The mouse deafness locus (dn) is associated with an inversion on chromosome 19

Recombination data for the mouse deafness locus (dn) on chromosome 19 are consistent with the presence of an inversion for which one of the breakpoints is between D19Mit14 and D19Mit96, a distance of less than 226 kb. Fluorescence in situ hybridization studies using a bacterial artificial chromosome on interphase (G1) nuclei provide additional support for the presence of an inversion. The dn gene is probably the orthologue of the human DFNB7/DFNB11 gene on chromosome 9. Copyright (C) 1998 Elsevier Science B.V

Assembly of a high-resolution map of the Acadian Usher syndrome region and localization of the nuclear EF-hand acidic gene

Usher syndrome type 1C (USH1C) occurs in a small population of Acadian descendants from southwestern Louisiana. Linkage and linkage disequilibrium analyses localize USH1C to chromosome 11p between markers D11S1397 and D11S1888, an interval of less than 680 kb. Here, we refine the USH1C linkage to a region less than 400 kb, between genetic markers D11S1397 and D11S1890. Using 17 genetic markers from this interval, we have isolated a contiguous set of 60 bacterial artificial chromosomes (BACs) that span the USH1C critical region. Exon trapping of BAC clones from this region resulted in the recovery of an exon of the nuclear EF-hand acidic (NEFA) gene. However, DNA sequence analysis of the NEFA cDNA from lymphocytes of affected individuals provided no evidence of mutation, making structural mutations in the NEFA protein unlikely as the cellular cause of Acadian Usher syndrome. Copyright (C) 1998 Elsevier Science B.V

Discovery of Molecular Mechanisms of Traditional Chinese Medicinal Formula Si-Wu-Tang Using Gene Expression Microarray and Connectivity Map

To pursue a systematic approach to discovery of mechanisms of action of traditional Chinese medicine (TCM), we used microarrays, bioinformatics and the “Connectivity Map” (CMAP) to examine TCM-induced changes in gene expression. We demonstrated that this approach can be used to elucidate new molecular targets using a model TCM herbal formula Si-Wu-Tang (SWT) which is widely used for women's health. The human breast cancer MCF-7 cells treated with 0.1 µM estradiol or 2.56 mg/ml of SWT showed dramatic gene expression changes, while no significant change was detected for ferulic acid, a known bioactive compound of SWT. Pathway analysis using differentially expressed genes related to the treatment effect identified that expression of genes in the nuclear factor erythroid 2-related factor 2 (Nrf2) cytoprotective pathway was most significantly affected by SWT, but not by estradiol or ferulic acid. The Nrf2-regulated genes HMOX1, GCLC, GCLM, SLC7A11 and NQO1 were upreguated by SWT in a dose-dependent manner, which was validated by real-time RT-PCR. Consistently, treatment with SWT and its four herbal ingredients resulted in an increased antioxidant response element (ARE)-luciferase reporter activity in MCF-7 and HEK293 cells. Furthermore, the gene expression profile of differentially expressed genes related to SWT treatment was used to compare with those of 1,309 compounds in the CMAP database. The CMAP profiles of estradiol-treated MCF-7 cells showed an excellent match with SWT treatment, consistent with SWT's widely claimed use for women's diseases and indicating a phytoestrogenic effect. The CMAP profiles of chemopreventive agents withaferin A and resveratrol also showed high similarity to the profiles of SWT. This study identified SWT as an Nrf2 activator and phytoestrogen, suggesting its use as a nontoxic chemopreventive agent, and demonstrated the feasibility of combining microarray gene expression profiling with CMAP mining to discover mechanisms of actions and to identify new health benefits of TCMs

Improved clinical outcomes in response to a 12-week blended digital and community-based long-COVID-19 rehabilitation programme

IntroductionTwo million people in the UK are experiencing long COVID (LC), which necessitates effective and scalable interventions to manage this condition. This study provides the first results from a scalable rehabilitation programme for participants presenting with LC.Methods601 adult participants with symptoms of LC completed the Nuffield Health COVID-19 Rehabilitation Programme between February 2021 and March 2022 and provided written informed consent for the inclusion of outcomes data in external publications. The 12-week programme included three exercise sessions per week consisting of aerobic and strength-based exercises, and stability and mobility activities. The first 6 weeks of the programme were conducted remotely, whereas the second 6 weeks incorporated face-to-face rehabilitation sessions in a community setting. A weekly telephone call with a rehabilitation specialist was also provided to support queries and advise on exercise selection, symptom management and emotional wellbeing.ResultsThe 12-week rehabilitation programme significantly improved Dyspnea-12 (D-12), Duke Activity Status Index (DASI), World Health Orginaisation-5 (WHO-5) and EQ-5D-5L utility scores (all p < 0.001), with the 95% confidence intervals (CI) for the improvement in each of these outcomes exceeding the minimum clinically important difference (MCID) for each measure (mean change [CI]: D-12: −3.4 [−3.9, −2.9]; DASI: 9.2 [8.2, 10.1]; WHO-5: 20.3 [18.6, 22.0]; EQ-5D-5L utility: 0.11 [0.10, 0.13]). Significant improvements exceeding the MCID were also observed for sit-to-stand test results (4.1 [3.5, 4.6]). On completion of the rehabilitation programme, participants also reported significantly fewer GP consultations (p < 0.001), sick days (p = 0.003) and outpatient visits (p = 0.007) during the previous 3 months compared with baseline.DiscussionThe blended and community design of this rehabilitation model makes it scalable and meets the urgent need for an effective intervention to support patients experiencing LC. This rehabilitation model is well placed to support the NHS (and other healthcare systems worldwide) in its aim of controlling the impacts of COVID-19 and delivering on its long-term plan.Clinical trial registrationhttps://www.isrctn.com/ISRCTN14707226, identifier 14707226

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN