This collection showcases journal articles, preprints, book chapters, and other publications and presentations produced by faculty, postdocs, and researchers at UMass Chan Medical School.


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Recently Published

  • Renewal of oligodendrocyte lineage reverses dysmyelination and CNS neurodegeneration through corrected N-acetylaspartate metabolism

    Lotun, Anoushka; Li, Danning; Xu, Hongxia; Su, Qin; Tuncer, Serafettin; Sanmiguel, Julio; Mooney, Morgan; Baer, Christina E; Ulbrich, Russell; Eyles, Stephen J; et al. (2023-05-04)
    Myelinating oligodendrocytes are essential for neuronal communication and homeostasis of the central nervous system (CNS). One of the most abundant molecules in the mammalian CNS is N-acetylaspartate (NAA), which is catabolized into L-aspartate and acetate by the enzyme aspartoacylase (ASPA) in oligodendrocytes. The resulting acetate moiety is thought to contribute to myelin lipid synthesis. In addition, affected NAA metabolism has been implicated in several neurological disorders, including leukodystrophies and demyelinating diseases such as multiple sclerosis. Genetic disruption of ASPA function causes Canavan disease, which is hallmarked by increased NAA levels, myelin and neuronal loss, large vacuole formation in the CNS, and early death in childhood. Although NAA's direct role in the CNS is inconclusive, in peripheral adipose tissue, NAA-derived acetate has been found to modify histones, a mechanism known to be involved in epigenetic regulation of cell differentiation. We hypothesize that a lack of cellular differentiation in the brain contributes to the disruption of myelination and neurodegeneration in diseases with altered NAA metabolism, such as Canavan disease. Our study demonstrates that loss of functional Aspa in mice disrupts myelination and shifts the transcriptional expression of neuronal and oligodendrocyte markers towards less differentiated stages in a spatiotemporal manner. Upon re-expression of ASPA, these oligodendrocyte and neuronal lineage markers are either improved or normalized, suggesting that NAA breakdown by Aspa plays an essential role in the maturation of neurons and oligodendrocytes. Also, this effect of ASPA re-expression is blunted in old mice, potentially due to limited ability of neuronal, rather than oligodendrocyte, recovery.
  • Implications of Non-Specific Effects for Testing, Approving, and Regulating Vaccines

    Benn, Christine Stabell; Amenyogbe, Nelly; Björkman, Anders; Domínguez-Andrés, Jorge; Fish, Eleanor N; Flanagan, Katie L; Klein, Sabra L; Kollmann, Tobias R; Kyvik, Kirsten Ohm; Netea, Mihai G; et al. (2023-04-19)
    The current framework for testing and regulating vaccines was established before the realization that vaccines, in addition to their effect against the vaccine-specific disease, may also have "non-specific effects" affecting the risk of unrelated diseases. Accumulating evidence from epidemiological studies shows that vaccines in some situations can affect all-cause mortality and morbidity in ways that are not explained by the prevention of the vaccine-targeted disease. Live attenuated vaccines have sometimes been associated with decreases in mortality and morbidity that are greater than anticipated. In contrast, some non-live vaccines have in certain contexts been associated with increases in all-cause mortality and morbidity. The non-specific effects are often greater for female than male individuals. Immunological studies have provided several mechanisms that explain how vaccines might modulate the immune response to unrelated pathogens, such as through trained innate immunity, emergency granulopoiesis, and heterologous T-cell immunity. These insights suggest that the framework for the testing, approving, and regulating vaccines needs to be updated to accommodate non-specific effects. Currently, non-specific effects are not routinely captured in phase I-III clinical trials or in the post-licensure safety surveillance. For instance, an infection with Streptococcus pneumoniae occurring months after a diphtheria-tetanus-pertussis vaccination would not be considered an effect of the vaccination, although evidence indicates it might well be for female individuals. Here, as a starting point for discussion, we propose a new framework that considers the non-specific effects of vaccines in both phase III trials and post-licensure.
  • Atypical Fragility Fractures due to Bony or Soft Tissue Phosphaturic Mesenchymal Tumors: A Report of Two Cases

    Clegg, Stephanie M; Eiel, Emily S; Fine, Sara; Gafni, Rachel I; Most, Mathew J (2023-04-12)
    Introduction: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic disorder where patients present with hypophosphatemia, chronic diffuse bone pain, and occasionally fractures. Benign phosphaturic mesenchymal tumors (PMT) are responsible for the TIO and are largely soft tissue tumors. Cases: Two male patients with TIO secondary to PMT were reported-one in the bony scapula and the other in the plantar foot soft tissue. The first case describes a 63-year-old Caucasian male, who sustained an intertrochanteric proximal femur stress fracture and approximately two years of diffuse bone pain and hypophosphatemia. Wide excision of a left scapula boney lesion resulted in immediate resolution of his electrolyte abnormalities and bone pain. Case 2 describes a 58-year-old male with four years of multifocal bone pain and atraumatic fractures. A 68Ga-DOTATATE-positron emission tomography/computed tomography (PET/CT) scan identified a soft tissue tumor in his plantar foot, which was ultimately excised. He also experienced near immediate resolution of his pain and no additional fractures. Conclusion: TIO is a rare condition presenting with chronic multifocal bone pain, stress fractures, and hypophosphatemia. These two cases highlight that the causative tumor may originate in soft tissue or bone. Furthermore, a high index of suspicion, along with fibroblast growth factor-23 testing and DOTATATE-PET/CT localization, can help with diagnosis and minimize treatment delays.
  • Advancing Maternal Health Equity Among Migrant Communities

    Johnson-Agbakwu, Crista (2023-04-06)
    Crista Johnson-Agbakwu, MD, is the inaugural executive director of the new UMass Chan Medical School Collaborative in Health Equity. Dr. Johnson-Agbawku, professor of obstetrics & gynecology and population & quantitative health sciences, is an accomplished physician who has focused her career on reducing the disparities between social determinants of health and health care. This talk was planned in conjunction with the National Library of Medicine traveling exhibit, "Outside/Inside: Immigration, Migration, and Health Care in the United States," hosted at the UMass Chan Medical School Lamar Soutter Library March 13 - April 22, 2023.
  • Genomic Investigation of Remission and Relapse of Psychotic Depression Treated with Sertraline plus Olanzapine: The STOP-PD II Study

    Men, Xiaoyu; Marshe, Victoria; Elsheikh, Samar S; Alexopoulos, George S; Marino, Patricia; Meyers, Barnett S; Mulsant, Benoit H; Rothschild, Anthony J; Voineskos, Aristotle N; Whyte, Ellen M; et al. (2023-04-04)
    Introduction: Little is known regarding genetic factors associated with treatment outcome of psychotic depression. We explored genomic associations of remission and relapse of psychotic depression treated with pharmacotherapy. Methods: Genomic analyses were performed in 171 men and women aged 18-85 years with an episode of psychotic depression who participated in the Study of the Pharmacotherapy of Psychotic Depression II (STOP-PD II). Participants were treated with open-label sertraline plus olanzapine for up to 12 weeks; those who achieved remission or near-remission and maintained it following 8 weeks of stabilization were eligible to participate in a 36-week randomized controlled trial that compared sertraline plus olanzapine with sertraline plus placebo in preventing relapse. Results: There were no genome-wide significant associations with either remission or relapse. However, at a suggestive threshold, SNP rs1026501 (31 kb from SYNPO2) in the whole sample and rs6844137 (within the intronic region of SYNPO2) in the European ancestry subsample were associated with a decreased likelihood of remission. In polygenic risk analyses, participants who had greater improvement after antidepressant treatments showed a higher likelihood of reaching remission. Those who achieved remission and had a higher polygenic risk for Alzheimer's disease had a significantly decreased likelihood of relapse. Conclusion: Our analyses provide preliminary insights into the genetic architecture of remission and relapse in a well-characterized group of patients with psychotic depression.
  • Improved Performance of ChatGPT-4 on the OKAP Exam: A Comparative Study with ChatGPT-3.5 [preprint]

    Teebagy, Sean; Colwell, Lauren; Wood, Emma; Yaghy, Antonio; Faustina, Misha (2023-04-03)
    This study aims to evaluate the performance of ChatGPT-4, an advanced Artificial Intelligence (AI) language model, on the Ophthalmology Knowledge Assessment Program (OKAP) examination compared to its predecessor, ChatGPT-3.5. Both models were tested on 180 OKAP practice questions covering various ophthalmology subject categories. Results showed that ChatGPT-4 significantly outperformed ChatGPT-3.5 (81% vs. 57%; p<0.001), indicating improvements in medical knowledge assessment. The superior performance of ChatGPT-4 suggests potential applicability in ophthalmologic education and clinical decision support systems. Future research should focus on refining AI models, ensuring a balanced representation of fundamental and specialized knowledge, and determining the optimal method of integrating AI into medical education and practice.
  • The European Guidelines on Diagnosis and Management of Neutropenia in Adults and Children: A Consensus Between the European Hematology Association and the EuNet-INNOCHRON COST Action

    Fioredda, Francesca; Skokowa, Julia; Tamary, Hannah; Spanoudakis, Michail; Farruggia, Piero; Almeida, Antonio; Guardo, Daniela; Höglund, Petter; Newburger, Peter E; Palmblad, Jan; et al. (2023-03-30)
    Neutropenia, as an isolated blood cell deficiency, is a feature of a wide spectrum of acquired or congenital, benign or premalignant disorders with a predisposition to develop myelodysplastic neoplasms/acute myeloid leukemia that may arise at any age. In recent years, advances in diagnostic methodologies, particularly in the field of genomics, have revealed novel genes and mechanisms responsible for etiology and disease evolution and opened new perspectives for tailored treatment. Despite the research and diagnostic advances in the field, real world evidence, arising from international neutropenia patient registries and scientific networks, has shown that the diagnosis and management of neutropenic patients is mostly based on the physicians' experience and local practices. Therefore, experts participating in the European Network for the Innovative Diagnosis and Treatment of Chronic Neutropenias have collaborated under the auspices of the European Hematology Association to produce recommendations for the diagnosis and management of patients across the whole spectrum of chronic neutropenias. In the present article, we describe evidence- and consensus-based guidelines for the definition and classification, diagnosis, and follow-up of patients with chronic neutropenias including special entities such as pregnancy and the neonatal period. We particularly emphasize the importance of combining the clinical findings with classical and novel laboratory testing, and advanced germline and/or somatic mutational analyses, for the characterization, risk stratification, and monitoring of the entire spectrum of neutropenia patients. We believe that the wide clinical use of these practical recommendations will be particularly beneficial for patients, families, and treating physicians.
  • Synthesis and validation of click-modified of NOD1/2 agonists [preprint]

    Bharadwaj, Ravi; Anonick, Madison V.; Mashayekh, Siavash; Brown, Ashley; Wodzanowski, Kimberly A.; Okuda, Kendi; Silverman, Neal; Grimes, Catherine L. (2023-03-28)
    NOD1 and NOD2 sense small bacterial peptidoglycan fragments often called muropeptides. These muropeptides include iE-DAP and MDP, the minimal agonists for NOD1 and NOD2, respectively. Here, we synthesized and validated alkyne-modified muropeptides, iE-DAP-Alk and MDP-Alk, for use in click-chemistry reactions. While it has long been known that many cell types respond to extracellular exposure to muropeptides, it is unclear how these innate immune activators access their cytosolic innate immune receptors, NOD1 and NOD2. The subcellular trafficking and transport mechanisms by which muropeptides access these cytosolic innate immune receptors are a major gap in our understanding of these critical host responses. The clickchemistry-enabled agonists developed here will be particularly powerful to decipher the underlying cell biology and biochemistry of NOD1 and NOD2 innate immune sensing.
  • From primordial clocks to circadian oscillators

    Pitsawong, Warintra; Pádua, Ricardo A P; Grant, Timothy; Hoemberger, Marc; Otten, Renee; Bradshaw, Niels; Grigorieff, Nikolaus; Kern, Dorothee (2023-03-22)
    Circadian rhythms play an essential part in many biological processes, and only three prokaryotic proteins are required to constitute a true post-translational circadian oscillator1. The evolutionary history of the three Kai proteins indicates that KaiC is the oldest member and a central component of the clock2. Subsequent additions of KaiB and KaiA regulate the phosphorylation state of KaiC for time synchronization. The canonical KaiABC system in cyanobacteria is well understood3-6, but little is known about more ancient systems that only possess KaiBC. However, there are reports that they might exhibit a basic, hourglass-like timekeeping mechanism7-9. Here we investigate the primordial circadian clock in Rhodobacter sphaeroides, which contains only KaiBC, to elucidate its inner workings despite missing KaiA. Using a combination of X-ray crystallography and cryogenic electron microscopy, we find a new dodecameric fold for KaiC, in which two hexamers are held together by a coiled-coil bundle of 12 helices. This interaction is formed by the carboxy-terminal extension of KaiC and serves as an ancient regulatory moiety that is later superseded by KaiA. A coiled-coil register shift between daytime and night-time conformations is connected to phosphorylation sites through a long-range allosteric network that spans over 140 Å. Our kinetic data identify the difference in the ATP-to-ADP ratio between day and night as the environmental cue that drives the clock. They also unravel mechanistic details that shed light on the evolution of self-sustained oscillators.
  • Cryo-EM structure of the human Sirtuin 6-nucleosome complex [preprint]

    Chio, Un Seng; Rechiche, Othman; Bryll, Alysia R; Zhu, Jiang; Feldman, Jessica L; Peterson, Craig L; Tan, Song; Armache, Jean-Paul (2023-03-18)
    Sirtuin 6 (SIRT6) is a multifaceted protein deacetylase/deacylase and a major target for small-molecule modulators of longevity and cancer. In the context of chromatin, SIRT6 removes acetyl groups from histone H3 in nucleosomes, but the molecular basis for its nucleosomal substrate preference is unknown. Our cryo-electron microscopy structure of human SIRT6 in complex with the nucleosome shows that the catalytic domain of SIRT6 pries DNA from the nucleosomal entry-exit site and exposes the histone H3 N-terminal helix, while the SIRT6 zinc-binding domain binds to the histone acidic patch using an arginine anchor. In addition, SIRT6 forms an inhibitory interaction with the C-terminal tail of histone H2A. The structure provides insights into how SIRT6 can deacetylate both H3 K9 and H3 K56. Teaser: The structure of the SIRT6 deacetylase/nucleosome complex suggests how the enzyme acts on both histone H3 K9 and K56 residues.
  • De novo lipogenesis fuels adipocyte autophagosome and lysosome membrane dynamics

    Rowland, Leslie A; Guilherme, Adilson; Henriques, Felipe; DiMarzio, Chloe; Munroe, Sean; Wetoska, Nicole; Kelly, Mark; Reddig, Keith; Hendricks, Gregory; Pan, Meixia; et al. (2023-03-13)
    Adipocytes robustly synthesize fatty acids (FA) from carbohydrate through the de novo lipogenesis (DNL) pathway, yet surprisingly DNL contributes little to their abundant triglyceride stored in lipid droplets. This conundrum raises the hypothesis that adipocyte DNL instead enables membrane expansions to occur in processes like autophagy, which requires an abundant supply of phospholipids. We report here that adipocyte Fasn deficiency in vitro and in vivo markedly impairs autophagy, evident by autophagosome accumulation and severely compromised degradation of the autophagic substrate p62. Our data indicate the impairment occurs at the level of autophagosome-lysosome fusion, and indeed, loss of Fasn decreases certain membrane phosphoinositides necessary for autophagosome and lysosome maturation and fusion. Autophagy dependence on FA produced by Fasn is not fully alleviated by exogenous FA in cultured adipocytes, and interestingly, imaging studies reveal that Fasn colocalizes with nascent autophagosomes. Together, our studies identify DNL as a critical source of FAs to fuel autophagosome and lysosome maturation and fusion in adipocytes.
  • Endemic Burkitt lymphoma avatar mouse models for exploring inter-patient tumor variation and testing targeted therapies

    Saikumar Lakshmi, Priya; Oduor, Cliff I; Forconi, Catherine S; M'Bana, Viriato; Bly, Courtney; Gerstein, Rachel M; Otieno, Juliana A; Ong'echa, John M; Münz, Christian; Luftig, Micah A; et al. (2023-03-06)
    Endemic Burkitt lymphoma (BL) is a childhood cancer in sub-Saharan Africa characterized by Epstein-Barr virus and malaria-associated aberrant B-cell activation and MYC chromosomal translocation. Survival rates hover at 50% after conventional chemotherapies; therefore, clinically relevant models are necessary to test additional therapies. Hence, we established five patient-derived BL tumor cell lines and corresponding NSG-BL avatar mouse models. Transcriptomics confirmed that our BL lines maintained fidelity from patient tumors to NSG-BL tumors. However, we found significant variation in tumor growth and survival among NSG-BL avatars and in Epstein-Barr virus protein expression patterns. We tested rituximab responsiveness and found one NSG-BL model exhibiting direct sensitivity, characterized by apoptotic gene expression counterbalanced by unfolded protein response and mTOR pro-survival pathways. In rituximab-unresponsive tumors, we observed an IFN-α signature confirmed by the expression of IRF7 and ISG15. Our results demonstrate significant inter-patient tumor variation and heterogeneity, and that contemporary patient-derived BL cell lines and NSG-BL avatars are feasible tools to guide new therapeutic strategies and improve outcomes for these children.
  • Career self-efficacy disparities in underrepresented biomedical scientist trainees

    Chatterjee, Deepshikha; Jacob, Gabrielle A; Varvayanis, Susi Sturzenegger; Wefes, Inge; Chalkley, Roger; Nogueira, Ana T; Fuhrmann, Cynthia N; Varadarajan, Janani; Hubbard, Nisaan M; Gaines, Christiann H; et al. (2023-03-01)
    The present study examines racial, ethnic, and gender disparities in career self-efficacy amongst 6077 US citizens and US naturalized graduate and postdoctoral trainees. Respondents from biomedical fields completed surveys administered by the National Institutes of Health Broadening Experiences in Scientific Training (NIH BEST) programs across 17 US institutional sites. Graduate and postdoctoral demographic and survey response data were examined to evaluate the impact of intersectional identities on trainee career self-efficacy. The study hypothesized that race, ethnicity and gender, and the relations between these identities, would impact trainee career self-efficacy. The analysis demonstrated that racial and ethnic group, gender, specific career interests (academic principal investigator vs. other careers), and seniority (junior vs. senior trainee level) were, to various degrees, all associated with trainee career self-efficacy and the effects were consistent across graduate and postdoctoral respondents. Implications for differing levels of self-efficacy are discussed, including factors and events during training that may contribute to (or undermine) career self-efficacy. The importance of mentorship for building research and career self-efficacy of trainees is discussed, especially with respect to those identifying as women and belonging to racial/ethnic populations underrepresented in biomedical sciences. The results underscore the need for change in the biomedical academic research community in order to retain a diverse biomedical workforce.
  • Performance of Rapid Antigen Tests Based on Symptom Onset and Close Contact Exposure: A secondary analysis from the Test Us At Home prospective cohort study [preprint]

    Herbert, Carly; Wang, Biqi; Lin, Honghuang; Hafer, Nathaniel; Pretz, Caitlin; Stamegna, Pamela; Tarrant, Seanan; Hartin, Paul; Ferranto, Julia; Behar, Stephanie; et al. (2023-02-24)
    Background: The performance of rapid antigen tests for SARS-CoV-2 (Ag-RDT) in temporal relation to symptom onset or exposure is unknown, as is the impact of vaccination on this relationship. Objective: To evaluate the performance of Ag-RDT compared with RT-PCR based on day after symptom onset or exposure in order to decide on 'when to test'. Design setting and participants: The Test Us at Home study was a longitudinal cohort study that enrolled participants over 2 years old across the United States between October 18, 2021 and February 4, 2022. All participants were asked to conduct Ag-RDT and RT-PCR testing every 48 hours over a 15-day period. Participants with one or more symptoms during the study period were included in the Day Post Symptom Onset (DPSO) analyses, while those who reported a COVID-19 exposure were included in the Day Post Exposure (DPE) analysis. Exposure: Participants were asked to self-report any symptoms or known exposures to SARS-CoV-2 every 48-hours, immediately prior to conducting Ag-RDT and RT-PCR testing. The first day a participant reported one or more symptoms was termed DPSO 0, and the day of exposure was DPE 0. Vaccination status was self-reported. Main outcome and measures: Results of Ag-RDT were self-reported (positive, negative, or invalid) and RT-PCR results were analyzed by a central laboratory. Percent positivity of SARS-CoV-2 and sensitivity of Ag-RDT and RT-PCR by DPSO and DPE were stratified by vaccination status and calculated with 95% confidence intervals. Results: A total of 7,361 participants enrolled in the study. Among them, 2,086 (28.3%) and 546 (7.4%) participants were eligible for the DPSO and DPE analyses, respectively. Unvaccinated participants were nearly twice as likely to test positive for SARS-CoV-2 than vaccinated participants in event of symptoms (PCR+: 27.6% vs 10.1%) or exposure (PCR+: 43.8% vs. 22.2%). The highest proportion of vaccinated and unvaccinated individuals tested positive on DPSO 2 and DPE 5-8. Performance of RT-PCR and Ag-RDT did not differ by vaccination status. Ag-RDT detected 78.0% (95% Confidence Interval: 72.56-82.61) of PCR-confirmed infections by DPSO 4. For exposed participants, Ag-RDT detected 84.9% (95% CI: 75.0-91.4) of PCR-confirmed infections by day five post-exposure (DPE 5). Conclusions and relevance: Performance of Ag-RDT and RT-PCR was highest on DPSO 0-2 and DPE 5 and did not differ by vaccination status. These data suggests that serial testing remains integral to enhancing the performance of Ag-RDT.
  • Cross-reactivity influences changes in human influenza A virus and Epstein Barr virus specific CD8 memory T cell receptor alpha and beta repertoires between young and old

    Clark, Fransenio; Gil, Anna; Thapa, Ishwor; Aslan, Nuray; Ghersi, Dario; Selin, Liisa K. (2023-02-24)
    Older people have difficulty controlling infection with common viruses such as influenza A virus (IAV), RNA virus which causes recurrent infections due to a high rate of genetic mutation, and Epstein Barr virus (EBV), DNA virus which persists in B cells for life in the 95% of people that become acutely infected. We questioned whether changes in epitope-specific memory CD8 T cell receptor (TCR) repertoires to these two common viruses could occur with increasing age and contribute to waning immunity. We compared CD8 memory TCR alpha and beta repertoires in two HLA-A2+ EBV- and IAV-immune donors, young (Y) and older (O) donors to three immunodominant epitopes known to be cross-reactive, IAV-M158-66 (IAV-M1), EBV-BMLF1280-288 (EBV-BM), and EBV-BRLF1109-117 (EBV-BR). We, therefore, also designed these studies to examine if TCR cross-reactivity could contribute to changes in repertoire with increasing age. TCR high throughput sequencing showed a significant difference in the pattern of TRBV usage between Y and O. However, there were many more differences in AV and AJ usage, between the age groups suggesting that changes in TCRα usage may play a greater role in evolution of the TCR repertoire emphasizing the importance of studying TRAV repertoires. With increasing age there was a preferential retention of TCR for all three epitopes with features in their complementarity-determining region (CDR3) that increased their ease of generation, and their cross-reactive potential. Young and older donors differed in the patterns of AV/AJ and BV/BJ pairings and usage of dominant CDR3 motifs specific to all three epitopes. Both young and older donors had cross-reactive responses between these 3 epitopes, which were unique and differed from the cognate responses having features that suggested they could interact with either ligand. There was an increased tendency for the classic IAV-M1 specific clone BV19-IRSS-JB2.7/AV27-CAGGGSQGNLIF-AJ42 to appear among the cross-reactive clones, suggesting that the dominance of this clone may relate to its cross-reactivity with EBV. These results suggest that although young and older donors retain classic TCR features for each epitope their repertoires are gradually changing with age, maintaining TCRs that are cross-reactive between these two common human viruses, one with recurrent infections and the other a persistent virus which frequently reactivates.
  • Epigenetic and chromosomal features drive transposon insertion in Drosophila melanogaster

    Cao, Jichuan; Yu, Tianxiong; Xu, Bo; Hu, Zhongren; Zhang, Xiao-Ou; Theurkauf, William E; Weng, Zhiping (2023-02-10)
    Transposons are mobile genetic elements prevalent in the genomes of most species. The distribution of transposons within a genome reflects the actions of two opposing processes: initial insertion site selection, and selective pressure from the host. By analyzing whole-genome sequencing data from transposon-activated Drosophila melanogaster, we identified 43 316 de novo and 237 germline insertions from four long-terminal-repeat (LTR) transposons, one LINE transposon (I-element), and one DNA transposon (P-element). We found that all transposon types favored insertion into promoters de novo, but otherwise displayed distinct insertion patterns. De novo and germline P-element insertions preferred replication origins, often landing in a narrow region around transcription start sites and in regions of high chromatin accessibility. De novo LTR transposon insertions preferred regions with high H3K36me3, promoters and exons of active genes; within genes, LTR insertion frequency correlated with gene expression. De novo I-element insertion density increased with distance from the centromere. Germline I-element and LTR transposon insertions were depleted in promoters and exons, suggesting strong selective pressure to remove transposons from functional elements. Transposon movement is associated with genome evolution and disease; therefore, our results can improve our understanding of genome and disease biology.
  • Disease progression rates in ambulatory Duchenne muscular dystrophy by steroid type, patient age and functional status

    McDonald, Craig M; Marden, Jessica R; Shieh, Perry B; Wong, Brenda L; Lane, Henry; Zhang, Adina; Nguyen, Ha; Frean, Molly; Trifillis, Panayiota; Koladicz, Karyn; et al. (2023-02-07)
    Aim: To examine benefits of corticosteroids for Duchenne muscular dystrophy (DMD) by age and disease progression. Methods: Data from daily steroid users (placebo-treated) were pooled from four phase 2b/3 trials in DMD. Outcomes assessed overall and among subgroups included changes from baseline to 48 weeks in six-minute walk distance (6MWD), timed function tests and North Star Ambulatory Assessment total score. Results: Among 231 patients receiving deflazacort (n = 127) or prednisone (n = 104), observed differences in 6MWD favoring deflazacort over prednisone were significant for patients with relatively older age (≥8-years-old), greater disease progression (baseline timed stand from supine ≥5 s), or longer corticosteroid use (>3 years). Conclusion: Daily deflazacort had greater benefits than daily prednisone particularly among older/more progressed patients.
  • Large-scale organoid study suggests effects of trisomy 21 on early fetal neurodevelopment are more subtle than variability between isogenic lines and experiments

    Czerminski, Jan T; King, Oliver D; Lawrence, Jeanne B (2023-02-03)
    This study examines cortical organoids generated from a panel of isogenic trisomic and disomic iPSC lines (subclones) as a model of early fetal brain development in Down syndrome (DS). An initial experiment comparing organoids from one trisomic and one disomic line showed many genome-wide transcriptomic differences and modest differences in cell-type proportions, suggesting there may be a neurodevelopmental phenotype that is due to trisomy of chr21. To better control for multiple sources of variation, we undertook a highly robust study of ∼1,200 organoids using an expanded panel of six all-isogenic lines, three disomic, and three trisomic. The power of this experimental design was indicated by strong detection of the ∼1.5-fold difference in chr21 genes. However, the numerous expression differences in non-chr21 genes seen in the smaller experiment fell away, and the differences in cell-type representation between lines did not correlate with trisomy 21. Results suggest that the initial smaller experiment picked up differences between small organoid samples and individual isogenic lines, which "averaged out" in the larger panel of isogenic lines. Our results indicate that even when organoid and batch variability are better controlled for, variation between isogenic cell lines (even subclones) may obscure, or be conflated with, subtle neurodevelopmental phenotypes that may be present in ∼2nd trimester DS brain development. Interestingly, despite this variability between organoid batches and lines, and the "fetal stage" of these organoids, an increase in secreted Aβ40 peptide levels-an Alzheimer-related cellular phenotype-was more strongly associated with trisomy 21 status than were neurodevelopmental shifts in cell-type composition.
  • DMD Genotypes and Motor Function in Duchenne Muscular Dystrophy: A Multi-institution Meta-analysis With Implications for Clinical Trials

    Muntoni, Francesco; Signorovitch, James; Sajeev, Gautam; Lane, Henry; Jenkins, Madeline; Dieye, Ibrahima; Ward, Susan J; McDonald, Craig; Goemans, Nathalie; Niks, Erik H; et al. (2023-02-01)
    Background and objectives: Clinical trials of genotype-targeted treatments in Duchenne muscular dystrophy (DMD) traditionally compare treated patients with untreated patients with the same DMD genotype class. This avoids confounding of drug efficacy by genotype effects but also shrinks the pool of eligible controls, increasing challenges for trial enrollment in this already rare disease. To evaluate the suitability of genotypically unmatched controls in DMD, we quantified effects of genotype class on 1-year changes in motor function endpoints used in clinical trials. Methods: More than 1,600 patient-years of follow-up (>700 patients) were studied from 6 real-world/natural history data sources (UZ Leuven, PRO-DMD-01 shared by CureDuchenne, iMDEX, North Star UK, Cincinnati Children's Hospital Medical Center, and the DMD Italian Group), with genotypes classified as amenable to skipping exons 44, 45, 51, or 53, or other skippable, nonsense, and other mutations. Associations between genotype class and 1-year changes in North Star Ambulatory Assessment total score (ΔNSAA) and in 10-m walk/run velocity (Δ10MWR) were studied in each data source with and without adjustment for baseline prognostic factors. Results: The studied genotype classes accounted for approximately 2% of variation in ΔNSAA outcomes after 12 months, whereas other prognostic factors explained >30% of variation in large data sources. Based on a meta-analysis across all data sources, pooled effect estimates for the studied skip-amenable mutation classes were all small in magnitude (<2 units in ΔNSAA total score in 1-year follow up), smaller than clinically important differences in NSAA, and were precisely estimated with standard errors <1 unit after adjusting for nongenotypic prognostic factors. Discussion: These findings suggest the viability of trial designs incorporating genotypically mixed or unmatched controls for up to 12 months in duration for motor function outcomes, which would ease recruitment challenges and reduce numbers of patients assigned to placebos. Such trial designs, including multigenotype platform trials and hybrid designs, should ensure baseline balance between treatment and control groups for the most important prognostic factors, while accounting for small remaining genotype effects quantified in this study.
  • Exploration of the Nuclear Proteomes in the Ciliate Oxytricha trifallax

    Lu, Michael W; Beh, Leslie Y; Yerlici, V Talya; Fang, Wenwen; Kulej, Katarzyna; Garcia, Benjamin A; Landweber, Laura F (2023-01-30)
    Nuclear dimorphism is a fundamental feature of ciliated protozoa, which have separate somatic and germline genomes in two distinct organelles within a single cell. The transcriptionally active somatic genome, contained within the physically larger macronucleus, is both structurally and functionally different from the silent germline genome housed in the smaller micronucleus. This difference in genome architecture is particularly exaggerated in Oxytricha trifallax, in which the somatic genome comprises tens of thousands of gene-sized nanochromosomes maintained at a high and variable ploidy, while the germline has a diploid set of megabase-scale chromosomes. To examine the compositional differences between the nuclear structures housing the genomes, we performed a proteomic survey of both types of nuclei and of macronuclear histones using quantitative mass spectrometry. We note distinct differences between the somatic and germline nuclei, with many functional proteins being highly enriched in one of the two nuclei. To validate our conclusions and the efficacy of nuclear separation, we used protein localization through a combination of transformations and immunofluorescence. We also note that the macronuclear histones strikingly display only activating marks, consistent with the conclusion that the macronucleus is the hub of transcription. These observations suggest that the compartmentalization of different genome features into separate structures has been accompanied by a similar specialization of nuclear components that maintain and facilitate the functions of the genomes specific to each nucleus.

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