DNA sensor-associated type I interferon signaling is increased in ulcerative colitis and induces JAK-dependent inflammatory cell death in colonic organoids.

DNA sensor pathways can initiate inflammasome, cell death, and type I interferon (IFN) signaling in immune-mediated inflammatory diseases (IMIDs), including type I interferonopathies. We investigated the involvement of these pathways in the pathogenesis of ulcerative colitis (UC) by analyzing the expression of DNA sensor, inflammasome, and type I IFN biomarker genes in colonic mucosal biopsy tissue from control (n = 31), inactive UC (n = 31), active UC (n = 33), and a UC single-cell RNA-Seq dataset. The effects of type I IFN (IFN-ß), IFN-γ, and TNF-α on gene expression, cytokine production, and cell death were investigated in human colonic organoids. In organoids treated with cytokines alone, or in combination with NLR family pyrin domain-containing 3 (NLRP3), caspase, or JAK inhibitors, cell death was measured, and supernatants were assayed for IL-1ß/IL-18/CXCL10. The expression of DNA sensor pathway genes-PYHIN family members [absent in melanoma 2 (AIM2), IFI16, myeloid cell nuclear differentiation antigen (MNDA), and pyrin and HIN domain family member 1 (PYHIN1)- as well as Z-DNA-binding protein 1 (ZBP1), cyclic GMP-AMP synthase (cGAS), and DDX41 was increased in active UC and expressed in a cell type-restricted pattern. Inflammasome genes (CASP1, IL1B, and IL18), type I IFN inducers [stimulator of interferon response cGAMP interactor 1 (STING), TBK1, and IRF3), IFNB1, and type I IFN biomarker genes (OAS2, IFIT2, and MX2) were also increased in active UC. Cotreatment of organoids with IFN-ß or IFN-γ in combination with TNFα increased expression of IFI16, ZBP1, CASP1, cGAS, and STING induced cell death and IL-1ß/IL-18 secretion. This inflammatory cell death was blocked by the JAK inhibitor tofacitinib but not by inflammasome or caspase inhibitors. Increased type I IFN activity may drive elevated expression of DNA sensor genes and JAK-dependent but inflammasome-independent inflammatory cell death of colonic epithelial cells in UC.NEW & NOTEWORTHY This study found that patients with active UC have significantly increased colonic gene expression of cytosolic DNA sensor, inflammasome, STING, and type I IFN signaling pathways. The type I IFN, IFN-ß, in combination with TNF-α induced JAK-dependent but NLRP3 and inflammasome-independent inflammatory cell death of colonic organoids. This novel inflammatory cell death phenotype is relevant to UC immunopathology and may partially explain the efficacy of the JAKinibs tofacitinib and upadacitinib in patients with UC.

Interprofessional grant writing seminar for early career faculty in a small, isolated teaching center.

Small, isolated teaching centers have difficulty mentoring interprofessional junior faculty in research methods and grant writing. Peer mentoring programs for grant writing at larger institutions have been successful. In this short report, we describe our program that leveraged mentor experience using four framing seminars followed by project refinement in three-person peer groups and monthly mentored works in progress meetings. In its first year, ten faculty from medicine, psychology, and pharmacy completed the program and successfully obtained six funded grants. Five of the projects transitioned from single profession applications to interprofessional applications as participants connected and profession-specific expertise was identified. Refinements for future cohorts are discussed.

The Incidence of Diabetic Ketoacidosis During "Emerging Adulthood" in the USA and Canada: a Population-Based Study.

BACKGROUND: As children with diabetes transition to adulthood, they may be especially vulnerable to diabetic ketoacidosis (DKA). Cross-national comparisons may inform efforts to avoid this complication. OBJECTIVE: To compare DKA hospitalization rates in the USA and Manitoba, Canada, during the vulnerable years known as "emerging adulthood." DESIGN: Cross-sectional study using inpatient administrative databases in the USA (years 1998-2014) and Manitoba, Canada (years 2003-2013). PARTICIPANTS: Individuals aged 12-30 years hospitalized with DKA, identified using ICD-9 (USA) or ICD-10 codes (Manitoba). MAIN MEASURES: DKA hospitalization rates per 10,000 population by age (with a focus on those aged 15-17 vs. 19-21). Admissions were characterized by gender, socioeconomic status, year of hospitalization, and mortality during hospitalization. KEY RESULTS: The DKA rate was slightly higher in the USA among those aged 15-17: 4.8 hospitalizations/10,000 population vs. 3.7/10,000 in Manitoba. Among those aged 19-21, the DKA hospitalization rate rose 90% in the USA to 9.2/10,000, vs. 23% in Manitoba, to 4.5/10,000. In both the USA and Manitoba, rates were higher among those from poorer areas, and among adolescent girls compared with adolescent boys. DKA admissions rose gradually during the period under study in the USA, but not in Manitoba. CONCLUSIONS: In years of "emerging adulthood," the Canadian healthcare system appears to perform better than that of the USA in preventing hospitalizations for DKA. Although many factors likely contribute to this difference, universal and seamless coverage over the lifespan in Canada may contribute.

The Effects of Household Medical Expenditures on Income Inequality in the United States.

OBJECTIVES: To assess the effect of households' outlays for medical expenditures on income inequality and changes since the implementation of the Affordable Care Act (ACA). METHODS: We analyzed data from the US Current Population Surveys for calendar years 2010 through 2014. We calculated the Gini index of income inequality before and after subtracting households' medical outlays (including insurance premiums and out-of-pocket costs) from income, the financial burden of medical outlays for each income decile, and the number of individuals pushed below poverty by medical outlays. RESULTS: In 2014, the Gini index was 47.84, which rose to 49.21 after medical outlays were subtracted, indicating that medical outlays effectively redistributed about 1.37% of total income from poorer to richer individuals, a slightly smaller redistribution compared with the years before the ACA. Medical outlays reduced the median income of the poorest decile by 47.6% versus 2.7% for the wealthiest decile and pushed 7.013 million individuals into poverty. CONCLUSIONS: The way we finance medical care exacerbates income inequality and impoverishes millions of Americans. This regressive financing pattern improved minimally in the wake of the ACA.

Modelling Robust Feedback Control Mechanisms That Ensure Reliable Coordination of Histone Gene Expression with DNA Replication.

Histone proteins are key elements in the packing of eukaryotic DNA into chromosomes. A little understood control system ensures that histone gene expression is balanced with DNA replication so that histone proteins are produced in appropriate amounts. Disturbing or disrupting this system affects genome stability and gene expression, and has detrimental consequences for human development and health. It has been proposed that feedback control involving histone proteins contributes to this regulation and there is evidence implicating cell cycle checkpoint molecules activated when DNA synthesis is impaired in this control. We have developed mathematical models that incorporate these control modes in the form of inhibitory feedback of histone gene expression from free histone proteins, and alternatively a direct link that couples histone RNA synthesis to DNA synthesis. Using our experimental evidence and related published data we provide a simplified description of histone protein synthesis during S phase. Both models reproduce the coordination of histone gene expression with DNA replication during S phase and the down-regulation of histone RNA when DNA synthesis is interrupted, but only the model incorporating histone protein feedback control was able to effectively simulate the coordinate expression of a simplified histone gene family. Our combined theoretical and experimental approach supports the hypothesis that the regulation of histone gene expression involves feedback control.

Access to Care and Chronic Disease Outcomes Among Medicaid-Insured Persons Versus the Uninsured.

OBJECTIVES: We sought to determine the association between Medicaid coverage and the receipt of appropriate clinical care. METHODS: Using the 1999 to 2012 National Health and Nutritional Examination Surveys, we identified adults aged 18 to 64 years with incomes below the federal poverty level, and compared outpatient visit frequency, awareness, and control of chronic diseases between the uninsured (n = 2975) and those who had Medicaid (n = 1485). RESULTS: Respondents with Medicaid were more likely than the uninsured to have at least 1 outpatient physician visit annually, after we controlled for patient characteristics (odds ratio [OR] = 5.0; 95% confidence interval [CI] = 3.8, 6.6). Among poor persons with evidence of hypertension, Medicaid coverage was associated with greater awareness (OR = 1.83; 95% CI = 1.26, 2.66) and control (OR = 1.69; 95% CI = 1.32, 2.27) of their condition. Medicaid coverage was also associated with awareness of being overweight (OR = 1.30; 95% CI = 1.02, 1.67), but not with awareness or control of diabetes or hypercholesterolemia. CONCLUSIONS: Among poor adults nationally, Medicaid coverage appears to facilitate outpatient physician care and to improve blood pressure control.

Circadian desynchronization of core body temperature and sleep stages in the rat.

Proper functioning of the human circadian timing system is crucial to physical and mental health. Much of what we know about this system is based on experimental protocols that induce the desynchronization of behavioral and physiological rhythms within individual subjects, but the neural (or extraneural) substrates for such desynchronization are unknown. We have developed an animal model of human internal desynchrony in which rats are exposed to artificially short (22-h) light-dark cycles. Under these conditions, locomotor activity, sleep-wake, and slow-wave sleep (SWS) exhibit two rhythms within individual animals, one entrained to the 22-h light-dark cycle and the other free-running with a period >24 h (tau(>24 h)). Whereas core body temperature showed two rhythms as well, further analysis indicates this variable oscillates more according to the tau(>24 h) rhythm than to the 22-h rhythm, and that this oscillation is due to an activity-independent circadian regulation. Paradoxical sleep (PS), on the other hand, shows only one free-running rhythm. Our results show that, similarly to humans, (i) circadian rhythms can be internally dissociated in a controlled and predictable manner in the rat and (ii) the circadian rhythms of sleep-wake and SWS can be desynchronized from the rhythms of PS and core body temperature within individual animals. This model now allows for a deeper understanding of the human timekeeping mechanism, for testing potential therapies for circadian dysrhythmias, and for studying the biology of PS and SWS states in a neurologically intact model.