The telomerase essential N-terminal domain promotes DNA synthesis by stabilizing short RNA-DNA hybrids.

Telomerase is an enzyme that adds repetitive DNA sequences to the ends of chromosomes and consists of two main subunits: the telomerase reverse transcriptase (TERT) protein and an associated telomerase RNA (TER). The telomerase essential N-terminal (TEN) domain is a conserved region of TERT proposed to mediate DNA substrate interactions. Here, we have employed single molecule telomerase binding assays to investigate the function of the TEN domain. Our results reveal telomeric DNA substrates bound to telomerase exhibit a dynamic equilibrium between two states: a docked conformation and an alternative conformation. The relative stabilities of the docked and alternative states correlate with the number of basepairs that can be formed between the DNA substrate and the RNA template, with more basepairing favoring the docked state. The docked state is further buttressed by the TEN domain and mutations within the TEN domain substantially alter the DNA substrate structural equilibrium. We propose a model in which the TEN domain stabilizes short RNA-DNA duplexes in the active site of the enzyme, promoting the docked state to augment telomerase processivity

Using Innovation-Corps (I-Corps™) methods to adapt a mobile health (mHealth) obesity treatment for community mental health settings

BACKGROUND: We employed Innovation Corps (I-Corps™) methods to adaptation of a mobile health (mHealth) short-message-system (SMS) -based interactive obesity treatment approach (iOTA) for adults with severe mentall illness receiving care in community settings. METHODS: We hypothesized jobs to be done in three broad stakeholder groups: decision makers (DM = state and community clinic administrators), clinician consumers (CC = case managers, peer supports, nurses, prescribers) and service consumers (SC = patients, peers and family members). Semistructured interviews ( RESULTS: Four themes emerged across groups: education, inertia, resources and ownership. Sub-themes in education and ownership differed between DM and CC groups on implementation ownership, intersecting with professional development, suggesting the importance of training and supervision in scalability. Sub-themes in resources and intertia differed between CC and SC groups, suggesting illness severity and access to healthy food as major barriers to engagement, whereas the SC group identified the need for enhanced emotional support, in addition to pragmatic skills like menu planning and cooking, to promote health behavior change. Although SMS was percieved as a viable education and support tool, CC and DM groups had limited familiarity with use in clinical care delivery. CONCLUSIONS: Based on customer discovery, the characteristics of a minimum viable iOTA for implementation, scalability and sustainability include population- and context-specific adaptations to treatment content, interventionist training and delivery mechanism. Successful implementation of an SMS-based intervention will likely require micro-adaptations to fit specific clinical settings

Linewidth of single photon transitions in Mn12_{12}-acetate

We use time-domain terahertz spectroscopy to measure the position and linewidth of single photon transitions in Mn$_{12}$-acetate. This linewidth is compared to the linewidth measured in tunneling experiments. We conclude that local magnetic fields (due to dipole or hyperfine interactions) cannot be responsible for the observed linewidth, and suggest that the linewidth is due to variations in the anisotropy constants for different clusters. We also calculate a lower limit on the dipole field distribution that would be expected due to random orientations of clusters and find that collective effects must narrow this distribution in tunneling measurements.Comment: 5 pages, accepted to Physical Review

Adaptation of a mobile interactive obesity treatment approach for early severe mental illness: Protocol for a mixed methods implementation and pilot randomized controlled trial

BACKGROUND: Obesity is common in individuals with severe mental illness (SMI), contributing to a significantly shortened lifespan when compared to the general population. Available weight loss treatments have attenuated efficacy in this population, underscoring the importance of prevention and early intervention. OBJECTIVE: Here, we describe a type 1 hybrid study design for adapting and pilot-testing an existing mobile health intervention for obesity prevention in individuals with early SMI and Class I or early-stage obesity, defined as a BMI of 30-35. METHODS: An existing, evidence-based interactive obesity treatment approach using low-cost, semiautomated SMS text messaging was selected for adaptation. Community mental health clinics and Clubhouse settings in Eastern Missouri and South Florida were identified to participate. This study has the following 3 aims. First, using the Enhanced Framework for Reporting Adaptations and Modifications to Evidence-based interventions, contextual aspects of the clinical and digital treatment environments are identified for adaptation, considering 5 main stakeholder groups (clinical administrators, prescribing clinicians, case managers, nurses, and patients). Following a 2-week trial of unadapted SMS text messaging, Innovation Corps methods are used to discover needed intervention adaptations by stakeholder group and clinical setting. Second, adaptations to digital functionality and intervention content will be made based on themes identified in aim 1, followed by rapid usability testing with key stakeholders. A process for iterative treatment adaptation will be developed for making unplanned modifications during the aim 3 implementation pilot study. Individuals working in partner community mental health clinics and Clubhouse settings will be trained in intervention delivery. Third, in a randomized pilot and feasibility trial, adults with 5 years or less of treatment for an SMI diagnosis will be randomized 2:1 to 6 months of an adapted interactive obesity treatment approach or to an attentional control condition, followed by a 3-month extension phase of SMS text messages only. Changes in weight, BMI, and behavioral outcomes, as well as implementation challenges, will be evaluated at 6 and 9 months. RESULTS: Institutional review board approval for aims 1 and 2 was granted on August 12, 2018, with 72 focus group participants enrolled; institutional review board approval for aim 3 was granted on May 6, 2020. To date, 52 participants have been enrolled in the study protocol. CONCLUSIONS: In this type 1 hybrid study design, we apply an evidence-based treatment adaptation framework to plan, adapt, and feasibility test a mobile health intervention in real-world treatment settings. Resting at the intersection of community mental health treatment and physical health promotion, this study aims to advance the use of simple technology for obesity prevention in individuals with early-stage mental illness. TRIAL REGISTRATION: ClinicalTrials.gov NCT03980743; https://clinicaltrials.gov/ct2/show/NCT03980743. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/42114

'To live and die [for] Dixie': Irish civilians and the Confederate States of America

Around 20,000 Irishmen served in the Confederate army in the Civil War. As a result, they left behind, in various Southern towns and cities, large numbers of friends, family, and community leaders. As with native-born Confederates, Irish civilian support was crucial to Irish participation in the Confederate military effort. Also, Irish civilians served in various supporting roles: in factories and hospitals, on railroads and diplomatic missions, and as boosters for the cause. They also, however, suffered in bombardments, sieges, and the blockade. Usually poorer than their native neighbours, they could not afford to become 'refugees' and move away from the centres of conflict. This essay, based on research from manuscript collections, contemporary newspapers, British Consular records, and Federal military records, will examine the role of Irish civilians in the Confederacy, and assess the role this activity had on their integration into Southern communities. It will also look at Irish civilians in the defeat of the Confederacy, particularly when they came under Union occupation. Initial research shows that Irish civilians were not as upset as other whites in the South about Union victory. They welcomed a return to normalcy, and often 'collaborated' with Union authorities. Also, Irish desertion rates in the Confederate army were particularly high, and I will attempt to gauge whether Irish civilians played a role in this. All of the research in this paper will thus be put in the context of the Drew Gilpin Faust/Gary Gallagher debate on the influence of the Confederate homefront on military performance. By studying the Irish civilian experience one can assess how strong the Confederate national experiment was. Was it a nation without a nationalism

Outcomes in patients with gunshot wounds to the brain.

Introduction:Gunshot wounds to the brain (GSWB) confer high lethality and uncertain recovery. It is unclear which patients benefit from aggressive resuscitation, and furthermore whether patients with GSWB undergoing cardiopulmonary resuscitation (CPR) have potential for survival or organ donation. Therefore, we sought to determine the rates of survival and organ donation, as well as identify factors associated with both outcomes in patients with GSWB undergoing CPR. Methods:We performed a retrospective, multicenter study at 25 US trauma centers including dates between June 1, 2011 and December 31, 2017. Patients were included if they suffered isolated GSWB and required CPR at a referring hospital, in the field, or in the trauma resuscitation room. Patients were excluded for significant torso or extremity injuries, or if pregnant. Binomial regression models were used to determine predictors of survival/organ donation. Results:825 patients met study criteria; the majority were male (87.6%) with a mean age of 36.5 years. Most (67%) underwent CPR in the field and 2.1% (n=17) survived to discharge. Of the non-survivors, 17.5% (n=141) were considered eligible donors, with a donation rate of 58.9% (n=83) in this group. Regression models found several predictors of survival. Hormone replacement was predictive of both survival and organ donation. Conclusion:We found that GSWB requiring CPR during trauma resuscitation was associated with a 2.1% survival rate and overall organ donation rate of 10.3%. Several factors appear to be favorably associated with survival, although predictions are uncertain due to the low number of survivors in this patient population. Hormone replacement was predictive of both survival and organ donation. These results are a starting point for determining appropriate treatment algorithms for this devastating clinical condition. Level of evidence:Level II

Rheumatic Heart Disease-Attributable Mortality at Ages 5-69 Years in Fiji: A Five-Year, National, Population-Based Record-Linkage Cohort Study.

BACKGROUND: Rheumatic heart disease (RHD) is considered a major public health problem in developing countries, although scarce data are available to substantiate this. Here we quantify mortality from RHD in Fiji during 2008-2012 in people aged 5-69 years. METHODS AND FINDINGS: Using 1,773,999 records derived from multiple sources of routine clinical and administrative data, we used probabilistic record-linkage to define a cohort of 2,619 persons diagnosed with RHD, observed for all-cause mortality over 11,538 person-years. Using relative survival methods, we estimated there were 378 RHD-attributable deaths, almost half of which occurred before age 40 years. Using census data as the denominator, we calculated there were 9.9 deaths (95% CI 9.8-10.0) and 331 years of life-lost (YLL, 95% CI 330.4-331.5) due to RHD per 100,000 person-years, standardised to the portion of the WHO World Standard Population aged 0-69 years. Valuing life using Fiji's per-capita gross domestic product, we estimated these deaths cost United States Dollar $6,077,431 annually. Compared to vital registration data for 2011-2012, we calculated there were 1.6-times more RHD-attributable deaths than the number reported, and found our estimate of RHD mortality exceeded all but the five leading reported causes of premature death, based on collapsed underlying cause-of-death diagnoses. CONCLUSIONS: Rheumatic heart disease is a leading cause of premature death as well as an important economic burden in this setting. Age-standardised death rates are more than twice those reported in current global estimates. Linkage of routine data provides an efficient tool to better define the epidemiology of neglected diseases