bluuebunny/crossref_metadata_2025_split huggingface dataset:
DNA damage-induced paraspeckle formation enhances DNA repair and tumor radioresistance by recruiting ribosomal protein P0
Authors: Wang Yun-Long , Zhao Wan-Wen , Bai Shao-Mei , Ma Yan , Yin Xin-Ke , Feng Li-Li , Zeng Guang-Dong , Wang Fang , Feng Wei-Xing , Zheng Jian , Wang Ying-Nai , Zeng Bing , Liu Quentin , Hung Mien-Chie , Wan Xiang-Bo 
Published: August 2022

AbstractParaspeckles are mammal-specific membraneless nuclear bodies that participate in various biological processes. NONO, a central paraspeckle component, has been shown to play pivotal roles in DNA double-strand breaks (DSB) repair, whereas its underlying mechanism needs to be further disclosed. Here, using co-immunoprecipitation and mass spectrum, we identified ribosomal protein P0 (RPLP0) as a DSB-induced NONO-binding protein; RPLP0 binds to the RRM1 and RRM2 domains of NONO. Similar to NONO, RPLP0 enhances non-homologous end joining-mediated DSB repair, which was ascribed to a ribosome-independent manner. Interestingly, paraspeckles were induced as early as 15 min after irradiation; it further recruited nuclear RPLP0 to enhance its interaction with NONO. Radiation-induced NONO/RPLP0 complex subsequently anchored at the damaged DNA and increased the autophosphorylation of DNA-PK at Thr2609, thereby enhancing DSB repair. Consistently, in vivo and in vitro experiments showed that depletion of NONO sensitizes tumor cells to radiation. For patients with locally advanced rectal cancer, NONO expression was remarkably increased in tumor tissues and correlated with a poor response to radiochemotherapy. Our findings suggest a pivotal role of radiation-induced paraspeckles in DNA repair and tumor radioresistance, and provide a new insight into the ribosome-independent function of ribosomal proteins.
Glycosylated modification of MUC1 maybe a new target to promote drug sensitivity and efficacy for breast cancer chemotherapy
Authors: Xi Xiaomin , Wang Jiting , Qin Yue , Huang Weidong , You Yilin , Zhan Jicheng 
Published: August 2022

AbstractBreast cancer, the most common cancer in women, usually exhibits intrinsic insensitivity to drugs, even without drug resistance. MUC1 is a highly glycosylated transmembrane protein, overexpressed in breast cancer, contributing to tumorigenesis and worse prognosis. However, the molecular mechanism between MUC1 and drug sensitivity still remains unclear. Here, natural flavonoid apigenin was used as objective due to the antitumor activity and wide availability. MUC1 knockout (KO) markedly sensitized breast cancer cells to apigenin cytotoxicity in vitro and in vivo. Both genetical and pharmacological inhibition significantly enhanced the chemosensitivity to apigenin and clinical drugs whereas MUC1 overexpression conversely aggravated such drug resistance. Constitutively re-expressing wild type MUC1 in KO cells restored the drug resistance; however, the transmembrane domain deletant could not rescue the phenotype. Notably, further investigation discovered that membrane-dependent drug resistance relied on the extracellular glycosylated modification since removing O-glycosylation via inhibitor, enzyme digestion, or GCNT3 (MUC1 related O-glycosyltransferase) knockout markedly reinvigorated the chemosensitivity in WT cells, but had no effect on KO cells. Conversely, inserting O-glycosylated sites to MUC1-N increased the drug tolerance whereas the O-glycosylated deletant (Ser/Thr to Ala) maintained high susceptibility to drugs. Importantly, the intracellular concentration of apigenin measured by UPLC and fluorescence distribution firmly revealed the increased drug permeation in MUC1 KO and BAG-pretreated cells. Multiple clinical chemotherapeutics with small molecular were tested and obtained the similar conclusion. Our findings uncover a critical role of the extracellular O-glycosylation of MUC1-N in weakening drug sensitivity through acting as a barrier, highlighting a new perspective that targeting MUC1 O-glycosylation has great potential to promote drug sensitivity and efficacy.
Loss of FOXA2 induces ER stress and hepatic steatosis and alters developmental gene expression in human iPSC-derived hepatocytes
Authors: Aghadi Maryam , Elgendy Ramy , Abdelalim Essam M. 
Published: August 2022

AbstractFOXA2 has been known to play important roles in liver functions in rodents. However, its role in human hepatocytes is not fully understood. Recently, we generated FOXA2 mutant induced pluripotent stem cell (FOXA2−/−iPSC) lines and illustrated that loss of FOXA2 results in developmental defects in pancreatic islet cells. Here, we used FOXA2−/−iPSC lines to understand the role of FOXA2 on the development and function of human hepatocytes. Lack of FOXA2 resulted in significant alterations in the expression of key developmental and functional genes in hepatic progenitors (HP) and mature hepatocytes (MH) as well as an increase in the expression of ER stress markers. Functional assays demonstrated an increase in lipid accumulation, bile acid synthesis and glycerol production, while a decrease in glucose uptake, glycogen storage, and Albumin secretion. RNA-sequencing analysis further validated the findings by showing a significant increase in genes associated with lipid metabolism, bile acid secretion, and suggested the activation of hepatic stellate cells and hepatic fibrosis in MH lacking FOXA2. Overexpression of FOXA2 reversed the defective phenotypes and improved hepatocyte functionality in iPSC-derived hepatic cells lacking FOXA2. These results highlight a potential role of FOXA2 in regulating human hepatic development and function and provide a human hepatocyte model, which can be used to identify novel therapeutic targets for FOXA2-associated liver disorders.
USP21 promotes self-renewal and tumorigenicity of mesenchymal glioblastoma stem cells by deubiquitinating and stabilizing FOXD1
Authors: Zhang Qixiang , Chen Zhengxin , Tang Qikai , Wang Zhangjie , Lu Jiacheng , You Yongping , Wang Huibo 
Published: August 2022

AbstractRecent studies suggest that Forkhead box D1 (FOXD1) plays an indispensable role in maintaining the mesenchymal (MES) properties of glioblastoma (GBM) stem cells (GSCs). Thus, understanding the mechanisms that control FOXD1 protein expression is critical for guiding GBM treatment, particularly in patients with therapy-resistant MES subtypes. In this study, we identify the ubiquitin-specific peptidase 21 (USP21) as a critical FOXD1 deubiquitinase in MES GSCs. We find that USP21 directly interacts with and stabilizes FOXD1 by reverting its proteolytic ubiquitination. Silencing of USP21 enhances polyubiquitination of FOXD1, promotes its proteasomal degradation, and ultimately attenuates MES identity in GSCs, while these effects could be largely restored by reintroduction of FOXD1. Remarkably, we show that disulfiram, a repurposed drug that could block the enzymatic activities of USP21, suppresses GSC tumorigenicity in MES GSC-derived GBM xenograft model. Additionally, we demonstrate that USP21 is overexpressed and positively correlated with FOXD1 protein levels in GBM tissues, and its expression is inversely correlated with patient survival. Collectively, our work reveals that USP21 maintains MES identity by antagonizing FOXD1 ubiquitination and degradation, suggesting that USP21 is a potential therapeutic target for the MES subtype of GBM.
Long noncoding RNA NONMMUT015745 inhibits doxorubicin-mediated cardiomyocyte apoptosis by regulating Rab2A-p53 axis
Authors: Cai Hongjing , Tian Pengchao , Ju Jie , Wang Tao , Chen Xinzhe , Wang Kai , Wang Fei , Yu Xue , Wang Shaocong , Wang Yin , Shan Chan , Li Peifeng 
Published: August 2022

AbstractDoxorubicin (DOX) is an efficacious and widely used drug for human malignancy treatment, but its clinical application is limited due to side effects, especially cardiotoxicity. Our present study revealed that DOX could induce apoptosis in cardiomyocytes. Herein, we screened the dysregulated long noncoding RNAs (lncRNAs) in DOX-treated cardiomyocytes. Notably, overexpression of lncRNA NONMMUT015745 (lnc5745) could alleviate DOX-induced cardiomyocyte apoptosis both in vitro and in vivo. Conversely, silencing lnc5745 promotes cardiomyocyte apoptosis. Moreover, Rab2A, a direct target of lnc5745, possesses a protective effect in DOX-induced cardiotoxicity once knocked down. Importantly, we verified that the p53-related apoptotic signalling pathway was responsible for the lnc5745-mediated protective role against DOX-induced cardiomyocyte apoptosis. Mechanistically, Rab2A interacts with p53 and phosphorylated p53 on Ser 33 (p53 (Phospho-Ser 33)), promotes p53 phosphorylation, thereby activating the apoptotic pathway. Taken together, our results suggested that lnc5745 protects against DOX-induced cardiomyocyte apoptosis through suppressing Rab2A expression, modifying p53 phosphorylation, thereby regulating p53-related apoptotic signalling pathway. Our findings establish the functional mode of the lnc5745-Rab2A-p53 axis in DOX-induced cardiotoxicity. The development of new strategies targeting the lnc5745-Rab2A-p53 axis could attenuate DOX-induced cardiotoxicity, which is beneficial to its clinical anti-tumour application.
Compound marine heatwaves and ocean acidity extremes
Authors: Burger Friedrich A. , Terhaar Jens , Frölicher Thomas L. 
Published: August 2022

AbstractCompound MHW-OAX events, during which marine heatwaves (MHWs) co-occur with ocean acidity extreme (OAX) events, can have larger impacts on marine ecosystems than the individual extremes. Using monthly open-ocean observations over the period 1982–2019, we show that globally 1.8 in 100 months (or about one out of five present-day MHW months) are compound MHW-OAX event months under a present-day baseline, almost twice as many as expected for 90th percentile extreme event exceedances if MHWs and OAX events were statistically independent. Compound MHW-OAX events are most likely in the subtropics (2.7 in 100 months; 10°−40° latitude) and less likely in the equatorial Pacific and the mid-to-high latitudes (0.7 in 100 months; >40° latitude). The likelihood pattern results from opposing effects of temperature and dissolved inorganic carbon on [H+]. The likelihood is higher where the positive effect on [H+] from increased temperatures during MHWs outweighs the negative effect on [H+] from co-occurring decreases in dissolved inorganic carbon. Daily model output from a large-ensemble simulation of an Earth system model is analyzed to assess changes in the MHW-OAX likelihood under climate change. The projected long-term mean warming and acidification trends have the largest effect on the number of MHW-OAX days per year, increasing it from 12 to 265 days per year at 2 °C global warming relative to a fixed pre-industrial baseline. Even when long-term trends are removed, an increase in [H+] variability leads to a 60% increase in the number of MHW-OAX days under 2 °C global warming. These projected increases may cause severe impacts on marine ecosystems.
Impedance-based forecasting of lithium-ion battery performance amid uneven usage
Authors: Jones Penelope K. , Stimming Ulrich , Lee Alpha A. 
Published: August 2022

AbstractAccurate forecasting of lithium-ion battery performance is essential for easing consumer concerns about the safety and reliability of electric vehicles. Most research on battery health prognostics focuses on the research and development setting where cells are subjected to the same usage patterns. However, in practical operation, there is great variability in use across cells and cycles, thus making forecasting challenging. To address this challenge, here we propose a combination of electrochemical impedance spectroscopy measurements with probabilistic machine learning methods. Making use of a dataset of 88 commercial lithium-ion coin cells generated via multistage charging and discharging (with currents randomly changed between cycles), we show that future discharge capacities can be predicted with calibrated uncertainties, given the future cycling protocol and a single electrochemical impedance spectroscopy measurement made immediately before charging, and without any knowledge of usage history. The results are robust to cell manufacturer, the distribution of cycling protocols, and temperature. The research outcome also suggests that battery health is better quantified by a multidimensional vector rather than a scalar state of health.
A TrkB agonist prodrug prevents bone loss via inhibiting asparagine endopeptidase and increasing osteoprotegerin
Authors: Xiong Jing , Liao Jianming , Liu Xia , Zhang Zhaohui , Adams Jonathan , Pacifici Roberto , Ye Keqiang 
Published: August 2022

AbstractBrain-derived neurotrophic factor (BDNF) and its tropomyosin-related kinase B receptor (TrkB) are expressed in human osteoblasts and mediate fracture healing. BDNF/TrkB signaling activates Akt that phosphorylates and inhibits asparagine endopeptidase (AEP), which regulates the differentiation fate of human bone marrow stromal cells (hBMSC) and is altered in postmenopausal osteoporosis. Here we show that R13, a small molecular TrkB receptor agonist prodrug, inhibits AEP and promotes bone formation. Though both receptor activator of nuclear factor kappa-Β ligand (RANK-L) and osteoprotegerin (OPG) induced by ovariectomy (OVX) remain comparable between WT and BDNF+/− mice, R13 treatment significantly elevates OPG in both mice without altering RANKL, blocking trabecular bone loss. Strikingly, both R13 and anti-RANK-L exhibit equivalent therapeutic efficacy. Moreover, OVX increases RANK-L and OPG in WT and AEP KO mice with RANK-L/OPG ratio lower in the latter than the former, attenuating bone turnover. 7,8-DHF, released from R13, activates TrkB and its downstream effector CREB, which is critical for OPG augmentation. Consequently, 7,8-DHF represses C/EBPβ/AEP pathway, inhibiting RANK-L-induced RAW264.7 osteoclastogenesis. Therefore, our findings support that R13 exerts its therapeutic efficacy toward osteoporosis via inhibiting AEP and escalating OPG.
Two-colour high-purity Einstein-Podolsky-Rosen photonic state
Authors: Brasil Tulio Brito , Novikov Valeriy , Kerdoncuff Hugo , Lassen Mikael , Polzik Eugene S. 
Published: August 2022

AbstractWe report a high-purity Einstein-Podolsky-Rosen (EPR) state between light modes with the wavelengths separated by more than 200 nm. We demonstrate highly efficient EPR-steering between the modes with the product of conditional variances $${{{{{{{{\mathcal{E}}}}}}}}}^{2}=0.11\pm 0.01\ll 1$$

E

2

=
0.11
±
0.01
≪
1
. The modes display − 7.7 ± 0.5 dB of two-mode squeezing and an overall state purity of 0.63 ± 0.16. EPR-steering is observed over five octaves of sideband frequencies from RF down to audio-band. The demonstrated combination of high state purity, strong quantum correlations, and extended frequency range enables new matter-light quantum protocols.
A functional role of meningeal lymphatics in sex difference of stress susceptibility in mice
Authors: Dai Weiping , Yang Mengqian , Xia Pei , Xiao Chuan , Huang Shuying , Zhang Zhan , Cheng Xin , Li Wenchang , Jin Jian , Zhang Jingyun , Wu Binghuo , Zhang Yingying , Wu Pei-hui , Lin Yangyang , Wu Wen , Zhao Hu , Zhang Yan , Lin Wei-Jye , Ye Xiaojing 
Published: August 2022

AbstractMajor depressive disorder is one of the most common mental health conditions. Meningeal lymphatics are essential for drainage of molecules in the cerebrospinal fluid to the peripheral immune system. Their potential role in depression-like behaviour has not been investigated. Here, we show in mice, sub-chronic variable stress as a model of depression-like behaviour impairs meningeal lymphatics in females but not in males. Manipulations of meningeal lymphatics regulate the sex difference in the susceptibility to stress-induced depression- and anxiety-like behaviors in mice, as well as alterations of the medial prefrontal cortex and the ventral tegmental area, brain regions critical for emotional regulation. Together, our findings suggest meningeal lymphatic impairment contributes to susceptibility to stress in mice, and that restoration of the meningeal lymphatics might have potential for modulation of depression-like behaviour.
Human supplementation with Pediococcus acidilactici GR-1 decreases heavy metals levels through modifying the gut microbiota and metabolome
Authors: Feng Pengya , Yang Jinfeng , Zhao Shuai , Ling Zhenmin , Han Rong , Wu Ying , Salama Ei-Sayed , Kakade Apurva , Khan Aman , Jin Weilin , Zhang Weibing , Jeon Byong-Hun , Fan Jingjing , Liu Minrui , Mamtimin Tursunay , Liu Pu , Li Xiangkai 
Published: August 2022

AbstractExposure to heavy metals (HMs) is a threat to human health. Although probiotics can detoxify HMs in animals, their effectiveness and mechanism of action in humans have not been studied well. Therefore, we conducted this randomized, double-blind, controlled trial on 152 occupational workers from the metal industry, an at-risk human population, to explore the effectiveness of probiotic yogurt in reducing HM levels. Participants were randomly assigned to two groups: one consumed probiotic yogurt containing the HM-resistant strain Pediococcus acidilactici GR-1 and the other consumed conventional yogurt for 12 weeks. Analysis of metal contents in the blood revealed that the consumption of probiotic yogurt resulted in a higher and faster decrease in copper (34.45%) and nickel (38.34%) levels in the blood than the consumption of conventional yogurt (16.41% and 27.57%, respectively). Metagenomic and metabolomic studies identified a close correlation between gut microbiota (GM) and host metabolism. Significantly enriched members of Blautia and Bifidobacterium correlated positively with the antioxidant capacities of GM and host. Further murine experiments confirmed the essential role of GM and protective effect of GR-1 on the antioxidative role of the intestine against copper. Thus, the use of probiotic yogurt may be an effective and affordable approach for combating toxic metal exposure through the protection of indigenous GM in humans.ClinicalTrials.gov identifier: ChiCTR2100053222
Mapping the dynamics of insulin-responsive pathways in the blood–brain barrier endothelium using time-series transcriptomics data
Authors: Wang Zengtao , Tang Xiaojia , Swaminathan Suresh K. , Kandimalla Karunya K. , Kalari Krishna R. 
Published: August 2022

AbstractCritical functions of the blood–brain barrier (BBB), including cerebral blood flow, energy metabolism, and immunomodulation, are regulated by insulin signaling pathways. Therefore, endothelial insulin resistance could lead to BBB dysfunction, which is associated with neurodegenerative diseases such as Alzheimer’s disease (AD). The current study aims to map the dynamics of insulin-responsive pathways in polarized human cerebral microvascular endothelial cell (hCMEC/D3) monolayers. RNA-Sequencing was performed on hCMEC/D3 monolayers with and without insulin treatment at various time points. The Short Time-series Expression Miner (STEM) method was used to identify gene clusters with distinct and representative expression patterns. Functional annotation and pathway analysis of genes from selected clusters were conducted using Webgestalt and Ingenuity Pathway Analysis (IPA) software. Quantitative expression differences of 16,570 genes between insulin-treated and control monolayers were determined at five-time points. The STEM software identified 12 significant clusters with 6880 genes that displayed distinct temporal patterns upon insulin exposure, and the clusters were further divided into three groups. Gene ontology (GO) enrichment analysis demonstrated that biological processes protecting BBB functions such as regulation of vascular development and actin cytoskeleton reorganization were upregulated after insulin treatment (Group 1 and 2). In contrast, GO pathways related to inflammation, such as response to interferon-gamma, were downregulated (Group 3). The IPA analyses further identified insulin-responsive cellular and molecular pathways that are associated with AD pathology. These findings unravel the dynamics of insulin action on the BBB endothelium and inform about downstream signaling cascades that are potentially disrupted due to brain insulin resistance prevalent in AD.
Current status of traumatic spinal cord injury caused by traffic accident in Northern China
Authors: Wu Yao , Zhang Zhenrong , Wang Fangyong , Wang Wenjing 
Published: August 2022

AbstractThe study aims to investigate the characteristics of traumatic spinal cord injury (TSCI) caused by motor vehicle collisions (MVCs). The study included 649 cases who experienced MVC-induced TSCI. The mean age was 37.3 years old, ranging from 1 to 82 years old. The male-to-female ratio was 2.7:1. We extracted data of gender, age, occupation, neurological level of injury, fracture level, complications, vehicle type, accident type and other features. The results showed that the most common vehicles involved in accidents were passenger cars (65.1%). Collision was the leading cause of MVCs (35.8%). The lesion level was cervical in 51.6% and thoracic in 42.2%. The most common fracture levels in drivers and passengers were C3–C7, while those in pedestrians were T11–L2. The frequency of tetraplegia (51.6%) was slightly higher than paraplegia (48.4%), and cases with tetraplegia with incomplete injury accounted for 61.2%. MVC-induced TSCI has unique clinical features. Collision was the most common cause. People sitting in cars were more likely to suffer from cervical fractures, while thoracolumbar fractures were more common in pedestrians. Tetraplegic cases were mainly incomplete injuries, while paraplegic cases were mainly complete injuries.
Nanopore metatranscriptomics reveals cryptic catfish species as potential Shigella flexneri vectors in Kenya
Authors: Tighe Andrew J. , Grayson Sean , Byrne John , Hintikka Sanni , Jessen Lisa , Dempsey Jake , Browne Lauren , Kelly-Quinn Mary , Fulanda Bernerd , Ruane Neil M. , Carlsson Jens 
Published: August 2022

AbstractBacteria in the Shigella genus remain a major cause of dysentery in sub-Saharan Africa, and annually cause an estimated 600,000 deaths worldwide. Being spread by contaminated food and water, this study highlights how wild caught food, in the form of freshwater catfish, can act as vectors for Shigella flexneri in Southern Kenya. A metatranscriptomic approach was used to identify the presence of Shigella flexneri in the catfish which had been caught for consumption from the Galana river. The use of nanopore sequencing was shown to be a simple and effective method to highlight the presence of Shigella flexneri and could represent a potential new tool in the detection and prevention of this deadly pathogen. Rather than the presence/absence results of more traditional testing methods, the use of metatranscriptomics highlighted how primarily one SOS response gene was being transcribed, suggesting the bacteria may be dormant in the catfish. Additionally, COI sequencing of the vector catfish revealed they likely represent a cryptic species. Morphological assignment suggested the fish were widehead catfish Clarotes laticeps, which range across Africa, but the COI sequences from the Kenyan fish are distinctly different from C. laticeps sequenced in West Africa.