Research Square最新文献

{"title":"[WITHDRAWN] Overlapping Targets of Shh and Gata3 during Craniofacial Development.","authors":"","doi":"10.21203/rs.3.rs-2973064/v1","DOIUrl":"10.21203/rs.3.rs-2973064/v1","url":null,"abstract":"<p><p>The full text of this preprint has been withdrawn by the authors while they make corrections to the work. Therefore, the authors do not wish this work to be cited as a reference. Questions should be directed to the corresponding author.</p>","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10312961/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9763673","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":"Impaired long-range excitatory time scale predicts abnormal neural oscillations and cognitive deficits in Alzheimer's disease.","authors":"Parul Verma, Kamalini Ranasinghe, Janani Prasad, Chang Cai, Xihe Xie, Hannah Lerner, Danielle Mizuiri, Bruce Miller, Katherine Rankin, Keith Vossel, Steven W Cheung, Srikantan Nagarajan, Ashish Raj","doi":"10.21203/rs.3.rs-2579392/v3","DOIUrl":"10.21203/rs.3.rs-2579392/v3","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is the most common form of dementia, progressively impairing memory and cognition. While neuroimaging studies have revealed functional abnormalities in AD, how these relate to aberrant neuronal circuit mechanisms remains unclear. Using magnetoencephalography imaging we documented abnormal local neural synchrony patterns in patients with AD. To identify abnormal biophysical mechanisms underlying these abnormal electrophysiological patterns, we estimated the parameters of a spectral graph-theory model (SGM). SGM is an analytic model that describes how long-range fiber projections in the brain mediate the excitatory and inhibitory activity of local neuronal subpopulations. The long-range excitatory time scale was associated with greater deficits in global cognition and was able to distinguish AD patients from controls with high accuracy. These results demonstrate that long-range excitatory time scale of neuronal activity, despite being a global measure, is a key determinant in the spatiospectral signatures and cognition in AD.</p>","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10055509/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10295369","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":"Economic Burden of Sanfilippo Syndrome in the United States.","authors":"Frederick Ashby, Haesuk Park, Mikael Svensson, Coy D Heldermon","doi":"10.21203/rs.3.rs-3001450/v1","DOIUrl":"10.21203/rs.3.rs-3001450/v1","url":null,"abstract":"<p><strong>Introduction: </strong>Sanfilippo syndrome is a rare disease and fatal genetic disorder with no FDA-approved treatment in the United States (US), and no comprehensive assessment of economic disease burden is available.</p><p><strong>Objectives: </strong>To develop a model to estimate the economic burden associated with Sanfilippo syndrome in the US using direct costs, indirect costs and valued intangibles (disability-adjusted life years, or DALYs) from 2023 onward.</p><p><strong>Design and setting: </strong>A multistage comorbidity model was generated based on Sanfilippo syndrome symptoms, and disability weights from the 2010 Global Burden of Disease Study. Attributable increase in caregiver mental health burden were estimated using data from the CDC National Comorbidity Survey and retrospective studies on caregiver burden. Direct costs were approximated from the 2019 EveryLife Foundation survey, and indirect costs were estimated from Federal income data. Monetary valuations were adjusted to USD 2023 and given a 3% discount rate from 2023 onward.</p><p><strong>Main outcome measures: </strong>Incidence of Sanfilippo syndrome was calculated for each year, and year-over-year DALYs due to patient years lived with disability (YLDs) and years life lost (YLLs) were calculated by comparing to the health-adjusted life expectancy (HALE) in the US. Direct and indirect costs were calculated for each simulated patient from onset of symptoms to death.</p><p><strong>Results: </strong>From 2023-2043, overall economic burden in the US attributable to Sanfilippo syndrome was estimated to be $2.04 billion USD present value (2023) with current standard of care. The burden to individual families exceeded $8 million present value from time of birth per child born with Sanfilippo syndrome.</p><p><strong>Conclusion: </strong>Sanfilippo syndrome is a rare lysosomal storage disease, however the severe burden associated with the disease for individual families demonstrates a considerable cumulative impact. Our model represents the first disease burden value estimate associated with Sanfilippo syndrome, and underscores the substantial morbidity and mortality burden of Sanfilippo syndrome.</p>","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10312916/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10440298","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":"Stressful life events in electronic health records: a scoping review","authors":"Dmitry Scherbakov, Abolfazl Mollalo, Leslie Lenert","doi":"10.21203/rs.3.rs-3458708/v2","DOIUrl":"https://doi.org/10.21203/rs.3.rs-3458708/v2","url":null,"abstract":"Objective. Stressful life events, such as going through divorce, can have an important impact on human health. However, there are challenges in capturing these events in electronic health records (EHR). We conducted a scoping review aimed to answer two major questions: how stressful life events are documented in EHR and how they are utilized in research and clinical care. Materials and Methods. Three online databases (EBSCOhost platform, PubMed, and Scopus) were searched to identify papers that included information on stressful life events in EHR; paper titles and abstracts were reviewed for relevance by two independent reviewers. Results. 557 unique papers were retrieved, and of these 70 were eligible for data extraction. Most articles (n=36, 51.4%) were focused on the statistical association between one or several stressful life events and health outcomes, followed by clinical utility (n=15, 21.4%), extraction of events from free-text notes (n=12, 17.1%), discussing privacy and other issues of storing life events (n=5, 7.1%), and new EHR features related to life events (n=4, 5.7%). The most frequently mentioned stressful life events in the publications were child abuse/neglect, arrest/legal issues, and divorce/relationship breakup. Almost half of the papers (n=7, 46.7%) that analyzed clinical utility of stressful events were focused on decision support systems for child abuse, while others (n=7, 46.7%) were discussing interventions related to social determinants of health in general. Discussion and Conclusions. Few citations are available on the prevalence and use of stressful life events in EHR reflecting challenges in screening and storing of stressful life events.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139315897","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":"Critical evaluation of the reliability of DNA methylation probes on the Illumina MethylationEPIC BeadChip microarrays.","authors":"Wei Zhang, Juan I Young, Lissette Gomez, Michael A Schmidt, David Lukacsovich, Achintya Varma, X Steven Chen, Brian Kunkle, Eden R Martin, Lily Wang","doi":"10.21203/rs.3.rs-3068938/v1","DOIUrl":"10.21203/rs.3.rs-3068938/v1","url":null,"abstract":"<p><p>DNA methylation (DNAm) plays a crucial role in a number of complex diseases. However, the reliability of DNAm levels measured using Illumina arrays varies across different probes. Previous research primarily assessed probe reliability by comparing duplicate samples between the 450k-450k or 450k-EPIC platforms, with limited investigations on Illumina EPIC arrays. We conducted a comprehensive assessment of the EPIC array probe reliability using 138 duplicated blood DNAm samples generated by the Alzheimer's Disease Neuroimaging Initiative study. We introduced a novel statistical measure, the modified intraclass correlation, to better account for the disagreement in duplicate measurements. We observed higher reliability in probes with average methylation beta values of 0.2 to 0.8, and lower reliability in type I probes or those within the promoter and CpG island regions. Importantly, we found that probe reliability has significant implications in the analyses of Epigenome-wide Association Studies (EWAS). Higher reliability is associated with more consistent effect sizes in different studies, the identification of differentially methylated regions (DMRs) and methylation quantitative trait locus (mQTLs), and significant correlations with downstream gene expression. Moreover, blood DNAm measurements obtained from probes with higher reliability are more likely to show concordance with brain DNAm measurements. Our findings, which provide crucial reliable information for probes on the EPIC array, will serve as a valuable resource for future DNAm studies.</p>","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10350239/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9859663","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":"Genotype-based \"virtual\" metabolomics in a clinical biobank identifies novel metabolite-disease associations.","authors":"Minoo Bagheri, Andrei Bombin, Mingjian Shi, Venkatesh L Murthy, Ravi Shah, Jonathan D Mosley, Jane F Ferguson","doi":"10.21203/rs.3.rs-3222588/v1","DOIUrl":"10.21203/rs.3.rs-3222588/v1","url":null,"abstract":"<p><p>Circulating metabolites act as biomarkers of dysregulated metabolism, and may inform disease pathophysiology. A portion of the inter-individual variability in circulating metabolites is influenced by common genetic variation. We evaluated whether a genetics-based \"virtual\" metabolomics approach can identify novel metabolite-disease associations. We examined the association between polygenic scores for 726 metabolites (derived from OMICSPRED) with 1,247 clinical phenotypes in 57,735 European ancestry and 15,754 African ancestry participants from the BioVU DNA Biobank. We probed significant relationships through Mendelian randomization (MR) using genetic instruments constructed from the METSIM Study, and validated significant MR associations using independent GWAS of candidate phenotypes. We found significant associations between 336 metabolites and 168 phenotypes in European ancestry and 107 metabolites and 56 phenotypes among African ancestry. Of these metabolite-disease pairs, MR analyses confirmed associations between 73 metabolites and 53 phenotypes in European ancestry. Of 22 metabolite-phenotype pairs evaluated for replication in independent GWAS, 16 were significant (false discovery rate p<0.05). Validated findings included the metabolites bilirubin and X-21796 with cholelithiasis, phosphatidylcholine(16:0/22:5n3,18:1/20:4) and arachidonate(20:4n6) with inflammatory bowel disease and Crohn's disease, and campesterol with coronary artery disease and myocardial infarction. These associations may represent biomarkers or potentially targetable mediators of disease risk.</p>","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10543429/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41145446","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 brain-bone marrow axis and its implications for chronic traumatic brain injury.","authors":"Rodney M Ritzel, Yun Li, Yun Jiao, Sarah J Doran, Niaz Khan, Rebecca J Henry, Kavitha Brunner, David J Loane, Alan I Faden, Gregory L Szeto, Junfang Wu","doi":"10.21203/rs.3.rs-3356007/v1","DOIUrl":"10.21203/rs.3.rs-3356007/v1","url":null,"abstract":"<p><p>Traumatic brain injury (TBI) causes acute and chronic alterations in systemic immune function which contribute to posttraumatic neuroinflammation and neurodegeneration. However, how TBI affects bone marrow (BM) hematopoietic stem/progenitor cells chronically and to what extent such changes may negatively impact innate immunity and neurological function has not been examined. To further understand the role of BM cell derivatives on TBI outcome, we generated BM chimeric mice by transplanting BM from chronically injured or sham congenic donor mice into otherwise healthy, age-matched, irradiated hosts. After 8 weeks of reconstitution, peripheral myeloid cells from TBI→WT mice showed significantly higher oxidative stress levels and reduced phagocytic activity. At eight months after reconstitution, TBI→WT chimeric mice were leukopenic, with continued alterations in phagocytosis and oxidative stress responses, as well as persistent neurological deficits. Gene expression analysis revealed BM-driven changes in neuroinflammation and neuropathology after 8 weeks and 8 months of reconstitution, respectively. Chimeric mice subjected to TBI showed that longer reconstitution periods were associated with increased microgliosis and leukocyte infiltration. Thus, TBI causes chronic activation and progressive dysfunction of the BM stem/progenitor cell pool, which drives long-term deficits in innate immunity and neurological function, as well as altered sensitivity to subsequent brain injury.</p>","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10543403/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41179790","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":"5'UTR G-quadruplex structure enhances translation in size dependent manner.","authors":"Sua Myong, Chun-Ying Lee, Meera Joshi, Ashley Wang","doi":"10.21203/rs.3.rs-3352233/v1","DOIUrl":"10.21203/rs.3.rs-3352233/v1","url":null,"abstract":"<p><p>Translation initiation in bacteria is frequently regulated by various structures in the 5' untranslated region (5'UTR). Previously, we demonstrated that G-quadruplex (G4) formation in non-template DNA enhances transcription. In this study, we aimed to explore how G4 formation in mRNA (RG4) at 5'UTR impacts translation using a T7-based in vitro translation system and in <i>E. coli.</i> We showed that RG4 strongly promotes translation efficiency in a size-dependent manner. Additionally, inserting a hairpin upstream of the RG4 further enhances translation efficiency, reaching up to a 12-fold increase. We found that the RG4-dependent effect is not due to increased ribosome affinity, ribosome binding site accessibility, or mRNA stability. We proposed a physical barrier model in which bulky structures in 5'UTR prevent ribosome dislodging and thereby increase the translation output. This study provides biophysical insights into the regulatory role of 5'UTR structures in bacterial translation, highlighting their potential applications in tuning gene expression.</p>","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10543253/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41111162","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":"Functional Characterization of Cooperating MGA Mutations in RUNX1::RUNX1T1 Acute Myeloid Leukemia.","authors":"Jeffery Klco, Melvin Thomas, Wenqing Qi, Michael Walsh, Jing Ma, Tamara Westover, Sherif Abdelhamed, Lauren Ezzell, Chandra Rolle, Emily Xiong, Wojciech Rosikiewicz, Beisi Xu, Shondra Pruett-Miller, Allister Loughran, Laura Janke","doi":"10.21203/rs.3.rs-3315059/v1","DOIUrl":"10.21203/rs.3.rs-3315059/v1","url":null,"abstract":"<p><p>MGA (Max-gene associated) is a dual-specificity transcription factor that negatively regulates MYC-target genes to inhibit proliferation and promote differentiation. Loss-of-function mutations in <i>MGA</i> have been commonly identified in several hematological neoplasms, including acute myeloid leukemia (AML) with <i>RUNX1::RUNX1T1,</i> however, very little is known about the impact of these <i>MGA</i> alterations on normal hematopoiesis or disease progression. We show that representative <i>MGA</i> mutations identified in patient samples abolish protein-protein interactions and transcriptional activity. Using a series of human and mouse model systems, including a newly developed conditional knock-out mouse strain, we demonstrate that loss of <i>MGA</i> results in upregulation of MYC and E2F targets, cell cycle genes, mTOR signaling, and oxidative phosphorylation in normal hematopoietic cells, leading to enhanced proliferation. The loss of <i>MGA</i> induces an open chromatin state at promotors of genes involved in cell cycle and proliferation. <i>RUNX1::RUNX1T1</i> expression in Mga-deficient murine hematopoietic cells leads to a more aggressive AML with a significantly shortened latency. These data show that MGA regulates multiple pro-proliferative pathways in hematopoietic cells and cooperates with the RUNX1::RUNX1 T1 fusion oncoprotein to enhance leukemogenesis.</p>","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10543392/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41150131","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":"Rapid intestinal and systemic metabolic reprogramming in an immunosuppressed environment.","authors":"Bing Ma, Samuel J Gavzy, Michael France, Yang Song, Hnin Wai Lwin, Allison Kensiski, Vikas Saxena, Wenji Piao, Ram Lakhan, Jegan Iyyathurai, Lushen Li, Christina Paluskievicz, Long Wu, Marina WillsonShirkey, Emmanuel F Mongodin, Valeria R Mas, Jonathan Bromberg","doi":"10.21203/rs.3.rs-3364037/v1","DOIUrl":"10.21203/rs.3.rs-3364037/v1","url":null,"abstract":"<p><p>Intrinsic metabolism shapes the immune environment associated with immune suppression and tolerance in settings such as organ transplantation and cancer. However, little is known about the metabolic activities in an immunosuppressive environment. In this study, we employed metagenomic, metabolomic, and immunological approaches to profile the early effects of the immunosuppressant drug tacrolimus, antibiotics, or both in gut lumen and circulation using a murine model. Tacrolimus induced rapid and profound alterations in metabolic activities within two days of treatment, prior to alterations in gut microbiota composition and structure. The metabolic profile and gut microbiome after seven days of treatment was distinct from that after two days of treatment, indicating continuous drug effects on both gut microbial ecosystem and host metabolism. The most affected taxonomic groups are Clostriales and Verrucomicrobiae (i.e., <i>Akkermansia muciniphila</i>), and the most affected metabolic pathways included a group of interconnected amino acids, bile acid conjugation, glucose homeostasis, and energy production. Highly correlated metabolic changes were observed between lumen and serum metabolism, supporting their significant interactions. Despite a small sample size, this study explored the largely uncharacterized microbial and metabolic events in an immunosuppressed environment and demonstrated that early changes in metabolic activities can have significant implications that may serve as antecedent biomarkers of immune activation or quiescence. To understand the intricate relationships among gut microbiome, metabolic activities, and immune cells in an immune suppressed environment is a prerequisite for developing strategies to monitor and optimize alloimmune responses that determine transplant outcomes.</p>","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10543476/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41133018","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}