FEBS Open Bio最新文献

{"title":"Beyond digital twins: the role of foundation models in enhancing the interpretability of multiomics modalities in precision medicine.","authors":"Sakhaa Alsaedi, Xin Gao, Takashi Gojobori","doi":"10.1002/2211-5463.70003","DOIUrl":"https://doi.org/10.1002/2211-5463.70003","url":null,"abstract":"<p><p>Medical digital twins (MDTs) are virtual representations of patients that simulate the biological, physiological, and clinical processes of individuals to enable personalized medicine. With the increasing complexity of omics data, particularly multiomics, there is a growing need for advanced computational frameworks to interpret these data effectively. Foundation models (FMs), large-scale machine learning models pretrained on diverse data types, have recently emerged as powerful tools for improving data interpretability and decision-making in precision medicine. This review discusses the integration of FMs into MDT systems, particularly their role in enhancing the interpretability of multiomics data. We examine current challenges, recent advancements, and future opportunities in leveraging FMs for multiomics analysis in MDTs, with a focus on their application in precision medicine.</p>","PeriodicalId":12187,"journal":{"name":"FEBS Open Bio","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143491439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mapping Hsp104 interactions using cross-linking mass spectrometry.","authors":"Kinga Westphal, Karolina Michalska, Andrzej Joachimiak, Lukasz A Joachimiak","doi":"10.1002/2211-5463.70007","DOIUrl":"https://doi.org/10.1002/2211-5463.70007","url":null,"abstract":"<p><p>Molecular machines from the AAA+ (ATPases Associated with diverse cellular Activity) superfamily of protein disaggregases play important roles in protein folding, disaggregation and DNA processing. Recent cryo-EM structures of AAA+ molecular machines have uncovered nuanced changes in their conformation that underlie their specialized functions. Structural knowledge of these molecular machines in complex with substrates begins to explain their mechanism of activity. Here, we explore how cross-linking mass spectrometry (XL-MS) can be used to interpret changes in conformation induced by ATP in Hsp104 and how a substrate may interact with Hsp104. We applied a panel of cross-linking reagents to produce cross-linking maps of Hsp104 and interpret our data on previously determined X-ray and cryo-EM structures of Hsp104 from a thermophilic yeast, Calcarisporiella thermophila. We developed an analysis pipeline to differentiate between intra-subunit and inter-subunit contacts within the hexameric homo-oligomer. We identify cross-links that break the asymmetry that is present in Hsp104 in an ATP-hydrolysis competent conformation but is absent in an ATP-hydrolysis-defective mutant. Finally, we identify contacts between Hsp104 and a selected protein (proprotein convertase subtilisin/kexin type 9 PCSK9) to reveal contacts on the central channel of Hsp104 across the length of this protein indicating that we might have trapped interactions consistent with its translocation. Our simple and robust XL-MS-based experiments and methods help interpret how these molecular machines change conformation and bind to other proteins even in the context of homo-oligomeric assemblies enabling coupling state-of-the-art modeling approaches with XL-MS.</p>","PeriodicalId":12187,"journal":{"name":"FEBS Open Bio","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143491440","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterisation of the role played by ELMO1, GPR141 and the intergenic polymorphism rs918980 in Fuchs' dystrophy in the Indian population.","authors":"Susmita Sharma, Samar Kumar Basak, Sujata Das, Debasmita Pankaj Alone","doi":"10.1002/2211-5463.70006","DOIUrl":"https://doi.org/10.1002/2211-5463.70006","url":null,"abstract":"<p><p>Fuchs' endothelial corneal dystrophy (FECD) is the most common type of primary corneal dystrophy and can result in corneal transplantation. Here, we investigated the genetic association of SNP rs918980 (A>G) with FECD and the role of its surrounding genes ELMO1 and GPR141. First, 128 patients and 379 controls were genotyped by Sanger sequencing. Our results show that rs918980 is significantly associated with FECD in the Indian population. Furthermore, in silico analysis suggested that rs918980 and its surrounding 150 bp region could regulate the transcriptional activities of nearby genes. Thus, we assessed whether ELMO1 and GPR141 were differentially expressed in FECD patients and in the corneal tissue of a UVA-induced FECD mice model. Both genes were significantly upregulated and western blots studies concluded that protein levels of ELMO1 and GPR141 were also higher in the corneal endothelium of the UVA-exposed eye compared to the control eye. Taken together, our results suggest that ELMO1 and GPR141 might play a significant role in FECD progression. However, further studies are required to better characterize the possible role of rs918980 and its nearby region in the regulation of ELMO1 and GPR141.</p>","PeriodicalId":12187,"journal":{"name":"FEBS Open Bio","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143448706","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Piezo1 channels enhance anabolic signaling activation induced by electrical stimulation of cultured myotubes.","authors":"Natalia A Vilchinskaya, Ksenia V Sergeeva, Boris S Shenkman, Timur M Mirzoev","doi":"10.1002/2211-5463.70008","DOIUrl":"https://doi.org/10.1002/2211-5463.70008","url":null,"abstract":"<p><p>Mechanically activated (MA) Piezo1 channels play an important role in both normal physiology and pathological dysfunction in multiple tissues and organs. In skeletal muscle cells, Piezo1 channels are involved in the regulation of postnatal myogenesis and muscle regeneration after injury. To further understand the role of MA Piezo1 channels as potential critical sensors of mechanical perturbations during muscle contractions, we studied the possible contribution of MA Piezo1 channels to enhanced protein synthetic response of C2C12 myotubes to mechanical simulation. C2C12 myotubes were subjected to mechanical stimulation by electrical pulse stimulation (EPS) alone or EPS in combination with Yoda1, Gadolinium or Yoda1 + Gadolinium. EPS alone elicited an increase in anabolic signaling and protein synthesis (PS). Incubation with Yoda1 during EPS enhanced anabolic signaling and PS compared to EPS alone. Gadolinium or Yoda1 + gadolinium during EPS abolished or diminished the Yoda1 + EPS-induced effects on anabolic signaling and PS. Our work demonstrates that chemical activation of Piezo1 channels during mechanical stimulation contributes to enhanced protein anabolism in C2C12 myotubes.</p>","PeriodicalId":12187,"journal":{"name":"FEBS Open Bio","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143439639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of inhibitors of the Salmonella FraB deglycase, a drug target.","authors":"Jamison D Law, Yuan Gao, Sravya Kovvali, Pankajavalli Thirugnanasambantham, Vicki H Wysocki, Brian M M Ahmer, Venkat Gopalan","doi":"10.1002/2211-5463.70001","DOIUrl":"https://doi.org/10.1002/2211-5463.70001","url":null,"abstract":"<p><p>Nontyphoidal Salmonella is one of the most prevalent causes of human foodborne illnesses worldwide, with no narrow-spectrum antibiotics or vaccines available. Here, we seek to address this gap. During the host inflammatory response, Salmonella metabolizes fructose-asparagine as a nutrient using proteins encoded in the fra operon. Deletion of fraB leads to a build-up of 6-phosphofructose-aspartate, the substrate of FraB, and intoxicates Salmonella. Because fra genes are absent in mammals and most members of the human gut microbiome, FraB inhibitors are expected to have limited off-target effects and offer prospects as potential therapeutics. To identify such inhibitors, we conducted a high-throughput screening of small-molecule libraries using a FraB activity-based biochemical assay. We screened 131,165 compounds and identified 126 hits that could be obtained commercially for further characterization. When tested at 25 μm inhibitor in the presence of 1 mm 6-phosphofructose-aspartate, FraB activity was reduced ~ 30-100% by 65 compounds. Guided by preliminary cell-based data, we further characterized six compounds (one triazolidine, two thiadiazolidines, and three triazolothiadiazoles) and found them to exhibit IC₅₀ values from ~ 3 to 100 μm and K_I (inhibitor constant) values from ~ 1 to 29 μm. Native mass spectrometry revealed that all three triazolothiadiazoles were capable of binding FraB; we also obtained evidence that one of the triazolothiadiazoles binds FraB even in the presence of substrate. The recurrence of multiple pharmacophores bolsters prospects for farming more hits from compound libraries and for designing therapeutics against nontyphoidal Salmonella.</p>","PeriodicalId":12187,"journal":{"name":"FEBS Open Bio","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143406498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A potential tumor suppressor role of PLK2 in glioblastoma.","authors":"Xiangping Xia, Peirui Wang, Hua Xiao, Qishan Ran, Yan Li, Shengtao Yao","doi":"10.1002/2211-5463.70000","DOIUrl":"https://doi.org/10.1002/2211-5463.70000","url":null,"abstract":"<p><p>Glioblastoma (GBM) is a highly malignant brain tumor with limited treatment options. Polo-like kinase 2 (PLK2), a member of the polo-like kinase family, has been variably implicated in cancer, but its role in GBM has not been fully elucidated. We utilized RNA-seq data from multiple databases, including Gene Expression Omnibus (GEO), the Cancer Genome Atlas (TCGA), and the Chinese Glioma Genome Atlas (CGGA), and conducted experiments on human glioma cell lines to explore PLK2's expression and function. The effects of PLK2 overexpression on GBM cell viability, proliferation, migration, cell cycle, and apoptosis were assessed, and the tumorigenic potential of PLK2 was evaluated in a mouse model. PLK2 was consistently downregulated in GBM tissues compared to normal brain tissues across several datasets. Overexpression of PLK2 in GBM cell lines U87MG and U251 reduced their tumorigenic potential and enhanced cell cycle arrest and apoptosis, with significant reductions observed in apoptosis markers. Our findings suggest that PLK2 may potentially function as a tumor suppressor in GBM. Hence, PLK2 overexpression could potentially be leveraged as a therapeutic strategy to inhibit tumor progression and enhance apoptosis, providing new avenues for GBM treatment.</p>","PeriodicalId":12187,"journal":{"name":"FEBS Open Bio","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143382080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acacetin reduces endoplasmic reticulum stress through the P-eNOS/PERK signaling pathway to attenuate MGO-induced vascular endothelial cell dysfunction.","authors":"Zhen Zhang, Kaien Hu, Zhaohui Fang, Sihai Wang, Jie Chen, Dengke Yin, Caiyun Zhang, Gefei Ma","doi":"10.1002/2211-5463.70004","DOIUrl":"https://doi.org/10.1002/2211-5463.70004","url":null,"abstract":"<p><p>Diabetic macrovascular disease is one of the most morbid and deadly complications of diabetes. Endothelial dysfunction plays a key role in diabetic macrovascular complications and endothelial cell apoptosis is one of the key indicators of endothelial dysfunction. Methylglyoxal (MGO), a highly reactive dicarbonyl compound generated during glycolysis, is related to the pathogenesis of cardiovascular diseases and may also promote endothelial dysfunction. Acacetin (ACA) is a naturally occurring flavonoid that can inhibit apoptosis, oxidative stress and inflammation to slow the progression of coronary heart disease; however, its effects on endothelial dysfunction are unknown. The present study investigated whether ACA may ameliorate MGO-induced endothelial dysfunction in human umbilical vein endothelial cells. The results revealed that the viability and apoptosis of human umbilical vein endothelial cells induced by MGO decreased after ACA treatment, which was reflected in the expression levels of the apoptosis-related proteins b-cell lymphoma 2 (Bcl-2)-associated death, Bcl-2-associated x protein and Bcl-2. Additionally, ACA downregulated the expression of key protein markers of MGO-induced endoplasmic reticulum stress, physical evidence recovery kit, eukaryotic initiation factor 2 alpha, activating transcription factor 4 and C/EBP homologous protein, with which calcium inward currents may be closely related. ACA significantly downregulated the MGO-induced expression of the cytosolic calcium channel proteins stromal interaction molecule 1, transient receptor potential canonical 1, ORAI calcium release-activated calcium modulator 1, transient receptor potential vanilloid 1 and 4, and the trans-endoplasmic reticulum membrane protein, transmembrane and coiled-coil domains 1. Finally, ACA increased the expression of phosphorylated endothelial nitric oxide synthase (Ser1177), thus increasing the expression of nitric oxide in endothelial cells. Overall, acacetin could reduce endoplasmic reticulum stress through the phosphorylated-endothelial nitric oxide/physical evidence recovery kit signaling pathway to attenuate MGO-induced vascular endothelial cell dysfunction. These findings may hold potential for the use of acacetin in diabetic macrovascular complications.</p>","PeriodicalId":12187,"journal":{"name":"FEBS Open Bio","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143382025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HDAC4 regulates apoptosis in Acan-Cre^ERT2;HDAC4^d ^/d mice with osteoarthritis by downregulating ATF4.","authors":"Jingrui Huang, Yukun Xu, Yujia Li, Yiming Pang, Xueting Ding, Raorao Zhou, Dan Liang, Xianda Che, Yuanyu Zhang, Chunfang Wang, Wenjin Li, Pengcui Li","doi":"10.1002/2211-5463.13965","DOIUrl":"https://doi.org/10.1002/2211-5463.13965","url":null,"abstract":"<p><p>Several studies have previously shown that histone deacetylase 4 (HDAC4) can regulate endoplasmic reticulum stress-induced apoptosis through the activating transcription factor 4 (ATF4)/CAAT/enhancer binding protein homologous (CHOP) signaling pathway, thereby affecting the progression of osteoarthritis (OA). The present study investigated the regulatory mechanism of HDAC4 in chondrocyte apoptosis in OA using Acan-Cre^ERT2;HDAC4^fl/fl gene knockout mice. Forty mice were divided into four groups: TM-DMM group [tamoxifen (TM) injection at 2 months of age and destabilization of the medial meniscus (DMM) surgery at 3 months], TM-sham group (TM injection at 2 months of age and sham surgery at 3 months), no TM-DMM group (corn oil injection at 2 months of age and DMM surgery at 3 months) and no TM-sham group (corn oil injection at 2 months of age and sham surgery at 3 months). Apoptosis and cartilage damage were assessed through imaging, histological analysis, immunohistochemistry, reverse transcriptase-PCR and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining. HDAC4 knockdown resulted in increased osteophyte formation, significant narrowing of the joint space and increased articular cartilage damage. Furthermore, expression levels of key apoptosis-related markers, ATF4, CHOP, caspase-3 and caspase-9, were significantly higher in the TM groups than in their respective control groups. Taken together, our results suggest that HDAC4 deficiency leads to increased apoptosis induced by the ATF4/CHOP signaling pathway in the pathogenesis of OA. Therefore, upregulation of HDAC4 may represent a potential therapeutic strategy.</p>","PeriodicalId":12187,"journal":{"name":"FEBS Open Bio","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143079174","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural Bioinformatics: exciting times in a rapidly evolving field","authors":"Cláudio M. Soares,&nbsp;Diana Lousa","doi":"10.1002/2211-5463.13968","DOIUrl":"10.1002/2211-5463.13968","url":null,"abstract":"<p>Structural Bioinformatics is a multidisciplinary field at the intersection of chemistry, physics, biology, and computer science. Its methods and approaches have been crucial in advancing scientific knowledge and breaking new ground. By extracting valuable insights from experimental data, generating predictions that accelerate research and reduce costs, and offering novel insights and testable hypotheses, Structural Bioinformatics plays a pivotal role in modern science. The field is undergoing transformative advancements, driven by developments in areas such as Artificial Intelligence. This special issue of <i>FEBS Open Bio</i> features five mini-review articles by leading experts, providing an overview of some of the most recent advancements in Structural Bioinformatics.</p>","PeriodicalId":12187,"journal":{"name":"FEBS Open Bio","volume":"15 2","pages":"200-201"},"PeriodicalIF":2.8,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/2211-5463.13968","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143079179","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regorafenib as a potential drug for severe COVID-19: inhibition of inflammasome activation in mice.","authors":"Ju Hwan Jeong, Sun-Ok Kim, Seong Cheol Min, Eung-Gook Kim, Min-Suk Song, Eun-Young Shin","doi":"10.1002/2211-5463.70002","DOIUrl":"https://doi.org/10.1002/2211-5463.70002","url":null,"abstract":"<p><p>SARS-CoV-2 infection can lead to severe COVID-19, particularly in elderly individuals and those with compromised immunity. Cellular senescence has been implicated as a key pathogenic mechanism. This study investigated the therapeutic potential of regorafenib, a previously characterized senomorphic drug, for severe COVID-19. SARS-CoV-2 virus-infected K18-hACE2 mice, overexpressing the human ACE2 receptor, exhibited 100% mortality by 10 days post infection. Regorafenib treatment significantly improved survival rates, approximately 43% remaining alive. Mechanistically, regorafenib effectively suppressed type I and II interferon and cytokine signaling. Notably, regorafenib inhibited NLR family pyrin domain containing 3 (NLRP3) inflammasome activation, a key driver of the cytokine storm associated with severe COVID-19. Our findings elucidate the molecular mechanisms underlying therapeutic effects of regorafenib and suggest its potential use as a promising treatment option for severe COVID-19.</p>","PeriodicalId":12187,"journal":{"name":"FEBS Open Bio","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143079176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}