Research square最新文献

{"title":"Democratizing cardiac imaging with an automated magnetic resonance exam.","authors":"Danielle Kara, Ashmita Deb, Hoa Le, Daniel Wee, Makiya Nakashima, Mohsen Darayi, Tassia Ribeiro Salles Moura, Mary Robakowski, Heather Kohut, Madihah Kazim, Yuncong Mao, Lifu Deng, Fayez Kanj, Yea-Lyn Pak, Zackary Goff, Angel Houston, Kathy Kohut, Dingheng Mai, Thomas Garrett, Emma Wexler, Jeffrey Mlakar, Andrew Dupuis, Yiling Fan, Masafumi Sugawara, Ellen Roche, Mark Griswold, Richard Grimm, Samir Kapadia, Lars Svensson, Oussama Wazni, Stephen Jones, Hiroshi Nakagawa, H W Wilson Tang, Michael Bolen, Daniel Lockwood, Debkalpa Goswami, Deborah Kwon, David Chen, Christopher Nguyen","doi":"10.21203/rs.3.rs-6857034/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-6857034/v1","url":null,"abstract":"<p><p>Advanced imaging of the heart, including cardiovascular magnetic resonance imaging (CMR), has revolutionized the diagnosis and prognosis for cardiovascular disease ^1-3 . For the past 40 years, CMR has primarily relied on the acquisition of numerous breath-held 2D images resulting in complex scanner operation, patient discomfort, long scan durations, and cumbersome image interpretation ^4,5 . These limitations constrain CMR use to major academic hospital systems and severely limit patient access to CMR, which makes up < 1% of total cardiovascular imaging despite being represented in two thirds of all AHA/ACC guidelines ^6,7 . By leveraging advanced multidimensional physics and artificial intelligence, we overcome these challenges by developing a 30-minute end-to-end automated CMR exam (AutoCMR) that delivers 4D anatomical, functional, and tissue characterization of the whole heart in a single click without breath-holds. AutoCMR was rigorously validated in three cohorts: preclinical large animals, patients scanned in an academic hospital setting with over 40 years of CMR experience, and patients scanned in a community health center with no prior CMR experience. While providing simplified CMR acquisition and automated analysis, we demonstrated that AutoCMR was not significantly different than conventional CMR in imaging biomarkers and human interpretation. With its 4D whole thoracic coverage, we further showcased that AutoCMR can enable next generation patient analytics including personalized digital twins, 3D printing, virtual reality, and automated clinical structured summaries. Due to its inherent scalability, we anticipate AutoCMR will promote the democratization of CMR, increasing patient access for all including underserved health communities, while enabling powerful downstream cutting-edge technologies aimed at personalized medicine.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12288535/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144710502","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Subcutaneous administration of adipose-tropic gene therapy for congenital leptin deficiency.","authors":"Lei Cao, Wei Huang, Min Xiao, Xunchang Zou","doi":"10.21203/rs.3.rs-7030870/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-7030870/v1","url":null,"abstract":"<p><p>AAV-based gene therapy targeting adipose tissue has been underdeveloped due to lack of adipose-tropic AAV vectors with sufficient transduction efficiency. We previously demonstrated that an engineered capsid variant of Rec2 capsid with F503Y, Y708D and K709I substitution (named V7 capsid) exhibited highly selective adipo-tropism while ablating liver transduction upon intraperitoneal injection or intravenous injection. In this study, we investigated the feasibility of subcutaneous administration of V7 vector harboring human leptin (V7-LEP) in a congenital leptin deficiency model <i>ob/ob</i> mice. Subcutaneous administration of V7-LEP vector at a low dose of 4x10 ¹⁰ viral genome per mouse restored circulating leptin levels and completely normalized metabolic abnormalities associated with leptin deficiency. In an ongoing long-term experiment, one-time subcutaneous administration of V7-LEP to extreme obese <i>ob/ob</i> mice has led to sustained weight loss at least up to 9 months post injection associated with stable circulating human leptin levels throughout the long-term study. These data indicate subcutaneous injection is a feasible and relevant administration route for gene therapy targeting adipose tissue, and V7-LEP is highly efficacious for congenital leptin deficiency and potentially other lipodystrophy disorders with leptin deficiency.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12288548/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144710514","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vagus nerve stimulation modulates synaptic plasticity induced by cocaine- seeking in reward-related circuitry.","authors":"Reza Arezoomandan, Lily Vu, Christopher Driskill, Sven Kroener","doi":"10.21203/rs.3.rs-7014180/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-7014180/v1","url":null,"abstract":"<p><p>Cocaine use alters brain networks and connections, impairing inhibitory control over drug-seeking. Cortical-limbic circuits, including the infralimbic (IL), prelimbic (PL) cortices, and basolateral amygdala (BLA), regulate extinction learning and drug-seeking via projections to the nucleus accumbens (NAc). Vagus nerve stimulation (VNS) paired with extinction enhances learning and reduces reinstatement, but its effects on extinction-related networks remain unclear. This study examined how cocaine and VNS affect plasticity in relapse-related pathways. Evoked local field potentials (eLFP) were recorded in the IL, NAc core, and NAc shell following self-administration or reinstatement sessions. In the BLA-IL pathway, cocaine-treated (COC) and sham-VNS (SHAM) groups exhibited the highest baseline eLFP amplitudes and increased long-term potentiation (LTP) induction, which VNS restored to yoked-saline (YS) levels. In the PL-NAc core pathway, high-frequency stimulation (HFS) had no effect on EFPs in VNS-treated animals, significantly differing from the long-term depression (LTD) observed in COC and SHAM groups, which had the highest baseline eLFP amplitudes. In the IL-NAc shell pathway, VNS-treated rats displayed the largest baseline amplitudes, and unlike YS, COC, and SHAM groups, HFS in the IL induced persistent LTP in the NAc shell. These findings suggest cocaine use and craving induce maladaptive neuroplasticity within cortical-limbic circuits, and VNS may modulate these changes, contributing its beneficial effects in preventing reinstatement.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12288537/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144710520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Germline polymorphisms in the immunoglobulin kappa and lambda loci explain variation in the expressed light chain antibody repertoire.","authors":"Corey Watson, Eric Engelbrecht, Oscar Rodriguez, William Lees, Zachary Vanwinkle, Kaitlyn Shields, Steven Schultze, William Gibson, David Smith, Uddalok Jana, Swati Saha, Ayelet Peres, Gur Yaari, Melissa Smith","doi":"10.21203/rs.3.rs-6994086/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-6994086/v1","url":null,"abstract":"<p><p>Variation in antibody (Ab) responses contributes to variable disease outcomes and therapeutic responsiveness, the determinants of which are incompletely understood. This study demonstrates that polymorphisms in immunoglobulin (IG) light chain loci dictate the composition of the Ab repertoire, establishing fundamental baseline differences that preclude functional Ab-mediated responses. Using long-read genomic sequencing of the IG kappa (IGK) and IG lambda (IGL) loci, we comprehensively resolved genetic variation, including novel structural variants, single nucleotide variants, and gene alleles. By integrating these genetic data with Ab repertoire profiling, we found that all forms of IG germline variation contributed to inter-individual gene usage differences for >70% of light chain genes in the repertoire, directly impacting the amino acids of expressed light chain transcripts, including complementarity determining region domains. The genomic locations of usage-associated variants in both intergenic and coding regions indicated that IG polymorphisms modulate gene usage via diverse mechanisms, likely including the modulation of V(D)J recombination, heavy and light chain pairing biases, and transcription/translation. Finally, relative to IGL, IGK was characterized by more extensive linkage disequilibrium and genetic co-regulation of gene usage, illuminating differential regulatory and evolutionary features between the two light chain loci. These results firmly establish the critical contribution of IG light chain polymorphism in Ab repertoire diversity, with important implications for investigating Ab responses in health and disease.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12288531/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144710505","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elevated apolipoprotein C3 heightens atherosclerosis risk by mediating arterial accumulation of free cholesterol and local inflammation in diabetes.","authors":"Karin Bornfeldt, Jenny Kanter, Cheng-Chieh Hsu, Farah Kramer, Baohai Shao, Tomas Vaisar, Laura den Hartigh, Abigail Reed, Jason Luo, Alan Tran, Jingjing Tang, Henry Mangalapalli, Jocelyn Cervantes, Masami Shimizu-Albergine, Peter Reaven, Juraj Koska, Majken Jensen, Brandon Davies, Edward Fisher, Nicholas Davidson, Nathan Stitziel, Adam Mullick, Ira Goldberg","doi":"10.21203/rs.3.rs-6979508/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-6979508/v1","url":null,"abstract":"<p><p>Cardiovascular outcome trials are being considered for therapeutics that silence apolipoprotein C3 (APOC3) or angiopoietin-like 3 (ANGPTL3) because of their abilities to lower triglyceride-rich lipoproteins (TRLs) and their remnants in individuals with increased cardiovascular disease (CVD) risk1-4. Here we demonstrate that plasma APOC3 predicts CVD events in individuals with diabetes more strongly than in those without diabetes. Accordingly, plasma APOC3 levels are elevated, clearance of TRLs/remnants is slowed, and plasma TRL remnants are increased in two mouse models of diabetes-accelerated atherosclerosis. Silencing mouse APOC3 by a liver-targeted antisense oligonucleotide lowers both cholesterol and triglycerides carried by TRL/remnants and LDL and prevents aortic free cholesterol accumulation in diabetes, while ANGPTL3 silencing reduces triglycerides. Single-cell RNA-sequencing revealed that APOC3 silencing prevents a majority of diabetes-induced pathways in macrophages, endothelial cells, and smooth muscle cells, with inflammation as a major predicted upstream regulator, adding promise to APOC3 as a CVD target in diabetes.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12288534/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144710504","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modulation of IRAK4 as a Therapeutic Strategy Against Monosodium Urate- and Xanthine-Induced Inflammation in Macrophages and HepG2 Cells.","authors":"Sadiq Umar, Huan T Chang, Mark Maienschein-Cline, Sriram Ravindran","doi":"10.21203/rs.3.rs-6908346/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-6908346/v1","url":null,"abstract":"<p><p><b>Background</b> Interleukin-1 receptor-associated kinase 4 (IRAK4) is a pivotal mediator of toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling, critically involved in innate immune activation and pro-inflammatory cytokine production. Dysregulated IRAK4 activity contributes to chronic inflammation in both immune and non-immune cells. In this study, we evaluated the immunomodulatory potential of a selective IRAK4 inhibitor on monosodium urate (MSU) crystals-stimulated macrophages and xanthine-challenged HepG2 cells to assess its therapeutic potential. <b>Methods</b> Human PBMCs were pretreated with 1 µM IRAK4 inhibitor (IRAK4i) overnight, followed by stimulation with 100 µg/ml MSU for either 30 minutes or 24 hours. Conditioned medium was collected for ELISA and RNA for qPCR to quantify pro- and anti-inflammatory factors. Cell lysates were prepared to analyze various TLR/IL-1β signaling proteins, including phosphorylated IRAK4, P38, ERK, and JNK. Phagocytosis was assessed using a Vybrant™ phagocytosis assay kit in PBMCs. We also utilize HepG2 cells and pretreated with 1 µM IRAK4 inhibitor (IRAK4i) overnight, followed by stimulation with 2.5mM of xanthine for 24 hours to assess the expression of cytokine and xanthine oxidoreductase. <b>Results</b> Primary macrophages and HepG2 cells were treated with a potent IRAK4 inhibitor in the presence and absence of MSU or xanthine. In macrophages, IRAK4 inhibition significantly reduced the expression of TNF-α, IL-6, and IL-1β at both mRNA and protein levels, while promoting polarization toward an anti-inflammatory (M2-like) phenotype alongside reduced activation of NF-κB and MAPK pathways. In HepG2 cells, IRAK4 blockade attenuated xanthine-induced expression of xanthine dehydrogenase and inflammatory cytokines. <b>Conclusion</b> These findings demonstrate the dual anti-inflammatory effect of IRAK4 inhibition in both immune and hepatic cells and suggest a promising strategy to mitigate inflammation in gout.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12288545/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144710511","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cross-tissue immune profiling of APOE ε4 reveals early dysregulation in Alzheimer's disease.","authors":"Caitlin Finney, Artur Shvetcov, Shannon Thomson, Mark Graham, Brittany Hauger, Jessica Keller, Christine Smoyer, Sarah Tague, Ann-Na Cho, Farhad Imam, Varsha Krish, Global Neurodegeneration Proteomics Consortium Global Neurod Consortium, Matthew Taylor, Jonathan Mahnken, Debra Sullivan, Joanne Reed, Jeffrey Burns, Chad Slawson, Russell Swerdlow, Heather Wilkins","doi":"10.21203/rs.3.rs-7089423/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-7089423/v1","url":null,"abstract":"<p><p>APOE ε4 is the strongest genetic risk factor for late-onset Alzheimer's disease (AD), but its contribution to disease pathogenesis remains incompletely understood. Here, we integrate proteomic profiling of plasma, cerebrospinal fluid (CSF), and brain tissue from over 10,000 individuals to define the immune phenotype associated with APOE ε4. We identify a conserved, allele dose-dependent pro-inflammatory immune signature across peripheral and central tissues independent of AD diagnosis. This signature is enriched in adaptive immune cells and white matter-resident glial and vascular cells. It also emerges in patient-derived cortical organoids prior to amyloid-β and tau pathology, supporting a causal, genotype-driven mechanism. Cross-tissue comparisons reveal shared innate and antiviral responses alongside tissue-specific immune signaling. Notably, a 12-week medical ketogenic diet partially reversed the APOE ε4 immune signature. These findings position immune dysregulation as an early and tractable driver of AD risk in APOE ε4 carriers with direct implications for targeted prevention strategies.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12288544/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144710501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Systematic evaluation of analytical methods for CSF proteomics.","authors":"Aastha Aastha, Leonardo Jose Monteiro Macedo Filho, Michael Woolman, Vladimir Ignatchenko, Alexander Keszei, Gabriela Remite-Berthet, Alireza Mansouri, Thomas Kislinger","doi":"10.21203/rs.3.rs-7031998/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-7031998/v1","url":null,"abstract":"<p><p>Cerebrospinal fluid (CSF) provides a unique window into brain pathology, yet challenges in unbiased mass-spectrometric (MS) discovery persist due to sample complexity and the need for optimized analytical workflows. Multiple laboratory workflows have been developed for CSF proteomics, each with distinct advantages for specific applications. To interrogate which laboratory workflow is most suitable for this biological matrix, we benchmarked five orthogonal sample-preparation strategies-MStern, Proteograph™ nanoparticle enrichment (Seer), <i>N</i> -glycopeptide capture (N-Gp), and two extracellular-vesicle (EV) fractions isolated by differential ultracentrifugation (P20- and P150-EV)-in CSF from 19 patients with central nervous system lymphoma. The protocols span a practical spectrum of input volume (6000-50 µL), hands-on time, and reagent cost, enabling informed method selection for translational applications. In total we performed 82 LC-MS/MS experiments and detected over 38,000 unique peptides and more than 3000 proteins across all modalities. Seer achieved the best proteomic depth (~ 17,000 unique peptides) and the tightest detection across samples, followed by P20-EV (~ 9,000), MStern (~ 5,500), P150-EV (~ 5,000), and N-Gp (~ 1,000). None of the methods introduced systematic bias in peptide or protein isoelectric point or hydrophobicity, yet each selectively highlighted distinct biological niches: P20-EVs favoured mitochondrial signatures, N-Gp capture lysosomal and plasma membrane signatures and Seer enhanced nuclear representation. These findings demonstrate that no single protocol suffices for every research question; instead, workflow selection should align with sample-volume constraints, budget and biological question. Our comparative framework empowers investigators to match CSF proteomics strategies to specific neuro-oncological objectives, thereby accelerating the translation of CSF biomarkers into clinically actionable assays.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12288533/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144710516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Delphi Study to prioritize implementation strategies to increase the adoption of screening and referral for brain injury among survivors of intimate partner violence and sexual assault within community-based organizations.","authors":"Shireen S Rajaram, Emiliane Lemos Pereira, Kathy Chiou, Peggy Reisher, Christopher Wichman, Megan N Miller, Paul A Estabrooks","doi":"10.21203/rs.3.rs-6925920/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-6925920/v1","url":null,"abstract":"<p><p><b>Background</b> Women who experience intimate partner violence (IPV) are at a high risk for injuries to the head, neck, and face that can result in a traumatic brain injury (BI). Despite increasing evidence of the high risk for BI in this vulnerable population, BI screenings remain critically under-implemented in community-based organizations (CBOs) serving IPV survivors. The aim of this community-engaged dissemination and implementation project was to co-identify implementation strategies to increase the adoption of brain injury (BI) screening and referral within intimate partner violence (IPV)-serving CBOs. <b>Methods</b> We used a modified Delphi method to prioritize 47 CBO relevant strategies from the Expert Recommendations for Implementation Change compendium to increase the adoption of BI screening and referral among IPV-serving CBOs. In Round-1, 14 Community-campus advisory board (CAB) members, including representatives from 10 CBOs prioritized relevant strategies in a virtual meeting. In Round-2, 62 CBOs staff members responded to a survey to refine a subset of prioritized strategies to 6-8 primary strategies that could be tested across the CBOs. <b>Results</b> CAB participants identified 21 strategies as particularly relevant to CBOs including 4 educational, 2 technical assistance, 5 staff and leadership, 4 management and evaluation, and 6 organizational workflow strategies. Survey responses indicated rated 7 of the 21 strategies were most consistently rated as relevant and feasible. The final list of 7 strategies included training opportunities, ongoing consultation, developing implementation plans, establishing local screening and referral protocols, soliciting survivor feedback, promoting adaptability, and tailoring strategies to CBOs contexts. <b>Conclusions</b> This study highlights the importance of creating tailored implementation strategies within IPV-serving CBOs to enhance the adoption of brain injury screening and referral protocols. The identified strategies offer valuable insights into optimizing support for IPV survivors and advancing public health interventions.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12288521/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144710485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Trimeric superoxide dismutase 1 antibody as a universal biomarker for ALS.","authors":"Nikolay Dokholyan, Brianna Hnath, Rachel Dokholyan, Zachary Simmons","doi":"10.21203/rs.3.rs-6941118/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-6941118/v1","url":null,"abstract":"<p><p>Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that leads to the loss of motor neurons, resulting in paralysis and death. Currently, there are no specific biomarkers available for diagnosing ALS. As a result, diagnosis currently relies on excluding other conditions, which forces patients to endure months or even years of uncertainty. The absence of a specific, reliable diagnostic tool has hindered both early intervention and therapeutic progress. Here we develop a novel synthetic antibody that can detect a toxic form of a known protein linked to ALS. This trimeric assembly of superoxide dismutase 1 (SOD1) is a soluble, structurally distinct oligomer that is highly toxic in cell models. The antibody selectively binds this trimer and differentiates individuals with the disease from healthy people and from those with other neurodegenerative diseases (Alzheimer's and Parkinson's disease). This breakthrough provides the first disease-specific diagnostic tool for this condition and reveals a shared pathological signature across patients, even in cases without genetic mutations. After decades without a specific diagnostic tool, this antibody signifies a long-awaited breakthrough, finally offering clinicians and researchers a reliable window into ALS pathology.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12288539/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144710519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}