Biochemistry and Biophysics Reports最新文献

{"title":"Characterizing carbonate mineral-forming bacterial strains and their carbonic anhydrase activities in two coastal sabkhas","authors":"Khaled Naja ,&nbsp;Sara H. Alhadidi ,&nbsp;Hadil Elsayed ,&nbsp;Jassim Abdulla A. Al-Khayat ,&nbsp;Fadhil Sadooni ,&nbsp;Hamad Al Saad Al-Kuwari ,&nbsp;Zulfa Ali Al Disi","doi":"10.1016/j.bbrep.2025.102064","DOIUrl":"10.1016/j.bbrep.2025.102064","url":null,"abstract":"<div><div>The enzyme carbonic anhydrase (CA) plays a key role in carbonate mineral formation by facilitating the interconversion between CO₂ and bicarbonate ions, thus influencing carbonate precipitation processes in natural environments. This study investigates the biomineralization potential of <em>Virgibacillus</em> strains isolated from two distinct coastal sabkhas in Qatar—Dohat Faishakh Sabkha (DFS) and Khor Al-Adaid Sabkha (KAS)—to better understand the enzymatic mechanisms driving carbonate formation in hypersaline environments. The isolated strains were evaluated for mineral formation and CA activity using three artificial media designed to simulate natural conditions: MD1, seawater-based with tryptone (SWTr), and evaporated seawater-based with tryptone (EWTr). While all strains demonstrated the ability to form minerals in MD1, only <em>Virgibacillus salarius</em> and <em>Virgibacillus marismortui</em>, both exclusive to DFS, exhibited robust mineral precipitation in SWTr and EWTr media. These strains also showed significantly higher CA activity compared to <em>Virgibacillus chiguensis</em> and <em>Virgibacillus dokdonensis</em>, which were present in both sabkhas but displayed limited mineralization and low enzymatic activity under saline conditions.</div><div>Statistical analyses, including ANOVA and principal component analysis (PCA), confirmed the significant role of CA activity and salinity in modulating biomineralization potential among these strains. This research underscores the potential of CA-driven biomineralization for environmental applications. The ability of <em>V. salarius</em> and <em>V. marismortui</em> to precipitate carbonates under high-salinity conditions positions them as promising candidates for bio-based carbon sequestration technologies.</div></div>","PeriodicalId":8771,"journal":{"name":"Biochemistry and Biophysics Reports","volume":"43 ","pages":"Article 102064"},"PeriodicalIF":2.3,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144138727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interplay between tunneling nanotubes and Wnt Signaling: Insights into cytoskeletal regulation and therapeutic potential","authors":"Tengfei Feng ,&nbsp;Qi Xu ,&nbsp;Shuangshuang Wang ,&nbsp;Dongyu Hou ,&nbsp;Xunwei Wu","doi":"10.1016/j.bbrep.2025.102065","DOIUrl":"10.1016/j.bbrep.2025.102065","url":null,"abstract":"<div><div>Tunneling nanotubes (TNTs) are membranous structures that enable direct intercellular transfer of mitochondria, proteins, RNAs, and signaling molecules, playing key roles in tissue repair, immune coordination, and stress adaptation. Among their critical functions, TNT-mediated mitochondrial transfer rescues metabolically impaired cells, yet the regulatory mechanisms governing TNT formation and function remain incompletely understood. Recent studies highlight the Wnt signaling pathway—a conserved regulator of cell fate, polarity, and cytoskeletal remodeling—as a central modulator of TNT dynamics. Through its canonical (Wnt/β-catenin) and non-canonical (Wnt/PCP and Wnt/Ca²⁺) branches, Wnt signaling orchestrates actin filament organization, bundling, and turnover, all of which are essential for TNT biogenesis and stability. This review critically examines the mechanistic intersection between Wnt signaling and TNTs, with an emphasis on how Wnt-driven cytoskeletal remodeling supports intercellular connectivity. Beyond basic mechanistic insights, we also explore the physiological and pathological relevance of this crosstalk—including its roles in tissue regeneration, immune modulation, cancer progression, and neurodegeneration. While the Wnt–TNT axis offers therapeutic promise, its context-dependent effects demand careful consideration.</div></div>","PeriodicalId":8771,"journal":{"name":"Biochemistry and Biophysics Reports","volume":"43 ","pages":"Article 102065"},"PeriodicalIF":2.3,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144138726","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A comprehensive risk model of disulfidoptosis-related lncRNAs predicts prognosis and therapeutic implications in bladder cancer","authors":"Zhixiong Zhang ,&nbsp;Jinghua Zhong ,&nbsp;Muhammad Sarfaraz Iqbal ,&nbsp;Zhiwen Zeng ,&nbsp;Xiaolu Duan","doi":"10.1016/j.bbrep.2025.102060","DOIUrl":"10.1016/j.bbrep.2025.102060","url":null,"abstract":"<div><h3>Background</h3><div>Disulfidoptosis is an emerging form of regulated cell death; however, the roles of its associated long non-coding RNAs (dr-lncRNAs) in bladder cancer (BLCA) remain poorly characterized. By leveraging the most comprehensive curated dataset of disulfidoptosis-related genes to date, we systematically developed and validated a novel dr-lncRNA signature that elucidates the prognostic significance and immune microenvironmental dynamics in BLCA.</div></div><div><h3>Methods</h3><div>The Cancer Genome Atlas (TCGA) database was utilized to extract significant clinical and RNA sequencing data of BLCA patients. Cox and Lasso regression with several variables was used to create a risk model. ROC, Kaplan-Meier, and nomogram analyses were carefully reviewed for validity. The validated study evaluated intricate interactions between functional enrichment, immune cell infiltration, cancer mutation load, and treatment sensitivity. Unsupervised consensus clustering identified subgroup patterns that reflected immune system alterations, medication susceptibility, and prognosis.</div></div><div><h3>Results</h3><div>Nine lncRNAs significantly correlated with prognosis were collectively identified, subsequently forming the basis for constructing a risk model consisting of seven lncRNAs. The model exhibited significant superiority in predicting patient outcomes, effectively distinguishing between high-risk from low-risk individuals. Functional enrichment analysis uncovered their potential involvement in immune-related biological pathways. Patients in the high-risk group exhibited higher tumor mutation burdens, more active immune functions and a higher sensitivity to chemotherapeutic drugs. Variations among BLCA subgroups were identified by consensus cluster analysis, including clinical characteristics, prognosis, lncRNA expression, immune cell infiltration, and immune checkpoint profiles.</div></div><div><h3>Conclusion</h3><div>The dr-lncRNAs-based risk model presents a promising tool for predicting prognosis and guiding personalized immunotherapy and treatment strategies in BLCA patients.</div></div>","PeriodicalId":8771,"journal":{"name":"Biochemistry and Biophysics Reports","volume":"42 ","pages":"Article 102060"},"PeriodicalIF":2.3,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144135124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spinal cord injury models: Advantages and disadvantages in the view of pathophysiology and clinical significance","authors":"Min-Qi Li ,&nbsp;Qing-Hua Wang ,&nbsp;Chuan-Ming Dong ,&nbsp;Long-Ju Qi","doi":"10.1016/j.bbrep.2025.102063","DOIUrl":"10.1016/j.bbrep.2025.102063","url":null,"abstract":"<div><div>Over recent decades, SCI research has advanced in understanding its pathophysiology and related mechanisms. Researchers developed many rodent SCI models to mimic injury processes, which are crucial for evaluating therapies and understanding pathology. But choosing the right model for specific research is challenging due to distinct pathological changes. This review overviews SCI pathophysiology and examines rodent models. It emphasizes model - related challenges, application value, simulation degrees, and replication of pathologies. It also discusses model advantages and limitations, and references recent reverse-engineering projects, which provide a brand-new perspective for promoting SCI research.</div></div>","PeriodicalId":8771,"journal":{"name":"Biochemistry and Biophysics Reports","volume":"42 ","pages":"Article 102063"},"PeriodicalIF":2.3,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144139339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prognostic value and immune infiltration analysis of a novel lactylation-related gene signature in endometrial cancer","authors":"Liqin Gu ,&nbsp;Chunnian Zhang ,&nbsp;Minjuan Xu ,&nbsp;Fang Peng ,&nbsp;Ruo-Hui Huang ,&nbsp;Deping Luo","doi":"10.1016/j.bbrep.2025.102056","DOIUrl":"10.1016/j.bbrep.2025.102056","url":null,"abstract":"<div><h3>Background</h3><div>Lactylation has been implicated in tumor growth, proliferation, and metastasis; however, its precise relationship with cancer remains poorly understood. This study aims to elucidate the role of lactylation-related genes (LRGs) in the development of endometrial cancer (EC).</div></div><div><h3>Methods</h3><div>We utilized data from The Cancer Genome Atlas (TCGA) database to analyze the expression and mutation patterns of LRGs in EC. Univariate Cox regression analysis and Lasso-Cox regression analysis were employed to identify prognosis-related genes and construct a risk model. EC samples were stratified into high-risk and low-risk groups based on the risk values derived from the model. These groups were validated using both training and validation cohorts. Additionally, we assessed differences in the immune microenvironment, tumor mutation burden (TMB), and drug response between the high-risk and low-risk groups.</div></div><div><h3>Results</h3><div>Differentially expressed genes (DEGs) between EC and control samples were identified, and their intersection with LRGs yielded differentially expressed lactylation-related genes (DLRGs). A total of six prognostic DLRGs (PFKM, H3C1, SIRT3, VIM, WAS, and LSP1) were selected and used to construct an EC risk model. Significant differences in prognosis, immune microenvironment, TMB, and drug sensitivity were observed between the high-expression and low-expression groups.</div></div><div><h3>Conclusion</h3><div>LRGs play a significant role in endometrial cancer by influencing cell growth, the immune microenvironment, and drug response. The six DLRGs included in the risk model may serve as potential prognostic markers and therapeutic targets for EC.</div></div>","PeriodicalId":8771,"journal":{"name":"Biochemistry and Biophysics Reports","volume":"42 ","pages":"Article 102056"},"PeriodicalIF":2.3,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144135125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multidirectional therapeutic effects of synthesized HMGB1 peptide on liver cirrhosis in mice","authors":"Masaki Mito ,&nbsp;Atsunori Tsuchiya ,&nbsp;Soichi Ishii ,&nbsp;Takafumi Tonouchi ,&nbsp;Kaito Furuyama ,&nbsp;Ryo Jinbo ,&nbsp;Nobutaka Takeda ,&nbsp;Hiroyuki Abe ,&nbsp;Katsuto Tamai ,&nbsp;Shuji Terai","doi":"10.1016/j.bbrep.2025.102061","DOIUrl":"10.1016/j.bbrep.2025.102061","url":null,"abstract":"<div><h3>Aim</h3><div>Liver cirrhosis is a serious disease characterized by liver dysfunction and severe fibrosis; however, no breakthrough drugs have effectively improved fibrosis, making it an unmet medical need. We have previously reported that the HMGB1 peptide, synthesized from box A of the HMGB1 protein, ameliorates liver fibrosis and is a promising candidate for fibrosis-improving drugs against liver cirrhosis. In this study, we used spatial analysis to observe treatment-induced changes over time.</div></div><div><h3>Methods</h3><div>Liver cirrhosis was induced in C57BL/6J mice using carbon tetrachloride (CCl4) injections, followed by HMGB1 peptide treatment. To assess the temporal effects of HMGB1 on the liver in a CCl4-induced cirrhosis mouse model, we used GeoMx spatial analysis. We focused on αSMA-positive active hepatic stellate cells (HSCs), F4/80-positive macrophages, and CK8/18-positive hepatocytes to determine how each cell type was affected over time. Statistical analyses were conducted using GraphPad Prism9, with significance set at p &lt; 0.05.</div></div><div><h3>Results</h3><div>In cirrhotic mice, we first observed a decrease in the number of activated HSCs over time, two weeks after treatment initiation. Macrophage-associated genes ceased to induce fibrosis-related pathways early in the treatment. This suggests that the effect of macrophages on fibrosis was weakened by the treatment. We also confirmed that lipid metabolism of hepatocytes may be improved during treatment. Furthermore, <em>Cxcl12</em> and <em>Ccl25</em> expression were induced in the peptide-treated group, indicating possible cell migration to the liver.</div></div><div><h3>Conclusion</h3><div>Over time, macrophages followed by HSCs, showed the most notable changes with treatment, resulting in improved fibrosis. The HMGB1 peptide drug also affected lipid metabolism in hepatocytes, suggesting a positive therapeutic effect on steatohepatitis. Elevated factors that promote cell migration may have also enhanced the healing effect.</div></div>","PeriodicalId":8771,"journal":{"name":"Biochemistry and Biophysics Reports","volume":"42 ","pages":"Article 102061"},"PeriodicalIF":2.3,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144131336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The miR-146a-associated HDAC2 regulation of PI3K is involved in pancreatitis in vitro","authors":"Ding-wen Zhong ,&nbsp;Xiang-tian Zeng ,&nbsp;Wen-hui Chen ,&nbsp;Xian-yu Huang ,&nbsp;Jia-xin Liu ,&nbsp;Yong-hui Liao","doi":"10.1016/j.bbrep.2025.102057","DOIUrl":"10.1016/j.bbrep.2025.102057","url":null,"abstract":"<div><h3>Purpose</h3><div>To investigate the association between miR-146a/HDAC2 and their regulatory roles on the PI3K expression during pancreatitis.</div></div><div><h3>Methods</h3><div>Rat pancreatic AR42J cells were treated with LPS for simulating pancreatitis. Expression levels of inflammatory factors (IL-6, TNF-α) and miR-146a were d<strong>etected to</strong> determine the optimal LPS concentration for establishing an in vitro pancreatitis model<strong>.</strong> Cell proliferation and apoptosis were analyzed using CCK-8 and flow cytometry<strong>.</strong> Immunofluorescence was performed to assess co-localization of HDAC2 and PI3K. ELISA quantified TNF-α and IL-6 levels in cell supernatants. A dual-luciferase assay verified the targeting relationship between miR-146a and HDAC2.</div></div><div><h3>Results</h3><div>Compared to controls, the cell proliferation ability of the pancreatitis model group was decreased, whereas TSA and miR-146a mimic interventions restored proliferation. The expression of IL-6 and TNF-αin the LPS group was higher than that in the control group, and their expression decreases in the TSA and miR-146a mimic intervention group. Besides the dual luciferase detected the targeting relationship between miR-146a and HDAC2, the immunofluorescence showed co-localization of HDAC2 and PI3K.</div></div><div><h3>Conclusions</h3><div>TSA and miR-146a mimic enhance proliferation and reduce inflammation in pancreatitis cells. The miR-146a/HDAC2 axis may mediate therapeutic effects in pancreatitis by modulating the PI3K expression.</div></div>","PeriodicalId":8771,"journal":{"name":"Biochemistry and Biophysics Reports","volume":"42 ","pages":"Article 102057"},"PeriodicalIF":2.3,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144089154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fibrinogen based resuscitation mitigates lung injury in mice with bacterial pneumonia after hemorrhagic shock","authors":"Feng Wu,&nbsp;Jody Cantu,&nbsp;Rosemary A. Kozar","doi":"10.1016/j.bbrep.2025.102054","DOIUrl":"10.1016/j.bbrep.2025.102054","url":null,"abstract":"<div><div>While pneumonia is a common complication following severe trauma, the optimal treatment for this complication remains unclear. Our previous studies have shown that fibrinogen and fresh frozen plasma (FFP) administration have beneficial effects in mitigating lung dysfunction in mice after trauma and hemorrhagic shock (HS), due to the restoration of endothelial syndecan-1. The objective of the current study was to test these two therapeutics in a combined model of HS and pneumonia. We hypothesized they would be equally protective. C57BL/6 mice underwent HS [mean arterial pressure (MAP) of 40–45 mmHg for 1 h] and fluid resuscitation with lactated Ringer's (LR), fibrinogen concentrate (FIB, 5 mg/mouse in LR), and FFP all at 1x bled volume. Mice were then infected by P. aeruginosa [strain PA103, 3 × 10⁴ colony-forming units (CFUs)] via intratracheal instillation. After 24 h, mice were euthanized, and lung tissue, bronchoalveolar lavage (BAL) fluid, and plasma were harvested for assays. HS + P. aeruginosa infection induced increases in permeability, syndecan-1 cleavage, and MMP9 activation in the lungs, and an increase in plasma shed syndecan-1. These alterations were significantly attenuated by fibrinogen but not by FFP, implying that fibrinogen prevented the endothelial injury. Additionally, lung tissue MPO and neutrophil infiltration were significantly decreased after HS + P. aeruginosa. These alterations were reversed by fibrinogen but not by FFP, indicating fibrinogen is able to correct the neutrophil deficiency state caused by HS + P. aeruginosa infection. Taken together, these results suggest that fibrinogen has therapeutic benefit in a model of HS and pneumonia.</div></div>","PeriodicalId":8771,"journal":{"name":"Biochemistry and Biophysics Reports","volume":"42 ","pages":"Article 102054"},"PeriodicalIF":2.3,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144089155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SSR-based molecular characterization of Verticillium wilt resistance in Iranian cotton cultivars","authors":"Sanaz Shahbazi ,&nbsp;Sara Ghaffarian ,&nbsp;Mohammad Razinataj ,&nbsp;Mohammad Reza Zangi ,&nbsp;Rasmieh Hamid ,&nbsp;Bahman Panahi","doi":"10.1016/j.bbrep.2025.102059","DOIUrl":"10.1016/j.bbrep.2025.102059","url":null,"abstract":"<div><div>Verticillium wilt (VW) is one of the most devastating diseases affecting cotton (<em>Gossypium</em> spp.), causing significant yield losses worldwide. The development of resistant cultivars is a primary strategy for managing this disease; however, conventional breeding approaches often encounter challenges in balancing resistance with high yield potential. This study aimed to assess the genetic diversity of 25 cotton cultivars using simple sequence repeat (SSR) markers and to identify key polymorphic markers associated with VW resistance. A total of 16 SSR markers were utilized, of which five (DPL405, DPL752, DPL866, DPL890, and DPL0022) were polymorphic. The polymorphism information content (PIC) values ranged from 0 to 0.49, with DPL405, DPL866, and DPL890 being the most informative. Principal coordinates analysis (PCoA) demonstrated genetic differentiation between resistant and sensitive cultivars, with the first axis explaining 41.19 % of the total variation. Resistant cultivars such as Leader, Golestan, and Arya clustered distinctly from sensitive varieties, confirming the effectiveness of the selected markers in genetic differentiation. Despite the promising results, key limitations include the relatively low overall marker polymorphism and the limited number of SSRs used, which may constrain broader genomic coverage and resolution. Nonetheless, the findings provide valuable insights for cotton breeding programs and highlight the potential of SSR markers in supporting marker-assisted selection (MAS) for Verticillium wilt resistance.</div></div>","PeriodicalId":8771,"journal":{"name":"Biochemistry and Biophysics Reports","volume":"42 ","pages":"Article 102059"},"PeriodicalIF":2.3,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144089153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Benchmarking AlphaMissense pathogenicity predictions against APP, PSEN1, and PSEN2 variants of unknown significance","authors":"Joshua Pillai ,&nbsp;Sophia Liu ,&nbsp;Kijung Sung ,&nbsp;Linda Shi ,&nbsp;Chengbiao Wu","doi":"10.1016/j.bbrep.2025.102049","DOIUrl":"10.1016/j.bbrep.2025.102049","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by progressive cognitive decline. Over 200 pathogenic mutations in <em>amyloid-β precursor protein (APP)</em>, <em>presenilin-1</em> (<em>PSEN1</em>), and <em>presenilin-2</em> (<em>PSEN2</em>), have been implicated in AD. Yet, many rare and common variants have not been completely classified as protective or benign, risk-modifiers, or pathogenic, which is important for research on the disease mechanisms and discovery of treatment methods. The majority of these variants are missense mutations, and there is an active need for computational approaches to accurately predict their molecular consequences. AlphaMissense (AM) is a novel technology that uses population frequency data along with structural and sequential contexts from AlphaFold to predict the pathogenicity of missense mutations. Herein, we sought to evaluate the capabilities of AM on 114 variants of unknown significance (VUS), including 56 missense variants of <em>PSEN1</em>, 25 of <em>APP</em>, and 33 of <em>PSEN2</em> by benchmarking its prediction against their respective Aβ isoform levels <em>in vitro</em>, respectively. We found that the AM scores correlated moderately well with the critical Aβ42/Aβ40 biomarker and Aβ40 levels in the transmembrane proteins compared to weaker correlations in traditional approaches, including Combined Annotation Dependent Depletion (CADD) v1.7, evolutionary model of variant effect (EVE), and Evolutionary Scale Modeling-1b (ESM-1B). Yet, there were non-significant correlations identified with Aβ42 levels in all models. Furthermore, we found that AM does not rely completely on structural contexts from AlphaFold2, as it accurately predicted the effects of known variants on residues with a low predicted local distance difference test (pLDDT) score. Additionally, based on the receiver operating characteristic-area under the curve analysis (ROC-AUC), we found that AM retained a high performance on 263 validated variants of these amyloidogenic genes, and performed the greatest compared to other models for the 114 VUS. We believe this is the first study to provide comprehensive characterization and validation of AM in comparison to the widely utilized pathogenicity scoring models for VUS involved in proteins implicated in AD.</div></div>","PeriodicalId":8771,"journal":{"name":"Biochemistry and Biophysics Reports","volume":"42 ","pages":"Article 102049"},"PeriodicalIF":2.3,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144069322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}