DNA Dynamics Is Likely to Be a Factor in the Genomic Nucleotide Repeats Expansions Related to Diseases

Trinucleotide repeats sequences (TRS) represent a common type of genomic DNA motif whose expansion is associated with a large number of human diseases. The driving molecular mechanisms of the TRS ongoing dynamic expansion across generations and within tissues and its influence on genomic DNA functions are not well understood. Here we report results for a novel and notable collective breathing behavior of genomic DNA of tandem TRS, leading to propensity for large local DNA transient openings at physiological temperature. Our Langevin molecular dynamics (LMD) and Markov Chain Monte Carlo (MCMC) simulations demonstrate that the patterns of openings of various TRSs depend specifically on their length. The collective propensity for DNA strand separation of repeated sequences serves as a precursor for outsized intermediate bubble states independently of the G/C-content. We report that repeats have the potential to interfere with the binding of transcription factors to their consensus sequence by altered DNA breathing dynamics in proximity of the binding sites. These observations might influence ongoing attempts to use LMD and MCMC simulations for TRS–related modeling of genomic DNA functionality in elucidating the common denominators of the dynamic TRS expansion mutation with potential therapeutic applications

Listen Before You Auscultate Bedside Cardiac Assessment Trailer

Authors: James L. Meisel, MD, MHPE,1 Daniel C. R. Chen, MD, MSc,2 Gail March Cohen, PhD, MFA,3 Sheilah A. Bernard, MD,4 Hugo Carmona, MD,5 Emil R. Petrusa, PhD,6 Isaac O. Opole, MD, PhD,7 Deborah Navedo, PhD, CPNP, FNAP,8 Vladimir I. Valtchinov, PhD,9Ahmed H. Nahas, MD,10 Carly M. Eiduson, BA,11 Nick Papps, BS, MBA12 1 Associate Chief of Staff for Education, VA Bedford Healthcare System; Associate Professor of Medicine, Dept. of Medicine, Boston University Chobanian and Avedisian School of Medicine 2 Assistant Dean of Student Affairs and Clinical Associate Professor of Medicine, General Internal Medicine, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine 3 Medical Director, AMA Ed Hub 4 Associate Professor of Medicine, Cardiovascular Medicine, Dept. of Medicine, Boston University School of Medicine 5 Assistant Professor of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Washington 6 Professor of Surgery, Harvard Medical School; Department of Surgery, Learning Lab, Massachusetts General Hospital 7 Professor of Internal Medicine, Department of Internal Medicine, University of Kansas Medical Center 8 Director of Education, STRATUS Center for Simulation, Brigham and Women's Hospital 9 Assistant Professor of Radiology, Center for Evidence-Based Imaging, Department of Radiology, Brigham and Women’s Hospital; Department of Biomedical Informatics, Harvard Medical School 10 Advanced Geriatric Medicine Fellow, Veterans Health Administration, New England Geriatrics Research, Education, and Clinical Center, VA Boston Health Care System; Geriatrician, Yakima Valley Farm Workers Clinic, Yakima, WA, USA 11 Fourth-year medical student, University of Rochester School of Medicine & Dentistry 12 Multimedia producer, Synchro AgencyIntroduction: Bedside cardiac assessment (BCA) is deficient across a spectrum of non-cardiology trainees. Learners not taught BCA well may become instructors who do not teach well, creating a self-perpetuating problem. We aimed to improve BCA teaching and learning by developing a high-quality, patient-centered curriculum for medicine clerkship students that could be flexibly implemented and accessible to other health professions learners. Methods: With a constructivist perspective, we aligned learning goals, activities, and assessments. The curriculum used a “listen before you auscultate” framework, capturing patient history as context for a six-step, systematic approach. In the flipped classroom, short videos and practice questions preceded two, 1-hour class activities that integrated diagnostic reasoning, pathophysiology, physical diagnosis, and reflection. Activities included case discussions, JVP evaluation, heart sound competitions, and simulated conversations with patients. 268 students at four U.S. and international medical schools participated. We incorporated feedback, performed thematic analysis, and assessed learners’ confidence and knowledge. Results: Low post-test data capture limited quantitative results. Students reported increased confidence in BCA ability. Knowledge increased in both BCA and control groups. Thematic analysis suggested instructional design strategies were effective and peer encounters, skills practice, and encounters with educators were meaningful. Discussion: The curriculum supported active learning of day-to-day clinical competencies. Explicitly incorporating notions of trust, it promoted professional identity formation alongside BCA ability. Feedback and increased confidence on the late-clerkship post-test suggested durable learning. We recommended approaches to confirm this and other elements of knowledge, skill acquisition, or behaviors, and are surveying impacts on professional identity formation-related constructs

Concordance between gene expression in peripheral whole blood and colonic tissue in children with inflammatory bowel disease.

BACKGROUND:Presenting features of inflammatory bowel disease (IBD) are non-specific. We hypothesized that mRNA profiles could (1) identify genes and pathways involved in disease pathogenesis; (2) identify a molecular signature that differentiates IBD from other conditions; (3) provide insight into systemic and colon-specific dysregulation through study of the concordance of the gene expression. METHODS:Children (8-18 years) were prospectively recruited at the time of diagnostic colonoscopy for possible IBD. We used transcriptome-wide mRNA profiling to study gene expression in colon biopsies and paired whole blood samples. Using blood mRNA measurements, we fit a regression model for disease state prediction that was validated in an independent test set of adult subjects (GSE3365). RESULTS:Ninety-eight children were recruited [39 Crohn's disease, 18 ulcerative colitis, 2 IBDU, 39 non-IBD]. There were 1,118 significantly differentially (IBD vs non-IBD) expressed genes in colon tissue, and 880 in blood. The direction of relative change in expression was concordant for 106/112 genes differentially expressed in both tissue types. The regression model from the blood mRNA measurements distinguished IBD vs non-IBD disease status in the independent test set with 80% accuracy using only 6 genes. The overlap of 5 immune and metabolic pathways in the two tissue types was significant (p<0.001). CONCLUSIONS:Blood and colon tissue from patients with IBD share a common transcriptional profile dominated by immune and metabolic pathways. Our results suggest that peripheral blood expression levels of as few as 6 genes (IL7R, UBB, TXNIP, S100A8, ALAS2, and SLC2A3) may distinguish patients with IBD from non-IBD

Severe COVID-19 pneumonia leads to post-COVID-19 lung abnormalities on follow-up CT scans

Purpose: To investigate the association of the maximal severity of pneumonia on CT scans obtained within 6-week of diagnosis with the subsequent development of post-COVID-19 lung abnormalities (Co-LA). Methods: COVID-19 patients diagnosed at our hospital between March 2020 and September 2021 were studied retrospectively. The patients were included if they had (1) at least one chest CT scan available within 6-week of diagnosis; and (2) at least one follow-up chest CT scan available ≥ 6 months after diagnosis, which were evaluated by two independent radiologists. Pneumonia Severity Categories were assigned on CT at diagnosis according to the CT patterns of pneumonia and extent as: 1) no pneumonia (Estimated Extent, 0%); 2) non-extensive pneumonia (GGO and OP, 40%). Co-LA on follow-up CT scans, categorized using a 3-point Co-LA Score (0, No Co-LA; 1, Indeterminate Co-LA; and 2, Co-LA). Results: Out of 132 patients, 42 patients (32%) developed Co-LA on their follow-up CT scans 6–24 months post diagnosis. The severity of COVID-19 pneumonia was associated with Co-LA: In 47 patients with extensive pneumonia, 33 patients (70%) developed Co-LA, of whom 18 (55%) developed fibrotic Co-LA. In 52 with non-extensive pneumonia, 9 (17%) developed Co-LA: In 33 with no pneumonia, none (0%) developed Co-LA. Conclusions: Higher severity of pneumonia at diagnosis was associated with the increased risk of development of Co-LA after 6–24 months of SARS-CoV-2 infection

The TRS expansion has an effect on the DNA bubble spectrum.

<p>EPBD based LMD simulations have been conducted on the: a) (CAG.CTG)₄₅ repeats and healthy (CAG.CTG)₁₀ repeats with 30 bp flanking huntington gene sequence; b) (GAA.TTC)₁₂₀ and (GAA.TTC)₆ MRS that are embedded in 50 bp frataxin gene sequence; c) (CGG.GCC)₂₄₀ and (CGG.GCC)₂₀ repeats together with 50 bp FMR1 gene flanking sequence. The y-axis represents the length of the bubbles in bp; the x-axis represents the number of the base pairs; the color axis gives the bubble duration in psec. The brackets above the panels denote the repeated sequence; red arrows- the largest and long-lived base-pairs openings.</p