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-related epilepsy is an autosomal dominant neurodevelopmental disorder with at least 64 known human variants, each with unique electrophysiological and epileptic characteristics. A multi-disciplinary collaboration generated a novel mouse model (C57BL/6- ) carrying the G269S variant, corresponding to human G288S, located within the coding region of the channel pore. Network excitability of cultured cortical neurons from exhibited sustained hyperexcitability and hypersynchronous bursting while neurons showed early excessive bursting followed by network collapse, suggesting excitotoxicity. displayed poor motor coordination, erratic breathing, and increased apneas. Critically, were more susceptible to thermal-induced seizures in early life. In summary, these data: (i) provide a novel mouse model of KCNT1-related epilepsy, (ii) provide strong evidence of neuronal hyperexcitability, (iii) illustrate early-life seizures as a functional outcome measure, and (iv) lay the groundwork for future analysis of neural activity and modeling circuit level dynamics and . Gain-of-function mutations in the sodium-gated potassium channel KCNT1 have been linked to pediatric epilepsy of varying severity. The human variant G288S (G269S in mice) is linked to Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (ADNFLE), Epilepsy of Infancy with Migrating Focal Seizures (EIMFS), and other severe developmental epileptic encephalopathies. There are currently no therapeutics to prevent the progression of -related epilepsy, therefore, the scientific community requires a novel mouse model that is well characterized, and to screen and assess targeted therapeutics. Herein, we engineered a novel mouse to assess developmental and adult phenotypes resulting from the G288S/G269S variant, and , to advance translation toward therapeutic testing for individuals with -related epilepsy.

Gut bacteria might predispose to or protect from necrotising enterocolitis, a severe illness linked to prematurity. In this observational prospective study we aimed to assess whether one or more bacterial taxa in the gut differ between infants who subsequently develop necrotising enterocolitis (cases) and those who do not (controls). We enrolled very low birthweight (1500 g and lower) infants in the primary cohort (St Louis Children's Hospital) between July 7, 2009, and Sept 16, 2013, and in the secondary cohorts (Kosair Children's Hospital and Children's Hospital at Oklahoma University) between Sept 12, 2011 and May 25, 2013. We prospectively collected and then froze stool samples for all infants. Cases were defined as infants whose clinical courses were consistent with necrotising enterocolitis and whose radiographs fulfilled criteria for Bell's stage 2 or 3 necrotising enterocolitis. Control infants (one to four per case; not fixed ratios) with similar gestational ages, birthweight, and birth dates were selected from the population after cases were identified. Using primers specific for bacterial 16S rRNA genes, we amplified and then pyrosequenced faecal DNA from stool samples. With use of Dirichlet multinomial analysis and mixed models to account for repeated measures, we identified host factors, including development of necrotising enterocolitis, associated with gut bacterial populations. We studied 2492 stool samples from 122 infants in the primary cohort, of whom 28 developed necrotising enterocolitis; 94 infants were used as controls. The microbial community structure in case stools differed significantly from those in control stools. These differences emerged only after the first month of age. In mixed models, the time-by-necrotising-enterocolitis interaction was positively associated with Gammaproteobacteria (p=0·0010) and negatively associated with strictly anaerobic bacteria, especially Negativicutes (p=0·0019). We studied 1094 stool samples from 44 infants in the secondary cohorts. 18 infants developed necrotising enterocolitis (cases) and 26 were controls. After combining data from all cohorts (166 infants, 3586 stools, 46 cases of necrotising enterocolitis), there were increased proportions of Gammaproteobacteria (p=0·0011) and lower proportions of both Negativicutes (p=0·0013) and the combined Clostridia–Negativicutes class (p=0·0051) in infants who went on to develop necrotising enterocolitis compared with controls. These associations were strongest in both the primary cohort and the overall cohort for infants born at less than 27 weeks' gestation. A relative abundance of Gammaproteobacteria (ie, Gram-negative facultative bacilli) and relative paucity of strict anaerobic bacteria (especially Negativicutes) precede necrotising enterocolitis in very low birthweight infants. These data offer candidate targets for interventions to prevent necrotising enterocolitis, at least among infants born at less than 27 weeks' gestation. National Institutes of Health (NIH), Foundation for the NIH, the Children's Discovery Institute.

Human development involves multiple signaling pathways acting concertedly in an age- and sex-specific fashion. Trisomy 21, the genetic cause of Down syndrome, dysregulates human development leading to both early neurodevelopmental delays and atypical accelerated aging through unknown mechanisms. Here, we report an integrated multi-omic analysis of the effects of age, sexual dimorphism, and trisomy 21 in hundreds of research participants using matched transcriptome, proteome, metabolome, and immunome datasets. We find that age-related changes peak during puberty and decrease steadily afterwards, with minor changes past early adulthood. The effects of sexual dimorphism are negligible in early childhood but rise sharply during gonad activation and remain strong during reproductive age. Trisomy 21 impacts all life stages, with clear age-specific effects, whereby individuals with Down syndrome display varying pathophysiology at different life stages. Altogether, these analyses provide an advanced understanding of how human development is affected by sex chromosomes and a viable aneuploidy. Using multi-omic analyses, the authors reveal how aging, sex, and trisomy 21 shape human biology across the lifespan, showing that age- and sex-specific changes peak during puberty and adulthood, while trisomy 21 exerts differential effects over time.

Individuals with Down syndrome, the genetic condition caused by trisomy 21, exhibit strong inter-individual variability in terms of developmental phenotypes and diagnosis of co-occurring conditions. The mechanisms underlying this variable developmental and clinical presentation await elucidation. We report an investigation of human chromosome 21 gene overexpression in hundreds of research participants with Down syndrome, which led to the identification of two major subsets of co-expressed genes. Using clustering analyses, we identified three main molecular subtypes of trisomy 21, based on differential overexpression patterns of chromosome 21 genes. We subsequently performed multiomics comparative analyses among subtypes using whole blood transcriptomes, plasma proteomes and metabolomes, and immune cell profiles. These efforts revealed strong heterogeneity in dysregulation of key pathophysiological processes across the three subtypes, underscored by differential multiomics signatures related to inflammation, immunity, cell growth and proliferation, and metabolism. We also observed distinct patterns of immune cell changes across subtypes. These findings provide insights into the molecular heterogeneity of trisomy 21 and lay the foundation for the development of personalized medicine approaches for the clinical management of Down syndrome. Here, the authors reveal variability in chromosome 21 gene overexpression among individuals with Down syndrome, identifying three distinct molecular subtypes. Each subtype exhibits unique biosignatures and immune profiles, offering new insights into the complex biology of Down syndrome.

The impacts of interferon (IFN) signaling on COVID-19 pathology are multiple, with both protective and harmful effects being documented. We report here a multiomics investigation of systemic IFN signaling in hospitalized COVID-19 patients, defining the multiomics biosignatures associated with varying levels of 12 different type I, II, and III IFNs. The antiviral transcriptional response in circulating immune cells is strongly associated with a specific subset of IFNs, most prominently IFNA2 and IFNG. In contrast, proteomics signatures indicative of endothelial damage and platelet activation associate with high levels of IFNB1 and IFNA6. Seroconversion and time since hospitalization associate with a significant decrease in a specific subset of IFNs. Additionally, differential IFN subtype production is linked to distinct constellations of circulating myeloid and lymphoid immune cell types. Each IFN has a unique metabolic signature, with IFNG being the most associated with activation of the kynurenine pathway. IFNs also show differential relationships with clinical markers of poor prognosis and disease severity. For example, whereas IFNG has the strongest association with C-reactive protein and other immune markers of poor prognosis, IFNB1 associates with increased neutrophil to lymphocyte ratio, a marker of late severe disease. Altogether, these results reveal specialized IFN action in COVID-19, with potential diagnostic and therapeutic implications.

COVID19 is a heterogeneous medical condition involving diverse underlying pathophysiological processes including hyperinflammation, endothelial damage, thrombotic microangiopathy, and end-organ damage. Limited knowledge about the molecular mechanisms driving these processes and lack of staging biomarkers hamper the ability to stratify patients for targeted therapeutics. We report here the results of a cross-sectional multi-omics analysis of hospitalized COVID19 patients revealing that seroconversion status associates with distinct underlying pathophysiological states. Low antibody titers associate with hyperactive T cells and NK cells, high levels of IFN alpha, gamma and lambda ligands, markers of systemic complement activation, and depletion of lymphocytes, neutrophils, and platelets. Upon seroconversion, all of these processes are attenuated, observing instead increases in B cell subsets, emergency hematopoiesis, increased D-dimer, and hypoalbuminemia. We propose that seroconversion status could potentially be used as a biosignature to stratify patients for therapeutic intervention and to inform analysis of clinical trial results in heterogenous patient populations.

Trisomy 21 (T21) causes Down syndrome (DS), a condition characterized by high prevalence of autoimmune disorders. However, the molecular and cellular mechanisms driving this phenotype remain unclear. Building upon our previous finding that T cells from people with DS show increased expression of interferon (IFN)-stimulated genes, we have completed a comprehensive characterization of the peripheral T cell compartment in adults with DS with and without autoimmune conditions. CD8+ T cells from adults with DS are depleted of naïve subsets and enriched for differentiated subsets, express higher levels of markers of activation and senescence (e.g., IFN-γ, Granzyme B, PD-1, KLRG1), and overproduce cytokines tied to autoimmunity (e.g., TNF-α). Conventional CD4+ T cells display increased differentiation, polarization toward the Th1 and Th1/17 states, and overproduction of the autoimmunity-related cytokines IL-17A and IL-22. Plasma cytokine analysis confirms elevation of multiple autoimmunity-related cytokines (e.g., TNF-α, IL17A–D, IL-22) in people with DS, independent of diagnosis of autoimmunity. Although Tregs are more abundant in DS, functional assays show that CD8+ and CD4+ effector T cells with T21 are resistant to Treg-mediated suppression, regardless of Treg karyotype. Transcriptome analysis ofwhite blood cells and T cells reveals strong signatures of T cell differentiation and activation that correlate positively with IFN hyperactivity. Finally, mass cytometry analysis of 8 IFN-inducible phosphoepitopes demonstrates that T cell subsets with T21 show elevated levels of basal IFN signaling and hypersensitivity to IFN-α stimulation. Therefore, these results point to T cell dysregulation associated with IFN hyperactivity as a contributor to autoimmunity in DS.

Background/Objectives. Balance problems are well-established modifiable risk factors for falls, which are common in older adults. The objective of this study was to establish the efficacy of a Wii-Fit interactive video-game-led physical exercise program to improve balance in older Veterans. Methods. A prospective randomized controlled parallel-group trial was conducted at Veterans Affairs Medical Center. Thirty community dwelling Veterans aged 68 (±6.7) years were randomized to either the exercise or control groups. The exercise group performed Wii-Fit program while the control group performed a computer-based cognitive program for 45 minutes, three days per week for 8-weeks. The primary (Berg Balance Scale (BBS)) and secondary outcomes (fear of falling, physical activity enjoyment, and quality of life) were measured at baseline, 4 weeks, and 8 weeks. Results. Of 30 randomized subjects, 27 completed all aspects of the study protocol. There were no study-related adverse events. Intent-to-treat analysis showed a significantly greater improvement in BBS in the exercise group (6.0; 95% CI, 5.1–6.9) compared to the control group (0.5; 95% CI, −0.3–1.3) at 8 weeks (average intergroup difference (95% CI), 5.5 (4.3–6.7), p < 0.001) after adjusting for baseline. Conclusion. This study establishes that the Wii-Fit exercise program is efficacious in improving balance in community dwelling older Veterans. This trial is registered with ClinicalTrials.gov Identifier NCT02190045.

Individuals with Down syndrome (DS), the genetic condition caused by trisomy 21 (T21), display clear signs of immune dysregulation, including high rates of autoimmunity and severe complications from infections. Although it is well established that T21 causes increased interferon responses and JAK/STAT signaling, elevated autoantibodies, global immune remodeling, and hypercytokinemia, the interplay between these processes, the clinical manifestations of DS, and potential therapeutic interventions remain ill defined. We report a comprehensive analysis of immune dysregulation at the clinical, cellular, and molecular level in hundreds of individuals with DS, including autoantibody profiling, cytokine analysis, and deep immune mapping. We also report the interim analysis of a Phase II clinical trial investigating the safety and efficacy of the JAK inhibitor tofacitinib through multiple clinical and molecular endpoints. We demonstrate multi-organ autoimmunity of pediatric onset concurrent with unexpected autoantibody-phenotype associations in DS. Importantly, constitutive immune remodeling and hypercytokinemia occur from an early age prior to autoimmune diagnoses or autoantibody production. Analysis of the first 10 participants to complete 16 weeks of tofacitinib treatment shows a good safety profile and no serious adverse events. Treatment reduced skin pathology in alopecia areata, psoriasis, and atopic dermatitis, while decreasing interferon scores, cytokine scores, and levels of pathogenic autoantibodies without overt immune suppression. JAK inhibition is a valid strategy to treat autoimmune conditions in DS. Additional research is needed to define the effects of JAK inhibition on the broader developmental and clinical hallmarks of DS. NIAMS, Global Down Syndrome Foundation. NCT04246372.

Two major barriers hinder the holistic understanding of subsurface critical zone (CZ) evolution and its impacts: (a) an inability to measure, define, and share information and (b) a societal structure that inhibits inclusivity and creativity. In contrast to the aboveground portion of the CZ, which is visible and measurable, the bottom boundary is difficult to access and quantify. In the context of these barriers, we aim to expand the spatial reach of the CZ by highlighting existing and effective tools for research as well as the “human reach” of CZ science by expanding who performs such science and who it benefits. We do so by exploring the diversity of vocabularies and techniques used in relevant disciplines, defining terminology, and prioritizing research questions that can be addressed. Specifically, we explore geochemical, geomorphological, geophysical, and ecological measurements and modeling tools to estimate CZ base and thickness. We also outline the importance of and approaches to developing a diverse CZ workforce that looks like and harnesses the creativity of the society it serves, addressing historical legacies of exclusion. Looking forward, we suggest that to grow CZ science, we must broaden the physical spaces studied and their relationships with inhabitants, measure the “deep” CZ and make data accessible, and address the bottlenecks of scaling and data‐model integration. What is needed—and what we have tried to outline—are common and fundamental structures that can be applied anywhere and used by the diversity of researchers involved in investigating and recording CZ processes from a myriad of perspectives. Plain Language Summary The “critical zone” is the zone of the Earth from treetops to belowground water. It is where crops are grown, water is drawn for drinking and industry, and waste generated by humans ends up. Understanding how deep this section of the Earth is, and how it is changing, is key to being able to determine how impactful changes in land use or climate will be to human systems. That said, it is difficult to get below‐ground information, and scientists in different subfields of the Earth sciences define the depth of the critical zone differently. Here, we describe the tools and language we use to make those decisions. We also note that Earth scientists are not a diverse group, which means we miss out on the ideas, solutions, and impacts that those from historically excluded groups might have to address the big problems humans must solve. To advance critical zone science, we need to broaden the physical areas we study, access to these sites, and the inclusion and sense of belonging of people studying them. We also need to measure deep into the Earth where we can, make our data accessible, and tackle scientific obstacles in integrating data and models. Key Points CZ depth is defined by multiple processes key to human existence, yet is undermeasured and thus poorly understood Scientific jargon can make defining and communicating CZ processes difficult to stakeholders and even scientists in other fields Legacies in western science, upon which CZ science is based, can be countered to promote progress in the Earth sciences