bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting TACC3 represents a novel vulnerability in highly aggressive breast cancers with centrosome amplification
Authors: Saatci Ozge , Akbulut Ozge , Cetin Metin , Sikirzhytski Vitali , Uner Meral , Lengerli Deniz , O’Quinn Elizabeth C. , Romeo Martin J. , Caliskan Burcu , Banoglu Erden , Aksoy Sercan , Uner Aysegul , Sahin Ozgur 
Published: March 2023

AbstractCentrosome amplification (CA) is a hallmark of cancer that is strongly associated with highly aggressive disease and worse clinical outcome. Clustering extra centrosomes is a major coping mechanism required for faithful mitosis of cancer cells with CA that would otherwise undergo mitotic catastrophe and cell death. However, its underlying molecular mechanisms have not been fully described. Furthermore, little is known about the processes and players triggering aggressiveness of cells with CA beyond mitosis. Here, we identified Transforming Acidic Coiled-Coil Containing Protein 3 (TACC3) to be overexpressed in tumors with CA, and its high expression is associated with dramatically worse clinical outcome. We demonstrated, for the first time, that TACC3 forms distinct functional interactomes regulating different processes in mitosis and interphase to ensure proliferation and survival of cancer cells with CA. Mitotic TACC3 interacts with the Kinesin Family Member C1 (KIFC1) to cluster extra centrosomes for mitotic progression, and inhibition of this interaction leads to mitotic cell death via multipolar spindle formation. Interphase TACC3 interacts with the nucleosome remodeling and deacetylase (NuRD) complex (HDAC2 and MBD2) in nucleus to inhibit the expression of key tumor suppressors (e.g., p21, p16 and APAF1) driving G1/S progression, and its inhibition blocks these interactions and causes p53-independent G1 arrest and apoptosis. Notably, inducing CA by p53 loss/mutation increases the expression of TACC3 and KIFC1 via FOXM1 and renders cancer cells highly sensitive to TACC3 inhibition. Targeting TACC3 by guide RNAs or small molecule inhibitors strongly inhibits growth of organoids and breast cancer cell line- and patient-derived xenografts with CA by induction of multipolar spindles, mitotic and G1 arrest. Altogether, our results show that TACC3 is a multifunctional driver of highly aggressive breast tumors with CA and that targeting TACC3 is a promising approach to tackle this disease.
A SARS-CoV-2-specific CAR-T-cell model identifies felodipine, fasudil, imatinib, and caspofungin as potential treatments for lethal COVID-19
Authors: Xia Lin , Yuan Lun-zhi , Hu Ya-hong , Liu Jun-yi , Hu Guo-sheng , Qi Ruo-yao , Zhang Tian-ying , Xiong Hua-long , Zheng Zao-zao , Lin Hong-wei , Zhang Jia-mo , Yu Chao , Zhou Ming , Ma Jian , Cheng Tong , Chen Ri-rong , Guan Yi , Xia Ning-shao , Liu Wen 
Published: March 2023

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced cytokine storm is closely associated with coronavirus disease 2019 (COVID-19) severity and lethality. However, drugs that are effective against inflammation to treat lethal COVID-19 are still urgently needed. Here, we constructed a SARS-CoV-2 spike protein-specific CAR, and human T cells infected with this CAR (SARS-CoV-2-S CAR-T) and stimulated with spike protein mimicked the T-cell responses seen in COVID-19 patients, causing cytokine storm and displaying a distinct memory, exhausted, and regulatory T-cell phenotype. THP1 remarkably augmented cytokine release in SARS-CoV-2-S CAR-T cells when they were in coculture. Based on this “two-cell” (CAR-T and THP1 cells) model, we screened an FDA-approved drug library and found that felodipine, fasudil, imatinib, and caspofungin were effective in suppressing the release of cytokines, which was likely due to their ability to suppress the NF-κB pathway in vitro. Felodipine, fasudil, imatinib, and caspofungin were further demonstrated, although to different extents, to attenuate lethal inflammation, ameliorate severe pneumonia, and prevent mortality in a SARS-CoV-2-infected Syrian hamster model, which were also linked to their suppressive role in inflammation. In summary, we established a SARS-CoV-2-specific CAR-T-cell model that can be utilized as a tool for anti-inflammatory drug screening in a fast and high-throughput manner. The drugs identified herein have great potential for early treatment to prevent COVID-19 patients from cytokine storm-induced lethality in the clinic because they are safe, inexpensive, and easily accessible for immediate use in most countries.
Reciprocal causation mixture model for robust Mendelian randomization analysis using genome-scale summary data
Authors: Liu Zipeng , Qin Yiming , Wu Tian , Tubbs Justin D. , Baum Larry , Mak Timothy Shin Heng , Li Miaoxin , Zhang Yan Dora , Sham Pak Chung 
Published: March 2023

AbstractMendelian randomization using GWAS summary statistics has become a popular method to infer causal relationships across complex diseases. However, the widespread pleiotropy observed in GWAS has made the selection of valid instrumental variables problematic, leading to possible violations of Mendelian randomization assumptions and thus potentially invalid inferences concerning causation. Furthermore, current MR methods can examine causation in only one direction, so that two separate analyses are required for bi-directional analysis. In this study, we propose a ststistical framework, MRCI (Mixture model Reciprocal Causation Inference), to estimate reciprocal causation between two phenotypes simultaneously using the genome-scale summary statistics of the two phenotypes and reference linkage disequilibrium information. Simulation studies, including strong correlated pleiotropy, showed that MRCI obtained nearly unbiased estimates of causation in both directions, and correct Type I error rates under the null hypothesis. In applications to real GWAS data, MRCI detected significant bi-directional and uni-directional causal influences between common diseases and putative risk factors.
Cell surface protein aggregation triggers endocytosis to maintain plasma membrane proteostasis
Authors: Paul David , Stern Omer , Vallis Yvonne , Dhillon Jatinder , Buchanan Andrew , McMahon Harvey 
Published: March 2023

AbstractThe ability of cells to manage consequences of exogenous proteotoxicity is key to cellular homeostasis. While a plethora of well-characterised machinery aids intracellular proteostasis, mechanisms involved in the response to denaturation of extracellular proteins remain elusive. Here we show that aggregation of protein ectodomains triggers their endocytosis via a macroendocytic route, and subsequent lysosomal degradation. Using ERBB2/HER2-specific antibodies we reveal that their cross-linking ability triggers specific and fast endocytosis of the receptor, independent of clathrin and dynamin. Upon aggregation, canonical clathrin-dependent cargoes are redirected into the aggregation-dependent endocytosis (ADE) pathway. ADE is an actin-driven process, which morphologically resembles macropinocytosis. Physical and chemical stress-induced aggregation of surface proteins also triggers ADE, facilitating their degradation in the lysosome. This study pinpoints aggregation of extracellular domains as a trigger for rapid uptake and lysosomal clearance which besides its proteostatic function has potential implications for the uptake of pathological protein aggregates and antibody-based therapies.
Dietary restriction of cysteine and methionine sensitizes gliomas to ferroptosis and induces alterations in energetic metabolism
Authors: Upadhyayula Pavan S. , Higgins Dominique M. , Mela Angeliki , Banu Matei , Dovas Athanassios , Zandkarimi Fereshteh , Patel Purvi , Mahajan Aayushi , Humala Nelson , Nguyen Trang T. T. , Chaudhary Kunal R. , Liao Lillian , Argenziano Michael , Sudhakar Tejaswi , Sperring Colin P. , Shapiro Benjamin L. , Ahmed Eman R. , Kinslow Connor , Ye Ling F. , Siegelin Markus D. , Cheng Simon , Soni Rajesh , Bruce Jeffrey N. , Stockwell Brent R. , Canoll Peter 
Published: March 2023

AbstractFerroptosis is mediated by lipid peroxidation of phospholipids containing polyunsaturated fatty acyl moieties. Glutathione, the key cellular antioxidant capable of inhibiting lipid peroxidation via the activity of the enzyme glutathione peroxidase 4 (GPX-4), is generated directly from the sulfur-containing amino acid cysteine, and indirectly from methionine via the transsulfuration pathway. Herein we show that cysteine and methionine deprivation (CMD) can synergize with the GPX4 inhibitor RSL3 to increase ferroptotic cell death and lipid peroxidation in both murine and human glioma cell lines and in ex vivo organotypic slice cultures. We also show that a cysteine-depleted, methionine-restricted diet can improve therapeutic response to RSL3 and prolong survival in a syngeneic orthotopic murine glioma model. Finally, this CMD diet leads to profound in vivo metabolomic, proteomic and lipidomic alterations, highlighting the potential for improving the efficacy of ferroptotic therapies in glioma treatment with a non-invasive dietary modification.
In-situ forming dynamic covalently crosslinked nanofibers with one-pot closed-loop recyclability
Authors: Wang Sheng , Wang Nannan , Kai Dan , Li Bofan , Wu Jing , YEO Jayven Chee Chuan , Xu Xiwei , Zhu Jin , Loh Xian Jun , Hadjichristidis Nikos , Li Zibiao 
Published: March 2023

AbstractPolymeric nanofibers are attractive nanomaterials owing to their high surface-area-to-volume ratio and superior flexibility. However, a difficult choice between durability and recyclability continues to hamper efforts to design new polymeric nanofibers. Herein, we integrate the concept of covalent adaptable networks (CANs) to produce a class of nanofibers ⎯ referred to dynamic covalently crosslinked nanofibers (DCCNFs) via electrospinning systems with viscosity modulation and in-situ crosslinking. The developed DCCNFs possess homogeneous morphology, flexibility, mechanical robustness, and creep resistance, as well as good thermal and solvent stability. Moreover, to solve the inevitable issues of performance degradation and crack of nanofibrous membranes, DCCNF membranes can be one-pot closed-loop recycled or welded through thermal-reversible Diels-Alder reaction. This study may unlock strategies to fabricate the next generation nanofibers with recyclable features and consistently high performance via dynamic covalent chemistry for intelligent and sustainable applications.
Genomic and immune landscape Of metastatic pheochromocytoma and paraganglioma
Authors: Calsina Bruna , Piñeiro-Yáñez Elena , Martínez-Montes Ángel M. , Caleiras Eduardo , Fernández-Sanromán Ángel , Monteagudo María , Torres-Pérez Rafael , Fustero-Torre Coral , Pulgarín-Alfaro Marta , Gil Eduardo , Letón Rocío , Jiménez Scherezade , García-Martín Santiago , Martin Maria Carmen , Roldán-Romero Juan María , Lanillos Javier , Mellid Sara , Santos María , Díaz-Talavera Alberto , Rubio Ángeles , González Patricia , Hernando Barbara , Bechmann Nicole , Dona Margo , Calatayud María , Guadalix Sonsoles , Álvarez-Escolá Cristina , Regojo Rita M. , Aller Javier , Del Olmo-Garcia Maria Isabel , López-Fernández Adrià , Fliedner Stephanie M. J. , Rapizzi Elena , Fassnacht Martin , Beuschlein Felix , Quinkler Marcus , Toledo Rodrigo A. , Mannelli Massimo , Timmers Henri J. , Eisenhofer Graeme , Rodríguez-Perales Sandra , Domínguez Orlando , Macintyre Geoffrey , Currás-Freixes Maria , Rodríguez-Antona Cristina , Cascón Alberto , Leandro-García Luis J. , Montero-Conde Cristina , Roncador Giovanna , García-García Juan Fernando , Pacak Karel , Al-Shahrour Fátima , Robledo Mercedes 
Published: March 2023

AbstractThe mechanisms triggering metastasis in pheochromocytoma/paraganglioma are unknown, hindering therapeutic options for patients with metastatic tumors (mPPGL). Herein we show by genomic profiling of a large cohort of mPPGLs that high mutational load, microsatellite instability and somatic copy-number alteration burden are associated with ATRX/TERT alterations and are suitable prognostic markers. Transcriptomic analysis defines the signaling networks involved in the acquisition of metastatic competence and establishes a gene signature related to mPPGLs, highlighting CDK1 as an additional mPPGL marker. Immunogenomics accompanied by immunohistochemistry identifies a heterogeneous ecosystem at the tumor microenvironment level, linked to the genomic subtype and tumor behavior. Specifically, we define a general immunosuppressive microenvironment in mPPGLs, the exception being PD-L1 expressing MAML3-related tumors. Our study reveals canonical markers for risk of metastasis, and suggests the usefulness of including immune parameters in clinical management for PPGL prognostication and identification of patients who might benefit from immunotherapy.
Unintended consequences of combating desertification in China
Authors: Wang Xunming , Ge Quansheng , Geng Xin , Wang Zhaosheng , Gao Lei , Bryan Brett A. , Chen Shengqian , Su Yanan , Cai Diwen , Ye Jiansheng , Sun Jimin , Lu Huayu , Che Huizheng , Cheng Hong , Liu Hongyan , Liu Baoli , Dong Zhibao , Cao Shixiong , Hua Ting , Chen Siyu , Sun Fubao , Luo Geping , Wang Zhenting , Hu Shi , Xu Duanyang , Chen Mingxing , Li Danfeng , Liu Fa , Xu Xinliang , Han Dongmei , Zheng Yang , Xiao Feiyan , Li Xiaobin , Wang Ping , Chen Fahu 
Published: March 2023

AbstractSince the early 2000s, China has carried out extensive “grain-for-green” and grazing exclusion practices to combat desertification in the desertification-prone region (DPR). However, the environmental and socioeconomic impacts of these practices remain unclear. We quantify and compare the changes in fractional vegetation cover (FVC) with economic and population data in the DPR before and after the implementation of these environmental programmes. Here we show that climatic change and CO2 fertilization are relatively strong drivers of vegetation rehabilitation from 2001-2020 in the DPR, and the declines in the direct incomes of farmers and herders caused by ecological practices exceed the subsidies provided by governments. To minimize economic hardship, enhance food security, and improve the returns on policy investments in the DPR, China needs to adapt its environmental programmes to address the potential impacts of future climate change and create positive synergies to combat desertification and improve the economy in this region.
Allelic variation of TaWD40-4B.1 contributes to drought tolerance by modulating catalase activity in wheat
Authors: Tian Geng , Wang Shubin , Wu Jianhui , Wang Yanxia , Wang Xiutang , Liu Shuwei , Han Dejun , Xia Guangmin , Wang Mengcheng 
Published: March 2023

AbstractDrought drastically restricts wheat production, so to dissect allelic variations of drought tolerant genes without imposing trade-offs between tolerance and yield is essential to cope with the circumstance. Here, we identify a drought tolerant WD40 protein encoding gene TaWD40-4B.1 of wheat via the genome-wide association study. The full-length allele TaWD40-4B.1C but not the truncated allele TaWD40-4B.1T possessing a nonsense nucleotide variation enhances drought tolerance and grain yield of wheat under drought. TaWD40-4B.1C interacts with canonical catalases, promotes their oligomerization and activities, and reduces H2O2 levels under drought. The knock-down of catalase genes erases the role of TaWD40-4B.1C in drought tolerance. TaWD40-4B.1C proportion in wheat accessions is negatively correlative with the annual rainfall, suggesting this allele may be selected during wheat breeding. The introgression of TaWD40-4B.1C enhances drought tolerance of the cultivar harboring TaWD40-4B.1T. Therefore, TaWD40-4B.1C could be useful for molecular breeding of drought tolerant wheat.
Codon-specific KRAS mutations predict survival benefit of trifluridine/tipiracil in metastatic colorectal cancer
Authors: van de Haar Joris , Ma Xuhui , Ooft Salo N. , van der Helm Pim W. , Hoes Louisa R. , Mainardi Sara , Pinato David J. , Sun Kristi , Salvatore Lisa , Tortora Giampaolo , Zurlo Ina Valeria , Leo Silvana , Giampieri Riccardo , Berardi Rossana , Gelsomino Fabio , Merz Valeria , Mazzuca Federica , Antonuzzo Lorenzo , Rosati Gerardo , Stavraka Chara , Ross Paul , Rodriquenz Maria Grazia , Pavarana Michele , Messina Carlo , Iveson Timothy , Zoratto Federica , Thomas Anne , Fenocchio Elisabetta , Ratti Margherita , Depetris Ilaria , Cergnul Massimiliano , Morelli Cristina , Libertini Michela , Parisi Alessandro , De Tursi Michele , Zanaletti Nicoletta , Garrone Ornella , Graham Janet , Longarini Raffaella , Gobba Stefania Maria , Petrillo Angelica , Tamburini Emiliano , La Verde Nicla , Petrelli Fausto , Ricci Vincenzo , Wessels Lodewyk F. A. , Ghidini Michele , Cortellini Alessio , Voest Emile E. , Valeri Nicola 
Published: March 2023

AbstractGenomics has greatly improved how patients with cancer are being treated; however, clinical-grade genomic biomarkers for chemotherapies are currently lacking. Using whole-genome analysis of 37 patients with metastatic colorectal cancer (mCRC) treated with the chemotherapy trifluridine/tipiracil (FTD/TPI), we identified KRAS codon G12 (KRASG12) mutations as a potential biomarker of resistance. Next, we collected real-world data of 960 patients with mCRC receiving FTD/TPI and validated that KRASG12 mutations were significantly associated with poor survival, also in analyses restricted to the RAS/RAF mutant subgroup. We next analyzed the data of the global, double-blind, placebo-controlled, phase 3 RECOURSE trial (n = 800 patients) and found that KRASG12 mutations (n = 279) were predictive biomarkers for reduced overall survival (OS) benefit of FTD/TPI versus placebo (unadjusted interaction P = 0.0031, adjusted interaction P = 0.015). For patients with KRASG12 mutations in the RECOURSE trial, OS was not prolonged with FTD/TPI versus placebo (n = 279; hazard ratio (HR) = 0.97; 95% confidence interval (CI) = 0.73–1.20; P = 0.85). In contrast, patients with KRASG13 mutant tumors showed significantly improved OS with FTD/TPI versus placebo (n = 60; HR = 0.29; 95% CI = 0.15–0.55; P < 0.001). In isogenic cell lines and patient-derived organoids, KRASG12 mutations were associated with increased resistance to FTD-based genotoxicity. In conclusion, these data show that KRASG12 mutations are biomarkers for reduced OS benefit of FTD/TPI treatment, with potential implications for approximately 28% of patients with mCRC under consideration for treatment with FTD/TPI. Furthermore, our data suggest that genomics-based precision medicine may be possible for a subset of chemotherapies.
A promising approach using Fibonacci sequence-based optimization algorithms and advanced computing
Authors: Tran-Ngoc H. , Le-Xuan T. , Khatir S. , De Roeck G. , Bui-Tien T. , Abdel Wahab Magd 
Published: March 2023

AbstractIn this paper, the feasibility of Structural Health Monitoring (SHM) employing a novel Fibonacy Sequence (FS)-based Optimization Algorithms (OAs) and up-to-date computing techniques is investigated for a large-scale railway bridge. During recent decades, numerous metaheuristic intelligent OAs have been proposed and immediately gained a lot of momentum. However, the major concern is how to employ OAs to deal with real-world problems, especially the SHM of large-scale structures. In addition to the requirement of high accuracy, a high computational cost is putting up a major barrier to the real application of OAs. Therefore, this article aims at addressing these two aforementioned issues. First, we propose employing the optimal ability of the golden ratio formulated by the well-known FS to remedy the shortcomings and improve the accuracy of OAs, specifically, a recently proposed new algorithm, namely Salp Swarm Algorithm (SSA). On the other hand, to deal with the high computational cost problems of OAs, we propose employing an up-to-date computing technique, termed superscalar processor to conduct a series of iterations in parallel. Moreover, in this work, the vectorization technique is also applied to reduce the size of the data. The obtained results show that the proposed approach is highly potential to apply for SHM of real large-scale structures.
Comparative phylogenomic insights of KCS and ELO gene families in Brassica species indicate their role in seed development and stress responsiveness
Authors: Khan Uzair Muhammad , Rana Iqrar Ahmad , Shaheen Nabeel , Raza Qasim , Rehman Hafiz Mamoon , Maqbool Rizwana , Khan Iqrar Ahmad , Atif Rana Muhammad 
Published: March 2023

AbstractVery long-chain fatty acids (VLCFAs) possess more than twenty carbon atoms and are the major components of seed storage oil, wax, and lipids. FAE (Fatty Acid Elongation) like genes take part in the biosynthesis of VLCFAs, growth regulation, and stress responses, and are further comprised of KCS (Ketoacyl-CoA synthase) and ELO (Elongation Defective Elongase) sub-gene families. The comparative genome-wide analysis and mode of evolution of KCS and ELO gene families have not been investigated in tetraploid Brassica carinata and its diploid progenitors. In this study, 53 KCS genes were identified in B. carinata compared to 32 and 33 KCS genes in B. nigra and B. oleracea respectively, which suggests that polyploidization might has impacted the fatty acid elongation process during Brassica evolution. Polyploidization has also increased the number of ELO genes in B. carinata (17) over its progenitors B. nigra (7) and B. oleracea (6). Based on comparative phylogenetics, KCS, and ELO proteins can be classified into eight and four major groups, respectively. The approximate date of divergence for duplicated KCS and ELO genes varied from 0.03 to 3.20 million years ago (MYA). Gene structure analysis indicated that the maximum number of genes were intron-less and remained conserved during evolution. The neutral type of selection seemed to be predominant in both KCS and ELO genes evolution. String-based protein-protein interaction analysis suggested that bZIP53, a transcription factor might be involved in the activation of transcription of ELO/KCS genes. The presence of biotic and abiotic stress-related cis-regulatory elements in the promoter region suggests that both KCS and ELO genes might also play their role in stress tolerance. The expression analysis of both gene family members reflect their preferential seed-specific expression, especially during the mature embryo development stage. Furthermore, some KCS and ELO genes were found to be specifically expressed under heat stress, phosphorus starvation, and Xanthomonas campestris infection. The current study provides a basis to understand the evolution of both KCS and ELO genes in fatty acid elongation and their role in stress tolerance.
A new method for ferroresonance suppression in an IEEE 33-bus distribution system integrated with multi distributed generation
Authors: Abdel-hamed Alaa M. , El-Shafhy Mohamed M. , Badran Ebrahim A. 
Published: March 2023

AbstractAlthough integrating a distributed generation (DG) into a distribution system (DS) has several benefits, it may be accompanied by some issues, such as ferroresonance. Therefore, ferroresonance investigations in an integrated DS with multi-DGs have been identified as a research gap. To this end, this paper presents a new method to mitigate ferroresonance in distribution networks, after which ferroresonance in an IEEE-33 bus radial DS integrated with multi-DGs was investigated. Here the RLC shunt limiter is introduced as a method for mitigating ferroresonance, including a design approach for adjusting its dimensions to fit the system. Investigations revealed that this shunt relied on the negative sequence detector to connect it to the system during ferroresonance. Finally, the effectiveness and superiority of the proposed method have been demonstrated by comparing its result with those obtained using other existing ferroresonance mitigation methods used in the literature.