Muscle atrophy complicates many diseases as well as aging, and its presence predicts both decreased quality of life and survival. Much work has been conducted to define the molecular mechanisms involved in maintaining protein homeostasis in muscle. To date, the ubiquitin proteasome system (UPS) has been shown to play an important role in mediating muscle wasting. In this review, we have collated the enzymes in the UPS whose roles in muscle wasting have been confirmed through loss-of-function studies. We have integrated information on their mechanisms of action to create a model of how they work together to produce muscle atrophy. These enzymes are involved in promoting myofibrillar disassembly and degradation, activation of autophagy, inhibition of myogenesis as well as in modulating the signaling pathways that control these processes. Many anabolic and catabolic signaling pathways are involved in regulating these UPS genes, but none appear to coordinately regulate a large number of these genes. A number of catabolic signaling pathways appear to instead function by inhibition of the insulin/IGF-I/protein kinase B anabolic pathway. This pathway is a critical determinant of muscle mass, since it can suppress key ubiquitin ligases and autophagy, activate protein synthesis, and promote myogenesis through its downstream mediators such as forkhead box O, mammalian target of rapamycin, and GSK3β, respectively. Although much progress has been made, a more complete inventory of the UPS genes involved in mediating muscle atrophy, their mechanisms of action, and their regulation will be useful for identifying novel therapeutic approaches to this important clinical problem.

Anti-amyloid immunotherapies have recently emerged as treatments for Alzheimer’s disease. While these therapies have demonstrated efficacy in clearing amyloid-β and slowing cognitive decline, they have also been associated with amyloid-related imaging abnormalities (ARIA) which include both edema (ARIA-E) and hemorrhage (ARIA-H). Given that ARIA have been associated with significant morbidity in cases of antithrombotic or thrombolytic therapy, an understanding of mechanisms of and risk factors for ARIA is of critical importance for stroke care. We discuss the latest data regarding mechanisms of ARIA, including the role of underlying cerebral amyloid angiopathy, and implications for ischemic stroke prevention and management.

Background: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) can cause optic neuritis, transverse myelitis, or acute disseminated encephalomyelitis (ADEM). Immunotherapy is often used for relapsing disease, but there is variability in treatment decisions. Objective: The objective was to determine the annualized relapse rates (ARRs) and incidence rate ratios (IRRs) compared to pre-treatment and relapse-freedom probabilities among patients receiving steroids, B-cell depletion (BCD), intravenous immunoglobulin (IVIG), and mycophenolate mofetil (MMF). Methods: Retrospective cohort study of patients with relapsing MOGAD treated at Mass General Brigham. ARRs and IRRs compared to pre-treatment, and relapse-freedom probability and odds ratio for relapse-freedom compared to prednisone were calculated. Results: A total of 88 patients met the inclusion criteria. The ARR on IVIG was 0.13 (95% confidence interval (CI) = 0.06–0.27) and the relapse-freedom probability after at least 6 months of therapy was 72%. The ARR on BCD was 0.51 (95% CI = 0.34–0.77), and the relapse-freedom probability was 33%. The ARR on MMF was 0.32 (95% CI = 0.19–0.53) and the relapse-freedom probability was 49%. In pediatric-onset disease, MMF had the lowest ARRs (0.15, 95% CI = 0.07–0.33). Conclusion: IVIG had the lowest ARRs and IRRs compared to pre-treatment and the highest relapse-freedom odds ratio compared to prednisone, while BCD had the lowest. In pediatric-onset MOGAD, MMF had the lowest ARRs.

Remyelination in the human CNS is ascribed to progenitor cells rather than previously myelinating oligodendrocytes (OLs). The ganglioside-recognizing antibody A2B5 has been used to isolate putative progenitor cells, whose in vitro features resemble cells labeled as “pre-oligodendrocytes.” Here, we compare the transcriptional profiles of adult human brain-derived A2B5 antibody-selected cells (A+) after initial isolation (day in vitro (DIV1)) and after DIV6, with nonselected (A–) cells (mature OLs), with regard to their differentiation state and functional properties. While a number of previously recognized progenitor associated genes, specifically PTPRZ1 and PDGFRα, were upregulated in the A2B5+ population, a number of such genes were comparably expressed in the mature OLs, as were mature myelin genes. Additional progenitor-related genes were upregulated in the A+ population. We show that A2B5+ cells have greater capacity to ensheath nanofibers, a model of myelination potential; consistent with this, ingenuity pathway analysis indicated that A+ cells had upregulated expression of genes within cell growth and cell signaling pathways. Differential expression of cell death/survival pathways complements previous functional studies showing their increased susceptibility to metabolic stress. At DIV6, we observed significantly fewer differentially expressed genes; suggestive of cell maturation occurring in vitro, indicating the complexity in comparing in vitro and in situ cell properties.

Historically, students have been “consumers” of undergraduate medical education (UME) rather than stakeholders in its design and implementation. Student input has been retrospective, and although UME leaders have been open to feedback, matters most important to students have often been overlooked, leaving students feeling largely unheard. Student representation has also lacked structure and unity of feedback. A vision for effective student representation drove the creation of a partnered educational governance (PEG) model at McGill University in Montreal, Quebec, Canada, where sharing of expertise between student representatives and UME leadership has improved the UME program and the educational experience of students. The PEG model is grounded in the literature on student government, the student-as-partner framework, and theories of accountability. As part of the model, the student Medical Education Committee, an organized structure for discussion and reporting to student constituents, was established. This structure allows student representatives, entrusted by their peers and faculty, to proactively provide input to UME committees in the development of policies and curricula. The partnership between students and faculty facilitates a shared understanding of educational challenges and potential solutions. Within the first year, meaningful changes associated with the PEG model included increased student engagement in key program decisions, such as the redesign of a research course and an update to the absences and leaves policy. The PEG model enables unified student representation that is accountable and representative—and has a significant impact on outcomes—while maintaining the UME program’s ownership of and responsibility for the curriculum and policies.