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Lethal COVID-19 outcomes are attributed to classic cytokine storm. We revisit this using RNA sequencing of nasopharyngeal and 40 autopsy samples from patients dying of SARS-CoV-2. Subsets of the 100 top-upregulated genes in nasal swabs are upregulated in the heart, lung, kidney, and liver, but not mediastinal lymph nodes. Twenty-two of these are "noncanonical" immune genes, which we link to components of the renin-angiotensin-activation-system that manifest as increased fibrin deposition, leaky vessels, thrombotic tendency, PANoptosis, and mitochondrial dysfunction. Immunohistochemistry of mediastinal lymph nodes reveals altered architecture, excess collagen deposition, and pathogenic fibroblast infiltration. Many of the above findings are paralleled in animal models of SARS-CoV-2 infection and human peripheral blood mononuclear and whole blood samples from individuals with early and later SARS-CoV-2 variants. We then redefine cytokine storm in lethal COVID-19 as driven by upstream immune gene and mitochondrial signaling producing downstream RAAS (renin-angiotensin-aldosterone system) overactivation and organ damage, including compromised mediastinal lymph node function., Competing Interests: Competing interests statement:R.E.S. is on the scientific advisory of Miromatrix, Inc. and Lime Therapeutics and is a consultant for Alnylam, Inc. D.C.W. is on the scientific advisory boards of Pano Therapeutics, Inc., and Medical Excellent Capital.

Developmental and epileptic encephalopathies (DEEs) feature altered brain development, developmental delay and seizures, with seizures exacerbating developmental delay. Here we identify a cohort with biallelic variants in DENND5A, encoding a membrane trafficking protein, and develop animal models with phenotypes like the human syndrome. We demonstrate that DENND5A interacts with Pals1/MUPP1, components of the Crumbs apical polarity complex required for symmetrical division of neural progenitor cells. Human induced pluripotent stem cells lacking DENND5A fail to undergo symmetric cell division with an inherent propensity to differentiate into neurons. These phenotypes result from misalignment of the mitotic spindle in apical neural progenitors. Cells lacking DENND5A orient away from the proliferative apical domain surrounding the ventricles, biasing daughter cells towards a more fate-committed state, ultimately shortening the period of neurogenesis. This study provides a mechanism for DENND5A-related DEE that may be generalizable to other developmental conditions and provides variant-specific clinical information for physicians and families., (© 2024. The Author(s).)

Common and rare alleles are now being annotated across millions of human genomes, and omics technologies are increasingly being used to develop health and treatment recommendations. However, these alleles have not yet been systematically characterized relative to aerospace medicine. Here, we review published alleles naturally found in human cohorts that have a likely protective effect, which is linked to decreased cancer risk and improved bone, muscular, and cardiovascular health. Although some technical and ethical challenges remain, research into these protective mechanisms could translate into improved nutrition, exercise, and health recommendations for crew members during deep space missions., (© 2024. The Author(s).)

Future multi-year crewed planetary missions will motivate advances in aerospace nutrition and telehealth. On Earth, the Human Cell Atlas project aims to spatially map all cell types in the human body. Here, we propose that a parallel Human Cell Space Atlas could serve as an openly available, global resource for space life science research. As humanity becomes increasingly spacefaring, high-resolution omics on orbit could permit an advent of precision spaceflight healthcare. Alongside the scientific potential, we consider the complex ethical, cultural, and legal challenges intrinsic to the human space omics discipline, and how philosophical frameworks may benefit from international perspectives., (© 2024. The Author(s).)

Background: Spaceflight poses a unique set of challenges to humans and the hostile spaceflight environment can induce a wide range of increased health risks, including dermatological issues. The biology driving the frequency of skin issues in astronauts is currently not well understood., Methods: To address this issue, we used a systems biology approach utilizing NASA's Open Science Data Repository (OSDR) on space flown murine transcriptomic datasets focused on the skin, biochemical profiles of 50 NASA astronauts and human transcriptomic datasets generated from blood and hair samples of JAXA astronauts, as well as blood samples obtained from the NASA Twins Study, and skin and blood samples from the first civilian commercial mission, Inspiration4., Results: Key biological changes related to skin health, DNA damage & repair, and mitochondrial dysregulation are identified as potential drivers for skin health risks during spaceflight. Additionally, a machine learning model is utilized to determine gene pairings associated with spaceflight response in the skin. While we identified spaceflight-induced dysregulation, such as alterations in genes associated with skin barrier function and collagen formation, our results also highlight the remarkable ability for organisms to re-adapt back to Earth via post-flight re-tuning of gene expression., Conclusion: Our findings can guide future research on developing countermeasures for mitigating spaceflight-associated skin damage., (© 2024. The Author(s).)

Organismal adaptations to spaceflight have been characterized at the molecular level in model organisms, including Drosophila and C. elegans. Here, we extend molecular work to energy metabolism and sex hormone signaling in mice and humans. We found spaceflight induced changes in insulin and estrogen signaling in rodents and humans. Murine changes were most prominent in the liver, where we observed inhibition of insulin and estrogen receptor signaling with concomitant hepatic insulin resistance and steatosis. Based on the metabolic demand, metabolic pathways mediated by insulin and estrogen vary among muscles, specifically between the soleus and extensor digitorum longus. In humans, spaceflight induced changes in insulin and estrogen related genes and pathways. Pathway analysis demonstrated spaceflight induced changes in insulin resistance, estrogen signaling, stress response, and viral infection. These data strongly suggest the need for further research on the metabolic and reproductive endocrinologic effects of space travel, if we are to become a successful interplanetary species., (© 2024. The Author(s).)

Background: Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability. Early Check, a voluntary newborn screening study, screened 18,833 newborns for FXS over ∼3 years. Exploring parental attitudes and perspectives can provide insight to the potential future acceptability of public health screening., Methods and Procedures: Mothers of infants who received a screen positive result for FXS (n = 6) or fragile X premutation (FXPM; n = 18) were interviewed about their perceptions and experiences., Outcomes and Results: Mothers of children with FXS described utility in receiving information about their child, particularly to monitor for potential developmental issues and intervene early; overall mothers did not regret participating. Mothers reported various reactions to receiving the FXS or FXPM results including (1) stress and worry; (2) guilt; (3) sadness and disappointment; (4) neutrality, relief, and acceptance; and (5) confusion and uncertainty., Conclusions and Implications: Despite initial reactions such as sadness, stress, and worry, mothers found value in learning of their child's presymptomatic diagnosis of FXS, particularly the anticipated long-term benefits of early diagnosis to their child's health and wellbeing. Our results indicate that professionals returning positive newborn screening results should anticipate and prepare for reactions such as parental shock, guilt, sadness, and uncertainty. Genetic counseling and psychosocial support are critical to supporting families., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: Current and emerging treatments for Duchenne muscular dystrophy (DMD) position DMD as a candidate condition for newborn screening (NBS). In anticipation of the nomination of DMD for universal NBS, we conducted a prospective study under the Early Check voluntary NBS research program in North Carolina, United States., Methods: We performed screening for creatine kinase-MM (CK-MM), a biomarker of muscle damage, on residual routine newborn dried blood spots (DBS) from participating newborns. Total creatine kinase testing and next generation sequencing of an 86-neuromuscular gene panel that included DMD were offered to parents of newborns who screened positive. Bivariate and multivariable analyses were performed to assess effects of biological and demographic predictors on CK-MM levels in DBS., Results: We screened 13,354 newborns and identified 2 males with DMD. The provisional 1626 ng/mL cutoff was raised to 2032 ng/mL to improve specificity, and additional cutoffs (900 and 360 ng/mL) were implemented to improve sensitivity for older and low-birthweight newborns., Conclusion: Population-scale screening for elevated CK-MM in DBS is a feasible approach to identify newborns with DMD. Inclusion of birthweight- and age-specific cutoffs, repeat creatine kinase testing after 72 hours of age, and DMD sequencing improve sensitivity and specificity of screening., Competing Interests: Conflict of Interest Salaries of the following authors were supported in part by Sarepta Therapeutics and MDA: K.S.K., B.L.B., B.M., S.N.P., V.R.R., O.K., H.C., K.C.O., A.W., and H.L.P. K.S.K. has received research support from Centers for Disease Control and Prevention (CDC), NIH, Angelman Syndrome Foundation, Foundation for Angelman Syndrome Therapeutics, Foundation for Prader-Willi Research, Dup15q Alliance, and Ionis Pharmaceuticals; A.W. has received support from CDC, NIH, Angelman Syndrome Foundation, Foundation for Angelman Syndrome Therapeutics, Foundation for Prader-Willi Research, Dup15q Alliance, Ionis Pharmaceuticals, Ovid Pharmaceuticals, Roche, and Ultragenyx. C.W.R. has received support from NIH and Alexion Pharmaceuticals., E.C.S. has received support from Sarepta Therapeutics. H.L.P. has received support from the NIH, CDC, Food and Drug Administration (FDA), Duchenne UK, Parent Project Muscular Dystrophy, Cure GM1Foundation, EPIICAL, The John Merck Fund, The Leona M. and Harry B. Helmsley Charitable Trust, JDRF, Janssen Pharmaceuticals, Travere Therapeutics, and Orchard Therapeutics., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Duchenne muscular dystrophy (DMD) is a progressive, life-limiting, neuromuscular disorder. Clinicians play an important role in informing families about therapy options, including approved gene therapies and clinical trials of unapproved therapies., Objective: This study aimed to understand the perspectives of clinicians about gene therapy for DMD, which has not previously been studied., Methods: We conducted interviews with specialist clinicians treating patients with DMD in the United States (n = 8) and United Kingdom (n = 8). Interviews were completed in 2022, before any approved gene therapies, to gain insight into barriers and facilitators to implementing gene therapy and educational needs of clinicians., Results: Most respondents expressed cautious optimism about gene therapy. Responses varied regarding potential benefits with most expecting delayed progression and duration of benefit (1 year to lifelong). Concern about anticipated risks also varied; types of anticipated risks included immunological reactions, liver toxicity, and cardiac or renal dysfunction. Clinicians generally, but not uniformly, understood that gene therapy for DMD would not be curative. Most reported needing demonstrable clinical benefit to justify treatment-related risks., Conclusions: Our data demonstrate variability in knowledge and attitudes about gene therapy among clinicians who follow patients with DMD. As our knowledge base about DMD gene therapy grows, clinician education is vital to ensuring that accurate information is communicated to patients and families.