bluuebunny/crossref_metadata_2025_split huggingface dataset:
BACH1-induced ferroptosis drives lymphatic metastasis by repressing the biosynthesis of monounsaturated fatty acids
Authors: Xie Xiufeng , Tian Lusong , Zhao Yan , Liu Fang , Dai Shuyang , Gu Xinglu , Ye Yuxin , Zhou Lanping , Liu Xinmiao , Sun Yulin , Zhao Xiaohang 
Published: January 2023

AbstractEsophageal squamous cell carcinoma (ESCC) is one of the fatal malignancies worldwide. It has an increased propensity to metastasize via lymphogenous routes in an early stage. The prognosis of patients with lymph node metastases (LNM) is often worse than that of patients without metastases. Although several factors have been found to influence metastasis, the mechanisms of preference for specific metastatic routes remain poorly understood. Herein, we provide evidence that the intrinsic hypersensitivity of tumor cells to ferroptosis may proactively drive lymphatic metastasis. Serum autoantibodies associated with LNM of early ESCC were screened using a whole-proteome protein array containing 19 394 human recombinant proteins, and an anti-BACH1 autoantibody was first identified. Pan-cancer analysis of ferroptosis-related genes with preferential lymphatic metastasis and preferential hematogenous metastasis based on The Cancer Genome Atlas data was performed. Only BACH1 showed significant overexpression in tumors with preferential lymphatic metastasis, whereas it was downregulated in most tumors with preferential nonlymphatic metastasis. In addition, it was found that the serum levels of autoantibodies against BACH1 were elevated in early-stage patients with LNM. Interestingly, BACH1 overexpression and ferroptosis induction promoted LNM but inhibited hematogenous metastasis in mouse models. Transcriptomic and lipidomic analyses found that BACH1 repressed SCD1-mediated biosynthesis of monounsaturated fatty acids, especially oleic acid (OA). OA significantly attenuated the ferroptotic phenotypes and reversed the metastatic properties of BACH1-overexpressing cells. OA addition significantly rescued the ferroptotic phenotypes and reversed the metastatic properties of BACH1-overexpressing cells. Importantly, the concentration gradient of OA between primary lesions and the lymph resulted in the chemoattraction of tumor cells to promote invasion, thus facilitating lymphatic metastasis. BACH1-induced ferroptosis drives lymphatic metastasis via the BACH1-SCD1-OA axis. More importantly, this study confirms that ferroptosis is a double-edged sword in tumorigenesis and tumor progression. The clinical application of ferroptosis-associated agents requires a great caution.
Obesity promotes radioresistance through SERPINE1-mediated aggressiveness and DNA repair of triple-negative breast cancer
Authors: Su Yong-Han , Wu Yi-Zhen , Ann David K. , Chen Jenny Ling-Yu , Kuo Ching-Ying 
Published: January 2023

AbstractObesity is a risk factor in various types of cancer, including breast cancer. The disturbance of adipose tissue in obesity highly correlates with cancer progression and resistance to standard treatments such as chemo- and radio-therapies. In this study, in a syngeneic mouse model of triple-negative breast cancer (TNBC), diet-induced obesity (DIO) not only promoted tumor growth, but also reduced tumor response to radiotherapy. Serpine1 (Pai-1) was elevated in the circulation of obese mice and was enriched within tumor microenvironment. In vitro co-culture of human white adipocytes-conditioned medium (hAd-CM) with TNBC cells potentiated the aggressive phenotypes and radioresistance of TNBC cells. Moreover, inhibition of both cancer cell autonomous and non-autonomous SERPINE1 by either genetic or pharmacological strategy markedly dampened the aggressive phenotypes and radioresistance of TNBC cells. Mechanistically, we uncovered a previously unrecognized role of SERPINE1 in DNA damage response. Ionizing radiation-induced DNA double-strand breaks (DSBs) increased the expression of SERPINE1 in cancer cells in an ATM/ATR-dependent manner, and promoted nuclear localization of SERPINE1 to facilitate DSB repair. By analyzing public clinical datasets, higher SERPINE1 expression in TNBC correlated with patients’ BMI as well as poor outcomes. Elevated SERPINE1 expression and nuclear localization were also observed in radioresistant breast cancer cells. Collectively, we reveal a link between obesity and radioresistance in TNBC and identify SERPINE1 to be a crucial factor mediating obesity-associated tumor radioresistance.
Crocetin antagonizes parthanatos in ischemic stroke via inhibiting NOX2 and preserving mitochondrial hexokinase-I
Authors: Wu Hao , Li Ying , Zhang Qian , Wang Hanxun , Xiu Wenyu , Xu Pu , Deng Yujie , Huang Wanxu , Wang Dan Ohtan 
Published: January 2023

AbstractParthanatos is one of the major pathways of programmed cell death in ischemic stroke characterized by DNA damage, poly (ADP-ribose) polymerases (PARP) activation, and poly (ADP-ribose) (PAR) formation. Here we demonstrate that crocetin, a natural potent antioxidant compound from Crocus sativus, antagonizes parthanatos in ischemic stroke. We reveal that mechanistically, crocetin inhibits NADPH oxidase 2 (NOX2) activation to reduce reactive oxygen species (ROS) and PAR production at the early stage of parthanatos. Meanwhile we demonstrate that PARylated hexokinase-I (HK-I) is a novel substrate of E3 ligase RNF146 and that crocetin interacts with HK-I to suppress RNF146-mediated HK-I degradation at the later stage of parthanatos, preventing mitochondrial dysfunction and DNA damage that ultimately trigger the irreversible cell death. Our study supports further development of crocetin as a potential drug candidate for preventing and/or treating ischemic stroke.
miR-150-5p in neutrophil-derived extracellular vesicles associated with sepsis-induced cardiomyopathy in septic patients
Authors: Ye Rongzong , Lin Qiuyun , Xiao Wenkai , Mao Lixia , Zhang Pengfei , Zhou Lingshan , Wu Xiaoxia , Jiang Nannan , Zhang Xihe , Zhang Yinhua , Ma Daqing , Huang Jiahao , Wang Xiaoyan , Deng Liehua 
Published: January 2023

Abstract
Introduction
Early diagnosis and potential therapeutic targets of sepsis-induced cardiomyopathy (SIC) remain challenges clinically. Circulating extracellular vesicles from immune cells carrying crucial injurious mediators, including miRNAs in sepsis. However, the impacts of neutrophil-derived extracellular vesicles and their miRNAs in the SIC development are unknown.

Objectives
The present study focused on the in-depth miRNA expression profiles of neutrophil-derived extracellular vesicles and explored the potential molecular biomarkers during the process of SIC.

Methods
Neutrophil-derived extracellular vesicles were isolated from the blood samples in three sepsis patients with or without cardiomyopathy on day 1 and day 3 after ICU admission in comparison with three healthy controls. miRNAs were determined by RNA sequencing. The closely related differentially expressed miRNAs with SIC were further validated through qRT-PCR in the other cohorts of sepsis patients with (30 patients) or without cardiomyopathy (20 patients) and the association between miRNAs and the occurrence or disease severity of septic cardiomyopathy were stratified with logistic regression analysis.

Results
Sixty-eight miRNAs from neutrophil-derived extracellular vesicles were changed significantly between healthy controls and without septic cardiomyopathy patients (61 miRNAs upregulated and seven downregulated). Thirty-eight miRNAs were differentially expressed in the septic cardiomyopathy patients. 27 common differentially expressed miRNAs were found in both groups with similar kinetics (23 miRNAs upregulated and four downregulated). The enriched cellular signaling pathway mediated by miRNAs from sepsis to septic cardiomyopathy was the HIF-1 signaling system modulated septic inflammation. Using multivariate logistic regression analysis, miR-150-5p coupled with NT-pro BNP, LVEF, and SOFA score (AUC = 0.941) were found to be the independent predictors of septic cardiomyopathy.

Conclusion
miRNAs derived from neutrophil-derived extracellular vesicles play an important role in septic disease severity development towards cardiomyopathy. miR-150-5p may be a predictor of sepsis severity development but warrants further study.
Time-resolved RNA signatures of CD4+ T cells in Parkinson’s disease
Authors: Diener Caroline , Hart Martin , Kehl Tim , Becker-Dorison Anouck , Tänzer Tanja , Schub David , Krammes Lena , Sester Martina , Keller Andreas , Unger Marcus , Walch-Rückheim Barbara , Lenhof Hans-Peter , Meese Eckart 
Published: January 2023

AbstractParkinson’s disease (PD) emerges as a complex, multifactorial disease. While there is increasing evidence that dysregulated T cells play a central role in PD pathogenesis, elucidation of the pathomechanical changes in related signaling is still in its beginnings. We employed time-resolved RNA expression upon the activation of peripheral CD4+ T cells to track and functionally relate changes on cellular signaling in representative cases of patients at different stages of PD. While only few miRNAs showed time-course related expression changes in PD, we identified groups of genes with significantly altered expression for each different time window. Towards a further understanding of the functional consequences, we highlighted pathways with decreased or increased activity in PD, including the most prominent altered IL-17 pathway. Flow cytometric analyses showed not only an increased prevalence of Th17 cells but also a specific subtype of IL-17 producing γδ-T cells, indicating a previously unknown role in PD pathogenesis.
Epigenomic charting and functional annotation of risk loci in renal cell carcinoma
Authors: Nassar Amin H. , Abou Alaiwi Sarah , Baca Sylvan C. , Adib Elio , Corona Rosario I. , Seo Ji-Heui , Fonseca Marcos A. S. , Spisak Sandor , El Zarif Talal , Tisza Viktoria , Braun David A. , Du Heng , He Monica , Flaifel Abdallah , Alchoueiry Michel , Denize Thomas , Matar Sayed G. , Acosta Andres , Shukla Sachet , Hou Yue , Steinharter John , Bouchard Gabrielle , Berchuck Jacob E. , O’Connor Edward , Bell Connor , Nuzzo Pier Vitale , Mary Lee Gwo-Shu , Signoretti Sabina , Hirsch Michelle S. , Pomerantz Mark , Henske Elizabeth , Gusev Alexander , Lawrenson Kate , Choueiri Toni K. , Kwiatkowski David J. , Freedman Matthew L. 
Published: January 2023

AbstractWhile the mutational and transcriptional landscapes of renal cell carcinoma (RCC) are well-known, the epigenome is poorly understood. We characterize the epigenome of clear cell (ccRCC), papillary (pRCC), and chromophobe RCC (chRCC) by using ChIP-seq, ATAC-Seq, RNA-seq, and SNP arrays. We integrate 153 individual data sets from 42 patients and nominate 50 histology-specific master transcription factors (MTF) to define RCC histologic subtypes, including EPAS1 and ETS-1 in ccRCC, HNF1B in pRCC, and FOXI1 in chRCC. We confirm histology-specific MTFs via immunohistochemistry including a ccRCC-specific TF, BHLHE41. FOXI1 overexpression with knock-down of EPAS1 in the 786-O ccRCC cell line induces transcriptional upregulation of chRCC-specific genes, TFCP2L1, ATP6V0D2, KIT, and INSRR, implicating FOXI1 as a MTF for chRCC. Integrating RCC GWAS risk SNPs with H3K27ac ChIP-seq and ATAC-seq data reveals that risk-variants are significantly enriched in allelically-imbalanced peaks. This epigenomic atlas in primary human samples provides a resource for future investigation.
Surface charge as activity descriptors for electrochemical CO2 reduction to multi-carbon products on organic-functionalised Cu
Authors: Lim Carina Yi Jing , Yilmaz Meltem , Arce-Ramos Juan Manuel , Handoko Albertus D. , Teh Wei Jie , Zheng Yuangang , Khoo Zi Hui Jonathan , Lin Ming , Isaacs Mark , Tam Teck Lip Dexter , Bai Yang , Ng Chee Koon , Yeo Boon Siang , Sankar Gopinathan , Parkin Ivan P. , Hippalgaonkar Kedar , Sullivan Michael B. , Zhang Jia , Lim Yee-Fun 
Published: January 2023

AbstractIntensive research in electrochemical CO2 reduction reaction has resulted in the discovery of numerous high-performance catalysts selective to multi-carbon products, with most of these catalysts still being purely transition metal based. Herein, we present high and stable multi-carbon products selectivity of up to 76.6% across a wide potential range of 1 V on histidine-functionalised Cu. In-situ Raman and density functional theory calculations revealed alternative reaction pathways that involve direct interactions between adsorbed histidine and CO2 reduction intermediates at more cathodic potentials. Strikingly, we found that the yield of multi-carbon products is closely correlated to the surface charge on the catalyst surface, quantified by a pulsed voltammetry-based technique which proved reliable even at very cathodic potentials. We ascribe the surface charge to the population density of adsorbed species on the catalyst surface, which may be exploited as a powerful tool to explain CO2 reduction activity and as a proxy for future catalyst discovery, including organic-inorganic hybrids.
Dynamic rhenium dopant boosts ruthenium oxide for durable oxygen evolution
Authors: Jin Huanyu , Liu Xinyan , An Pengfei , Tang Cheng , Yu Huimin , Zhang Qinghua , Peng Hong-Jie , Gu Lin , Zheng Yao , Song Taeseup , Davey Kenneth , Paik Ungyu , Dong Juncai , Qiao Shi-Zhang 
Published: January 2023

AbstractHeteroatom-doping is a practical means to boost RuO2 for acidic oxygen evolution reaction (OER). However, a major drawback is conventional dopants have static electron redistribution. Here, we report that Re dopants in Re0.06Ru0.94O2 undergo a dynamic electron accepting-donating that adaptively boosts activity and stability, which is different from conventional dopants with static dopant electron redistribution. We show Re dopants during OER, (1) accept electrons at the on-site potential to activate Ru site, and (2) donate electrons back at large overpotential and prevent Ru dissolution. We confirm via in situ characterizations and first-principle computation that the dynamic electron-interaction between Re and Ru facilitates the adsorbate evolution mechanism and lowers adsorption energies for oxygen intermediates to boost activity and stability of Re0.06Ru0.94O2. We demonstrate a high mass activity of 500 A gcata.−1 (7811 A gRe-Ru−1) and a high stability number of S-number = 4.0 × 106 noxygen nRu−1 to outperform most electrocatalysts. We conclude that dynamic dopants can be used to boost activity and stability of active sites and therefore guide the design of adaptive electrocatalysts for clean energy conversions.
Jag1-Notch cis-interaction determines cell fate segregation in pancreatic development
Authors: Xu Xiaochan , Seymour Philip Allan , Sneppen Kim , Trusina Ala , Egeskov-Madsen Anuska la Rosa , Jørgensen Mette Christine , Jensen Mogens Høgh , Serup Palle 
Published: January 2023

AbstractThe Notch ligands Jag1 and Dll1 guide differentiation of multipotent pancreatic progenitor cells (MPCs) into unipotent pro-acinar cells (PACs) and bipotent duct/endocrine progenitors (BPs). Ligand-mediated trans-activation of Notch receptors induces oscillating expression of the transcription factor Hes1, while ligand-receptor cis-interaction indirectly represses Hes1 activation. Despite Dll1 and Jag1 both displaying cis- and trans-interactions, the two mutants have different phenotypes for reasons not fully understood. Here, we present a mathematical model that recapitulates the spatiotemporal differentiation of MPCs into PACs and BPs. The model correctly captures cell fate changes in Notch pathway knockout mice and small molecule inhibitor studies, and a requirement for oscillatory Hes1 expression to maintain the multipotent state. Crucially, the model entails cell-autonomous attenuation of Notch signaling by Jag1-mediated cis-inhibition in MPC differentiation. The model sheds light on the underlying mechanisms, suggesting that cis-interaction is crucial for exiting the multipotent state, while trans-interaction is required for adopting the bipotent fate.
Epithelial disruption drives mesendoderm differentiation in human pluripotent stem cells by enabling TGF-β protein sensing
Authors: Legier Thomas , Rattier Diane , Llewellyn Jack , Vannier Thomas , Sorre Benoit , Maina Flavio , Dono Rosanna 
Published: January 2023

AbstractThe processes of primitive streak formation and fate specification in the mammalian epiblast rely on complex interactions between morphogens and tissue organization. Little is known about how these instructive cues functionally interact to regulate gastrulation. We interrogated the interplay between tissue organization and morphogens by using human induced pluripotent stem cells (hiPSCs) downregulated for the morphogen regulator GLYPICAN-4, in which defects in tight junctions result in areas of disrupted epithelial integrity. Remarkably, this phenotype does not affect hiPSC stemness, but impacts on cell fate acquisition. Strikingly, cells within disrupted areas become competent to perceive the gastrulation signals BMP4 and ACTIVIN A, an in vitro surrogate for NODAL, and thus differentiate into mesendoderm. Yet, disruption of epithelial integrity sustains activation of BMP4 and ACTIVIN A downstream effectors and correlates with enhanced hiPSC endoderm/mesoderm differentiation. Altogether, our results disclose epithelial integrity as a key determinant of TGF-β activity and highlight an additional mechanism guiding morphogen sensing and spatial cell fate change within an epithelium.
Circular RNA circGlis3 protects against islet β-cell dysfunction and apoptosis in obesity
Authors: Liu Yue , Yang Yue , Xu Chenying , Liu Jianxing , Chen Jiale , Li Guoqing , Huang Bin , Pan Yi , Zhang Yanfeng , Wei Qiong , Pandol Stephen J. , Zhang Fangfang , Li Ling , Jin Liang 
Published: January 2023

AbstractPancreatic β-cell compensation is a major mechanism in delaying T2DM progression. Here we report the abnormal high expression of circGlis3 in islets of male mice with obesity and serum of people with obesity. Increasing circGlis3 is regulated by Quaking (QKI)-mediated splicing circularization. circGlis3 overexpression enhances insulin secretion and inhibits obesity-induced apoptosis in vitro and in vivo. Mechanistically, circGlis3 promotes insulin secretion by up-regulating NeuroD1 and Creb1 via sponging miR-124-3p and decreases apoptosis via interacting with the pro-apoptotic factor SCOTIN. The RNA binding protein FUS recruits circGlis3 and collectively assemble abnormal stable cytoplasmic stress granules (SG) in response to cellular stress. These findings highlight a physiological role for circRNAs in β-cell compensation and indicate that modulation of circGlis3 expression may represent a potential strategy to prevent β-cell dysfunction and apoptosis after obesity.
Mapping nucleolus-associated chromatin interactions using nucleolus Hi-C reveals pattern of heterochromatin interactions
Authors: Peng Ting , Hou Yingping , Meng Haowei , Cao Yong , Wang Xiaotian , Jia Lumeng , Chen Qing , Zheng Yang , Sun Yujie , Chen Hebing , Li Tingting , Li Cheng 
Published: January 2023

AbstractAs the largest substructures in the nucleus, nucleoli are the sites of ribosome biogenesis. Increasing evidence indicates that nucleoli play a key role in the organization of 3D genome architecture, but systematic studies of nucleolus-associated chromatin interactions are lacking. Here, we developed a nucleolus Hi-C (nHi-C) experimental technique to enrich nucleolus-associated chromatin interactions. Using the nHi-C experiment, we identify 264 high-confidence nucleolus-associated domains (hNADs) that form strong heterochromatin interactions associated with the nucleolus and consist of 24% of the whole genome in HeLa cells. Based on the global hNAD inter-chromosomal interactions, we find five nucleolar organizer region (NOR)-bearing chromosomes formed into two clusters that show different interaction patterns, which is concordant with their epigenetic states and gene expression levels. hNADs can be divided into three groups that display distinct cis/trans interaction signals, interaction frequencies associated with nucleoli, distance from the centromeres, and overlap percentage with lamina-associated domains (LADs). Nucleolus disassembly caused by Actinomycin D (ActD) significantly decreases the strength of hNADs and affects compartment/TAD strength genome-wide. In summary, our results provide a global view of heterochromatin interactions organized around nucleoli and demonstrate that nucleoli act as an inactive inter-chromosomal hub to shape both compartments and TADs.
Closing the gap to effective gene drive in Aedes aegypti by exploiting germline regulatory elements
Authors: Anderson Michelle A. E. , Gonzalez Estela , Ang Joshua X. D. , Shackleford Lewis , Nevard Katherine , Verkuijl Sebald A. N. , Edgington Matthew P. , Harvey-Samuel Tim , Alphey Luke 
Published: January 2023

AbstractCRISPR/Cas9-based homing gene drives have emerged as a potential new approach to mosquito control. While attempts have been made to develop such systems in Aedes aegypti, none have been able to match the high drive efficiency observed in Anopheles species. Here we generate Ae. aegypti transgenic lines expressing Cas9 using germline-specific regulatory elements and assess their ability to bias inheritance of an sgRNA-expressing element (kmosgRNAs). Four shu-Cas9 and one sds3-Cas9 isolines can significantly bias the inheritance of kmosgRNAs, with sds3G1-Cas9 causing the highest average inheritance of ~86% and ~94% from males and females carrying both elements outcrossed to wild-type, respectively. Our mathematical model demonstrates that sds3G1-Cas9 could enable the spread of the kmosgRNAs element to either reach a higher (by ~15 percentage point) maximum carrier frequency or to achieve similar maximum carrier frequency faster (by 12 generations) when compared to two other established split drive systems.
Structural analysis of an anthrol reductase inspires enantioselective synthesis of enantiopure hydroxycycloketones and β-halohydrins
Authors: Hou Xiaodong , Xu Huibin , Yuan Zhenbo , Deng Zhiwei , Fu Kai , Gao Yue , Liu Changmei , Zhang Yan , Rao Yijian 
Published: January 2023

AbstractAsymmetric reduction of prochiral ketones, particularly, reductive desymmetrization of 2,2-disubstituted prochiral 1,3-cyclodiketones to produce enantiopure chiral alcohols is challenging. Herein, an anthrol reductase CbAR with the ability to accommodate diverse bulky substrates, like emodin, for asymmetric reduction is identified. We firstly solve crystal structures of CbAR and CbAR-Emodin complex. It reveals that Tyr210 is critical for emodin recognition and binding, as it forms a hydrogen-bond interaction with His162 and π-π stacking interactions with emodin. This ensures the correct orientation for the stereoselectivity. Then, through structure-guided engineering, variant CbAR-H162F can convert various 2,2-disubstituted 1,3-cyclodiketones and α-haloacetophenones to optically pure (2S, 3S)-ketols and (R)-β-halohydrins, respectively. More importantly, their stereoselectivity mechanisms are also well explained by the respective crystal structures of CbAR-H162F-substrate complex. Therefore, this study demonstrates that an in-depth understanding of catalytic mechanism is valuable for exploiting the promiscuity of anthrol reductases to prepare diverse enantiopure chiral alcohols.