Now showing items 1-20 of 15236

    • Functional genomics reveals an off-target dependency of drug synergy in gastric cancer therapy [preprint]

      Leylek, Ozen; Honeywell, Megan E; Lee, Michael J; Hemann, Michael T; Ozcan, Gulnihal (2023-11-19)
      The rational combination of anticancer agents is critical to improving patient outcomes in cancer. Nonetheless, most combination regimens in the clinic result from empirical methodologies disregarding insight into the mechanism of action and missing the opportunity to improve therapy outcomes incrementally. Deciphering the genetic dependencies and vulnerabilities responsible for synergistic interactions is crucial for rationally developing effective anticancer drug combinations. Hence, we screened pairwise pharmacological interactions between molecular-targeted agents and conventional chemotherapeutics and examined the genome-scale genetic dependencies in gastric adenocarcinoma cell models. Since this type of cancer is mainly chemoresistant and incurable, clinical situations demand effective combination strategies. Our pairwise combination screen revealed SN38/erlotinib as the drug pair with the most robust synergism. Genome-wide CRISPR screening and a shRNA-based signature assay indicated that the genetic dependency/vulnerability signature of SN38/erlotinib is the same as SN38 alone. Additional investigation revealed that the enhanced cell death with improved death kinetics caused by the SN38/erlotinib combination is surprisingly due to erlotinib's off-target effect that inhibits ABCG2 but not its on-target effect on EGFR. Our results confirm that a genetic dependency signature different from the single-drug application may not be necessary for the synergistic interaction of molecular-targeted agents with conventional chemotherapeutics in gastric adenocarcinoma. The findings also demonstrated the efficacy of functional genomics approaches in unveiling biologically validated mechanisms of pharmacological interactions.
    • Distinct members of the C. elegans CeMbio reference microbiota exert cryptic virulence and infection protection [preprint]

      Gonzalez, Xavier; Irazoqui, Javier E (2023-11-05)
      Microbiotas are complex microbial communities that colonize specific niches in the host and provide essential organismal functions that are important in health and disease. A key aspect is the ability of each distinct community member to promote or impair host health, alone or in the context of the community, in hosts with varied levels of immune competence. Understanding such interactions is limited by the complexity and experimental accessibility of current systems and models. Recently, a reference twelve-member microbiota for the model organism C. elegans, known as CeMbio, was defined to aid the dissection of conserved host-microbiota interactions. Understanding the physiological impact of the CeMbio bacteria on C. elegans is in its infancy. Here, we show the differential ability of each CeMbio bacterial species to activate innate immunity through the conserved PMK-1/p38 MAPK, ACh/WNT, and HLH-30/TFEB pathways. Using immunodeficient animals, we uncovered several examples of bacterial 'cryptic' virulence, or virulence that was masked by the host defense response. The ability to activate the PMK-1/p38 pathway did not correlate with bacterial virulence in wild type or immunodeficient animals. In contrast, ten out of twelve species activated HLH-30/TFEB, and most showed virulence towards hlh-30-deficient animals. In addition, we identified Pseudomonas lurida as a pathogen in wild type animals, and Acinetobacter guillouiae as avirulent despite activating all three pathways. Moreover, short pre-exposure to A. guillouiae promoted host survival of infection with P. lurida, which was dependent on PMK-1/p38 MAPK and HLH-30/TFEB. These results suggest that the microbiota of C. elegans is rife with "opportunistic" pathogens, and that HLH-30/TFEB is a fundamental and key host protective factor. Furthermore, they support the idea that bacteria like A. guillouiae evolved the ability to induce host innate immunity to improve host fitness when confronted with pathogens, providing new insights into how colonization order impacts host health.
    • Sexually dimorphic mechanisms of VGLUT-mediated protection from dopaminergic neurodegeneration [preprint]

      Buck, Silas A; Rubin, Sophie A; Kunkhyen, Tenzin; Treiber, Christoph D; Xue, Xiangning; Fenno, Lief E; Mabry, Samuel J; Sundar, Varun R; Yang, Zilu; Shah, Divia; et al. (2023-10-03)
      Parkinson's disease (PD) targets some dopamine (DA) neurons more than others. Sex differences offer insights, with females more protected from DA neurodegeneration. The mammalian vesicular glutamate transporter VGLUT2 and Drosophila ortholog dVGLUT have been implicated as modulators of DA neuron resilience. However, the mechanisms by which VGLUT2/dVGLUT protects DA neurons remain unknown. We discovered DA neuron dVGLUT knockdown increased mitochondrial reactive oxygen species in a sexually dimorphic manner in response to depolarization or paraquat-induced stress, males being especially affected. DA neuron dVGLUT also reduced ATP biosynthetic burden during depolarization. RNA sequencing of VGLUT+ DA neurons in mice and flies identified candidate genes that we functionally screened to further dissect VGLUT-mediated DA neuron resilience across PD models. We discovered transcription factors modulating dVGLUT-dependent DA neuroprotection and identified dj-1β as a regulator of sex-specific DA neuron dVGLUT expression. Overall, VGLUT protects DA neurons from PD-associated degeneration by maintaining mitochondrial health.
    • Physical activity regulates the immune response to breast cancer by a hematopoietic stem cell-autonomous mechanism [preprint]

      Khair, Lyne; Hayes, Katherine; Tutto, Amanda; Samant, Amruta; Ferreira, Lindsay; Nguyen, Tammy T; Brehm, Michael; Messina, Louis M (2023-10-02)
      Physical activity is a modifiable lifestyle factor that is associated with a decreased risk for the development of breast cancer. While the exact mechanisms for the reduction in cancer risk due to physical activity are largely unknown, it is postulated that the biological reduction in cancer risk is driven by improvements in inflammation and immune function with exercise. Hematopoietic stem cells (HSCs) are the progenitor for all of the cells of the immune system and are involved in cancer immunosurveillance through differentiation into cytotoxic cell population. In this study, we investigate the role of physical activity (PA) in a spontaneously occurring model of breast cancer over time, with a focus on tumor incidence, circulating and tumor-infiltrating immune cells as well gene expression profiles of tumors and hematopoietic stem cells. Furthermore, we show that, in addition to a direct effect of PA on the immune cells of tumor-bearing mice, PA reduces the oxidative stress in HSCs of wildtype and tumor-bearing mice, and by doing so, alters the differentiation of the HSCs towards T cells in order to enhance cancer immunosurveillance.
    • Loss of TDP-43 function contributes to genomic instability in amyotrophic lateral sclerosis

      Fang, Minggang; Deibler, Sara K; Nana, Alissa L; Vatsavayai, Sarat C; Banday, Shahid; Zhou, You; Almeida, Sandra; Weiss, Alexandra; Brown, Robert H; Seeley, William W; et al. (2023-10-02)
      A common pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the cytoplasmic mislocalization and aggregation of the DNA/RNA-binding protein TDP-43, but how loss of nuclear TDP-43 function contributes to ALS and FTD pathogenesis remains largely unknown. Here, using large-scale RNAi screening, we identify TARDBP, which encodes TDP-43, as a gene whose loss-of-function results in elevated DNA mutation rate and genomic instability. Consistent with this finding, we observe increased DNA damage in induced pluripotent stem cells (iPSCs) and iPSC-derived post-mitotic neurons generated from ALS patients harboring TARDBP mutations. We find that the increase in DNA damage in ALS iPSC-derived neurons is due to defects in two major pathways for DNA double-strand break repair: non-homologous end joining and homologous recombination. Cells with defects in DNA repair are sensitive to DNA damaging agents and, accordingly, we find that ALS iPSC-derived neurons show a marked reduction in survival following treatment with a DNA damaging agent. Importantly, we find that increased DNA damage is also observed in neurons with nuclear TDP-43 depletion from ALS/FTD patient brain tissues. Collectively, our results demonstrate that ALS neurons with loss of nuclear TDP-43 function have elevated levels of DNA damage and contribute to the idea that genomic instability is a defining pathological feature of ALS/FTD patients with TDP-43 pathology.
    • The Importance of Quality Assurance in Radiation Oncology Clinical Trials

      FitzGerald, Thomas J; Bishop-Jodoin, Maryann; Laurie, Fran; Iandoli, Matthew; Smith, Koren; Ulin, Kenneth; Ding, Linda; Moni, Janaki; Cicchetti, M Giulia; Knopp, Michael; et al. (2023-10-01)
      Clinical trials have been the center of progress in modern medicine. In oncology, we are fortunate to have a structure in place through the National Clinical Trials Network (NCTN). The NCTN provides the infrastructure and a forum for scientific discussion to develop clinical concepts for trial design. The NCTN also provides a network group structure to administer trials for successful trial management and outcome analyses. There are many important aspects to trial design and conduct. Modern trials need to ensure appropriate trial conduct and secure data management processes. Of equal importance is the quality assurance of a clinical trial. If progress is to be made in oncology clinical medicine, investigators and patient care providers of service need to feel secure that trial data is complete, accurate, and well-controlled in order to be confident in trial analysis and move trial outcome results into daily practice. As our technology has matured, so has our need to apply technology in a uniform manner for appropriate interpretation of trial outcomes. In this article, we review the importance of quality assurance in clinical trials involving radiation therapy. We will include important aspects of institution and investigator credentialing for participation as well as ongoing processes to ensure that each trial is being managed in a compliant manner. We will provide examples of the importance of complete datasets to ensure study interpretation. We will describe how successful strategies for quality assurance in the past will support new initiatives moving forward.
    • Risk of Subsequent Neoplasms in Childhood Cancer Survivors After Radiation Therapy: A Comprehensive PENTEC Review

      Casey, Dana L; Vogelius, Ivan R; Brodin, N Patrik; Roberts, Kenneth B; Avanzo, Michele; Moni, Janaki; Owens, Constance; Ronckers, Cécile M; Constine, Louis S; Bentzen, Soren M; et al. (2023-09-29)
      Purpose: A Pediatric Normal Tissue Effects in the Clinic (PENTEC) analysis of published investigations of central nervous system (CNS) subsequent neoplasms (SNs), subsequent sarcomas, and subsequent lung cancers in childhood cancer survivors who received radiation therapy (RT) was performed to estimate the effect of RT dose on the risk of SNs and the modification of this risk by host and treatment factors. Methods and materials: A systematic literature review was performed to identify data published from 1975 to 2022 on SNs after prior RT in childhood cancer survivors. After abstract review, usable quantitative and qualitative data were extracted from 83 studies for CNS SNs, 118 for subsequent sarcomas, and 10 for lung SNs with 4 additional studies (3 for CNS SNs and 1 for lung SNs) later added. The incidences of SNs, RT dose, age, sex, primary cancer diagnosis, chemotherapy exposure, and latent time from primary diagnosis to SNs were extracted to assess the factors influencing risk for SNs. The excess relative ratio (ERR) for developing SNs as a function of dose was analyzed using inverse-variance weighted linear regression, and the ERR/Gy was estimated. Excess absolute risks were also calculated. Results: The ERR/Gy for subsequent meningiomas was estimated at 0.44 (95% CI, 0.19-0.68); for malignant CNS neoplasms, 0.15 (95% CI, 0.11-0.18); for sarcomas, 0.045 (95% CI, 0.023-0.067); and for lung cancer, 0.068 (95% CI, 0.03-0.11). Younger age at time of primary diagnosis was associated with higher risk of subsequent meningioma and sarcoma, whereas no significant effect was observed for age at exposure for risk of malignant CNS neoplasm, and insufficient data were available regarding age for lung cancer. Females had a higher risk of subsequent meningioma (odds ratio, 1.46; 95% CI, 1.22-1.76; P < .0001) relative to males, whereas no statistically significant sex difference was seen in risk of malignant CNS neoplasms, sarcoma SNs, or lung SNs. There was an association between chemotherapy receipt (specifically alkylating agents and anthracyclines) and subsequent sarcoma risk, whereas there was no clear association between specific chemotherapeutic agents and risk of CNS SNs and lung SNs. Conclusions: This PENTEC systematic review shows a significant radiation dose-response relationship for CNS SNs, sarcomas, and lung SNs. Given the linear dose response, improved conformality around the target volume that limits the high dose volume might be a promising strategy for reducing the risk of SNs after RT. Other host- and treatment-related factors such as age and chemotherapy play a significant contributory role in the development of SNs and should be considered when estimating the risk of SNs after RT among childhood cancer survivors.
    • Group Acupuncture Therapy With Yoga Therapy for Chronic Neck, Low Back, and Osteoarthritis Pain in Safety Net Settings for an Underserved Population: A Feasibility Pilot Study

      Teets, Raymond; Nielsen, Arya; Moonaz, Steffany; Anderson, Belinda J; Mah, Donna M; Walter, Eve; Milanes, Mirta; Jyung, Hyowoun; Soto Cossio, Luz E; Meissner, Paul; et al. (2023-09-28)
      Background: Acupuncture and yoga have both been shown to be effective in chronic pain. Underrepresented populations have poorer pain outcomes with less access to effective pain care. Objective: To assess the feasibility of bundling group acupuncture with yoga therapy for chronic neck, back or osteoarthritis pain in safety net settings. Methods: This was a feasibility pilot in Bronx and Harlem primary care community health centers. Participants with chronic neck, back or osteoarthritis pain received acupuncture and yoga therapy over a 10-week period. Participants received 10 weekly acupuncture treatments in group setting; with Yoga therapy sessions beginning immediately following the 3rd session. Primary outcome was pain interference and pain intensity on the Brief Pain Inventory (BPI); Outcomes were measured at baseline, 10-week close of intervention, and 24-week follow-up. Results: 93 patients were determined to be eligible and completed the baseline interview. The majority of participants were non-White and Medicaid recipients. 78 (84%) completed the intervention and 10-week survey, and 58 (62%) completed the 24-week post intervention survey. Participants received an average number of 6.5 acupuncture sessions (out of a possible 10), and 4 yoga sessions (out of a possible 8) over the 10-week intervention. Patients showed statistically significant improvements in pain at the close of the intervention and at a somewhat lesser rate, at 24-weeks post intervention. Challenges included telephone outreach and site coordination integrating acupuncture with yoga therapy. The trial also had to be stopped early due to the COVID-19 pandemic. Conclusions: Bundling acupuncture therapy and yoga therapy is feasible for an underrepresented population with chronic pain in urban community health centers with preliminary indications of acceptability and benefit to participants.
    • The RITA-T (Rapid Interactive Screening Test for Autism in Toddlers) Community Model to Improve Access and Early Identification of Autism in Young Children

      Choueiri, Roula; Garrison, William T; Tokatli, Valerie; Daneshvar, Naaz; Belgrad, Jillian; Zhu, Guangyu; Zhang, Bo (2023-09-28)
      Objective: To evaluate improved identification and the generalization of the RITA-T (Rapid interactive Screening Test for Autism in Toddlers) model through partnerships with Primary Care (PC), Early Intervention (EI), and Autism Diagnosticians. Methods: Over 3 years (2018-2021), 15 EI and 9 PC (MD and NP) centers participated in this project. We trained providers on the RITA-T and established screening models. We reviewed charts of all toddlers referred through this model and compared wait times, and diagnoses, to those evaluated through regular referral in a tertiary-based autism clinic. We also examined the RITA-T psychometrics. Results: 377 toddlers met our inclusion criteria. Wait time for diagnosis was an average of 2.8 months and led to further collaboration between community providers. RITA-T cut-off scores stayed consistent. Providers reported improved confidence and easy integration of this model. Conclusions: This model is generalizable and improves the Early Identification of ASD.
    • Multicomponent Pharmacist Intervention Did Not Reduce Clinically Important Medication Errors for Ambulatory Patients Initiating Direct Oral Anticoagulants

      Kapoor, Alok; Patel, Parth; Mbusa, Daniel; Pham, Thu; Cicirale, Carrie; Tran, Wenisa; Beavers, Craig; Javed, Saud; Wagner, Joann; Swain, Dawn; et al. (2023-09-27)
      Background: Anticoagulants including direct oral anticoagulants (DOACs) are among the highest-risk medications in the United States. We postulated that routine consultation and follow-up from a clinical pharmacist would reduce clinically important medication errors (CIMEs) among patients beginning or resuming a DOAC in the ambulatory care setting. Objective: To evaluate the effectiveness of a multicomponent intervention for reducing CIMEs. Design: Randomized controlled trial. Participants: Ambulatory patients initiating a DOAC or resuming one after a complication. Intervention: Pharmacist evaluation and monitoring based on the implementation of a recently published checklist. Key elements included evaluation of the appropriateness of DOAC, need for DOAC affordability assistance, three pharmacist-initiated telephone consultations, access to a DOAC hotline, documented hand-off to the patient's continuity provider, and monitoring of follow-up laboratory tests. Control: Coupons and assistance to increase the affordability of DOACs. Main measure: Anticoagulant-related CIMEs (Anticoagulant-CIMEs) and non-anticoagulant-related CIMEs over 90 days from DOAC initiation; CIMEs identified through masked assessment process including two physician adjudication of events presented by a pharmacist distinct from intervention pharmacist who reviewed participant electronic medical records and interview data. Analysis: Incidence and incidence rate ratio (IRR) of CIMEs (intervention vs. control) using multivariable Poisson regression modeling. Key results: A total of 561 patients (281 intervention and 280 control patients) contributed 479 anticoagulant-CIMEs including 31 preventable and ameliorable ADEs and 448 significant anticoagulant medication errors without subsequent documented ADEs (0.95 per 100 person-days). Failure to perform required blood tests and concurrent, inappropriate usage of a DOAC with aspirin or NSAIDs were the most common anticoagulant-related CIMEs despite pharmacist documentation systematically identifying these issues when present. There was no reduction in anticoagulant-related CIMEs among intervention patients (IRR 1.17; 95% CI 0.98-1.42) or non-anticoagulant-related CIMEs (IRR 1.05; 95% CI 0.80-1.37). Conclusion: A multi-component intervention in which clinical pharmacists implemented an evidence-based DOAC Checklist did not reduce CIMEs. Nih trial number: NCT04068727.
    • Beyond genome-wide association studies: Investigating the role of noncoding regulatory elements in primary sclerosing cholangitis

      Pratt, Henry E; Wu, Tong; Elhajjajy, Shaimae I; Zhou, Jeffrey Y.; Fitzgerald, Kate; Fazzio, Tom; Weng, Zhiping; Pratt, Daniel S (2023-09-27)
      Background: Genome-wide association studies (GWAS) have identified 30 risk loci for primary sclerosing cholangitis (PSC). Variants within these loci are found predominantly in noncoding regions of DNA making their mechanisms of conferring risk hard to define. Epigenomic studies have shown noncoding variants broadly impact regulatory element activity. The possible association of noncoding PSC variants with regulatory element activity has not been studied. We aimed to (1) determine if the noncoding risk variants in PSC impact regulatory element function and (2) if so, assess the role these regulatory elements have in explaining the genetic risk for PSC. Methods: Available epigenomic datasets were integrated to build a comprehensive atlas of cell type-specific regulatory elements, emphasizing PSC-relevant cell types. RNA-seq and ATAC-seq were performed on peripheral CD4+ T cells from 10 PSC patients and 11 healthy controls. Computational techniques were used to (1) study the enrichment of PSC-risk variants within regulatory elements, (2) correlate risk genotype with differences in regulatory element activity, and (3) identify regulatory elements differentially active and genes differentially expressed between PSC patients and controls. Results: Noncoding PSC-risk variants are strongly enriched within immune-specific enhancers, particularly ones involved in T-cell response to antigenic stimulation. In total, 250 genes and >10,000 regulatory elements were identified that are differentially active between patients and controls. Conclusions: Mechanistic effects are proposed for variants at 6 PSC-risk loci where genotype was linked with differential T-cell regulatory element activity. Regulatory elements are shown to play a key role in PSC pathophysiology.
    • A 4D transcriptomic map for the evolution of multiple sclerosis-like lesions in the marmoset brain [preprint]

      Lin, Jing-Ping; Brake, Alexis; Donadieu, Maxime; Lee, Amanda; Kawaguchi, Riki; Sati, Pascal; Geschwind, Daniel H; Jacobson, Steven; Schafer, Dorothy P; Reich, Daniel S (2023-09-27)
      Single-time-point histopathological studies on postmortem multiple sclerosis (MS) tissue fail to capture lesion evolution dynamics, posing challenges for therapy development targeting development and repair of focal inflammatory demyelination. To close this gap, we studied experimental autoimmune encephalitis (EAE) in the common marmoset, the most faithful animal model of these processes. Using MRI-informed RNA profiling, we analyzed ~600,000 single-nucleus and ~55,000 spatial transcriptomes, comparing them against EAE inoculation status, longitudinal radiological signals, and histopathological features. We categorized 5 groups of microenvironments pertinent to neural function, immune and glial responses, tissue destruction and repair, and regulatory network at brain borders. Exploring perilesional microenvironment diversity, we uncovered central roles of EAE-associated astrocytes, oligodendrocyte precursor cells, and ependyma in lesion formation and resolution. We pinpointed imaging and molecular features capturing the pathological trajectory of WM, offering potential for assessing treatment outcomes using marmoset as a platform.
    • Integrative medical group visits for patients with chronic pain: results of a pilot single-site hybrid implementation-effectiveness feasibility study

      Roth, Isabel; Tiedt, Malik; Miller, Vanessa; Barnhill, Jessica; Chilcoat, Aisha; Gardiner, Paula; Faurot, Keturah; Karvelas, Kris; Busby, Kenneth; Gaylord, Susan; et al. (2023-09-27)
      Background: Approximately 20% of adults in the United States experience chronic pain. Integrative Medical Group Visit (IMGV) offers an innovative approach to chronic pain management through training in mindfulness, nutrition, and other mind-body techniques combined with peer support. To date, there are no studies on IMGV implementation, despite its promise as a feasible non-pharmacological intervention for chronic pain management. In this study, we assessed the feasibility of implementing IMGV and assessing its effectiveness for chronic pain. Methods: Implementation Mapping was used to develop and evaluate implementation strategies for IMGV. Strategies included disseminating educational materials, conducting ongoing training, and conducting educational meetings. IMGV was delivered by three healthcare providers: an allopathic physician, registered yoga teacher, and naturopathic physician. The effectiveness of IMGV on patient health outcomes was assessed through qualitative interviews and a Patient-Reported Outcomes Scale (PROMIS-29). Provider perspectives of acceptability, appropriateness, and feasibility were assessed through periodic reflections (group interviews reflecting on the process of implementation) and field notes. Paired t-tests were used to assess changes between scores at baseline and post intervention. Qualitative data were coded by three experienced qualitative researchers using thematic content analysis. Results: Of the initial 16 patients enrolled in research, 12 completed at least two sessions of the IMGV. Other than fatigue, there was no statistically significant difference between the pre- and post-scores. Patients reported high satisfaction with IMGV, noting the development of new skills for self-care and the supportive community of peers. Themes from patient interviews and periodic reflections included the feasibility of virtual delivery, patient perspectives on acceptability, provider perspectives of feasibility and acceptability, ease of recruitment, complexity of referral and scheduling process, balancing medical check-in with group engagement, and nursing staff availability. Conclusions: IMGV was feasible, acceptable, and effective from the perspectives of patients and providers. Although statistically significant differences were not observed for most PROMIS measures, qualitative results suggested that participants experienced increased social support and increased pain coping skills. Providers found implementation strategies effective, except for engaging nurses, due to staff being overwhelmed from the pandemic. Lessons learned from this pilot study can inform future research on implementation of IMGV.
    • Awake intracerebroventricular delivery and safety assessment of oligonucleotides in a large animal model

      Benatti, Hector Ribeiro; Prestigiacomo, Rachel D; Taghian, Toloo; Miller, Rachael; King, Robert; Gounis, Matthew J; Celik, Ugur; Bertrand, Stephanie; Tuominen, Susan; Bierfeldt, Lindsey; et al. (2023-09-26)
      Oligonucleotide therapeutics offer great promise in the treatment of previously untreatable neurodegenerative disorders; however, there are some challenges to overcome in pre-clinical studies. (1) They carry a well-established dose-related acute neurotoxicity at the time of administration. (2) Repeated administration into the cerebrospinal fluid may be required for long-term therapeutic effect. Modifying oligonucleotide formulation has been postulated to prevent acute toxicity, but a sensitive and quantitative way to track seizure activity in pre-clinical studies is lacking. The use of intracerebroventricular (i.c.v.) catheters offers a solution for repeated dosing; however, fixation techniques in large animal models are not standardized and are not reliable. Here we describe a novel surgical technique in a sheep model for i.c.v. delivery of neurotherapeutics based on the fixation of the i.c.v. catheter with a 3D-printed anchorage system composed of plastic and ceramic parts, compatible with magnetic resonance imaging, computed tomography, and electroencephalography (EEG). Our technique allowed tracking electrical brain activity in awake animals via EEG and video recording during and for the 24-h period after administration of a novel oligonucleotide in sheep. Its anchoring efficiency was demonstrated for at least 2 months and will be tested for up to a year in ongoing studies.
    • A single neuron in C. elegans orchestrates multiple motor outputs through parallel modes of transmission

      Huang, Yung-Chi; Luo, Jinyue; Huang, Wenjia; Baker, Casey M; Gomes, Matthew A; Meng, Bohan; Byrne, Alexandra B; Flavell, Steven W (2023-09-21)
      Animals generate a wide range of highly coordinated motor outputs, which allows them to execute purposeful behaviors. Individual neurons in the circuits that generate behaviors have a remarkable capacity for flexibility as they exhibit multiple axonal projections, transmitter systems, and modes of neural activity. How these multi-functional properties of neurons enable the generation of adaptive behaviors remains unknown. Here, we show that the HSN neuron in C. elegans evokes multiple motor programs over different timescales to enable a suite of behavioral changes during egg laying. Using HSN activity perturbations and in vivo calcium imaging, we show that HSN acutely increases egg laying and locomotion while also biasing the animals toward low-speed dwelling behavior over minutes. The acute effects of HSN on egg laying and high-speed locomotion are mediated by separate sets of HSN transmitters and different HSN axonal compartments. The long-lasting effects on dwelling are mediated in part by HSN release of serotonin, which is taken up and re-released by NSM, another serotonergic neuron class that directly evokes dwelling. Our results show how the multi-functional properties of a single neuron allow it to induce a coordinated suite of behaviors and also reveal that neurons can borrow serotonin from one another to control behavior.
    • Dual Residency Training in Neurology and Psychiatry: History and Current Practice

      Benjamin, Sheldon (2023-09-20)
      In the early 20th century, neurology training included more experience in psychiatry, and psychiatry training included more training in neurology than what is currently required. After World War I, the increased need for differential diagnosis of what might now be called functional neurological disorders resulted in the military encouraging combined residency training in neurology and psychiatry and the promulgation of the term "neuropsychiatry" for this specialty. Thirty-six percent of physicians certified by the American Board of Psychiatry and Neurology in its first decade (1935-1945) held certification in both neurology and psychiatry. However, the term neuropsychiatry gradually became used interchangeably with general psychiatry-to distinguish it from psychoanalysis-and lost its specificity. It is widely held that the popularity of psychoanalysis resulted in psychiatrists perceiving less need for neurological knowledge, and inclusion of neurology content in psychiatry training decreased. Dual residency training programs in neurology and psychiatry began to increase in popularity again in the 1980s as advances in neuroscience, neuroimaging, and pharmacology, paired with the growth of behavioral neurology, laid the foundation for meaningful practice of neuropsychiatry. The author surveyed 207 physicians who graduated from both a neurology and psychiatry residency and 18 current trainees in combined neuropsychiatry residency programs to collect information on their current practice, academic activity, and opinions about their training. The response rate was 64%. Respondents' attitudes toward the value of their dual neurology and psychiatry training were overwhelmingly positive. Reasons for the lack of growth of combined residency programs in neurology and psychiatry are examined.
    • Nanoparticle delivery of innate immune agonists combines with senescence-inducing agents to mediate T cell control of pancreatic cancer [preprint]

      Chibaya, Loretah; Lusi, Christina F; DeMarco, Kelly D; Kane, Griffin I; Brassil, Meghan L; Parikh, Chaitanya N; Murphy, Katherine C; Li, Junhui; Naylor, Tiana E; Cerrutti, Julia; et al. (2023-09-18)
      Pancreatic ductal adenocarcinoma has quickly risen to become the 3rd leading cause of cancer-related death. This is in part due to its fibrotic tumor microenvironment (TME) that contributes to poor vascularization and immune infiltration and subsequent chemo- and immunotherapy failure. Here we investigated an innovative immunotherapy approach combining local delivery of STING and TLR4 innate immune agonists via lipid-based nanoparticles (NPs) co-encapsulation with senescence-inducing RAS-targeted therapies that can remodel the immune suppressive PDAC TME through the senescence-associated secretory phenotype. Treatment of transplanted and autochthonous PDAC mouse models with these regimens led to enhanced uptake of NPs by multiple cell types in the PDAC TME, induction of type I interferon and other pro-inflammatory signaling, increased antigen presentation by tumor cells and antigen presenting cells, and subsequent activation of both innate and adaptive immune responses. This two-pronged approach produced potent T cell-driven and Type I interferon-dependent tumor regressions and long-term survival in preclinical PDAC models. STING and TLR4-mediated Type I interferon signaling were also associated with enhanced NK and CD8+ T cell immunity in human PDAC. Thus, combining localized immune agonist delivery with systemic tumor-targeted therapy can synergize to orchestrate a coordinated innate and adaptive immune assault to overcome immune suppression and activate durable anti-tumor T cell responses against PDAC.
    • Interferon-α promotes neo-antigen formation and preferential HLA-B-restricted antigen presentation in pancreatic β-cells [preprint]

      Carré, Alexia; Zhou, Zhicheng; Perez-Hernandez, Javier; Samassa, Fatoumata; Lekka, Christiana; Manganaro, Anthony; Oshima, Masaya; Liao, Hanqing; Parker, Robert; Nicastri, Annalisa; et al. (2023-09-17)
      Interferon (IFN)-α is the earliest cytokine signature observed in individuals at risk for type 1 diabetes (T1D), but its effect on the repertoire of HLA Class I (HLA-I)-bound peptides presented by pancreatic β-cells is unknown. Using immunopeptidomics, we characterized the peptide/HLA-I presentation in in-vitro resting and IFN-α-exposed β-cells. IFN-α increased HLA-I expression and peptide presentation, including neo-sequences derived from alternative mRNA splicing, post-translational modifications - notably glutathionylation - and protein cis-splicing. This antigenic landscape relied on processing by both the constitutive and immune proteasome. The resting β-cell immunopeptidome was dominated by HLA-A-restricted ligands. However, IFN-α only marginally upregulated HLA-A and largely favored HLA-B, translating into a major increase in HLA-B-restricted peptides and into an increased activation of HLA-B-restricted vs. HLA-A-restricted CD8+ T-cells. A preferential HLA-B hyper-expression was also observed in the islets of T1D vs. non-diabetic donors, and we identified islet-infiltrating CD8+ T-cells from T1D donors reactive to HLA-B-restricted granule peptides. Thus, the inflammatory milieu of insulitis may skew the autoimmune response toward epitopes presented by HLA-B, hence recruiting a distinct T-cell repertoire that may be relevant to T1D pathogenesis.
    • Whole Genome Sequencing Based Analysis of Inflammation Biomarkers in the Trans-Omics for Precision Medicine (TOPMed) Consortium [preprint]

      Jiang, Min-Zhi; Gaynor, Sheila M; Li, Xihao; Van Buren, Eric; Stilp, Adrienne; Buth, Erin; Wang, Fei Fei; Manansala, Regina; Gogarten, Stephanie M; Li, Zilin; et al. (2023-09-12)
      Inflammation biomarkers can provide valuable insight into the role of inflammatory processes in many diseases and conditions. Sequencing based analyses of such biomarkers can also serve as an exemplar of the genetic architecture of quantitative traits. To evaluate the biological insight, which can be provided by a multi-ancestry, whole-genome based association study, we performed a comprehensive analysis of 21 inflammation biomarkers from up to 38,465 individuals with whole-genome sequencing from the Trans-Omics for Precision Medicine (TOPMed) program. We identified 22 distinct single-variant associations across 6 traits - E-selectin, intercellular adhesion molecule 1, interleukin-6, lipoprotein-associated phospholipase A2 activity and mass, and P-selectin - that remained significant after conditioning on previously identified associations for these inflammatory biomarkers. We further expanded upon known biomarker associations by pairing the single-variant analysis with a rare variant set-based analysis that further identified 19 significant rare variant set-based associations with 5 traits. These signals were distinct from both significant single variant association signals within TOPMed and genetic signals observed in prior studies, demonstrating the complementary value of performing both single and rare variant analyses when analyzing quantitative traits. We also confirm several previously reported signals from semi-quantitative proteomics platforms. Many of these signals demonstrate the extensive allelic heterogeneity and ancestry-differentiated variant-trait associations common for inflammation biomarkers, a characteristic we hypothesize will be increasingly observed with well-powered, large-scale analyses of complex traits.
    • A brown fat-enriched adipokine, ASRA, is a leptin receptor antagonist that stimulates appetite [preprint]

      Huang, Lei; Liu, Pengpeng; Du, Yong; Pan, Dongning; Lee, Alexandra; Wolfe, Scot A; Wang, Yong-Xu (2023-09-12)
      The endocrine control of food intake remains incompletely understood, and whether the leptin receptor-mediated anorexigenic pathway in the hypothalamus is negatively regulated by a humoral factor is unknown. Here we identify an appetite-stimulating factor - ASRA - that acts as a leptin receptor antagonist. ASRA encodes an 8 kD protein that is abundantly and selectively expressed in adipose tissue and to a lesser extent, in liver, and is upregulated during fasting and cold. ASRA protein associates with autophagosomes and its secretion is induced by energy deficiency. Overexpression of ASRA in mice attenuates leptin receptor signaling leading to elevated blood glucose and development of severe hyperphagic obesity, whereas either adipose- or liver-specific ASRA knockout mice display increased leptin sensitivity, improved glucose homeostasis, reduced food intake, and resistance to high fat diet-induced obesity. Furthermore, ASRA is indispensable for cold-evoked feeding response. Recombinant ASRA (rASRA) protein binds to leptin receptor and suppresses leptin receptor signaling in cultured cells. In vivo, rASRA promotes food intake and increases blood glucose in a leptin receptor signaling-dependent manner. Our studies collectively show that ASRA, acting as a peripheral signal of energy deficit, stimulates appetite and regulates glucose metabolism by antagonizing leptin receptor signaling, thus revealing a previously unknown endocrine mechanism that has important implications for our understanding of leptin resistance.