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

  • LGBTQ+ Health Research Guides: A Cross-institutional Pilot Study of Usage Patterns

    Stevens, Gregg A.; Fajardo, Francisco J.; Morris, Martin; Berry, Jessica; Parker, Robin M. N.; McLean, Katie D. (2022-05-06)
    Objectives: Multiple authors have recommended that health sciences libraries use research guides to promote LGBTQ+ health information, connect with their users and the community, and improve health equity. However, little is known about LGBTQ+ health guide usage patterns and whether such guides really meet the information needs of their users. Based on usage patterns from LGBTQ+ health research guides, we assessed the types of LGBTQ+ health information of greatest interest to health sciences library users and how, if appropriate, these guides might be revised to be more relevant to user needs. Methods: The data for LGBTQ+ health research guides of five health sciences libraries (three in the United States and two in Canada) were studied. Usage data were retrieved for a three year period (July 2018-June 2021). Two separate factors were chosen for analysis: monthly guide usage over time and the individual types of resources used. Monthly usage was studied by generating line graphs in Excel with trendlines to calculate overall guide usage trends. To determine the most sought-after types of resources by users, clicks for individual resources were categorized by type and focus using open coding in Google Sheets. Results: Overall guide usage was mixed, with some libraries’ guides trending upward over time and others downward. Analysis of the resource links showed that links to local and community health resources were among the most heavily clicked (64.11% of clicks), as were resources designed to help patients find healthcare providers and services (53.23%). Links to library-owned resources, such as books, journals, and databases, were generally clicked less (2.44%), as were links aimed at healthcare professionals (11.36%). Conclusions: The usage statistics for the guides were relatively low. However, the size of the LGBTQ+ community is relatively low compared to the general population and therefore LGBTQ+ health can be considered a category of minority health. We argue that the importance of providing quality LGBTQ+ health information outweighs any concerns of large-scale usage, and that providing such guides promotes health equity. The higher usage numbers for local resources supports the idea that guides are most useful when they link users to services and providers in their own communities. This suggests a best practice for librarians to focus on local resources and collaborations, and on consumer health resources, when creating and editing these guides.
  • Whole-genome sequencing reveals that variants in the Interleukin 18 Receptor Accessory Protein 3'UTR protect against ALS

    Eitan, Chen; Werneburg, Sebastian; Schafer, Dorothy P.; Brown, Robert H. Jr.; Hornstein, Eran (2022-03-31)
    The noncoding genome is substantially larger than the protein-coding genome but has been largely unexplored by genetic association studies. Here, we performed region-based rare variant association analysis of > 25,000 variants in untranslated regions of 6,139 amyotrophic lateral sclerosis (ALS) whole genomes and the whole genomes of 70,403 non-ALS controls. We identified interleukin-18 receptor accessory protein (IL18RAP) 3' untranslated region (3'UTR) variants as significantly enriched in non-ALS genomes and associated with a fivefold reduced risk of developing ALS, and this was replicated in an independent cohort. These variants in the IL18RAP 3'UTR reduce mRNA stability and the binding of double-stranded RNA (dsRNA)-binding proteins. Finally, the variants of the IL18RAP 3'UTR confer a survival advantage for motor neurons because they dampen neurotoxicity of human induced pluripotent stem cell (iPSC)-derived microglia bearing an ALS-associated expansion in C9orf72, and this depends on NF-kappaB signaling. This study reveals genetic variants that protect against ALS by reducing neuroinflammation and emphasizes the importance of noncoding genetic association studies.
  • Medicinal Plant Extracts and Natural Compounds for the Treatment of Cutaneous Lupus Erythematosus: A Systematic Review

    Lubov, Janet E.; Jamison, Aisha S.; Baltich Nelson, Becky; Amudzi, Alice A.; Haas, Kelly N. (2022-03-31)
    Cutaneous lupus erythematosus (CLE) is a group of autoimmune connective tissue disorders that significantly impact quality of life. Current treatment approaches typically use antimalarial medications, though patients may become recalcitrant. Other treatment options include general immunosuppressants, highlighting the need for more and more targeted treatment options. The purpose of this systematic review was to identify potential compounds that could be repurposed for CLE from natural products since many rheumatologic drugs are derived from natural products, including antimalarials. This study was registered with PROSPERO, the international prospective register of systematic reviews (registration number CRD42021251048). We comprehensively searched Ovid Medline, Cochrane Library, and Scopus databases from inception to April 27th, 2021. These terms included cutaneous lupus erythematosus; general plant, fungus, bacteria terminology; selected plants and plant-derived products; selected antimalarials; and JAK inhibitors. Our search yielded 13,970 studies, of which 1,362 were duplicates. We screened 12,608 abstracts, found 12,043 to be irrelevant, and assessed 565 full-text studies for eligibility. Of these, 506 were excluded, and 59 studies were included in the data extraction. The ROBINS-I risk of bias assessment tool was used to assess studies that met our inclusion criteria. According to our findings, several natural compounds do reduce inflammation in lupus and other autoimmune skin diseases in studies using in vitro methods, mouse models, and clinical observational studies, along with a few randomized clinical trials. Our study has cataloged evidence in support of potential natural compounds and plant extracts that could serve as novel sources of active ingredients for the treatment of CLE. It is imperative that further studies in mice and humans are conducted to validate these findings.
  • Spatial transcriptomic reconstruction of the mouse olfactory glomerular map suggests principles of odor processing

    Wang, I-Hao; Andrews, Gregory; Donnard, Elisa; Duran-Laforet, Violeta; Faust, Travis E.; Garber, Manuel; Baer, Christina E.; Schafer, Dorothy P.; Weng, Zhiping; Greer, Paul L. (2022-03-21)
    The olfactory system's ability to detect and discriminate between the vast array of chemicals present in the environment is critical for an animal's survival. In mammals, the first step of this odor processing is executed by olfactory sensory neurons, which project their axons to a stereotyped location in the olfactory bulb (OB) to form glomeruli. The stereotyped positioning of glomeruli in the OB suggests an importance for this organization in odor perception. However, because the location of only a limited subset of glomeruli has been determined, it has been challenging to determine the relationship between glomerular location and odor discrimination. Using a combination of single-cell RNA sequencing, spatial transcriptomics and machine learning, we have generated a map of most glomerular positions in the mouse OB. These observations significantly extend earlier studies and suggest an overall organizational principle in the OB that may be used by the brain to assist in odor decoding.
  • Astrocytic GABA transporter controls sleep by modulating GABAergic signaling in Drosophila circadian neurons

    Chaturvedi, Ratna; Stork, Tobias; Yuan, Chunyan; Freeman, Marc R.; Emery, Patrick (2022-03-17)
    A precise balance between sleep and wakefulness is essential to sustain a good quality of life and optimal brain function. GABA is known to play a key and conserved role in sleep control, and GABAergic tone should, therefore, be tightly controlled in sleep circuits. Here, we examined the role of the astrocytic GABA transporter (GAT) in sleep regulation using Drosophila melanogaster. We found that a hypomorphic gat mutation (gat(33-1)) increased sleep amount, decreased sleep latency, and increased sleep consolidation at night. Interestingly, sleep defects were suppressed when gat(33-1) was combined with a mutation disrupting wide-awake (wake), a gene that regulates the cell-surface levels of the GABAA receptor resistance to dieldrin (RDL) in the wake-promoting large ventral lateral neurons (l-LNvs). Moreover, RNAi knockdown of rdl and its modulators dnlg4 and wake in these circadian neurons also suppressed gat(33-1) sleep phenotypes. Brain immunohistochemistry showed that GAT-expressing astrocytes were located near RDL-positive l-LNv cell bodies and dendritic processes. We concluded that astrocytic GAT decreases GABAergic tone and RDL activation in arousal-promoting LNvs, thus determining proper sleep amount and quality in Drosophila.
  • Nociception and hypersensitivity involve distinct neurons and molecular transducers in Drosophila

    Gu, Pengyu; Wang, Fei; Shang, Ye; Liu, Jingjing; Gong, Jiaxin; Xie, Wei; Han, Junhai; Xiang, Yang (2022-03-16)
    Significance: Functional plasticity of the nociceptive circuit is a remarkable feature and is of clinical relevance. As an example, nociceptors lower their threshold upon tissue injury, a process known as allodynia that would facilitate healing by guarding the injured areas. However, long-lasting hypersensitivity could lead to chronic pain, a debilitating disease not effectively treated. Therefore, it is crucial to dissect the mechanisms underlying basal nociception and nociceptive hypersensitivity. In both vertebrate and invertebrate species, conserved transient receptor potential (Trp) channels are the primary transducers of noxious stimuli. Here, we provide a precedent that in Drosophila larvae, heat sensing in the nociception and hypersensitivity states is mediated by distinct heat-sensitive neurons and TrpA1 alternative isoforms.
  • Vaccine Breakthrough Infection with the SARS-CoV-2 Delta or Omicron (BA.1) Variant Leads to Distinct Profiles of Neutralizing Antibody Responses [preprint]

    Seaman, Michael S.; Luban, Jeremy; Lemieux, Jacob E. (2022-03-03)
    There is increasing evidence that the risk of SARS-CoV-2 infection among vaccinated individuals is variant-specific, suggesting that protective immunity against SARS-CoV-2 may differ by variant. We enrolled vaccinated (n = 39) and unvaccinated (n = 11) individuals with acute, symptomatic SARS-CoV-2 Delta or Omicron infection and performed SARS-CoV-2 viral load quantification, whole-genome sequencing, and variant-specific antibody characterization at the time of acute illness and convalescence. Viral load at the time of infection was inversely correlated with antibody binding and neutralizing antibody responses. Increases in antibody titers and neutralizing activity occurred at convalescence in a variant-specific manner. Across all variants tested, convalescent neutralization titers in unvaccinated individuals were markedly lower than in vaccinated individuals. For individuals infected with the Delta variant, neutralizing antibody responses were weakest against BA.2, whereas infection with Omicron BA.1 variant generated a broader response against all tested variants, including BA.2.
  • Co-transmission of neuropeptides and monoamines choreograph the C. elegans escape response

    Florman, Jeremy T.; Alkema, Mark J. (2022-03-03)
    Co-localization and co-transmission of neurotransmitters and neuropeptides is a core property of neural signaling across species. While co-transmission can increase the flexibility of cellular communication, understanding the functional impact on neural dynamics and behavior remains a major challenge. Here we examine the role of neuropeptide/monoamine co-transmission in the orchestration of the C. elegans escape response. The tyraminergic RIM neurons, which coordinate distinct motor programs of the escape response, also co-express the neuropeptide encoding gene flp-18. We find that in response to a mechanical stimulus, flp-18 mutants have defects in locomotory arousal and head bending that facilitate the omega turn. We show that the induction of the escape response leads to the release of FLP-18 neuropeptides. FLP-18 modulates the escape response through the activation of the G-protein coupled receptor NPR-5. FLP-18 increases intracellular calcium levels in neck and body wall muscles to promote body bending. Our results show that FLP-18 and tyramine act in different tissues in both a complementary and antagonistic manner to control distinct motor programs during different phases of the C. elegans flight response. Our study reveals basic principles by which co-transmission of monoamines and neuropeptides orchestrate in arousal and behavior in response to stress.
  • Comparison of Rapid Antigen Tests' Performance between Delta (B.1.61.7; AY.X) and Omicron (B.1.1.529; BA1) Variants of SARS-CoV-2: Secondary Analysis from a Serial Home Self-Testing Study [preprint]

    Soni, Apurv; Herbert, Carly; Filippaios, Andreas; Broach, John P.; Colubri, Andres; Fahey, Nisha; Woods, Kelsey; Nanavati, Janvi; Wright, Colton; Orwig, Taylor; et al. (2022-03-02)
    Background: There is a need to understand the performance of rapid antigen tests (Ag-RDT) for detection of the Delta (B.1.61.7; AY.X) and Omicron (B.1.1.529; BA1) SARS-CoV-2 variants. Methods: Participants without any symptoms were enrolled from October 18, 2021 to January 24, 2022 and performed Ag-RDT and RT-PCR tests every 48 hours for 15 days. This study represents a non-pre-specified analysis in which we sought to determine if sensitivity of Ag-RDT differed in participants with Delta compared to Omicron variant. Participants who were positive on RT-PCR on the first day of the testing period were excluded. Delta and Omicron variants were defined based on sequencing and date of first RT-PCR positive result (RT-PCR+). Comparison of Ag-RDT performance between the variants was based on sensitivity, defined as proportion of participants with Ag-RDT+ results in relation to their first RT-PCR+ result, for different duration of testing with rapid Ag-RDT. Subsample analysis was performed based on the result of participants' second RT-PCR test within 48 hours of the first RT-PCR+ test. Results: From the 7,349 participants enrolled in the parent study, 5,506 met the eligibility criteria for this analysis. A total of 153 participants were RT-PCR+ (61 Delta, 92 Omicron); among this group, 36 (23.5%) tested Ag-RDT+ on the same day, and 84 (54.9%) tested Ag-RDT+ within 48 hours as first RT-PCR+. The differences in sensitivity between variants were not statistically significant (same-day: Delta 16.4% [95% CI: 8.2-28.1] vs Omicron 28.2% [95% CI: 19.4-38.6]; and 48-hours: Delta 45.9% [33.1-59.2] vs. Omicron 60.9% [50.1-70.9]). This trend continued among the 86 participants who had consecutive RT-PCR+ result (48-hour sensitivity: Delta 79.3% [60.3-92.1] vs. Omicron: 89.5% [78.5-96.0]). Conversely, the 38 participants who had an isolated RT-PCR+ remained consistently negative on Ag-RDT, regardless of the variant. Conclusions: The performance of Ag-RDT is not inferior among individuals infected with the SARS-CoV-2 Omicron variant as compared to the Delta variant. The improvement in sensitivity of Ag-RDT noted with serial testing is consistent between Delta and Omicron variant. Performance of Ag-RDT varies based on duration of RT-PCR+ results and more studies are needed to understand the clinical and public health significance of individuals who are RT-PCR+ for less than 48 hours.
  • Assessment of patient navigation programs for breast cancer patients across the city of Boston

    LeClair, Amy M.; Battaglia, Tracy A.; Casanova, Nicole L.; Haas, Jennifer S.; Freund, Karen M.; Moy, Beverly; Parsons, Susan K.; Ko, Naomi Y.; Ross, JoEllen; Ohrenberger, Ellen; et al. (2022-03-01)
    PURPOSE: Healthcare systems contribute to disparities in breast cancer outcomes. Patient navigation is a widely cited system-based approach to improve outcomes among populations at risk for delays in care. Patient navigation programs exist in all major Boston hospitals, yet disparities in outcomes persist. The objective of this study was to conduct a baseline assessment of navigation processes at six Boston hospitals that provide breast cancer care in preparation for an implementation trial of standardized navigation across the city. METHODS: We conducted a mixed methods study in six hospitals that provide treatment to breast cancer patients in Boston. We administered a web-based survey to clinical champions (n = 7) across six sites to collect information about the structure of navigation programs. We then conducted in-person workflow assessments at each site using a semi-structured interview guide to understand site-specific implementation processes for patient navigation programs. The target population included administrators, supervisors, and patient navigators who provided breast cancer treatment-focused care. RESULTS: All sites offered patient navigation services to their patients undergoing treatment for breast cancer. We identified wide heterogeneity in terms of how programs were funded/resourced, which patients were targeted for navigation, the type of services provided, and the continuity of those services relative to the patient's cancer treatment. CONCLUSIONS: The operationalization of patient navigation varies widely across hospitals especially in relation to three core principles in patient navigation: providing patient support across the care continuum, targeting services to those patients most likely to experience delays in care, and systematically screening for and addressing patients' health-related social needs. Gaps in navigation across the care continuum present opportunities for intervention. TRIAL REGISTRATION: Clinical Trial Registration Number NCT03514433, 5/2/2018.
  • Balanced chromosomal rearrangements offer insights into coding and noncoding genomic features associated with developmental disorders [preprint]

    Lowther, Chelsea; Hay, Beverly N.; Tommerup, Niels; Talkowski, Michael E. (2022-02-16)
    Balanced chromosomal rearrangements (BCRs), including inversions, translocations, and insertions, reorganize large sections of the genome and contribute substantial risk for developmental disorders (DDs). However, the rarity and lack of systematic screening for BCRs in the population has precluded unbiased analyses of the genomic features and mechanisms associated with risk for DDs versus normal developmental outcomes. Here, we sequenced and analyzed 1,420 BCR breakpoints across 710 individuals, including 406 DD cases and the first large-scale collection of 304 control BCR carriers. We found that BCRs were not more likely to disrupt genes in DD cases than controls, but were seven-fold more likely to disrupt genes associated with dominant DDs (21.3% of cases vs. 3.4% of controls; P = 1.60×10−12). Moreover, BCRs that did not disrupt a known DD gene were significantly enriched for breakpoints that altered topologically associated domains (TADs) containing dominant DD genes in cases compared to controls (odds ratio [OR] = 1.43, P = 0.036). We discovered six TADs enriched for noncoding BCRs (false discovery rate < 0.1) that contained known DD genes (MEF2C, FOXG1, SOX9, BCL11A, BCL11B, and SATB2) and represent candidate pathogenic long-range positional effect (LRPE) loci. These six TADs were collectively disrupted in 7.4% of the DD cohort. Phased Hi-C analyses of five cases with noncoding BCR breakpoints localized to one of these putative LRPEs, the 5q14.3 TAD encompassing MEF2C, confirmed extensive disruption to local 3D chromatin structures and reduced frequency of contact between the MEF2C promoter and annotated enhancers. We further identified six genomic features enriched in TADs preferentially disrupted by noncoding BCRs in DD cases versus controls and used these features to build a model to predict TADs at risk for LRPEs across the genome. These results emphasize the potential impact of noncoding structural variants to cause LRPEs in unsolved DD cases, as well as the complex interaction of features associated with predicting three-dimensional chromatin structures intolerant to disruption.
  • Analysis of 6.4 million SARS-CoV-2 genomes identifies mutations associated with fitness [preprint]

    Obermeyer, Fritz; Jankowiak, Martin; Barkas, Nikolaos; Schaffner, Stephen F.; Pyle, Jesse D.; Yurkovetskiy, Lonya; Bosso, Matteo; Park, Daniel J.; Babadi, Mehrtash; MacInnis, Bronwyn L.; et al. (2022-02-16)
    Repeated emergence of SARS-CoV-2 variants with increased fitness necessitates rapid detection and characterization of new lineages. To address this need, we developed PyR0, a hierarchical Bayesian multinomial logistic regression model that infers relative prevalence of all viral lineages across geographic regions, detects lineages increasing in prevalence, and identifies mutations relevant to fitness. Applying PyR0 to all publicly available SARS-CoV-2 genomes, we identify numerous substitutions that increase fitness, including previously identified spike mutations and many non-spike mutations within the nucleocapsid and nonstructural proteins. PyR0 forecasts growth of new lineages from their mutational profile, identifies viral lineages of concern as they emerge, and prioritizes mutations of biological and public health concern for functional characterization.
  • Outcome Measures in Facioscapulohumeral Muscular Dystrophy Clinical Trials

    Ghasemi, Mehdi; Emerson, Charles P. Jr.; Hayward, Lawrence J. (2022-02-16)
    Facioscapulohumeral muscular dystrophy (FSHD) is a debilitating muscular dystrophy with a variable age of onset, severity, and progression. While there is still no cure for this disease, progress towards FSHD therapies has accelerated since the underlying mechanism of epigenetic derepression of the double homeobox 4 (DUX4) gene leading to skeletal muscle toxicity was identified. This has facilitated the rapid development of novel therapies to target DUX4 expression and downstream dysregulation that cause muscle degeneration. These discoveries and pre-clinical translational studies have opened new avenues for therapies that await evaluation in clinical trials. As the field anticipates more FSHD trials, the need has grown for more reliable and quantifiable outcome measures of muscle function, both for early phase and phase II and III trials. Advanced tools that facilitate longitudinal clinical assessment will greatly improve the potential of trials to identify therapeutics that successfully ameliorate disease progression or permit muscle functional recovery. Here, we discuss current and emerging FSHD outcome measures and the challenges that investigators may experience in applying such measures to FSHD clinical trial design and implementation.
  • Adenine Base Editing in vivo with a Single Adeno-Associated Virus Vector [preprint]

    Zhang, Han; Bamidele, Nathan; Liu, Pengpeng; Ojelabi, Ogooluwa; Gao, Xin D.; Rodríguez, Tomás; Cheng, Haoyang; Xie, Jun; Gao, Guangping; Wolfe, Scot A.; et al. (2022-02-07)
    Base editors (BEs) have opened new avenues for the treatment of genetic diseases. However, advances in delivery approaches are needed to enable disease targeting of a broad range of tissues and cell types. Adeno-associated virus (AAV) vectors remain one of the most promising delivery vehicles for gene therapies. Currently, most BE/guide combinations and their promoters exceed the packaging limit (~5 kb) of AAVs. Dual-AAV delivery strategies often require high viral doses that impose safety concerns. In this study, we engineered an adenine base editor using a compact Cas9 from Neisseria meningitidis (Nme2Cas9). Compared to the well-characterized Streptococcus pyogenes Cas9-containing ABEs, Nme2-ABE possesses a distinct PAM (N4CC) and editing window, exhibits fewer off-target effects, and can efficiently install therapeutically relevant mutations in both human and mouse genomes. Importantly, we show that in vivo delivery of Nme2-ABE and its guide RNA by a single-AAV vector can efficiently edit mouse genomic loci and revert the disease mutation and phenotype in an adult mouse model of tyrosinemia. We anticipate that Nme2-ABE, by virtue of its compact size and broad targeting range, will enable a range of therapeutic applications with improved safety and efficacy due in part to packaging in a single-vector system.
  • Using wearable technology to detect prescription opioid self-administration

    Salgado Garcia, Francisco I.; Indic, Premananda; Stapp, Joshua; Chintha, Keerthi K.; He, Zhaomin; Brooks, Jeffrey H.; Carreiro, Stephanie P.; Derefinko, Karen J. (2022-02-01)
    Appropriate monitoring of opioid use in patients with pain conditions is paramount, yet it remains a very challenging task. The current work examined the use of a wearable sensor to detect self-administration of opioids after dental surgery using machine learning. Participants were recruited from an oral and maxillofacial surgery clinic. Participants were 46 adult patients (26 female) receiving opioids after dental surgery. Participants wore Empatica E4 sensors during the period they self-administered opioids. The E4 collected physiological parameters including accelerometer x-, y-, and z-axes, heart rate, and electrodermal activity. Four machine learning models provided validation accuracies greater than 80%, but the bagged-tree model provided the highest combination of validation accuracy (83.7%) and area under the receiver operating characteristic curve (0.92). The trained model had a validation sensitivity of 82%, a specificity of 85%, a positive predictive value of 85%, and a negative predictive value of 83%. A subsequent test of the trained model on withheld data had a sensitivity of 81%, a specificity of 88%, a positive predictive value of 87%, and a negative predictive value of 82%. Results from training and testing model of machine learning indicated that opioid self-administration could be identified with reasonable accuracy, leading to considerable possibilities of the use of wearable technology to advance prevention and treatment.
  • Dynamic activity of interpeduncular nucleus GABAergic neurons controls expression of nicotine withdrawal in male mice

    Klenowski, Paul M.; Zhao-Shea, Rubing; Freels, Timothy G.; Molas-Casacuberta, Susanna; Tapper, Andrew R. (2022-02-01)
    A critical brain area implicated in nicotine dependence is the interpeduncular nucleus (IPN) located in the ventral midbrain and consisting primarily of GABAergic neurons. Previous studies indicate that IPN GABAergic neurons contribute to expression of somatic symptoms of nicotine withdrawal; however, whether IPN neurons are dynamically regulated during withdrawal in vivo and how this may contribute to both somatic and affective withdrawal behavior is unknown. To bridge this gap in knowledge, we expressed GCaMP in IPN GABAergic neurons and used in vivo fiber photometry to record changes in fluorescence, as a proxy for neuronal activity, in male mice during nicotine withdrawal. Mecamylamine-precipitated withdrawal significantly increased activity of IPN GABAergic neurons in nicotine-dependent, but not nicotine-naive mice. Analysis of GCaMP signals time-locked with somatic symptoms including grooming and scratching revealed reduced IPN GABAergic activity during these behaviors, specifically in mice undergoing withdrawal. In the elevated plus maze, used to measure anxiety-like behavior, an affective withdrawal symptom, IPN GABAergic neuron activity was increased during open-arm versus closed-arm exploration in nicotine-withdrawn, but not non-withdrawn mice. Optogenetic silencing IPN GABAergic neurons during withdrawal significantly reduced withdrawal-induced increases in somatic behavior and increased open-arm exploration. Together, our data indicate that IPN GABAergic neurons are dynamically regulated during nicotine withdrawal, leading to increased anxiety-like symptoms and somatic behavior, which inherently decrease IPN GABAergic neuron activity as a withdrawal-coping mechanism. These results provide a neuronal basis underlying the role of the IPN in the expression of somatic and affective behaviors of nicotine withdrawal.
  • Caregiver-perceived neighborhood safety and pediatric asthma severity: 2017-2018 National Survey of Children's Health

    Hoque, Shushmita; Goulding, Melissa; Hazeltine, Max D.; Ferrucci, Katarina A.; Trivedi, Michelle K.; Liu, Shao-Hsien (2022-02-01)
    OBJECTIVE: To examine the association between caregiver-perceived neighborhood safety and pediatric asthma severity using a cross-sectional, nationally representative sample. STUDY DESIGN: Using data from the 2017-2018 National Survey of Children's Health, children aged 6-17 years with primary caregiver report of a current asthma diagnosis were included (unweighted N = 3209; weighted N = 3,909,178). Perceived neighborhood safety, asthma severity (mild vs. moderate/severe), demographic, household, and health/behavioral covariate data were collected from primary caregiver report. Poisson regression with robust error variance was used to estimate the association between perceived neighborhood safety and caregiver-reported pediatric asthma severity. RESULTS: Approximately one-third of children studied had moderate/severe asthma. A total of 42% of children with mild asthma and 52% of children with moderate/severe asthma identified as Hispanic or non-Hispanic Black. Nearly 20% of children with mild asthma and 40% of children with moderate/severe asthma were from families living below the federal poverty level (FPL). Children living in neighborhoods perceived by their caregiver to be unsafe had higher prevalence of moderate/severe asthma compared to those in the safest neighborhoods (adjusted prevalence ratio: 1.34; 95% confidence interval: 1.04-1.74). This association was found to be independent of race/ethnicity, household FPL, household smoking, and child's physical activity level after adjusting for covariates. CONCLUSIONS: Children living in neighborhoods perceived by their caregiver to be unsafe have higher prevalence of moderate or severe asthma. Further investigation of geographic context and neighborhood characteristics that influence childhood asthma severity may inform public health strategies to reduce asthma burden and improve disease outcomes.
  • Kinesin-3 mediated axonal delivery of presynaptic neurexin stabilizes dendritic spines and postsynaptic components

    Oliver, Devyn; Ramachandran, Shankar; Philbrook, Alison; Lambert, Christopher M.; Nguyen, Ken C. Q.; Hall, David H.; Francis, Michael M. (2022-01-28)
    The functional properties of neural circuits are defined by the patterns of synaptic connections between their partnering neurons, but the mechanisms that stabilize circuit connectivity are poorly understood. We systemically examined this question at synapses onto newly characterized dendritic spines of C. elegans GABAergic motor neurons. We show that the presynaptic adhesion protein neurexin/NRX-1 is required for stabilization of postsynaptic structure. We find that early postsynaptic developmental events proceed without a strict requirement for synaptic activity and are not disrupted by deletion of neurexin/nrx-1. However, in the absence of presynaptic NRX-1, dendritic spines and receptor clusters become destabilized and collapse prior to adulthood. We demonstrate that NRX-1 delivery to presynaptic terminals is dependent on kinesin-3/UNC-104 and show that ongoing UNC-104 function is required for postsynaptic maintenance in mature animals. By defining the dynamics and temporal order of synapse formation and maintenance events in vivo, we describe a mechanism for stabilizing mature circuit connectivity through neurexin-based adhesion.
  • iMyoblasts for ex vivo and in vivo investigations of human myogenesis and disease modeling

    Guo, Dongsheng; Daman, Katelyn; Chen, Jennifer Jc; Shi, Meng-Jiao; Yan, Jing; Matijasevic, Zdenka; Maehr, Rene; King, Oliver D.; Hayward, Lawrence J.; Emerson, Charles P. Jr. (2022-01-25)
    Skeletal muscle myoblasts (iMyoblasts) were generated from human induced pluripotent stem cells (iPSCs) using an efficient and reliable transgene-free induction and stem cell selection protocol. Immunofluorescence, flow cytometry, qPCR, digital RNA expression profiling, and scRNA-Seq studies identify iMyoblasts as a PAX3+/MYOD1+ skeletal myogenic lineage with a fetal-like transcriptome signature, distinct from adult muscle biopsy myoblasts (bMyoblasts) and iPSC-induced muscle progenitors. iMyoblasts can be stably propagated for > 12 passages or 30 population doublings while retaining their dual commitment for myotube differentiation and regeneration of reserve cells. iMyoblasts also efficiently xenoengrafted into irradiated and injured mouse muscle where they undergo differentiation and fetal-adult MYH isoform switching, demonstrating their regulatory plasticity for adult muscle maturation in response to signals in the host muscle. Xenograft muscle retains PAX3+ muscle progenitors and can regenerate human muscle in response to secondary injury. As models of disease, iMyoblasts from individuals with Facioscapulohumeral Muscular Dystrophy revealed a previously unknown epigenetic regulatory mechanism controlling developmental expression of the pathological DUX4 gene. iMyoblasts from Limb-Girdle Muscular Dystrophy R7 and R9 and Walker Warburg Syndrome patients modeled their molecular disease pathologies and were responsive to small molecule and gene editing therapeutics. These findings establish the utility of iMyoblasts for ex vivo and in vivo investigations of human myogenesis and disease pathogenesis and for the development of muscle stem cell therapeutics.
  • Novel gamma-sarcoglycan interactors in murine muscle membranes

    Smith, Tara C.; Vasilakos, Georgios; Shaffer, Scott A.; Puglise, Jason M.; Chou, Chih-Hsuan; Barton, Elisabeth R.; Luna, Elizabeth J. (2022-01-22)
    BACKGROUND: The sarcoglycan complex (SC) is part of a network that links the striated muscle cytoskeleton to the basal lamina across the sarcolemma. The SC coordinates changes in phosphorylation and Ca(++)-flux during mechanical deformation, and these processes are disrupted with loss-of-function mutations in gamma-sarcoglycan (Sgcg) that cause Limb girdle muscular dystrophy 2C/R5. METHODS: To gain insight into how the SC mediates mechano-signaling in muscle, we utilized LC-MS/MS proteomics of SC-associated proteins in immunoprecipitates from enriched sarcolemmal fractions. Criteria for inclusion were co-immunoprecipitation with anti-Sgcg from C57BL/6 control muscle and under-representation in parallel experiments with Sgcg-null muscle and with non-specific IgG. Validation of interaction was performed in co-expression experiments in human RH30 rhabdomyosarcoma cells. RESULTS: We identified 19 candidates as direct or indirect interactors for Sgcg, including the other 3 SC proteins. Novel potential interactors included protein-phosphatase-1-catalytic-subunit-beta (Ppp1cb, PP1b) and Na(+)-K(+)-Cl(-)-co-transporter NKCC1 (SLC12A2). NKCC1 co-localized with Sgcg after co-expression in human RH30 rhabdomyosarcoma cells, and its cytosolic domains depleted Sgcg from cell lysates upon immunoprecipitation and co-localized with Sgcg after detergent permeabilization. NKCC1 localized in proximity to the dystrophin complex at costameres in vivo. Bumetanide inhibition of NKCC1 cotransporter activity in isolated muscles reduced SC-dependent, strain-induced increases in phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2). In silico analysis suggests that candidate SC interactors may cross-talk with survival signaling pathways, including p53, estrogen receptor, and TRIM25. CONCLUSIONS: Results support that NKCC1 is a new SC-associated signaling protein. Moreover, the identities of other candidate SC interactors suggest ways by which the SC and NKCC1, along with other Sgcg interactors such as the membrane-cytoskeleton linker archvillin, may regulate kinase- and Ca(++)-mediated survival signaling in skeletal muscle.

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