These collections showcase journal articles, preprints, book chapters, and other publications and presentations produced by faculty, postdocs, and researchers at UMass Chan Medical School, including a dedicated collection for research on COVID-19 and related viruses.

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  • Individual Development Plan for Career Development Professionals

    Ismael, Amber; Campbell, Brian; Chremos, Ioannis Vasileios; Fuhrmann, Cynthia N; Nordell, Shawn (2024-06-21)
    The Individual Development Plan for Career Development Professionals is an IDP worksheet to guide individuals who are pursuing careers in graduate/postdoctoral career development through the process of creating their own IDP. The worksheet is designed as an IDP tool for all career levels, including those preparing to enter this field, practitioners seeking to grow within their current positions, or those looking to advance or pursue a career transition. The tool includes prompts to guide one through exercises that help one assess their skills, values, interests, progress and growth; set goals and define an action plan; and consider the resources, mentorship, and community that they may need to help develop a fulfilling career. Though designed for professionals in the career development field, this tool may also be helpful for those in other academic administration or education roles. This tool was designed by members of the Professional Development Committee of the Graduate Career Consortium, an international member organization to help individuals advance the field of graduate and postdoctoral career and professional development.
  • Apheresis practice variation during the COVID-19 pandemic: Results of a survey

    Tanhehco, Yvette C; Alsammak, Mohamed; Chhibber, Vishesh; Ibeh, Nnaemeka; Li, Yanhua; Stephens, Laura D; Noland, Daniel K; Wu, Ding Wen; Zantek, Nicole D; DeChristopher, Phillip J; et al. (2024-06-01)
    Background: The COVID-19 pandemic affected healthcare delivery across all specialties including apheresis. To describe the changes in apheresis service practices that occurred during the pandemic, the American Society for Apheresis (ASFA) Apheresis Medicine Attending Physician Subcommittee conducted a survey study. Study design and methods: A 32-question survey was designed and distributed to 400 ASFA physician members on September 7, 2022. Attending physicians responded to questions about whether and how apheresis service practices changed during the COVID-19 pandemic compared with the time period prior to the pandemic in terms of: (1) procedure types and volumes, (2) patient consultation workflow, and (3) the use of telemedicine. Descriptive analyses were reported as number and frequency of responses. Results: The survey response rate was 13.8% (55/400). Of these respondents, 96.4% (53/55) were attending physicians. The majority of respondents (42/53, 79.2%) indicated that the types of procedures performed during COVID-19 compared to pre-pandemic did not change. Most frequently for apheresis procedure volume, respondents reported: no change in their monthly inpatient volume (21/47, 44.7%) and a decrease in their monthly outpatient volume (28/46, 60.9%). Prior to COVID-19, 75.0% (30/40) of respondents performed consultations at bedside for inpatients and 67.4% (29/43) performed consultations at bedside for outpatients. Bedside consultations decreased in both settings during the pandemic but were still most frequently performed by attending physicians. At the same time, the use of telemedicine increased for 15.4% of survey respondents during COVID-19. Conclusion: Some, but not all, respondents observed or made changes to their apheresis service during the COVID-19 pandemic. A subset of changes, such as increased utilization of telemedicine, may persist.
  • SARS-CoV-2 infection is associated with an increase in new diagnoses of schizophrenia spectrum and psychotic disorder: A study using the US national COVID cohort collaborative (N3C)

    Rahman, Asif; Russell, Michael; Zheng, Wanhong; Eckrich, Daniel; Ahmed, Imtiaz (2024-05-30)
    Amid the ongoing global repercussions of SARS-CoV-2, it is crucial to comprehend its potential long-term psychiatric effects. Several recent studies have suggested a link between COVID-19 and subsequent mental health disorders. Our investigation joins this exploration, concentrating on Schizophrenia Spectrum and Psychotic Disorders (SSPD). Different from other studies, we took acute respiratory distress syndrome (ARDS) and COVID-19 lab-negative cohorts as control groups to accurately gauge the impact of COVID-19 on SSPD. Data from 19,344,698 patients, sourced from the N3C Data Enclave platform, were methodically filtered to create propensity matched cohorts: ARDS (n = 222,337), COVID-19 positive (n = 219,264), and COVID-19 negative (n = 213,183). We systematically analyzed the hazard rate of new-onset SSPD across three distinct time intervals: 0-21 days, 22-90 days, and beyond 90 days post-infection. COVID-19 positive patients consistently exhibited a heightened hazard ratio (HR) across all intervals [0-21 days (HR: 4.6; CI: 3.7-5.7), 22-90 days (HR: 2.9; CI: 2.3 -3.8), beyond 90 days (HR: 1.7; CI: 1.5-1.)]. These are notably higher than both ARDS and COVID-19 lab-negative patients. Validations using various tests, including the Cochran Mantel Haenszel Test, Wald Test, and Log-rank Test confirmed these associations. Intriguingly, our data indicated that younger individuals face a heightened risk of SSPD after contracting COVID-19, a trend not observed in the ARDS and COVID-19 negative groups. These results, aligned with the known neurotropism of SARS-CoV-2 and earlier studies, accentuate the need for vigilant psychiatric assessment and support in the era of Long-COVID, especially among younger populations.
  • Burnout Among Young Adults With Type 1 Diabetes

    Perez, Danielle; Sullivan-Bolyai, Susan L; Bova, Carol A; Fain, James A (2024-05-30)
    Purpose: The purpose of this qualitative descriptive study was to describe the experience of diabetes burnout in young adults with type 1 diabetes (T1DM). In addition, aims included participant perspectives of risk and protective factors associated with burnout and ways to balance everyday life with diabetes self-management (DSM). Methods: Young adults with T1DM (N = 11) were recruited through social media platforms and modified snowball sampling and interviewed. Informational redundancy was achieved. Qualitative thematic coding and analysis were conducted within and across transcripts. Results: Diabetes burnout was described as the willingness to put diabetes and DSM on the "back burner" and let things slide due to exhaustion, frustration, apathy, and the desire to be like everyone else for a while. Risk and protective factors were identified along with strategies to achieve balance of DSM in everyday life. Conclusions: This study identified a clear definition of diabetes burnout and acknowledges this concept as distinct and separate from other psychosocial conditions. Health care providers can utilize this information to identify individuals at risk for diabetes burnout and offer more effective support to lessen the overall burden associated with T1DM.
  • Pairtools: From sequencing data to chromosome contacts

    Abdennur, Nezar; Fudenberg, Geoffrey; Flyamer, Ilya M; Galitsyna, Aleksandra A; Goloborodko, Anton; Imakaev, Maxim; Venev, Sergey V (2024-05-29)
    The field of 3D genome organization produces large amounts of sequencing data from Hi-C and a rapidly-expanding set of other chromosome conformation protocols (3C+). Massive and heterogeneous 3C+ data require high-performance and flexible processing of sequenced reads into contact pairs. To meet these challenges, we present pairtools-a flexible suite of tools for contact extraction from sequencing data. Pairtools provides modular command-line interface (CLI) tools that can be flexibly chained into data processing pipelines. The core operations provided by pairtools are parsing of.sam alignments into Hi-C pairs, sorting and removal of PCR duplicates. In addition, pairtools provides auxiliary tools for building feature-rich 3C+ pipelines, including contact pair manipulation, filtration, and quality control. Benchmarking pairtools against popular 3C+ data pipelines shows advantages of pairtools for high-performance and flexible 3C+ analysis. Finally, pairtools provides protocol-specific tools for restriction-based protocols, haplotype-resolved contacts, and single-cell Hi-C. The combination of CLI tools and tight integration with Python data analysis libraries makes pairtools a versatile foundation for a broad range of 3C+ pipelines.
  • Dual engagement of the nucleosomal acidic patches is essential for deposition of histone H2A.Z by SWR1C

    Baier, Alexander S; Gioacchini, Nathan; Eek, Priit; Leith, Erik M; Tan, Song; Peterson, Craig L (2024-05-29)
    The yeast SWR1C chromatin remodeling enzyme catalyzes the ATP-dependent exchange of nucleosomal histone H2A for the histone variant H2A.Z, a key variant involved in a multitude of nuclear functions. How the 14-subunit SWR1C engages the nucleosomal substrate remains largely unknown. Studies on the ISWI, CHD1, and SWI/SNF families of chromatin remodeling enzymes have demonstrated key roles for the nucleosomal acidic patch for remodeling activity, however a role for this nucleosomal epitope in nucleosome editing by SWR1C has not been tested. Here, we employ a variety of biochemical assays to demonstrate an essential role for the acidic patch in the H2A.Z exchange reaction. Utilizing asymmetrically assembled nucleosomes, we demonstrate that the acidic patches on each face of the nucleosome are required for SWR1C-mediated dimer exchange, suggesting SWR1C engages the nucleosome in a 'pincer-like' conformation, engaging both patches simultaneously. Loss of a single acidic patch results in loss of high affinity nucleosome binding and nucleosomal stimulation of ATPase activity. We identify a conserved arginine-rich motif within the Swc5 subunit that binds the acidic patch and is key for dimer exchange activity. In addition, our cryoEM structure of a Swc5-nucleosome complex suggests that promoter proximal, histone H2B ubiquitylation may regulate H2A.Z deposition. Together these findings provide new insights into how SWR1C engages its nucleosomal substrate to promote efficient H2A.Z deposition.
  • Single-cell genomics and regulatory networks for 388 human brains

    Emani, Prashant S; Liu, Jason J; Clarke, Declan; Jensen, Matthew; Warrell, Jonathan; Gupta, Chirag; Meng, Ran; Lee, Che Yu; Xu, Siwei; Dursun, Cagatay; et al. (2024-05-24)
    Single-cell genomics is a powerful tool for studying heterogeneous tissues such as the brain. Yet little is understood about how genetic variants influence cell-level gene expression. Addressing this, we uniformly processed single-nuclei, multiomics datasets into a resource comprising >2.8 million nuclei from the prefrontal cortex across 388 individuals. For 28 cell types, we assessed population-level variation in expression and chromatin across gene families and drug targets. We identified >550,000 cell type-specific regulatory elements and >1.4 million single-cell expression quantitative trait loci, which we used to build cell-type regulatory and cell-to-cell communication networks. These networks manifest cellular changes in aging and neuropsychiatric disorders. We further constructed an integrative model accurately imputing single-cell expression and simulating perturbations; the model prioritized ~250 disease-risk genes and drug targets with associated cell types.
  • Cross-ancestry atlas of gene, isoform, and splicing regulation in the developing human brain

    Wen, Cindy; Margolis, Michael; Dai, Rujia; Zhang, Pan; Przytycki, Pawel F; Vo, Daniel D; Bhattacharya, Arjun; Matoba, Nana; Tang, Miao; Jiao, Chuan; et al. (2024-05-24)
    Neuropsychiatric genome-wide association studies (GWASs), including those for autism spectrum disorder and schizophrenia, show strong enrichment for regulatory elements in the developing brain. However, prioritizing risk genes and mechanisms is challenging without a unified regulatory atlas. Across 672 diverse developing human brains, we identified 15,752 genes harboring gene, isoform, and/or splicing quantitative trait loci, mapping 3739 to cellular contexts. Gene expression heritability drops during development, likely reflecting both increasing cellular heterogeneity and the intrinsic properties of neuronal maturation. Isoform-level regulation, particularly in the second trimester, mediated the largest proportion of GWAS heritability. Through colocalization, we prioritized mechanisms for about 60% of GWAS loci across five disorders, exceeding adult brain findings. Finally, we contextualized results within gene and isoform coexpression networks, revealing the comprehensive landscape of transcriptome regulation in development and disease.
  • Using a comprehensive atlas and predictive models to reveal the complexity and evolution of brain-active regulatory elements

    Pratt, Henry E; Andrews, Gregory; Shedd, Nicole; Phalke, Nishigandha; Li, Tongxin; Pampari, Anusri; Jensen, Matthew; Wen, Cindy; Gandal, Michael J; Geschwind, Daniel H; et al. (2024-05-23)
    Most genetic variants associated with psychiatric disorders are located in noncoding regions of the genome. To investigate their functional implications, we integrate epigenetic data from the PsychENCODE Consortium and other published sources to construct a comprehensive atlas of candidate brain cis-regulatory elements. Using deep learning, we model these elements' sequence syntax and predict how binding sites for lineage-specific transcription factors contribute to cell type-specific gene regulation in various types of glia and neurons. The elements' evolutionary history suggests that new regulatory information in the brain emerges primarily via smaller sequence mutations within conserved mammalian elements rather than entirely new human- or primate-specific sequences. However, primate-specific candidate elements, particularly those active during fetal brain development and in excitatory neurons and astrocytes, are implicated in the heritability of brain-related human traits. Additionally, we introduce PsychSCREEN, a web-based platform offering interactive visualization of PsychENCODE-generated genetic and epigenetic data from diverse brain cell types in individuals with psychiatric disorders and healthy controls.
  • Inferring causal cell types of human diseases and risk variants from candidate regulatory elements [preprint]

    Kim, Artem; Zhang, Zixuan; Legros, Come; Lu, Zeyun; de Smith, Adam; Moore, Jill E; Mancuso, Nicholas; Gazal, Steven (2024-05-18)
    The heritability of human diseases is extremely enriched in candidate regulatory elements (cRE) from disease-relevant cell types. Critical next steps are to infer which and how many cell types are truly causal for a disease (after accounting for co-regulation across cell types), and to understand how individual variants impact disease risk through single or multiple causal cell types. Here, we propose CT-FM and CT-FM-SNP, two methods that leverage cell-type-specific cREs to fine-map causal cell types for a trait and for its candidate causal variants, respectively. We applied CT-FM to 63 GWAS summary statistics (average N = 417K) using nearly one thousand cRE annotations, primarily coming from ENCODE4. CT-FM inferred 81 causal cell types with corresponding SNP-annotations explaining a high fraction of trait SNP-heritability (~2/3 of the SNP-heritability explained by existing cREs), identified 16 traits with multiple causal cell types, highlighted cell-disease relationships consistent with known biology, and uncovered previously unexplored cellular mechanisms in psychiatric and immune-related diseases. Finally, we applied CT-FM-SNP to 39 UK Biobank traits and predicted high confidence causal cell types for 2,798 candidate causal non-coding SNPs. Our results suggest that most SNPs impact a phenotype through a single cell type, and that pleiotropic SNPs target different cell types depending on the phenotype context. Altogether, CT-FM and CT-FM-SNP shed light on how genetic variants act collectively and individually at the cellular level to impact disease risk.
  • ADAM9 promotes type I interferon-mediated innate immunity during encephalomyocarditis virus infection

    Bazzone, Lindsey E; Zhu, Junji; King, Michael; Liu, GuanQun; Guo, Zhiru; MacKay, Christopher R; Kyawe, Pyae P; Qaisar, Natasha; Rojas-Quintero, Joselyn; Owen, Caroline A; et al. (2024-05-16)
    Viral myocarditis, an inflammatory disease of the heart, causes significant morbidity and mortality. Type I interferon (IFN)-mediated antiviral responses protect against myocarditis, but the mechanisms are poorly understood. We previously identified A Disintegrin And Metalloproteinase domain 9 (ADAM9) as an important factor in viral pathogenesis. ADAM9 is implicated in a range of human diseases, including inflammatory diseases; however, its role in viral infection is unknown. Here, we demonstrate that mice lacking ADAM9 are more susceptible to encephalomyocarditis virus (EMCV)-induced death and fail to mount a characteristic type I IFN response. This defect in type I IFN induction is specific to positive-sense, single-stranded RNA (+ ssRNA) viruses and involves melanoma differentiation-associated protein 5 (MDA5)-a key receptor for +ssRNA viruses. Mechanistically, ADAM9 binds to MDA5 and promotes its oligomerization and thereby downstream mitochondrial antiviral-signaling protein (MAVS) activation in response to EMCV RNA stimulation. Our findings identify a role for ADAM9 in the innate antiviral response, specifically MDA5-mediated IFN production, which protects against virus-induced cardiac damage, and provide a potential therapeutic target for treatment of viral myocarditis.
  • Race-Based Differences in the Response to a Mindfulness Based Integrative Medical Group Visit Intervention for Chronic Pain

    Incollingo Rodriguez, Angela C; Nephew, Benjamin C; Polcari, Justin J; Melican, Veronica; King, Jean A; Gardiner, Paula (2024-05-16)
    Background: Chronic pain is one of the most common drivers of healthcare utilization and a marked domain for health disparities, as African American/Black populations experience high rates of chronic pain. Integrative Medical Group Visits (IMGV) combine mindfulness techniques, evidence-based integrative medicine, and medical group visits. In a parent randomized controlled trial, this approach was tested as an adjunct treatment in a diverse, medically underserved population with chronic pain and depression. Objective: To determine race-based heterogeneity in the effects of a mindfulness based treatment for chronic pain. Methods: This secondary analysis of the parent trial assessed heterogeneity of treatment effects along racialized identity in terms of primary patient-reported pain outcomes in a racially diverse sample suffering from chronic pain and depression. The analytic approach examined comorbidities and sociodemographics between racialized groups. RMANOVAs examined trajectories in pain outcomes (average pain, pain severity, and pain interference) over three timepoints (baseline, 9, and 21 weeks) between participants identifying as African American/Black (n = 90) vs White (n = 29) across both intervention and control conditions. Results: At baseline, African American/Black participants had higher pain severity and had significantly different age, work status, and comorbidity profiles. RMANOVA models also identified significant race-based differences in the response to the parent IMGV intervention. There was reduced pain severity in African American/Black subjects in the IMGV condition from baseline to 9 weeks. This change was not observed in White participants over this time period. However, there was a reduction in pain severity in White participants over the subsequent interval from 9 to 21 week where IMGV had no significant effect in African American/Black subjects during this latter time period. Conclusion: Interactions between pain and racialization require further investigation to understand how race-based heterogeneity in the response to integrative medicine treatments for chronic pain contribute to the broader landscape of health inequity.
  • Translational insights into the genetics and immunobiology of relapsed/refractory follicular lymphoma

    Yaniv, Benyamin; Tanenbaum, Benjamin; Kazakova, Vera; Patel, Shyam A (2024-05-11)
    Although follicular lymphoma (FL) is traditionally classified as an indolent subtype of B cell non-Hodgkin lymphoma, clinical trajectories are often diverse based on unique disease biology, and many patients will eventually experience relapse of their disease. Furthermore, progression of disease within 24 months is associated with increased mortality rates for FL. In the last five years, we have witnessed an upsurge in the commercial availability of targeted therapies for relapsed/refractory (R/R) FL, including chimeric antigen receptor-T (CAR-T) products, bispecific T cell engagers (BiTEs), epigenetic modifier therapies, and next-generation Bruton tyrosine kinase (BTK) inhibitors. Furthermore, clinical trial options have increased tremendously and now include combinatorial strategies that exert synergy against malignant germinal center B cells. Here, we provide a 2024 update of novel therapeutic agents whose development has been informed by recent advances in the genetics and immunobiology of R/R FL. Specifically, we emphasize high-value targeted therapeutics, including anti-CD3 x anti-CD20 BiTEs and adoptive T cell therapies. We discuss prospects on selection and sequencing of BiTEs and CAR-T therapies for patients with R/R FL. We underscore the principles of FL pathobiology that are paving way for future drug discovery and shed insight into therapeutic targeting within nodal basins based on our increasing understanding of the FL microenvironment. Finally, we summarize how a greater knowledge of FL immunobiology can inform risk stratification and therapy selection on a personalized basis for R/R FL in 2025.
  • Retinopathy of prematurity and neurodevelopmental outcome and quality of life at 10 years of age [preprint]

    Sriram, Sudhir; Jensen, Elizabeth; Msall, Michael; Yi, Joe; Zhabotynsky, Vasyl; Joseph, Robert; Kuban, Karl; Frazier, Jean A; Hooper, Stephen; Santos, Hudson; et al. (2024-05-08)
    Objective: In a cohort of 10-year-old children born extremely preterm, we evaluated the hypothesis that increasing severity of retinopathy of prematurity (ROP) is associated with increasing frequency of unfavorable neurodevelopmental and quality of life outcomes. Study design: Study participants were classified according to the severity of ROP. At 10 years of age, their neurocognitive abilities, academic achievement, and gross motor function were assessed, and they were evaluated for autism spectrum disorder, anxiety, depression, and quality of life. Results: After adjustment for sample attrition and confounders, only the association with lower quality of life persisted. Increasing severity of visual impairment was associated with worse neurodevelopmental outcomes and lower quality of life. Conclusion: Among extremely preterm children, severity of visual impairment, but not severity of ROP, was associated with adverse neurodevelopmental outcomes at 10 years of age. Both severe ROP and more severe visual impairment were associated with lower quality of life.
  • Cooltools: Enabling high-resolution Hi-C analysis in Python

    Abdennur, Nezar; Abraham, Sameer; Fudenberg, Geoffrey; Flyamer, Ilya M; Galitsyna, Aleksandra A; Goloborodko, Anton; Imakaev, Maxim; Akgol Oksuz, Betul; Venev, Sergey V; Xiao, Yao (2024-05-06)
    Chromosome conformation capture (3C) technologies reveal the incredible complexity of genome organization. Maps of increasing size, depth, and resolution are now used to probe genome architecture across cell states, types, and organisms. Larger datasets add challenges at each step of computational analysis, from storage and memory constraints to researchers' time; however, analysis tools that meet these increased resource demands have not kept pace. Furthermore, existing tools offer limited support for customizing analysis for specific use cases or new biology. Here we introduce cooltools (https://github.com/open2c/cooltools), a suite of computational tools that enables flexible, scalable, and reproducible analysis of high-resolution contact frequency data. Cooltools leverages the widely-adopted cooler format which handles storage and access for high-resolution datasets. Cooltools provides a paired command line interface (CLI) and Python application programming interface (API), which respectively facilitate workflows on high-performance computing clusters and in interactive analysis environments. In short, cooltools enables the effective use of the latest and largest genome folding datasets.
  • Safety and efficacy of losmapimod in facioscapulohumeral muscular dystrophy (ReDUX4): a randomised, double-blind, placebo-controlled phase 2b trial

    Tawil, Rabi; Wagner, Kathryn R; Hamel, Johanna I; Leung, Doris G; Statland, Jeffrey M; Wang, Leo H; Genge, Angela; Sacconi, Sabrina; Lochmüller, Hanns; Reyes-Leiva, David; et al. (2024-05-01)
    Background: Facioscapulohumeral muscular dystrophy is a hereditary progressive myopathy caused by aberrant expression of the transcription factor DUX4 in skeletal muscle. No approved disease-modifying treatments are available for this disorder. We aimed to assess the safety and efficacy of losmapimod (a small molecule that inhibits p38α MAPK, a regulator of DUX4 expression, and p38β MAPK) for the treatment of facioscapulohumeral muscular dystrophy. Methods: We did a randomised, double-blind, placebo-controlled phase 2b trial at 17 neurology centres in Canada, France, Spain, and the USA. We included adults aged 18-65 years with type 1 facioscapulohumeral muscular dystrophy (ie, with loss of repression of DUX4 expression, as ascertained by genotyping), a Ricci clinical severity score of 2-4, and at least one skeletal muscle judged using MRI to be suitable for biopsy. Participants were randomly allocated (1:1) to either oral losmapimod (15 mg twice a day) or matching placebo for 48 weeks, via an interactive response technology system. The investigator, study staff, participants, sponsor, primary outcome assessors, and study monitor were masked to the treatment allocation until study closure. The primary endpoint was change from baseline to either week 16 or 36 in DUX4-driven gene expression in skeletal muscle biopsy samples, as measured by quantitative RT-PCR. The primary efficacy analysis was done in all participants who were randomly assigned and who had available data for assessment, according to the modified intention-to-treat principle. Safety and tolerability were assessed as secondary endpoints. This study is registered at ClinicalTrials.gov, number NCT04003974. The phase 2b trial is complete; an open-label extension is ongoing. Findings: Between Aug 27, 2019, and Feb 27, 2020, 80 people were enrolled. 40 were randomly allocated to losmapimod and 40 to placebo. 54 (68%) participants were male and 26 (33%) were female, 70 (88%) were White, and mean age was 45·7 (SD 12·5) years. Least squares mean changes from baseline in DUX4-driven gene expression did not differ significantly between the losmapimod (0·83 [SE 0·61]) and placebo (0·40 [0·65]) groups (difference 0·43 [SE 0·56; 95% CI -1·04 to 1·89]; p=0·56). Losmapimod was well tolerated. 29 treatment-emergent adverse events (nine drug-related) were reported in the losmapimod group compared with 23 (two drug-related) in the placebo group. Two participants in the losmapimod group had serious adverse events that were deemed unrelated to losmapimod by the investigators (alcohol poisoning and suicide attempt; postoperative wound infection) compared with none in the placebo group. No treatment discontinuations due to adverse events occurred and no participants died during the study. Interpretation: Although losmapimod did not significantly change DUX4-driven gene expression, it was associated with potential improvements in prespecified structural outcomes (muscle fat infiltration), functional outcomes (reachable workspace, a measure of shoulder girdle function), and patient-reported global impression of change compared with placebo. These findings have informed the design and choice of efficacy endpoints for a phase 3 study of losmapimod in adults with facioscapulohumeral muscular dystrophy. Funding: Fulcrum Therapeutics.
  • Dominant negative mutations in yeast Hsp90 reveal triage decision mechanism targeting client proteins for degradation [preprint]

    Flynn, Julia M; Joyce, Margot E; Bolon, Daniel N A (2024-04-30)
    Most of the fundamental processes of cells are mediated by proteins. However, the biologically-relevant mechanism of most proteins are poorly understood. Dominant negative mutations have provided a valuable tool for investigating protein mechanisms but can be difficult to isolate because of their toxic effects. We used a mutational scanning approach to identify dominant negative mutations in yeast Hsp90. Hsp90 is a chaperone that forms dynamic complexes with many co-chaperones and client proteins. In vitro analyses have elucidated some key biochemical states and structures of Hsp90, co-chaperones, and clients; however, the biological mechanism of Hsp90 remains unclear. For example, high throughput studies have found that many E3 ubiquitin ligases bind to Hsp90, but it is unclear if these are primarily clients or acting to tag other clients for degradation. We introduced a library of all point mutations in the ATPase domain of Hsp90 into yeast and noticed that 176 were more than 10-fold depleted at the earliest point that we could analyze. There were two hot spot regions of the depleted mutations that were located at the hinges of a loop that closes over ATP. We quantified the dominant negative growth effects of mutations in the hinge regions using a library of mutations driven by an inducible promoter. We analyzed individual dominant negative mutations in detail and found that addition of the E33A mutation that prevents ATP hydrolysis by Hsp90 abrogated the dominant negative phenotype. Pull-down experiments did not reveal any stable binding partners, indicating that the dominant effects were mediated by dynamic complexes. DN Hsp90 decreased the expression level of two model Hsp90 clients, glucocorticoid receptor (GR) and v-src kinase. Using MG132, we found that GR was rapidly destabilized in a proteasome-dependent fashion. These findings provide evidence that the binding of E3 ligases to Hsp90 may serve a quality control function fundamental to eukaryotes.
  • Rationale and Design of Healthy at Home for COPD: an Integrated Remote Patient Monitoring and Virtual Pulmonary Rehabilitation Pilot Study [preprint]

    O'Connor, Laurel; Behar, Stephanie; Tarrant, Seanan; Stamegna, Pamela; Pretz, Caitlin; Wang, Biqi; Savage, Brandon; Scornavacca, Thomas; Shirshac, Jeanne; Wilkie, Tracey; et al. (2024-04-29)
    Chronic Obstructive Pulmonary Disease (COPD) is a common, costly, and morbid condition. Pulmonary rehabilitation, close monitoring, and early intervention during acute exacerbations of symptoms represent a comprehensive approach to improve outcomes, but the optimal means of delivering these services is uncertain. Logistical, financial, and social barriers to providing healthcare through face-to-face encounters, paired with recent developments in technology, have stimulated interest in exploring alternative models of care. The Healthy at Home study seeks to determine the feasibility of a multimodal, digitally enhanced intervention provided to participants with COPD longitudinally over six months. This paper details the recruitment, methods, and analysis plan for the study, which is recruiting 100 participants in its pilot phase. Participants were provided with several integrated services including a smartwatch to track physiological data, a study app to track symptoms and study instruments, access to a mobile integrated health program for acute clinical needs, and a virtual comprehensive pulmonary support service. Participants shared physiologic, demographic, and symptom reports, electronic health records, and claims data with the study team, facilitating a better understanding of their symptoms and potential care needs longitudinally. The Healthy at Home study seeks to develop a comprehensive digital phenotype of COPD by tracking and responding to multiple indices of disease behavior and facilitating early and nuanced responses to changes in participants' health status. This study is registered at Clinicaltrials.gov (NCT06000696).
  • Translation-dependent and -independent mRNA decay occur through mutually exclusive pathways defined by ribosome density during T cell activation

    Mercier, Blandine C; Labaronne, Emmanuel; Cluet, David; Guiguettaz, Laura; Fontrodona, Nicolas; Bicknell, Alicia; Corbin, Antoine; Wencker, Mélanie; Aube, Fabien; Modolo, Laurent; et al. (2024-04-25)
    mRNA translation and decay are tightly interconnected processes both in the context of mRNA quality-control pathways and for the degradation of functional mRNAs. Cotranslational mRNA degradation through codon usage, ribosome collisions, and the recruitment of specific proteins to ribosomes is an important determinant of mRNA turnover. However, the extent to which translation-dependent mRNA decay (TDD) and translation-independent mRNA decay (TID) pathways participate in the degradation of mRNAs has not been studied yet. Here we describe a comprehensive analysis of basal and signal-induced TDD and TID in mouse primary CD4+ T cells. Our results indicate that most cellular transcripts are decayed to some extent in a translation-dependent manner. Our analysis further identifies the length of untranslated regions, the density of ribosomes, and GC3 content as important determinants of TDD magnitude. Consistently, all transcripts that undergo changes in ribosome density within their coding sequence upon T cell activation display a corresponding change in their TDD level. Moreover, we reveal a dynamic modulation in the relationship between GC3 content and TDD upon T cell activation, with a reversal in the impact of GC3- and AU3-rich codons. Altogether, our data show a strong and dynamic interconnection between mRNA translation and decay in mammalian primary cells.
  • Teachers' Perceptions of the Impact of the COVID-19 Pandemic and Their Implementation of an Evidence-based HIV Prevention Program in the Bahamas

    Schieber, Elizabeth; Cottrell, Lesley; Deveaux, Lynette; Li, Xiaoming; Taylor, Marcellus; Adderley, Richard; Marshall, Sharon; Forbes, Nikkiah; Wang, Bo (2024-04-20)
    Information on how school-based programs is implemented and sustained during crises is limited. In this study, we assessed the impact of the COVID-19 pandemic on the implementation of a HIV prevention intervention in The Bahamas. Data were collected from 139 Grade 6 teachers in 2021-2022. Teachers attended virtual training and received implementation monitoring from coordinators. On average, teachers taught 26.4 (SD = 9.2) of the 35 core activities, and 7.4 (SD = 2.4) out of 9 sessions. More than half (58.3%) of teachers completed 28 or more core activities; 69.1% covered eight or all nine sessions, which is equivalent to 80% of the HIV intervention curriculum. Almost half of the teachers (43%) reported that the pandemic negatively impacted their ability to teach the program; 72% of teachers maintained that the program remained "very important" during times of crisis. Greater self-efficacy and supports increased implementation fidelity.

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