Research square最新文献

{"title":"Characterizing the Impact of the Covid-19 Pandemic on Adults with Autosomal Dominant Polycystic Kidney Disease: A Cross-Sectional Study.","authors":"Alok Shetty, Anthony Atalla, Charalett Diggs, Terry Watnick, Stephen Seliger","doi":"10.21203/rs.3.rs-4406167/v1","DOIUrl":"10.21203/rs.3.rs-4406167/v1","url":null,"abstract":"<p><strong>Background: </strong>The Covid-19 pandemic greatly affected those with chronic diseases, impacting healthcare access and healthcare seeking behaviors. The impact of the pandemic on adults with Autosomal Dominant Polycystic Kidney Disease (ADPKD) has not been investigated.</p><p><strong>Methods: </strong>Participants were recruited from a cohort of 239 ADPKD patients enrolled in a longitudinal study at the University of Maryland. Patients on renal replacement therapy were excluded. N = 66 patients participated in a phone questionnaire from June 2022-December 2022 about ADPKD-related complications, concern about contracting Covid-19, healthcare-seeking behaviors, and telehealth utilization before and after March 2020.</p><p><strong>Results: </strong>N = 34 (51.5%) of participants reported a positive Covid-19 test result and N = 29 (44%) expressed high concern of contracting Covid-19. Those who avoided medical care at least once (N = 17, 25.8%) had similar demographics and ADPKD severity to those who did not, but reported greater telehealth utilization (88.2% vs. 42.9%, p = 0.002), greater use of non-prescribed medication for Covid-19 treatment or prevention (35.3% vs. 8.2%, p = 0.01), and were more likely to contract Covid-19 (76.5% vs. 42.9%, p = 0.02). Among the N = 53 who reported very good or excellent ADPKD disease management pre-pandemic, N = 47(89%) reported no significant change during the pandemic.</p><p><strong>Conclusions: </strong>In this highly educated, high-income cohort with a mean age of 46.1 years, most people reported well-managed ADPKD prior to the pandemic. This may explain why less than half of participants expressed high concern for contracting Covid-19. Overall, there was no significant pandemic-related decline in self-reported ADPKD management, like due to excellent access to, and uptake of, telehealth services. Notably, 1 in 4 participants reported healthcare avoidant behavior, the effect of which may only be seen years from now. Future studies should investigate potential impacts of avoidant behaviors, as well as expand investigation to a more diverse cohort whose care may not have been as easily transitioned to telehealth.</p>","PeriodicalId":94282,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11177968/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141332816","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":"Prevalence of Oropharyngeal Candidiasis and distribution of <i>Candida</i> species among People Living with Human Immunodeficiency Virus in Africa: a systematic review and meta-analysis.","authors":"Benson Musinguzi, Ekwaro A Obuku, Alison Annet Kinengyere, Regina Ndagire, Andrew Baguma, Alex Mwesigwa, Herbert Itabangi, Gerald Mboowa, Obondo James Sande, Beatrice Achan","doi":"10.21203/rs.3.rs-4534730/v1","DOIUrl":"10.21203/rs.3.rs-4534730/v1","url":null,"abstract":"<p><strong>Background: </strong>The incidence of oropharyngeal candidiasis among people living with human immunodeficiency virus in Africa is on the rise. Oropharyngeal candidiasis is mainly caused by <i>C.albicans</i>; however, a shift in the etiology towards non-<i>Candida albicans</i> species is increasing. In addition, there are variations in the epidemiological distribution of <i>Candida</i> species causing oropharyngeal candidiasis among people living with human immunodeficiency virus in Africa.</p><p><strong>Objective: </strong>This review aimed to determine the prevalence of oropharyngeal candidiasis and the distribution of <i>Candida</i> species among people living with human immunodeficiency virus in Africa.</p><p><strong>Materials and methods: </strong>This systematic review protocol was registered in the base PROSPERO database prior to its conduct (CRD42021254473). The Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocol guidelines (PRISMA-P) were followed for this study. The PubMed, Scopus and EMBASE databases were searched to identify published studies published between 1^st January 2000 and 8^th October 2022. The eligible studies were included in the meta-analysis and analyzed using a random effects model. The risk of bias of the included studies was assessed using the Joanna Briggs Institute quality assessment tool for prevalence studies.</p><p><strong>Results: </strong>The database search yielded 370 titles from PubMed (n=192), EMBASE (n=162) and SCOPUS (n=16). Fourteen studies with a total of 3,863 participants were included in the meta-analysis. The pooled prevalence of oropharyngeal candidiasis was 49.0% (95% CI: 37% - 62%). A total of 2,688 <i>Candida</i> isolates were reported; approximately 76.6% (n=2,060) were <i>C. albicans</i>, and 21.7% (n=582) were non-<i>C. albicans</i>. Among the non-<i>Candida albicans</i> species, <i>C</i>. <i>glabrata</i> was the most common isolate (29.6%), followed by <i>C</i>. <i>tropicalis</i> (27.7%), <i>C</i>. <i>krusei</i> (17.0%), <i>C</i>. <i>parapsilosis</i> (8.1%) and <i>C</i>. <i>dubliniensis</i> (5.2%). Out of 14 studies, 7 (50.0%) had a low risk of bias, 5 (35.7%) had a moderate risk of bias, and 2 (14.3%) had a high risk of bias.</p><p><strong>Conclusion: </strong>Almost half of people living with HIV in Africa have oropharyngeal candidiasis, and <i>C. albicans</i> remains the most frequent cause of oropharyngeal candidiasis.</p>","PeriodicalId":94282,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11177986/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141332780","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":"The Neural Bases of Language Processing During Social and Non-Social Contexts: A fNIRS Study of Autistic and Neurotypical Preschool-Aged Children.","authors":"Meredith Pecukonis, Javier Gerson, Hailey Gustafson-Alm, Maegan Wood, Meryem Yücel, David Boas, Helen Tager-Flusberg","doi":"10.21203/rs.3.rs-4450882/v1","DOIUrl":"10.21203/rs.3.rs-4450882/v1","url":null,"abstract":"<p><strong>Background: </strong>Little is known about how the brains of autistic children process language during real-world \"social contexts,\" despite the fact that challenges with language, communication, and social interaction are core features of Autism Spectrum Disorder (ASD).</p><p><strong>Methods: </strong>We investigated the neural bases of language processing during social and non-social contexts in a sample of <i>N</i>=20 autistic and <i>N</i>=20 neurotypical (NT) preschool-aged children, 3 to 6 years old. Functional near-infrared spectroscopy (fNIRS) was used to measure children's brain response to \"live language\" spoken by a live experimenter during an in-person social context (i.e., book reading), and \"recorded language\" played via an audio recording during a non-social context (i.e., screen time). We examined within-group and between-group differences in the strength and localization of brain response to live language and recorded language, as well as correlations between children's brain response and language skills measured by the Preschool Language Scales.</p><p><strong>Results: </strong>In the NT group, brain response to live language was greater than brain response to recorded language in the right temporal parietal junction (TPJ). In the ASD group, the strength of brain response did not differ between conditions. The ASD group showed greater brain response to recorded language than the NT group in the right inferior and middle frontal gyrus (IMFG). Across groups, children's language skills were negatively associated with brain response to recorded language in the right IMFG, suggesting that processing recorded language required more cognitive effort for children with lower language skills. Children's language skills were also positively associated with the difference in brain response between conditions in the right TPJ, demonstrating that children who showed a greater difference in brain response to live language versus recorded language had higher language skills.</p><p><strong>Limitations: </strong>Findings should be considered preliminary until they are replicated in a larger sample.</p><p><strong>Conclusions: </strong>Findings suggest that the brains of NT children, but not autistic children, process language differently during social and non-social contexts. Individual differences in how the brain processes language during social and non-social contexts may help to explain why language skills are so variable across children with and without autism.</p>","PeriodicalId":94282,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11177967/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141332838","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":"Targeting of SUMOylation leads to cBAF complex stabilization and disruption of the SS18::SSX transcriptome in Synovial Sarcoma.","authors":"Konstantinos V Floros, Carter K Fairchild, Jinxiu Li, Kun Zhang, Jane L Roberts, Richard Kurupi, Bin Hu, Vita Kraskauskiene, Nayyerehalsadat Hosseini, Shanwei Shen, Melissa M Inge, Kyllie Smith-Fry, Li Li, Afroditi Sotiriou, Krista M Dalton, Asha Jose, Elsamani I Abdelfadiel, Yanli Xing, Ronald D Hill, Jamie M Slaughter, Mayuri Shende, Madelyn R Lorenz, Mandy R Hinojosa, Benjamin R Belvin, Zhao Lai, Sosipatros A Boikos, Angeliki M Stamatouli, Janina P Lewis, Masoud H Manjili, Kristoffer Valerie, Renfeng Li, Ana Banito, Andrew Poklepovic, Jennifer E Koblinski, Trevor Siggers, Mikhail G Dozmorov, Kevin B Jones, Senthil K Radhakrishnan, Anthony C Faber","doi":"10.21203/rs.3.rs-4362092/v1","DOIUrl":"10.21203/rs.3.rs-4362092/v1","url":null,"abstract":"<p><p>Synovial Sarcoma (SS) is driven by the SS18::SSX fusion oncoprotein and is ultimately refractory to therapeutic approaches. SS18::SSX alters ATP-dependent chromatin remodeling BAF (mammalian SWI/SNF) complexes, leading to the degradation of canonical (cBAF) complex and amplified presence of an SS18::SSX-containing non-canonical BAF (ncBAF or GBAF) that drives an SS-specific transcription program and tumorigenesis. We demonstrate that SS18::SSX activates the SUMOylation program and SSs are sensitive to the small molecule SAE1/2 inhibitor, TAK-981. Mechanistically, TAK-981 de-SUMOylates the cBAF subunit SMARCE1, stabilizing and restoring cBAF on chromatin, shifting away from SS18::SSX-ncBAF-driven transcription, associated with DNA damage and cell death and resulting in tumor inhibition across both human and mouse SS tumor models. TAK-981 synergized with cytotoxic chemotherapy through increased DNA damage, leading to tumor regression. Targeting the SUMOylation pathway in SS restores cBAF complexes and blocks the SS18::SSX-ncBAF transcriptome, identifying a therapeutic vulnerability in SS, positioning the in-clinic TAK-981 to treat SS.</p>","PeriodicalId":94282,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11177989/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141332796","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":"Key features of the innate immune response is mediated by the immunoproteasome in microglia.","authors":"Salman Izadjoo, Kasey E Moritz, Guzal Khayrullina, Elizabeth M Bergman, Brendan M Melvin, Matthew W Stinson, Summer G Paulson, Nikki M McCormack, Kelsey N Anderson, Lunndon A Lewis, Jeremy D Rotty, Barrington G Burnett","doi":"10.21203/rs.3.rs-4467983/v1","DOIUrl":"10.21203/rs.3.rs-4467983/v1","url":null,"abstract":"<p><p>Microglia are the resident immune cells of the central nervous system (CNS). We and others have shown that the inflammatory response of microglia is partially regulated by the immunoproteasome, an inducible form of the proteasome responsible for the generation of major histocompatibility complex (MHC) class I epitopes. While the role of the proteasome in the adaptive immune system is well established, emerging evidence suggests the immunoproteasome may have discrete functions in the innate immune response. Here, we show that inhibiting the immunoproteasome reduces the IFNγ-dependent induction of complement activator C1q, suppresses phagocytosis, and alters the cytokine expression profile in a microglial cell line and microglia derived from human inducible pluripotent stem cells. Moreover, we show that the immunoproteasome regulates the degradation of IκBα, a modulator of NF-κB signaling. Finally, we demonstrate that NADH prevents induction of the immunoproteasome, representing a potential pathway to suppress immunoproteasome-dependent immune responses.</p>","PeriodicalId":94282,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11177974/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141332760","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":"Structures and Strategies for Retaining an International Pediatric Cohort from Birth: Lessons from The Environmental Determinants of Diabetes in the Young (TEDDY) Study.","authors":"Patricia Gesualdo, Jessica Melin, Rachel Karban, Claire Crouch, Michael Killian, Diane Hopkins, Annika Adamsson, Joanna Stock, Suzanne Bennett Johnson, Judith Baxter","doi":"10.21203/rs.3.rs-4421364/v1","DOIUrl":"10.21203/rs.3.rs-4421364/v1","url":null,"abstract":"<p><strong>Background: </strong>Retention of study participants in observational studies is essential to maintaining the representativeness of the population, minimizing selection bias, and assuring sufficient statistical power. The aim of this report is to describe the structures and strategies used to retain participants in The Environmental Determinants of Diabetes in the Young (TEDDY) Study, an observational study of children at increased genetic risk for type 1 diabetes followed in an intense protocol with frequent clinic visits from birth until age 15.</p><p><strong>Methods: </strong>A systematic review of methodologies used to retain research subjects identified four domains: barrier reduction strategies; community building strategies; follow-up/reminder strategies; and tracing strategies. Independent reviewers categorized the retention strategies implemented by the TEDDY Study into each of these domains. Strategies not fitting into any of these categories were placed into a fifth category unique to TEDDY.</p><p><strong>Results: </strong>TEDDY identified over one hundred retention strategies used during the 15 years of follow-up; most could be categorized in these domains. Those unique to TEDDY included (1) study organization and structures to support retention; (2) efforts to meet the changing developmental needs of the TEDDY population, (3) implementation of efforts to address protocol challenges in real-time; and (4) employment of a re-engagement protocol for those who had dropped out of the study.</p><p><strong>Conclusion: </strong>Pediatric cohort studies should include strategies, structures, and resources addressing retention at the study's initiation. It is recommended that child and parent engagement in addition to the developmental needs of the child be an integrated focus of all strategies. Putting mechanisms in place to address protocol and retention challenges in real time would facilitate effectively addressing challenges as they arise.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov Identifier: NCT00279318.</p>","PeriodicalId":94282,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11177994/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141332794","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":"Selective classification with machine learning uncertainty estimates improves ACS prediction: A retrospective study in the prehospital setting.","authors":"Juan Jose Garcia, Rebecca Kitzmiller, Ashok Krishnamurthy, Jessica K Zégre-Hemsey","doi":"10.21203/rs.3.rs-4437265/v1","DOIUrl":"10.21203/rs.3.rs-4437265/v1","url":null,"abstract":"<p><p>Accurate identification of acute coronary syndrome (ACS) in the prehospital sestting is important for timely treatments that reduce damage to the compromised myocardium. Current machine learning approaches lack sufficient performance to safely rule-in or rule-out ACS. Our goal is to identify a method that bridges this gap. To do so, we retrospectively evaluate two promising approaches, an ensemble of gradient boosted decision trees (GBDT) and selective classification (SC) on consecutive patients transported by ambulance to the ED with chest pain and/or anginal equivalents. On the task of ACS classification with 23 prehospital covariates, we found the fusion of the two (GBDT+SC) improves the best reported sensitivity and specificity by 8% and 23% respectively. Accordingly, GBDT+SC is safer than current machine learning approaches to rule-in and rule-out of ACS in the prehospital setting.</p>","PeriodicalId":94282,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11177980/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141332782","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":"Intrinsic <i>Gata4</i> expression sensitizes the aortic root to dilation in a Loeys-Dietz syndrome mouse model.","authors":"Emily E Bramel, Wendy A Espinoza Camejo, Tyler J Creamer, Leda Restrepo, Muzna Saqib, Rustam Bagirzadeh, Anthony Zeng, Jacob T Mitchell, Genevieve L Stein-O'Brien, Albert J Pedroza, Michael P Fischbein, Harry C Dietz, Elena Gallo MacFarlane","doi":"10.21203/rs.3.rs-4420617/v1","DOIUrl":"10.21203/rs.3.rs-4420617/v1","url":null,"abstract":"<p><p>Loeys-Dietz syndrome (LDS) is an aneurysm disorder caused by mutations that decrease transforming growth factor-β (TGF-β) signaling. Although aneurysms develop throughout the arterial tree, the aortic root is a site of heightened risk. To identify molecular determinants of this vulnerability, we investigated the heterogeneity of vascular smooth muscle cells (VSMCs) in the aorta of <i>Tgfbr1</i> ^{<i>M318R</i>/+} LDS mice by single cell and spatial transcriptomics. Reduced expression of components of the extracellular matrix-receptor apparatus and upregulation of stress and inflammatory pathways were observed in all LDS VSMCs. However, regardless of genotype, a subset of <i>Gata4</i>-expressing VSMCs predominantly located in the aortic root intrinsically displayed a less differentiated, proinflammatory profile. A similar population was also identified among aortic VSMCs in a human scRNAseq dataset. Postnatal VSMC-specific <i>Gata4</i> deletion reduced aortic root dilation in LDS mice, suggesting that this factor sensitizes the aortic root to the effects of impaired TGF-β signaling.</p>","PeriodicalId":94282,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11177966/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141332759","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":"Multi-Modality Deep Infarct: Non-invasive identification of infarcted myocardium using composite in-silico-human data learning.","authors":"Rana Raza Mehdi, Nikhil Kadivar, Tanmay Mukherjee, Emilio A Mendiola, Dipan J Shah, George Karniadakis, Reza Avazmohammadi","doi":"10.21203/rs.3.rs-4468678/v1","DOIUrl":"10.21203/rs.3.rs-4468678/v1","url":null,"abstract":"<p><p>Myocardial infarction (MI) continues to be a leading cause of death worldwide. The precise quantification of infarcted tissue is crucial to diagnosis, therapeutic management, and post-MI care. Late gadolinium enhancement-cardiac magnetic resonance (LGE-CMR) is regarded as the gold standard for precise infarct tissue localization in MI patients. A fundamental limitation of LGE-CMR is the invasive intravenous introduction of gadolinium-based contrast agents that present potential high-risk toxicity, particularly for individuals with underlying chronic kidney diseases. Herein, we develop a completely non-invasive methodology that identifies the location and extent of an infarct region in the left ventricle via a machine learning (ML) model using only cardiac strains as inputs. In this transformative approach, we demonstrate the remarkable performance of a multi-fidelity ML model that combines rodent-based in-silico-generated training data (low-fidelity) with very limited patient-specific human data (high-fidelity) in predicting LGE ground truth. Our results offer a new paradigm for developing feasible prognostic tools by augmenting synthetic simulation-based data with very small amounts of in-vivo human data. More broadly, the proposed approach can significantly assist with addressing biomedical challenges in healthcare where human data are limited.</p>","PeriodicalId":94282,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11177985/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141332774","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":"Novel early-onset Alzheimer-associated genes influence risk through dysregulation of glutamate, immune activation, and intracell signaling pathways.","authors":"Carlos Cruchaga, Joseph Bradley, Daniel Western, Ciyang Wang, Eder Lucio Da Fonseca, Achal Neupane, Jiji Kurup, NIcholas Ray, Melissa Jean-Francois, Priyanka Gorijala, Kristy Bergmann, John Budde, Eden Martin, Margaret Pericak-Vance, Michael Cuccaro, Brian Kunkle, John Morris, David Holtzman, Richard Perrin, Adam Naj, Jonathan Haines, Gerard Schellenberg, Victoria Fernandez, Christiane Reitz, Gary Beecham","doi":"10.21203/rs.3.rs-4480585/v1","DOIUrl":"10.21203/rs.3.rs-4480585/v1","url":null,"abstract":"<p><p>Alzheimer Disease (AD) is a highly polygenic disease that presents with relatively earlier onset (≤70yo; EOAD) in about 5% of cases. Around 90% of these EOAD cases remain unexplained by pathogenic mutations. Using data from EOAD cases and controls, we performed a genome-wide association study (GWAS) and trans-ancestry meta-analysis on non-Hispanic Whites (NHW, NCase=6,282, NControl=13,386), African Americans (AA NCase=782, NControl=3,663) and East Asians (NCase=375, NControl=838 CO). We identified eight novel significant loci: six in the ancestry-specific analyses and two in the trans-ancestry analysis. By integrating gene-based analysis, eQTL, pQTL and functional annotations, we nominate four novel genes that are involved in microglia activation, glutamate production, and signaling pathways. These results indicate that EOAD, although sharing many genes with LOAD, harbors unique genes and pathways that could be used to create better prediction models or target identification for this type of AD.</p>","PeriodicalId":94282,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11177996/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141332776","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}