MECHANISMS OF TRINUCLEOTIDE REPEAT INSTABILITY DURING DNA SYNTHESIS

Genomic instability, in the form of gene mutations, insertions/deletions, and gene amplifications, is one of the hallmarks in many types of cancers and other inheritable genetic disorders. Trinucleotide repeat (TNR) disorders, such as Huntington’s disease (HD) and Myotonic dystrophy (DM) can be inherited and repeats may be extended through subsequent generations. However, it is not clear how the CAG repeats expand through generations in HD. Two possible repeat expansion mechanisms include: 1) polymerase mediated repeat extension; 2) persistent TNR hairpin structure formation persisting in the genome resulting in expansion after subsequent cell division. Recent in vitro studies suggested that a family A translesion polymerase, polymerase θ (Polθ), was able to synthesize DNA larger than the template DNA. Clinical and in vivo studies showed either overexpression or knock down of Polθ caused poor survival in breast cancer patients and genomic instability. However, the role of Polθ in TNR expansion remains unelucidated. Therefore, we hypothesize that Polθ can directly cause TNR expansion during DNA synthesis. The investigation of the functional properties of Polθ during DNA replication and TNR synthesis will provide insight for the mechanism of TNR expansion through generations

Consumption of Over-the-Counter Drugs and Attitudes Towards Over-the-Counter Drug Advertising: A Comparison Between The United States and Hong Kong

A survey of 547 adults from the United States and Hong Kong was conducted to compare their perceptions about functions and consequences of OTC drug advertising and medical decisions when encountering health problems. Results indicate that American and Hong Kong consumers were very similar in their overall perception of functions and consequences of OTC drugs. A large majority of American consumers relied heavily on OTC drugs for all five types of selected health problems in this study. In contrast, Hong Kong consumers took OTC drugs only for specific illness

The Last Mile in Academic Publishing: Revising a Manuscript

Abstract Most of our journal or book manuscript submissions result in a request for revision according to the reviewers' comments. This article outlines the process of revising a manuscript, the options we have, and the tips of responding to reviewers' comments. It helps to reduce the frustration and inertia, and hopefully to make the publication journey less bumpy and more enjoyable

The Last Mile in Academic Publishing: Revising a Manuscript

Abstract Most of our journal or book manuscript submissions result in a request for revision according to the reviewers' comments. This article outlines the process of revising a manuscript, the options we have, and the tips of responding to reviewers' comments. It helps to reduce the frustration and inertia, and hopefully to make the publication journey less bumpy and more enjoyable

Intégrer la formation, la pratique et la réflexion dans un nouveau modèle d’évaluation de la compétence des diplômés en médecine au Canada : un document conceptuel à l’intention du Conseil médical du Canada

In 2020 the Medical Council of Canada created a task force to make recommendations on the modernization of its practices for granting licensure to medical trainees. This task force solicited papers on this topic from subject matter experts. As outlined within this Concept Paper, our proposal would shift licensure away from the traditional focus on high-stakes summative exams in a way that integrates training, clinical practice, and reflection. Specifically, we propose a model of graduated licensure that would have three stages including: a trainee license for trainees that have demonstrated adequate medical knowledge to begin training as a closely supervised resident, a transition to practice license for trainees that have compiled a reflective educational portfolio demonstrating the clinical competence required to begin independent practice with limitations and support, and a fully independent license for unsupervised practice for attendings that have demonstrated competence through a reflective portfolio of clinical analytics. This proposal was reviewed by a diverse group of 30 trainees, practitioners, and administrators in medical education. Their feedback was analyzed and summarized to provide an overview of the likely reception that this proposal would receive from the medical education community.En 2020, le Conseil médical du Canada a créé un groupe de travail chargé de formuler des recommandations sur la modernisation de ses pratiques d’octroi du titre de licencié aux stagiaires en médecine. À cette fin, le groupe de travail a sollicité la contribution d’experts en la matière. Dans le présent document conceptuel, nous proposons de réorienter l’approche traditionnelle axée sur l’évaluation sommative par des examens à enjeux élevés vers l’intégration de la formation, la pratique clinique et la réflexion. Plus précisément, nous proposons un modèle d’octroi progressif du titre de compétence en trois étapes : un titre pour les stagiaires qui ont démontré qu’ils possèdent les connaissances nécessaires pour commencer leur formation en tant que résident étroitement supervisé, un titre de transition pour les stagiaires ayant un portfolio d’apprentissage réflexif qui démontre la compétence clinique requise pour entamer une pratique indépendante avec du soutien et certaines limites, et un titre permettant la pratique pleinement indépendante et non supervisée pour ceux dont le portfolio réflexif démontre une compétence en analyse clinique. Cette proposition a été examinée par un groupe diversifié de 30 stagiaires, praticiens et gestionnaires en éducation médicale. Leurs commentaires ont été analysés et résumés pour donner une idée de l’accueil que la proposition serait susceptible de recevoir de la part du milieu de l’éducation médicale

Monitoring and Control of Unstructured Manufacturing Big Data

Unstructured manufacturing big data silos are challenging for enabling various data-driven applications such as digital threads and digital twins in manufacturing. The management of big data silos requires to address the issues of large volume, data inconsistency, data redundancy, information silos and data security. This research developed a systematic approach to managing data silos using the state of art big data software. Applying this approach in the product life cycle can control data silos, data consistency, redundancy, timely update and enable the automatic workflow of each system

Cell surface IL-1α trafficking is specifically inhibited by interferon-γ, and associates with the membrane via IL-1R2 and GPI anchors.

IL-1 is a powerful cytokine that drives inflammation and modulates adaptive immunity. Both IL-1α and IL-1β are translated as proforms that require cleavage for full cytokine activity and release, while IL-1α is reported to occur as an alternative plasma membrane-associated form on many cell types. However, the existence of cell surface IL-1α (csIL-1α) is contested, how IL-1α tethers to the membrane is unknown, and signaling pathways controlling trafficking are not specified. Using a robust and fully validated system, we show that macrophages present bona fide csIL-1α after ligation of TLRs. Pro-IL-1α tethers to the plasma membrane in part through IL-1R2 or via association with a glycosylphosphatidylinositol-anchored protein, and can be cleaved, activated, and released by proteases. csIL-1α requires de novo protein synthesis and its trafficking to the plasma membrane is exquisitely sensitive to inhibition by IFN-γ, independent of expression level. We also reveal how prior csIL-1α detection could occur through inadvertent cell permeabilisation, and that senescent cells do not drive the senescent-associated secretory phenotype via csIL-1α, but rather via soluble IL-1α. We believe these data are important for determining the local or systemic context in which IL-1α can contribute to disease and/or physiological processes.Work was funded by British Heart Foundation Grants FS/13/3/30038, FS/18/19/33371 and RG/16/8/32388 to MCHC, the BHF Cambridge CRE RE/13/6/30180, and the Cambridge NIHR Biomedical Research Centr

Characterization of human mesenchymal stem cells from multiple donors and the implications for large scale bioprocess development

Cell-based therapies have the potential to contribute to global healthcare, whereby the use of living cells and tissues can be used as medicinal therapies. Despite this potential, many challenges remain before the full value of this emerging field can be realized. The characterization of input material for cell-based therapy bioprocesses from multiple donors is necessary to identify and understand the potential implications of input variation on process development. In this work, we have characterized bone marrow derived human mesenchymal stem cells (BM-hMSCs) from multiple donors and discussed the implications of the measurable input variation on the development of autologous and allogeneic cell-based therapy manufacturing processes. The range of cumulative population doublings across the five BM-hMSC lines over 30 days of culture was 5.93, with an 18.2% range in colony forming efficiency at the end of the culture process and a 55.1% difference in the production of interleukin-6 between these cell lines. It has been demonstrated that this variation results in a range in the process time between these donor hMSC lines for a hypothetical product of over 13 days, creating potential batch timing issues when manufacturing products from multiple patients. All BM-hMSC donor lines demonstrated conformity to the ISCT criteria but showed a difference in cell morphology. Metabolite analysis showed that hMSCs from the different donors have a range in glucose consumption of 26.98 pmol cell−1 day−1, Lactate production of 29.45 pmol cell−1 day−1 and ammonium production of 1.35 pmol cell−1 day−1, demonstrating the extent of donor variability throughout the expansion process. Measuring informative product attributes during process development will facilitate progress towards consistent manufacturing processes, a critical step in the translation cell-based therapies