , Goldstein Oron , Chamo Michael , Ilic Stefan , Gazit Roi 
Published: February 2021

AbstractAnimal models are necessary to study cancer and develop treatments. After decades of intensive research, effective treatments are available for only a few types of leukemia, while others are currently incurable. Our goal was to generate novel leukemia models in immunocompetent mice. We had achieved abilities for overexpression of multiple driving oncogenes simultaneously in normal primary cells, which can be transplanted and followed in vivo. Our experiments demonstrated the induction of primary malignant growth. Leukemia lines that model various types of leukemia, such as acute myeloid leukemia (AML) or chronic lymphocytic leukemia (CLL), were passaged robustly in congenic wild-type immunocompetent mice. These novel leukemia lines, which may complement previous models, offer the flexibility to generate tailored models of defined oncogenes of interest. The characterization of our leukemia models in immunocompetent animals can uncover the mechanisms of malignancy progression and offer a unique opportunity to stringently test anti-cancer chemotherapies.
Deletion of FGF9 in GABAergic neurons causes epilepsy
Authors: Guo Moran , Cui Can , Song Xueqin , Jia Lijing , Li Duan , Wang Xiuli , Dong Hui , Ma Yanqin , Liu Yaling , Cui Zhiqiang , Yi Le , Li Zhongyao , Bi Yue , Li Yuanyuan , Liu Yakun , Duan Weisong , Li Chunyan 
Published: February 2021

AbstractFibroblast growth factor 9 (FGF9) has long been assumed to modulate multiple biological processes, yet very little is known about the impact of FGF9 on neurodevelopment. Herein, we found that loss of Fgf9 in olig1 progenitor cells induced epilepsy in mice, with pathological changes in the cortex. Then depleting Fgf9 in different neural populations revealed that epilepsy was associated with GABAergic neurons. Fgf9 CKO in GABAergic neuron (CKOVGAT) mice exhibited not only the most severe seizures, but also the most severe growth retardation and highest mortality. Fgf9 deletion in CKOVGAT mice caused neuronal apoptosis and decreased GABA expression, leading to a GABA/Glu imbalance and epilepsy. The adenylate cyclase/cyclic AMP and ERK signaling pathways were activated in this process. Recombinant FGF9 proteoliposomes could significantly decrease the number of seizures. Furthermore, the decrease of FGF9 was commonly observed in serum of epileptic patients, especially those with focal seizures. Thus, FGF9 plays essential roles in GABAergic neuron survival and epilepsy pathology, which could serve as a new target for the treatment of epilepsy.
LncRNA CDKN2B-AS1 stabilized by IGF2BP3 drives the malignancy of renal clear cell carcinoma through epigenetically activating NUF2 transcription
Authors: Xie Xina , Lin Jiatian , Fan Xiaoqin , Zhong Yuantang , Chen Yequn , Liu Kaiqing , Ren Yonggang , Chen Xiangling , Lai Daihuan , Li Xuyi , Li Zesong , Tang Aifa 
Published: February 2021

AbstractBecause of the lack of sensitivity to radiotherapy and chemotherapy, therapeutic options for renal clear cell carcinoma (KIRC) are scarce. Long noncoding RNAs (lncRNAs) play crucial roles in the progression of cancer. However, their functional roles and upstream mechanisms in KIRC remain largely unknown. Exploring the functions of potential essential lncRNAs may lead to the discovery of novel targets for the diagnosis and treatment of KIRC. Here, according to the integrated analysis of RNA sequencing and survival data in TCGA-KIRC datasets, cyclin-dependent kinase inhibitor 2B antisense lncRNA (CDKN2B-AS1) was discovered to be the most upregulated among the 14 lncRNAs that were significantly overexpressed in KIRC and related to shorter survival. Functionally, CDKN2B-AS1 depletion suppressed cell proliferation, migration, and invasion both in vitro and in vivo. Mechanistically, CDKN2B-AS1 exerted its oncogenic activity by recruiting the CREB-binding protein and SET and MYND domain-containing 3 epigenetic-modifying complex to the promoter region of Ndc80 kinetochore complex component (NUF2), where it epigenetically activated NUF2 transcription by augmenting local H3K27ac and H3K4me3 modifications. Moreover, we also showed that CDKN2B-AS1 interacted with and was stabilized by insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), an oncofetal protein showing increased levels in KIRC. The Kaplan–Meier method and receiver operating curve analysis revealed that patients whose IGF2BP3, CDKN2B-AS1 and NUF2 are all elevated showed the shortest survival time, and the combined panel (containing IGF2BP3, CDKN2B-AS1, and NUF2) possessed the highest accuracy in discriminating high-risk from low-risk KIRC patients. Thus, we conclude that the stabilization of CDKN2B-AS1 by IGF2BP3 drives the malignancy of KIRC through epigenetically activating NUF2 transcription and that the IGF2BP3/CDKN2B-AS1/NUF2 axis may be an ideal prognostic and diagnostic biomarker and therapeutic target for KIRC.
Structural mechanism of cooperative activation of the human calcium-sensing receptor by Ca2+ ions and L-tryptophan
Authors: Ling Shenglong , Shi Pan , Liu Sanling , Meng Xianyu , Zhou Yingxin , Sun Wenjing , Chang Shenghai , Zhang Xing , Zhang Longhua , Shi Chaowei , Sun Demeng , Liu Lei , Tian Changlin 
Published: February 2021

AbstractThe human calcium-sensing receptor (CaSR) is a class C G protein-coupled receptor (GPCR) responsible for maintaining Ca2+ homeostasis in the blood. The general consensus is that extracellular Ca2+ is the principal agonist of CaSR. Aliphatic and aromatic L-amino acids, such as L-Phe and L-Trp, increase the sensitivity of CaSR towards Ca2+ and are considered allosteric activators. Crystal structures of the extracellular domain (ECD) of CaSR dimer have demonstrated Ca2+ and L-Trp binding sites and conformational changes of the ECD upon Ca2+/L-Trp binding. However, it remains to be understood at the structural level how Ca2+/L-Trp binding to the ECD leads to conformational changes in transmembrane domains (TMDs) and consequent CaSR activation. Here, we determined the structures of full-length human CaSR in the inactive state, Ca2+- or L-Trp-bound states, and Ca2+/L-Trp-bound active state using single-particle cryo-electron microscopy. Structural studies demonstrate that L-Trp binding induces the closure of the Venus flytrap (VFT) domain of CaSR, bringing the receptor into an intermediate active state. Ca2+ binding relays the conformational changes from the VFT domains to the TMDs, consequently inducing close contact between the two TMDs of dimeric CaSR, activating the receptor. Importantly, our structural and functional studies reveal that Ca2+ ions and L-Trp activate CaSR cooperatively. Amino acids are not able to activate CaSR alone, but can promote the receptor activation in the presence of Ca2+. Our data provide complementary insights into the activation of class C GPCRs and may aid in the development of novel drugs targeting CaSR.
Formative pluripotent stem cells show features of epiblast cells poised for gastrulation
Authors: Wang Xiaoxiao , Xiang Yunlong , Yu Yang , Wang Ran , Zhang Yu , Xu Qianhua , Sun Hao , Zhao Zhen-Ao , Jiang Xiangxiang , Wang Xiaoqing , Lu Xukun , Qin Dandan , Quan Yujun , Zhang Jiaqi , Shyh-Chang Ng , Wang Hongmei , Jing Naihe , Xie Wei , Li Lei 
Published: February 2021

AbstractThe pluripotency of mammalian early and late epiblast could be recapitulated by naïve embryonic stem cells (ESCs) and primed epiblast stem cells (EpiSCs), respectively. However, these two states of pluripotency may not be sufficient to reflect the full complexity and developmental potency of the epiblast during mammalian early development. Here we report the establishment of self-renewing formative pluripotent stem cells (fPSCs) which manifest features of epiblast cells poised for gastrulation. fPSCs can be established from different mouse ESCs, pre-/early-gastrula epiblasts and induced PSCs. Similar to pre-/early-gastrula epiblasts, fPSCs show the transcriptomic features of formative pluripotency, which are distinct from naïve ESCs and primed EpiSCs. fPSCs show the unique epigenetic states of E6.5 epiblast, including the super-bivalency of a large set of developmental genes. Just like epiblast cells immediately before gastrulation, fPSCs can efficiently differentiate into three germ layers and primordial germ cells (PGCs) in vitro. Thus, fPSCs highlight the feasibility of using PSCs to explore the development of mammalian epiblast.
The effect of oat β-glucan on postprandial blood glucose and insulin responses: a systematic review and meta-analysis
Authors: Zurbau Andreea , Noronha Jarvis C. , Khan Tauseef A. , Sievenpiper John L. , Wolever Thomas M. S. 
Published: February 2021

AbstractTo determine the effect of oat β‑glucan (OBG) on acute glucose and insulin responses and identify significant effect modifiers we searched the MEDLINE, EMBASE, and Cochrane databases through October 27, 2020 for acute, crossover, controlled feeding trials investigating the effect of adding OBG (concentrate or oat-bran) to carbohydrate-containing test-meals compared to comparable or different carbohydrate-matched control-meals in humans regardless of health status. The primary outcome was glucose incremental area-under-the-curve (iAUC). Secondary outcomes were insulin iAUC, and glucose and insulin incremental peak-rise (iPeak). Two reviewers extracted the data and assessed risk-of-bias and certainty-of-evidence (GRADE). Data were pooled using generic inverse-variance with random-effects model and expressed as ratio-of-means with [95% CIs]. We included 103 trial comparisons (N = 538). OBG reduced glucose iAUC and iPeak by 23% (0.77 [0.74, 0.81]) and 28% (0.72 [0.64, 0.76]) and insulin by 22% (0.78 [0.72, 0.85]) and 24% (0.76 [0.65, 0.88]), respectively. Dose, molecular-weight, and comparator were significant effect modifiers of glucose iAUC and iPeak. Significant linear dose-response relationships were observed for all outcomes. OBG molecular-weight >300 kg/mol significantly reduced glucose iAUC and iPeak, whereas molecular-weight <300 kg/mol did not. Reductions in glucose iAUC (27 vs 20%, p = 0.03) and iPeak (39 vs 25%, p < 0.01) were significantly larger with different vs comparable control-meals. Outcomes were similar in participants with and without diabetes. All outcomes had high certainty-of-evidence. In conclusion, current evidence indicates that adding OBG to carbohydrate-containing meals reduces glycaemic and insulinaemic responses. However, the magnitude of glucose reduction depends on OBG dose, molecular-weight, and the comparator.
Syndromic disorders caused by gain-of-function variants in KCNH1, KCNK4, and KCNN3—a subgroup of K+ channelopathies
Authors: Gripp Karen W. , Smithson Sarah F. , Scurr Ingrid J. , Baptista Julia , Majumdar Anirban , Pierre Germaine , Williams Maggie , Henderson Lindsay B. , Wentzensen Ingrid M. , McLaughlin Heather , Leeuwen Lisette , Simon Marleen E. H. , van Binsbergen Ellen , Dinulos Mary Beth P. , Kaplan Julie D. , McRae Anne , Superti-Furga Andrea , Good Jean-Marc , Kutsche Kerstin 
Published: February 2021

AbstractDecreased or increased activity of potassium channels caused by loss-of-function and gain-of-function (GOF) variants in the corresponding genes, respectively, underlies a broad spectrum of human disorders affecting the central nervous system, heart, kidney, and other organs. While the association of epilepsy and intellectual disability (ID) with variants affecting function in genes encoding potassium channels is well known, GOF missense variants in K+ channel encoding genes in individuals with syndromic developmental disorders have only recently been recognized. These syndromic phenotypes include Zimmermann–Laband and Temple–Baraitser syndromes, caused by dominant variants in KCNH1, FHEIG syndrome due to dominant variants in KCNK4, and the clinical picture associated with dominant variants in KCNN3. Here we review the presentation of these individuals, including five newly reported with variants in KCNH1 and three additional individuals with KCNN3 variants, all variants likely affecting function. There is notable overlap in the phenotypic findings of these syndromes associated with dominant KCNN3, KCNH1, and KCNK4 variants, sharing developmental delay and/or ID, coarse facial features, gingival enlargement, distal digital hypoplasia, and hypertrichosis. We suggest to combine the phenotypes and define a new subgroup of potassium channelopathies caused by increased K+ conductance, referred to as syndromic neurodevelopmental K+ channelopathies due to dominant variants in KCNH1, KCNK4, or KCNN3.
A unifying framework for mean-field theories of asymmetric kinetic Ising systems
Authors: Aguilera Miguel , Moosavi S. Amin , Shimazaki Hideaki 
Published: February 2021

AbstractKinetic Ising models are powerful tools for studying the non-equilibrium dynamics of complex systems. As their behavior is not tractable for large networks, many mean-field methods have been proposed for their analysis, each based on unique assumptions about the system’s temporal evolution. This disparity of approaches makes it challenging to systematically advance mean-field methods beyond previous contributions. Here, we propose a unifying framework for mean-field theories of asymmetric kinetic Ising systems from an information geometry perspective. The framework is built on Plefka expansions of a system around a simplified model obtained by an orthogonal projection to a sub-manifold of tractable probability distributions. This view not only unifies previous methods but also allows us to develop novel methods that, in contrast with traditional approaches, preserve the system’s correlations. We show that these new methods can outperform previous ones in predicting and assessing network properties near maximally fluctuating regimes.
Efficient overall water splitting in acid with anisotropic metal nanosheets
Authors: Wu Dongshuang , Kusada Kohei , Yoshioka Satoru , Yamamoto Tomokazu , Toriyama Takaaki , Matsumura Syo , Chen Yanna , Seo Okkyun , Kim Jaemyung , Song Chulho , Hiroi Satoshi , Sakata Osami , Ina Toshiaki , Kawaguchi Shogo , Kubota Yoshiki , Kobayashi Hirokazu , Kitagawa Hiroshi 
Published: February 2021

AbstractWater is the only available fossil-free source of hydrogen. Splitting water electrochemically is among the most used techniques, however, it accounts for only 4% of global hydrogen production. One of the reasons is the high cost and low performance of catalysts promoting the oxygen evolution reaction (OER). Here, we report a highly efficient catalyst in acid, that is, solid-solution Ru‒Ir nanosized-coral (RuIr-NC) consisting of 3 nm-thick sheets with only 6 at.% Ir. Among OER catalysts, RuIr-NC shows the highest intrinsic activity and stability. A home-made overall water splitting cell using RuIr-NC as both electrodes can reach 10 mA cm−2geo at 1.485 V for 120 h without noticeable degradation, which outperforms known cells. Operando spectroscopy and atomic-resolution electron microscopy indicate that the high-performance results from the ability of the preferentially exposed {0001} facets to resist the formation of dissolvable metal oxides and to transform ephemeral Ru into a long-lived catalyst.
Exploring beyond clinical routine SARS-CoV-2 serology using MultiCoV-Ab to evaluate endemic coronavirus cross-reactivity
Authors: Becker Matthias , Strengert Monika , Junker Daniel , Kaiser Philipp D. , Kerrinnes Tobias , Traenkle Bjoern , Dinter Heiko , Häring Julia , Ghozzi Stéphane , Zeck Anne , Weise Frank , Peter Andreas , Hörber Sebastian , Fink Simon , Ruoff Felix , Dulovic Alex , Bakchoul Tamam , Baillot Armin , Lohse Stefan , Cornberg Markus , Illig Thomas , Gottlieb Jens , Smola Sigrun , Karch André , Berger Klaus , Rammensee Hans-Georg , Schenke-Layland Katja , Nelde Annika , Märklin Melanie , Heitmann Jonas S. , Walz Juliane S. , Templin Markus , Joos Thomas O. , Rothbauer Ulrich , Krause Gérard , Schneiderhan-Marra Nicole 
Published: February 2021

AbstractThe humoral immune response to SARS-CoV-2 is a benchmark for immunity and detailed analysis is required to understand the manifestation and progression of COVID-19, monitor seroconversion within the general population, and support vaccine development. The majority of currently available commercial serological assays only quantify the SARS-CoV-2 antibody response against individual antigens, limiting our understanding of the immune response. To overcome this, we have developed a multiplex immunoassay (MultiCoV-Ab) including spike and nucleocapsid proteins of SARS-CoV-2 and the endemic human coronaviruses. Compared to three broadly used commercial in vitro diagnostic tests, our MultiCoV-Ab achieves a higher sensitivity and specificity when analyzing a well-characterized sample set of SARS-CoV-2 infected and uninfected individuals. We find a high response against endemic coronaviruses in our sample set, but no consistent cross-reactive IgG response patterns against SARS-CoV-2. Here we show a robust, high-content-enabled, antigen-saving multiplex assay suited to both monitoring vaccination studies and facilitating epidemiologic screenings for humoral immunity towards pandemic and endemic coronaviruses.
AI-based mobile application to fight antibiotic resistance
Authors: Pascucci Marco , Royer Guilhem , Adamek Jakub , Asmar Mai Al , Aristizabal David , Blanche Laetitia , Bezzarga Amine , Boniface-Chang Guillaume , Brunner Alex , Curel Christian , Dulac-Arnold Gabriel , Fakhri Rasheed M. , Malou Nada , Nordon Clara , Runge Vincent , Samson Franck , Sebastian Ellen , Soukieh Dena , Vert Jean-Philippe , Ambroise Christophe , Madoui Mohammed-Amin 
Published: February 2021

AbstractAntimicrobial resistance is a major global health threat and its development is promoted by antibiotic misuse. While disk diffusion antibiotic susceptibility testing (AST, also called antibiogram) is broadly used to test for antibiotic resistance in bacterial infections, it faces strong criticism because of inter-operator variability and the complexity of interpretative reading. Automatic reading systems address these issues, but are not always adapted or available to resource-limited settings. We present an artificial intelligence (AI)-based, offline smartphone application for antibiogram analysis. The application captures images with the phone’s camera, and the user is guided throughout the analysis on the same device by a user-friendly graphical interface. An embedded expert system validates the coherence of the antibiogram data and provides interpreted results. The fully automatic measurement procedure of our application’s reading system achieves an overall agreement of 90% on susceptibility categorization against a hospital-standard automatic system and 98% against manual measurement (gold standard), with reduced inter-operator variability. The application’s performance showed that the automatic reading of antibiotic resistance testing is entirely feasible on a smartphone. Moreover our application is suited for resource-limited settings, and therefore has the potential to significantly increase patients’ access to AST worldwide.
Cas12a-assisted precise targeted cloning using in vivo Cre-lox recombination
Authors: Enghiad Behnam , Huang Chunshuai , Guo Fang , Jiang Guangde , Wang Bin , Tabatabaei S. Kasra , Martin Teresa A. , Zhao Huimin 
Published: February 2021

AbstractDirect cloning represents the most efficient strategy to access the vast number of uncharacterized natural product biosynthetic gene clusters (BGCs) for the discovery of novel bioactive compounds. However, due to their large size, repetitive nature, or high GC-content, large-scale cloning of these BGCs remains an overwhelming challenge. Here, we report a scalable direct cloning method named Cas12a-assisted precise targeted cloning using in vivo Cre-lox recombination (CAPTURE) which consists of Cas12a digestion, a DNA assembly approach termed T4 polymerase exo + fill-in DNA assembly, and Cre-lox in vivo DNA circularization. We apply this method to clone 47 BGCs ranging from 10 to 113 kb from both Actinomycetes and Bacilli with ~100% efficiency. Heterologous expression of cloned BGCs leads to the discovery of 15 previously uncharacterized natural products including six cyclic head-to-tail heterodimers with a unique 5/6/6/6/5 pentacyclic carbon skeleton, designated as bipentaromycins A–F. Four of the bipentaromycins show strong antimicrobial activity to both Gram-positive and Gram-negative bacteria such as methicillin-resistant Staphylococcus aureus, vancomycinresistant Enterococcus faecium, and bioweapon Bacillus anthracis. Due to its robustness and efficiency, our direct cloning method coupled with heterologous expression provides an effective strategy for large-scale discovery of novel natural products.