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Inflammatory Bowel Disease Drivers Revealed in Human Organ Chips. 人体器官芯片揭示炎症性肠病驱动因素
Pub Date : 2024-12-08 DOI: 10.1101/2024.12.05.24318563
Alican Özkan, Gwenn Merry, David B Chou, Ryan R Posey, Anna Stejskalova, Karina Calderon, Megan Sperry, Viktor Horvath, Lorenzo E Ferri, Emanuela Carlotti, Stuart A C McDonald, Douglas J Winton, Rocco Riccardi, Lilianna Bordeianou, Sean Hall, Girija Goyal, Donald E Ingber

Inflammatory bowel disease (IBD) patients exhibit compromised intestinal barrier function and decreased mucus accumulation, as well as increased inflammation, fibrosis, and cancer risk, with symptoms often being exacerbated in women during pregnancy. Here, we show that these IBD hallmarks can be replicated using human Organ Chips lined by IBD patient-derived colon epithelial cells interfaced with matched fibroblasts cultured under flow. Use of heterotypic tissue recombinants revealed that IBD fibroblasts are the primary drivers of multiple IBD symptoms. Inflammation and fibrosis are accentuated by peristalsis-like motions in IBD Chips and when exposed to pregnancy-associated hormones in female IBD Chips. Carcinogen exposure also increases inflammation, gene mutations, and chromosome duplication in IBD Chips, but not in Healthy Chips. These data enabled by human Organ Chip technology suggest that the intestinal stroma and peristalsis-associated mechanical deformations play a key role in driving inflammation and disease progression in male and female IBD patients.

炎症性肠病(IBD)患者表现出肠道屏障功能受损、粘液积聚减少以及炎症、纤维化和癌症风险增加,妊娠期妇女的症状往往会加重。在这里,我们展示了这些 IBD 标志可以通过使用由 IBD 患者来源的结肠上皮细胞与在流动条件下培养的匹配成纤维细胞连接而成的人体器官芯片来复制。使用异型组织重组物发现,IBD 成纤维细胞是多种 IBD 症状的主要驱动因素。IBD 芯片的蠕动和女性 IBD 芯片暴露于妊娠相关激素时,炎症和纤维化会加剧。在 IBD 芯片中,接触致癌物质也会增加炎症、基因突变和染色体重复,但在健康芯片中则不会。利用人体器官芯片技术获得的这些数据表明,肠道基质和与蠕动相关的机械变形在推动男性和女性 IBD 患者的炎症和疾病进展方面起着关键作用。
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引用次数: 0
Leveraging DNA methylation to create Epigenetic Biomarker Proxies that inform clinical care: A new framework for Precision Medicine.
Pub Date : 2024-12-08 DOI: 10.1101/2024.12.06.24318612
Natàlia Carreras-Gallo, Qingwen Chen, Laura Balagué-Dobón, Andrea Aparicio, Ilinca M Giosan, Rita Dargham, Daniel Phelps, Tao Guo, Kevin M Mendez, Yulu Chen, Athena Carangan, Srikar Vempaty, Sayf Hassouneh, Michael McGeachie, Tavis Mendez, Florence Comite, Karsten Suhre, Ryan Smith, Varun B Dwaraka, Jessica A Lasky-Su

The lack of accurate, cost-effective, and clinically relevant biomarkers remains a major barrier to incorporating omic data into clinical practice. Previous studies have shown that DNA methylation algorithms have utility as surrogate measures for selected proteins and metabolites. We expand upon this work by creating DNAm surrogates, termed epigenetic biomarker proxies (EBPs), across clinical laboratories, the metabolome, and the proteome. After screening >2,500 biomarkers, we trained and tested 1,694 EBP models and assessed their incident relationship with 12 chronic diseases and mortality, followed up to 15 years. We observe broad clinical relevance: 1) there are 1,292 and 4,863 FDR significant incident and prevalent associations, respectively; 2) most of these associations are replicated when looking at the lab-based counterpart, and > 62% of the shared associations have higher odds and hazard ratios to disease outcomes than their respective observed measurements; 3) EBPs of current clinical biochemistries detect deviations from normal with high sensitivity and specificity. Longitudinal EBPs also demonstrate significant changes corresponding to the changes observed in lab-based counterparts. Using two cohorts and > 30,000 individuals, we found that EBPs validate across healthy and sick populations. While further study is needed, these findings highlight the potential of implementing EBPs in a simple, low-cost, high-yield framework that benefits clinical medicine.

缺乏准确、具有成本效益和临床相关性的生物标志物仍然是将 omic 数据纳入临床实践的主要障碍。之前的研究表明,DNA 甲基化算法可作为选定蛋白质和代谢物的替代指标。在此基础上,我们在临床实验室、代谢组和蛋白质组中创建了 DNAm 代用指标,称为表观遗传生物标志物代用指标(EBPs)。在筛选了超过 2500 个生物标志物后,我们训练并测试了 1694 个 EBP 模型,并评估了它们与 12 种慢性疾病和死亡率之间的关系,随访时间长达 15 年。我们观察到了广泛的临床相关性:1)分别有 1,292 和 4,863 个 FDR 显著的事件关联和流行关联;2)这些关联中的大多数在观察基于实验室的对应物时都得到了复制,超过 62% 的共享关联与疾病结果的几率和危险比高于各自的观察测量值;3)当前临床生化指标的 EBPs 能以高灵敏度和特异性检测到偏离正常值的情况。纵向 EBPs 也显示出与在实验室中观察到的相应变化相对应的显著变化。通过使用两个队列和超过 30,000 人的数据,我们发现 EBPs 在健康和患病人群中均有效。虽然还需要进一步研究,但这些发现凸显了在一个简单、低成本、高产出的框架内实施 EBPs 的潜力,有利于临床医学。
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引用次数: 0
Peritraumatic C-reactive protein levels predict pain outcomes following traumatic stress exposure in a sex-dependent manner.
Pub Date : 2024-12-07 DOI: 10.1101/2024.12.03.24318221
Lauren A McKibben, Miranda N Layne, Liz Marie Albertorio-Sáez, Ying Zhao, Erica M Branham, Stacey L House, Francesca L Beaudoin, Xinming An, Jennifer S Stevens, Thomas C Neylan, Gari D Clifford, Laura T Germine, Kenneth A Bollen, Scott L Rauch, John P Haran, Alan B Storrow, Christopher Lewandowski, Paul I Musey, Phyllis L Hendry, Sophia Sheikh, Christopher W Jones, Brittany E Punches, Robert A Swor, Lauren A Hudak, Jose L Pascual, Mark J Seamon, Elizabeth M Datner, David A Peak, Roland C Merchant, Robert M Domeier, Niels K Rathlev, Brian J O'Neil, Leon D Sanchez, Steven E Bruce, John F Sheridan, Steven E Harte, Ronald C Kessler, Karestan C Koenen, Kerry J Ressler, Samuel A McLean, Sarah D Linnstaedt

Background: Chronic pain following traumatic stress exposure (TSE) is common. Increasing evidence suggests inflammatory/immune mechanisms are induced by TSE, play a key role in the recovery process versus development of post-TSE chronic pain, and are sex specific. In this study, we tested the hypothesis that the inflammatory marker C-reactive protein (CRP) is associated with chronic pain after TSE in a sex-specific manner.

Methods: We utilized blood-plasma samples and pain questionnaire data from men (n=99) and (n=223) women enrolled in AURORA, a multi-site emergency department (ED)-based longitudinal study of TSE survivors. We measured CRP using Ella/ELISA from plasma samples collected in the ED ('peritraumatic CRP', n=322) and six months following TSE (n=322). Repeated measures mixed-effects models were used to assess the relationship between peritraumatic CRP and post-TSE chronic pain.

Results: Peritraumatic CRP levels significantly predicted post-TSE chronic pain, such that higher levels of CRP were associated with lower levels of pain over time following TSE, but only in men (men:β=-0.24, p=0.037; women:β=0.05, p=0.470). By six months, circulating CRP levels had decreased by more than half in men, but maintained similar levels in women (t(290)=1.926, p=0.055). More men with a decrease in CRP levels had decreasing pain over time versus women (men:83% women:65%; Z=2.21, p=0.027).

Conclusions: In men but not women, we found circulating peritraumatic CRP levels predict chronic pain outcomes following TSE and resolution of CRP levels in men over time might be associated with increased pain recovery. Further studies are needed to validate these results.

背景:创伤应激暴露(TSE)后的慢性疼痛很常见。越来越多的证据表明,TSE 会诱发炎症/免疫机制,这些机制在创伤应激暴露后慢性疼痛的恢复过程和发展过程中起着关键作用,而且具有性别特异性。在本研究中,我们测试了炎症标志物 C 反应蛋白(CRP)与 TSE 后慢性疼痛的相关性与性别特异性的假设:我们利用了参加 AURORA 的男性(人数=99)和女性(人数=223)的血浆样本和疼痛问卷数据,AURORA 是一项基于多站点急诊科(ED)的 TSE 幸存者纵向研究。我们使用 Ella/ELISA 测量了在急诊室采集的血浆样本("创伤周 CRP",人数=322)和 TSE 后 6 个月的 CRP(人数=322)。采用重复测量混合效应模型评估创伤周CRP与TSE后慢性疼痛之间的关系:创伤周CRP水平可显著预测TSE后的慢性疼痛,因此TSE后较高的CRP水平与较低的疼痛水平相关,但仅限于男性(男性:β=-0.24,p=0.037;女性:β=0.05,p=0.470)。六个月后,男性的循环 CRP 水平下降了一半以上,而女性则保持在相似水平(t(290)=1.926,p =0.055)。随着时间的推移,CRP水平下降的男性疼痛减轻的比例高于女性(男性:83%,女性:65%;Z=2.21,P=0.027):结论:我们发现,在男性而非女性中,循环创伤周CRP水平可预测TSE后的慢性疼痛结果,而随着时间的推移,男性CRP水平的降低可能与疼痛恢复程度的增加有关。结论:我们发现男性而非女性的循环创伤周CRP水平可预测TSE后的慢性疼痛结果,而且随着时间的推移,男性CRP水平的下降幅度大于女性。
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引用次数: 0
The mouth of America: the oral microbiome profile of the US population. 美国的口腔:美国人口口腔微生物组概况。
Pub Date : 2024-12-07 DOI: 10.1101/2024.12.03.24318415
Anil K Chaturvedi, Emily Vogtmann, Jianxin Shi, Yukiko Yano, Martin J Blaser, Nicholas A Bokulich, J Gregory Caporaso, Maura L Gillison, Barry I Graubard, Xing Hua, Autumn G Hullings, Lisa Kahle, Rob Knight, Shilan Li, Jody McLean, Vaishnavi Purandare, Yunhu Wan, Neal D Freedman, Christian C Abnet
<p><strong>Importance: </strong>The oral microbiome is increasingly recognized to play key roles in human health and disease; yet, population-representative characterizations are lacking.</p><p><strong>Objective: </strong>Characterize the composition, diversity, and correlates of the oral microbiome among US adults.</p><p><strong>Design: </strong>Cross-sectional population-representative survey.</p><p><strong>Setting: </strong>The National Health and Nutrition Examination Survey (NHANES, 2009-2012), a stratified multistage probability sample of the US population.</p><p><strong>Participants: </strong>NHANES participants aged 18-69 years (n=8,237, representing 202,314,000 individuals).</p><p><strong>Exposures: </strong>Demographic, socioeconomic, behavioral, anthropometric, metabolic, and clinical characteristics.</p><p><strong>Main outcomes: </strong>Oral microbiome, characterized through 16S rRNA sequencing. Microbiome metrics were alpha diversity (number of observed Amplicon Sequence Variants [ASV], Faith's Phylogenetic diversity, Shannon-Weiner Index, and Simpson Index); beta diversity (unweighted UniFrac, weighted UniFrac, and Bray-Curtis dissimilarity); and prevalence and relative abundance at taxonomic levels (phylum through genus). Analyses accounted for the NHANES complex sample design.</p><p><strong>Results: </strong>Among US adults aged 18-69 years, the oral microbiome encompassed 37 bacterial phyla, 99 classes, 212 orders, 446 families, and 1,219 genera. Five phyla-<i>Firmicutes, Actinobacteria, Bacteroidetes, Proteobacteria,</i> and <i>Fusobacteria</i> and six genera-<i>Veillonella, Streptococcus, Prevotella7, Rothia, Actinomyces, and Gemella</i>, were present in nearly all US adults (weighted-prevalence >99%). These genera also were the most abundant, accounting for 65.7% of abundance. Observed ASVs showed a quadratic pattern with age (peak at 30 years), was similar by sex, significantly lower among non-Hispanic White individuals, and increased with higher body mass index (BMI) categories, alcohol use, and periodontal disease severity. All covariates together accounted for a modest proportion of oral microbiome variability, as measured by beta diversity (unweighted UniFrac=8.7%, weighted UniFrac=7.2%, and Bray-Curtis=6.3%). By contrast, relative abundance of a few genera explained a high percentage of variability in beta diversity (weighted UniFrac: <i>Aggregatibacter</i>=22.4%, <i>Lactococcus</i>=21.6%, <i>Haemophilus</i>=18.4%). Prevalence and relative abundance of numerous genera were significantly associated (Bonferroni-corrected Wald-p<0.0002) with age, race and ethnicity, smoking, BMI categories, alcohol use, and periodontal disease severity.</p><p><strong>Conclusions: </strong>We provide a contemporary reference standard for the oral microbiome of the US adult population. Our results indicate that a few genera were universally present in US adults and a different set of genera explained a high percentage of oral microbiome dive
重要性:人们越来越认识到口腔微生物组在人类健康和疾病中发挥着关键作用;然而,目前还缺乏具有人群代表性的特征描述:目标:描述美国成年人口腔微生物组的组成、多样性和相关性:设计:横断面人群代表性调查:美国国家健康与营养调查(NHANES,2009-2012 年)是对美国人口进行的分层多级概率抽样调查:年龄在 18-69 岁之间的 NHANES 参与者(n=8,237,代表 202,314,000 人):主要结果:主要结果:口腔微生物组,通过 16S rRNA 测序定性。微生物组指标包括α多样性(观察到的扩增片段序列变异数[ASV]、费斯系统发育多样性、香农-韦纳指数和辛普森指数);β多样性(未加权UniFrac、加权UniFrac和布雷-柯蒂斯相似度);以及分类水平(门到属)上的流行率和相对丰度。分析考虑了 NHANES 的复杂样本设计:结果:在 18-69 岁的美国成年人中,口腔微生物组包括 37 个细菌门、99 个类、212 个目、446 个科和 1,219 个属。几乎所有美国成年人的口腔微生物组中都有 5 个菌门--固缩菌门、放线菌门、类杆菌门、蛋白菌门和镰刀菌门,以及 6 个菌属--维龙菌属、链球菌属、前驱菌属7、轮状菌属、放线菌属和宝石菌属(加权发生率大于 99%)。这些菌属的数量也最多,占总数的 65.7%。观察到的 ASVs 随年龄呈二次方模式(30 岁时达到峰值),性别相似,非西班牙裔白人明显较低,且随体重指数(BMI)类别、饮酒和牙周病严重程度的增加而增加。根据贝塔多样性(非加权 UniFrac=8.7%,加权 UniFrac=7.2%,Bray-Curtis=6.3%),所有协变量加在一起只占口腔微生物组变异性的一小部分。相比之下,少数几个菌属的相对丰度解释了贝塔多样性变异的很高比例(加权 UniFrac:Aggregatibacter=22.4%,Lactococcus=21.6%,Haemophilus=18.4%)。许多菌属的流行率和相对丰度有显著相关性(经 Bonferroni 校正的 Wald-p-结论):我们为美国成年人口腔微生物组提供了当代参考标准。我们的研究结果表明,少数几个菌属在美国成年人中普遍存在,而另一组不同的菌属解释了整个人群口腔微生物组多样性的很高比例。
{"title":"The mouth of America: the oral microbiome profile of the US population.","authors":"Anil K Chaturvedi, Emily Vogtmann, Jianxin Shi, Yukiko Yano, Martin J Blaser, Nicholas A Bokulich, J Gregory Caporaso, Maura L Gillison, Barry I Graubard, Xing Hua, Autumn G Hullings, Lisa Kahle, Rob Knight, Shilan Li, Jody McLean, Vaishnavi Purandare, Yunhu Wan, Neal D Freedman, Christian C Abnet","doi":"10.1101/2024.12.03.24318415","DOIUrl":"10.1101/2024.12.03.24318415","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Importance: &lt;/strong&gt;The oral microbiome is increasingly recognized to play key roles in human health and disease; yet, population-representative characterizations are lacking.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Objective: &lt;/strong&gt;Characterize the composition, diversity, and correlates of the oral microbiome among US adults.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Design: &lt;/strong&gt;Cross-sectional population-representative survey.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Setting: &lt;/strong&gt;The National Health and Nutrition Examination Survey (NHANES, 2009-2012), a stratified multistage probability sample of the US population.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Participants: &lt;/strong&gt;NHANES participants aged 18-69 years (n=8,237, representing 202,314,000 individuals).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Exposures: &lt;/strong&gt;Demographic, socioeconomic, behavioral, anthropometric, metabolic, and clinical characteristics.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Main outcomes: &lt;/strong&gt;Oral microbiome, characterized through 16S rRNA sequencing. Microbiome metrics were alpha diversity (number of observed Amplicon Sequence Variants [ASV], Faith's Phylogenetic diversity, Shannon-Weiner Index, and Simpson Index); beta diversity (unweighted UniFrac, weighted UniFrac, and Bray-Curtis dissimilarity); and prevalence and relative abundance at taxonomic levels (phylum through genus). Analyses accounted for the NHANES complex sample design.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Among US adults aged 18-69 years, the oral microbiome encompassed 37 bacterial phyla, 99 classes, 212 orders, 446 families, and 1,219 genera. Five phyla-&lt;i&gt;Firmicutes, Actinobacteria, Bacteroidetes, Proteobacteria,&lt;/i&gt; and &lt;i&gt;Fusobacteria&lt;/i&gt; and six genera-&lt;i&gt;Veillonella, Streptococcus, Prevotella7, Rothia, Actinomyces, and Gemella&lt;/i&gt;, were present in nearly all US adults (weighted-prevalence &gt;99%). These genera also were the most abundant, accounting for 65.7% of abundance. Observed ASVs showed a quadratic pattern with age (peak at 30 years), was similar by sex, significantly lower among non-Hispanic White individuals, and increased with higher body mass index (BMI) categories, alcohol use, and periodontal disease severity. All covariates together accounted for a modest proportion of oral microbiome variability, as measured by beta diversity (unweighted UniFrac=8.7%, weighted UniFrac=7.2%, and Bray-Curtis=6.3%). By contrast, relative abundance of a few genera explained a high percentage of variability in beta diversity (weighted UniFrac: &lt;i&gt;Aggregatibacter&lt;/i&gt;=22.4%, &lt;i&gt;Lactococcus&lt;/i&gt;=21.6%, &lt;i&gt;Haemophilus&lt;/i&gt;=18.4%). Prevalence and relative abundance of numerous genera were significantly associated (Bonferroni-corrected Wald-p&lt;0.0002) with age, race and ethnicity, smoking, BMI categories, alcohol use, and periodontal disease severity.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;We provide a contemporary reference standard for the oral microbiome of the US adult population. Our results indicate that a few genera were universally present in US adults and a different set of genera explained a high percentage of oral microbiome dive","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11643230/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142831615","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}
引用次数: 0
NIAGADS: A Comprehensive National Data Repository for Alzheimer's Disease and Related Dementia Genetics and Genomics Research. NIAGADS:阿尔茨海默病及相关痴呆症遗传学和基因组学研究国家综合数据库。
Pub Date : 2024-12-07 DOI: 10.1101/2024.10.07.24315029
Amanda Kuzma, Otto Valladares, Emily Greenfest-Allen, Heather Nicaretta, Maureen Kirsch, Youli Ren, Zivadin Katanic, Heather White, Andrew Wilk, Lauren Bass, Jascha Brettschneider, Luke Carter, Jeffrey Cifello, Wei-Hsuan Chuang, Kaylyn Clark, Prabhakaran Gangadharan, Jacob Haut, Pei-Chuan Ho, Wenhwai Horng, Taha Iqbal, Yumi Jin, Peter Keskinen, Alexis Lerro Rose, Michelle K Moon, Joseph Manuel, Liming Qu, Flawless Robbins, Naveensri Saravanan, Jin Sha, Sam Tate, Yi Zhao, Laura Cantwell, Jake Gardner, Shin-Yi Chou, Jung-Ying Tzeng, William Bush, Adam Naj, Pavel Kuksa, Wan-Ping Lee, Yuk Yee Leung, Gerard Schellenberg, Li-San Wang

NIAGADS is the National Institute on Aging (NIA) designated national data repository for human genetics research on Alzheimer's Disease and related dementia (ADRD). NIAGADS maintains a high-quality data collection for ADRD genetic/genomic research and supports genetics data production and analysis. NIAGADS hosts whole genome and exome sequence data from the Alzheimer's Disease Sequencing Project (ADSP) and other genotype/phenotype data, encompassing 209,000 samples. NIAGADS shares these data with hundreds of research groups around the world via the Data Sharing Service, a FISMA moderate compliant cloud-based platform that fully supports the NIH Genome Data Sharing Policy. NIAGADS Open Access consists of multiple knowledge bases with genome-wide association summary statistics and rich annotations on the biological significance of genetic variants and genes across the human genome. NIAGADS stands as a keystone in promoting collaborations to advance the understanding and treatment of Alzheimer's disease.

NIAGADS 是美国国家老龄化研究所 (NIA) 指定的阿尔茨海默病及相关痴呆症 (ADRD) 人类遗传学研究国家数据存储库。NIAGADS 为 ADRD 遗传学/基因组研究维护高质量的数据收集,并支持遗传学数据的生产和分析。NIAGADS 拥有来自阿尔茨海默病测序项目 (ADSP) 的全基因组和外显子组序列数据以及其他基因型/表型数据,涵盖 209,000 个样本。NIAGADS 通过 "数据共享服务 "与全球数百个研究小组共享这些数据。"数据共享服务 "是一个符合 FISMA 标准的云平台,完全支持 NIH 基因组数据共享政策。NIAGADS Open Access 包含多个知识库,其中有全基因组关联汇总统计数据,以及关于人类基因组中遗传变异和基因的生物学意义的丰富注释。NIAGADS 是促进合作,推动对阿尔茨海默病的了解和治疗的基石。
{"title":"NIAGADS: A Comprehensive National Data Repository for Alzheimer's Disease and Related Dementia Genetics and Genomics Research.","authors":"Amanda Kuzma, Otto Valladares, Emily Greenfest-Allen, Heather Nicaretta, Maureen Kirsch, Youli Ren, Zivadin Katanic, Heather White, Andrew Wilk, Lauren Bass, Jascha Brettschneider, Luke Carter, Jeffrey Cifello, Wei-Hsuan Chuang, Kaylyn Clark, Prabhakaran Gangadharan, Jacob Haut, Pei-Chuan Ho, Wenhwai Horng, Taha Iqbal, Yumi Jin, Peter Keskinen, Alexis Lerro Rose, Michelle K Moon, Joseph Manuel, Liming Qu, Flawless Robbins, Naveensri Saravanan, Jin Sha, Sam Tate, Yi Zhao, Laura Cantwell, Jake Gardner, Shin-Yi Chou, Jung-Ying Tzeng, William Bush, Adam Naj, Pavel Kuksa, Wan-Ping Lee, Yuk Yee Leung, Gerard Schellenberg, Li-San Wang","doi":"10.1101/2024.10.07.24315029","DOIUrl":"10.1101/2024.10.07.24315029","url":null,"abstract":"<p><p>NIAGADS is the National Institute on Aging (NIA) designated national data repository for human genetics research on Alzheimer's Disease and related dementia (ADRD). NIAGADS maintains a high-quality data collection for ADRD genetic/genomic research and supports genetics data production and analysis. NIAGADS hosts whole genome and exome sequence data from the Alzheimer's Disease Sequencing Project (ADSP) and other genotype/phenotype data, encompassing 209,000 samples. NIAGADS shares these data with hundreds of research groups around the world via the Data Sharing Service, a FISMA moderate compliant cloud-based platform that fully supports the NIH Genome Data Sharing Policy. NIAGADS Open Access consists of multiple knowledge bases with genome-wide association summary statistics and rich annotations on the biological significance of genetic variants and genes across the human genome. NIAGADS stands as a keystone in promoting collaborations to advance the understanding and treatment of Alzheimer's disease.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11483014/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142484939","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}
引用次数: 0
Diagnostic-avoiding Chlamydia trachomatis variants detected in cervical and endometrial specimens from women during 16S microbiome profiling. 在 16S 微生物组图谱分析过程中,从一组性活跃的顺性女性宫颈和子宫内膜标本中检测到的 Aptima Combo2-avoiding 变异。
Pub Date : 2024-12-07 DOI: 10.1101/2024.11.13.24316066
Sangmi Jeong, Tammy Tollison, Hayden Brochu, Hsuan Chou, Tammy Yu, Priyanka Baghaie, Kacy S Yount, Toni Darville, Harold C Wiesenfeld, Sharon L Hillier, Xinxia Peng, Catherine M O'Connell

Background: Performance of a 16S rRNA analysis of the cervicovaginal microbiome of 220 participants recruited into the T Cell Response against Chlamydia (TRAC) cohort between February 2011 and August 2014 in Allegheny County, Pennsylvania USA detected DNA encoding chlamydial 16S rRNA in samples from seven participants whose tests were negative for Chlamydia trachomatis (CT) and DNA encoding gonococcal 16S rRNA from five participants whose tests were negative for Neisseria gonorrhoeae (NG) infection with the Aptima Combo2 assay (Hologic).

Methods: We used targeted PCR amplification followed by sequencing to characterize the chlamydial 23S rRNA locus and qPCR to detect gonococcal DNA in residual diagnostic swab eluates or DNA used to generate 16S rRNA libraries.

Results: Discrepant specimens that contained chlamydial DNA carried a diagnostic-avoidant, G1526A variant in the 23S rRNA locus identical to variants previously detected in Finland, Denmark, and the UK. PCR validation of gonococcal DNA was confirmed for all participants whose tests were negative, with stochastic effects consistent with infection levels close to the limit of detection by the diagnostic assay.

Conclusions: These data indicate that this probe-avoidant CT mutant, and possibly others, were circulating in the northeastern US prior to their detection and characterization in 2019. Although infrequent, documentation of false negative results for CT indicates a need for clinicians to consider performance of a second test that uses alternate PCR targets if patients have persistent symptoms or have known contact to an infected sex partner and their initial NAAT is negative.

背景:对2011年2月至2014年8月期间在美国宾夕法尼亚州阿勒格尼县招募的T细胞抗衣原体(TRAC)队列的220名参与者的宫颈阴道微生物组进行了16S rRNA分析、用 Aptima Combo2 检测法(Hologic)在 7 名沙眼衣原体 (CT) 检测呈阴性的参与者样本中检测到了编码衣原体 16S rRNA 的 DNA,在 5 名淋病奈瑟菌 (NG) 感染检测呈阴性的参与者样本中检测到了编码淋球菌 16S rRNA 的 DNA。方法:我们使用靶向 PCR 扩增和测序来确定衣原体 23S rRNA 位点的特征,并使用 qPCR 检测残留诊断拭子洗脱液或用于生成 16S rRNA 文库的 DNA 中的淋球菌 DNA:结果:含有衣原体 DNA 的不确定标本携带了一种诊断规避型 23S rRNA 基因座 G1526A 变体,该变体与之前在芬兰、丹麦和英国检测到的变体相同。所有检测结果呈阴性的参与者都证实了淋球菌 DNA 的 PCR 验证,随机效应与感染水平接近诊断测定的检测极限相一致:这些数据表明,在 2019 年及其后检测到并确定其特征之前,这种探针规避 CT 突变体以及其他可能的突变体已在美国东北部地区流行。尽管 CT 的假阴性结果并不常见,但其记录表明,如果患者症状持续存在或已知与受感染的性伴侣有接触,而其初次 NAAT 结果为阴性,则临床医生有必要考虑进行第二次检测,即使用替代 PCR 探针进行检测。
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引用次数: 0
Integrating Whole Genome and Transcriptome Sequencing to Characterize the Genetic Architecture of Isoform Variation and its Implications for Health and Disease. 整合全基因组和转录组测序,描述同工酶变异的遗传结构及其对健康和疾病的影响。
Pub Date : 2024-12-06 DOI: 10.1101/2024.12.04.24318434
Chunyu Liu, Roby Joehanes, Jiantao Ma, Jiuyong Xie, Jian Yang, Mengyao Wang, Tianxiao Huan, Shih-Jen Hwang, Jia Wen, Quan Sun, Demirkale Y Cumhur, Nancy L Heard-Costa, Peter Orchard, April P Carson, Laura M Raffield, Alexander Reiner, Yun Li, George O'Connor, Joanne M Murabito, Peter Munson, Daniel Levy

We created a comprehensive whole blood splice variation quantitative trait locus (sQTL) resource by analyzing isoform expression ratio (isoform-to-gene) in Framingham Heart Study (FHS) participants (discovery: n=2,622; validation: n=1,094) with whole genome (WGS) and transcriptome sequencing (RNA-seq) data. External replication was conducted using WGS and RNA-seq from the Jackson Heart Study (JHS, n=1,020). We identified over 3.5 million cis -sQTL-isoform pairs ( p <5e-8), comprising 1,176,624 cis -sQTL variants and 10,883 isoform transcripts from 4,971 sGenes, with significant change in isoform-to-gene ratio due to allelic variation. We validated 61% of these pairs in the FHS validation sample ( p <1e-4). External validation ( p <1e-4) in JHS for the top 10,000 and 100,000 most significant cis -sQTL-isoform pairs was 88% and 69%, respectively, while overall pairs validated at 23%. For 20% of cis -sQTLs in the FHS discovery sample, allelic variation did not significantly correlate with overall gene expression. sQTLs are enriched in splice donor and acceptor sites, as well as in GWAS SNPs, methylation QTLs, and protein QTLs. We detailed several sentinel cis -sQTLs influencing alternative splicing, with potential causal effects on cardiovascular disease risk. Notably, rs12898397 (T>C) affects splicing of ULK3 , lowering levels of the full-length transcript ENST00000440863.7 and increasing levels of the truncated transcript ENST00000569437.5, encoding proteins of different lengths. Mendelian randomization analysis demonstrated that a lower ratio of the full-length isoform is causally associated with lower diastolic blood pressure and reduced lymphocyte percentages. This sQTL resource provides valuable insights into how transcriptomic variation may influence health outcomes.

我们利用全基因组(WGS)和转录组测序(RNA-seq)数据分析了弗雷明汉心脏研究(FHS)参与者(发现:n=2,622;验证:n=1,094)的同工酶表达比(同工酶-基因),从而创建了一个全面的全血剪接变异定量性状位点(sQTL)资源。利用杰克逊心脏研究(JHS,n=1,020)的 WGS 和 RNA-seq 数据进行了外部复制。我们发现了 350 多万个顺式 -sQTL - 同工酶对(p 顺式 -sQTL 变异和来自 4,971 个 s 基因的 10,883 个同工酶转录物,由于等位基因变异,同工酶与基因的比例发生了显著变化。我们在 FHS 验证样本中验证了 61% 的这些配对(顺式 -sQTL - 同工酶配对的验证率分别为 88% 和 69%,而整体配对的验证率为 23%)。在 FHS 发现样本中,有 20% 的顺式 -sQTL 的等位基因变异与整体基因表达没有显著相关性。sQTL 在剪接供体和受体位点以及 GWAS SNP、甲基化 QTL 和蛋白质 QTL 中富集。我们详细研究了几个影响替代剪接的前哨顺式-sQTLs,它们对心血管疾病风险具有潜在的因果效应。值得注意的是,rs12898397(T>C)会影响 ULK3 的剪接,降低全长转录本 ENST00000440863.7 的水平,增加截短转录本 ENST00000569437.5 的水平,编码不同长度的蛋白质。孟德尔随机分析表明,较低的全长异构体比例与较低的舒张压和较低的淋巴细胞百分比有因果关系。这一 sQTL 资源为了解转录组变异如何影响健康结果提供了宝贵的见解。
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引用次数: 0
Primary Central Nervous System Lymphoma Tumor Biopsies Show Heterogeneity in Gene Expression Profiles, Genetic Subtypes, and in vitro Drug Sensitivity to Kinase Inhibitors. 原发性中枢神经系统淋巴瘤活检显示基因表达谱、基因亚型和体外药物对激酶抑制剂的敏感性存在异质性。
Pub Date : 2024-12-06 DOI: 10.1101/2024.11.11.24316310
Yuan Xiao Zhu, Jasper Ch Wong, Talal Hilal, Alanna Maguire, Jon Ocal, Katie Zellner, Xianfeng Chen, Brian K Link, Thomas M Habermann, Matthew J Maurer, James R Cerhan, Patrick B Johnston, Andrew L Feldman, David W Scott, Allison Rosenthal, Lisa Rimsza

Primary central nervous system lymphoma (PCNSL) is clinically challenging due to its location and small biopsy size, leading to a lack of comprehensive molecular and biologic description. We previously demonstrated that 91% of PCNSL belong to the activated B-cell-like (ABC) molecular subtype of diffuse large B-cell lymphoma (DLBCL). Here we investigated the expression of 739 cancer related genes in HIV (-) patients using NanoString digital gene expression profiling in 25 ABC-PCNSL and 43 ABC-systemic DLBCL, all tumors were EBV (-). We found that two-thirds of ABC-PCNSL samples had a transcriptional landscape distinct from ABC-systemic DLBCL samples. Of the 739 genes measured, 135 were identified as differentially expressed between these ABC-PCNSL and ABC-systemic DLBCL (p<0.05). Compared with ABC-systemic DLBCL, ABC-PCNSL showed higher gene expression in several cancer related gene sets including genes related to Hedgehog, DNA damage repair, Wnt and MAPK signaling. Hierarchical clustering 28 PCNSL samples (25 ABC and 3 GCB subtypes) identified two transcriptional subgroups, P1 (n=9) and P2 (n=19). P2 showed higher activities across most of the cancer related pathways and had a significantly shorter patient survival time (p<0.01). Whole exome sequencing showed that some distinct genetic features of PCNSL compared to DLBCL. The genetic subtypes ("LymphGen") of PCNSL consisted mainly of "MCD" and "Other" subtypes, which did not correlate with clinical survival. These data provide more information about unique characters of PCNSL, which may help to identify novel drug targets for developing therapeutic strategies.

原发性中枢神经系统淋巴瘤(PCNSL)在临床上具有挑战性,因为它的位置和活检样本量较小,导致缺乏全面的分子和生物学描述。我们曾证实,91% 的 PCNSL 属于弥漫大 B 细胞淋巴瘤(DLBCL)的活化 B 细胞样(ABC)分子亚型。在此,我们使用 NanoString 数字基因表达谱分析技术,对 25 例 ABC-PCNSL 和 43 例 ABC 系统性 DLBCL(所有肿瘤均为 EBV(-))患者中 739 个癌症相关基因的表达进行了研究。我们发现,三分之二的 ABC-PCNSL 样本具有不同于 ABC 系统 DLBCL 样本的转录景观。在测得的 739 个基因中,135 个基因在 ABC-PCNSL 和 ABC 系统 DLBCL 之间有差异表达(p
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引用次数: 0
Consultation informs strategies to improve functional evidence use in variant classification. 咨询为改进变异分类中功能证据使用的策略提供信息。
Pub Date : 2024-12-06 DOI: 10.1101/2024.12.04.24318523
Rehan M Villani, Bronwyn Terrill, Emma Tudini, Maddison E McKenzie, Corrina C Cliffe, Christopher N Hahn, Ben Lundie, Tessa Mattiske, Ebony Matotek, Abbye E McEwen, Sarah L Nickerson, James Breen, Douglas M Fowler, John Christodoulou, Lea Starita, Alan F Rubin, Amanda B Spurdle

To determine if a variant identified by diagnostic genetic testing is causal for disease, applied genetics professionals evaluate all available evidence to assign a clinical classification. Experimental assay data can provide strong functional evidence for or against pathogenicity in variant classification, but appears to be underutilised. We surveyed genetic diagnostic professionals in Australasia to assess their application of functional evidence in clinical practice. Results indicated that survey respondents are not confident to apply functional evidence, mainly due to uncertainty around practice recommendations. Respondents also identified need for support resources, educational opportunities, and in particular requested expert recommendations and updated practice guidelines to improve translation of experimental data to curation evidence. As an initial step, we have collated a list of functional assays recommended by 19 ClinGen Variant Curation Expert Panels as a source of international expert opinion on functional evidence evaluation. Additional support resources for diagnostic practice are in development.

为了确定通过基因诊断检测发现的变异体是否是疾病的致病因素,应用遗传学专业人员会评估所有可用的证据,以进行临床分类。实验检测数据可为变异分类中的致病性提供有力的功能证据,但似乎未得到充分利用。我们对澳大拉西亚的遗传诊断专业人员进行了调查,以评估他们在临床实践中对功能证据的应用。结果显示,调查对象对应用功能证据缺乏信心,主要原因是实践建议的不确定性。受访者还指出需要支持资源和教育机会,特别是需要专家建议和更新实践指南,以改善将实验数据转化为整理证据的工作。作为第一步,我们整理了一份由 19 个 ClinGen 变异库专家小组推荐的功能检测列表,作为功能证据评估的国际专家意见来源。用于诊断实践的其他支持资源正在开发中。
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引用次数: 0
The striatum is an early, accurate indicator of amyloid burden using [11C]PiB in Down syndrome: comparison of two radiotracers. 使用[11 C]PiB 检测唐氏综合征患者纹状体是淀粉样蛋白负荷的早期准确指标:两种放射性同位素的比较。
Pub Date : 2024-12-06 DOI: 10.1101/2024.12.04.24318526
Max McLachlan, Brecca Bettcher, Andrew McVea, Alexandra DiFillipo, Matthew Zammit, Lisette LeMerise, Jeremy Rouanet, Julie Price, Dana Tudorascu, Charles Laymon, David Keator, Patrick Lao, Adam M Brickman, Tim Fryer, Sigan Hartley, Beau M Ances, Sterling Johnson, Tobey Betthauser, Charles K Stone, Shahid Zaman, Benjamin Handen, Elizabeth Head, Mark Mapstone, Bradley T Christian

Introduction: Adults with Down syndrome demonstrate striatum-first amyloid accumulation with [11C]PiB PET imaging, which has not been replicated with [18F]florbetapir (FBP). Early striatal accumulation has not been temporally quantified with respect to global cortical measures.

Methods: Longitudinal PiB (n=175 participants) and FBP (n=92 participants) data from the Alzheimer Biomarkers Consortium-Down Syndrome were used to measure cortical and striatal binding. Generalized temporal models for cortical and striatal amyloid accumulation were created using the sampled iterative local approximation (SILA) method.

Results: PiB demonstrated greater striatal-to-cortical ratios than FBP. SILA analysis revealed striatal amyloid burden occurs 3.40 (2.39) years earlier than the cortex in PiB. There was no difference between the cortex and striatum in FBP.

Discussion: Among adults with Down syndrome, the striatum consistently accumulates amyloid earlier than the cortex when measured with PiB. This suggests the striatum is more sensitive to the onset of PiB PET-detectable amyloid in Down syndrome.

简介:成人唐氏综合征患者的[11 C]PiB PET成像显示纹状体首先出现淀粉样蛋白聚集,而[18 F]氟贝他匹(FBP)尚未证实这一点。早期纹状体积聚尚未与整体皮质测量进行时间量化:方法:使用阿尔茨海默生物标记物联合会-唐氏综合征的纵向 PiB(175 名参与者)和 FBP(92 名参与者)数据来测量皮质和纹状体结合。使用采样迭代局部逼近(SILA)方法建立了皮质和纹状体淀粉样蛋白积累的广义时间模型:结果:与 FBP 相比,PiB 显示出更大的纹状体与皮质比率。SILA 分析显示,在 PiB 中,纹状体淀粉样蛋白负荷比皮质早出现 3.40(2.39)年。讨论:讨论:在患有唐氏综合征的成人中,用PiB测量纹状体时,纹状体的淀粉样蛋白累积始终早于大脑皮层。这表明纹状体对唐氏综合征患者开始出现 PiB PET 可检测到的淀粉样蛋白更为敏感。
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引用次数: 0
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