Research Square最新文献

{"title":"The therapeutically actionable long non-coding RNA ‘T-RECS’ is essential to cancer cells’ survival in NRAS/MAPK-driven melanoma","authors":"V. Feichtenschlager, Linan Chen, Yixuan Zheng, Wilson Ho, Martina Sanlorenzo, I. Vujic, Eleanor Fewings, Albert Lee, Christopher Chen, Ciara Callanan, Kevin Lin, Tiange Qu, Dasha Hohlova, M. Vujic, Yeonjoo Hwang, Kevin Lai, Stephanie Chen, Thuan Nguyen, Denise P Muñoz, Y. Kohwi, C. Posch, Adil Daud, Klemens Rappersberger, T. Kohwi-Shigematsu, Jean-Philippe Coppé, S. Ortiz-Urda","doi":"10.21203/rs.3.rs-1297358/v3","DOIUrl":"https://doi.org/10.21203/rs.3.rs-1297358/v3","url":null,"abstract":"Abstract Finding effective therapeutic targets to treat NRAS-mutated melanoma remains a challenge. Long non-coding RNAs (lncRNAs) recently emerged as essential regulators of tumorigenesis. Using a discovery approach combining experimental models and unbiased computational analysis complemented by validation in patient biospecimens, we identified a nuclear-enriched lncRNA ( AC004540.4 ) that is upregulated in NRAS/MAPK-dependent melanoma, and that we named T-RECS . Considering potential innovative treatment strategies, we designed antisense oligonucleotides (ASOs) to target T-RECS . T-RECS ASOs reduced the growth of melanoma cells and induced apoptotic cell death, while having minimal impacton normal primary melanocytes. Mechanistically, treatment with T-RECS ASOs downregulated the activity of pro-survival kinases and reduced the protein stability of hnRNPA2/B1, a pro-oncogenic regulator of MAPK signaling. Using patient- and cell line- derived tumor xenograft mouse models, we demonstrated that systemic treatment with T-RECS ASOs significantly suppressed the growth of melanoma tumors, with no noticeable toxicity. ASO-mediated T-RECS inhibition represents a promising RNA-targeting approach to improve the outcome of MAPK pathway-activated melanoma.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":"27 39","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138624644","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":"ChatGPT to enhance learning in dental education at a historically black medical college","authors":"Khandoker Rahad, Kianna Martin, Ihunna Amugo, Shania Ferguson, Angela Curtis, Anniya Davis, P. Gangula, Qingguo Wang","doi":"10.21203/rs.3.rs-3546693/v2","DOIUrl":"https://doi.org/10.21203/rs.3.rs-3546693/v2","url":null,"abstract":"Abstract The recent rise of powerful large language model (LLM)-based AI tools, exemplified by ChatGPT and Bard, poses a great challenge to contemporary dental education while simultaneously offering a unique resource and approach that potentially complements today’s teaching and learning, where existing widely available learning resources have often fallen short. Although both the clinical and educational aspects of dentistry will be shaped profoundly by the LLM tools, the didactic curricula, which primarily rely on lecture-based courses where instructors impart knowledge through presentations and discussions, need to be upgraded urgently. In this paper, we used dental course materials, syllabi, and textbooks adopted currently in the School of Dentistry (SOD) at Meharry Medical College to assess the potential utility and effectiveness of ChatGPT in dental education. We collected the responses of the chatbot to questions as well as students' interactions with it for assessment. Our results showed that ChatGPT can assist in dental essay writing and generate relevant content for dental students, in addition to other benefits. The limitations of ChatGPT were also discussed in the paper.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":"145 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139285671","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":"[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":" ","pages":""},"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":" ","pages":""},"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":" ","pages":""},"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":"29 1","pages":""},"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":" ","pages":""},"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":" ","pages":""},"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":" ","pages":""},"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":" ","pages":""},"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}