Ubiquitination and proteasomal degradation of ATG12 regulates its proapoptotic activity

During macroautophagy, conjugation of ATG12 to ATG5 is essential for LC3 lipidation and autophagosome formation. Additionally, ATG12 has ATG5-independent functions in diverse processes including mitochondrial fusion and mitochondrial-dependent apoptosis. In this study, we investigated the regulation of free ATG12. In stark contrast to the stable ATG12–ATG5 conjugate, we find that free ATG12 is highly unstable and rapidly degraded in a proteasome-dependent manner. Surprisingly, ATG12, itself a ubiquitin-like protein, is directly ubiquitinated and this promotes its proteasomal degradation. As a functional consequence of its turnover, accumulation of free ATG12 contributes to proteasome inhibitor-mediated apoptosis, a finding that may be clinically important given the use of proteasome inhibitors as anticancer agents. Collectively, our results reveal a novel interconnection between autophagy, proteasome activity, and cell death mediated by the ubiquitin-like properties of ATG12

Mediation of nitrogen by post-disturbance shelf communities experiencing organic matter enrichment

Microbes and benthic macro-invertebrates interact in sediments to play a major role in the biogeochemical cycling of organic matter, but the extent to which their contributions are modified following natural and anthropogenic changes has received little attention. Here, we investigate how nitrogen transformations, ascertained from changes in archaeal and bacterial N-cycling microbes and water macronutrient concentrations ([NH4–N], [NO2–N], [NO3–N]), in sand and sandy mud sediments differ when macrofaunal communities that have previously experienced contrasting levels of chronic fishing disturbance are exposed to organic matter enrichment. We find that differences in macrofaunal community structure related to differences in fishing activity affect the capacity of the macrofauna to mediate microbial nitrogen cycling in sand, but not in sandy mud environments. Whilst we found no evidence for a change in ammonia oxidiser community structure, we did find an increase in archaeal and bacterial denitrifier (AnirKa, nirS) and anammox (hzo) transcripts in macrofaunal communities characterized by higher ratios of suspension to deposit feeders, and a lower density but higher biomass of sediment-reworking fauna. Our findings suggest that nitrogen transformation in shelf sandy sediments is dependent on the stimulation of specific nitrogen cycling pathways that are associated with differences in the composition and context-dependent expression of the functional traits that belong to the resident bioturbating macrofauna community

The history of disaster nursing: from Nightingale to nursing in the 21st century

Background: Nurses have a rich history in performing their duty both domestically and internationally in response to a disaster. Comprising the largest proportion of the healthcare workforce, nurses possess a unique opportunity to inform disaster planning and management. With the ongoing threat from COVID-19 and continuing conflict, humanitarian aid needs, epidemics and natural disasters; the capacity of nurses to continue to respond in times of global need is unparalleled. Aims: The aim of this paper is to explore the developments in the field of disaster nursing. Mapping key changes in policy, practice and outcomes. Methods: A qualitative interpretive historical review was conducted to examine core developments in the history of disaster nursing, examining key organisations (e.g. World Health Organization, International Council of Nurses), national and international policies and historical accounts. Results: 29 articles were analysed, and politics, strategic perspectives and nursing identity (‘sense of duty’ and roles) emerged from the literature. The influence of professionalisation and public health/health promotion emerged next. A total of 10 articles refer to disaster nursing specifically, of which 4 of these are reports/policy. Conclusions: Nurses have spent centuries building the trust and legitimacy of the profession. Disaster nursing goes beyond the expectations of a registered nurse. The responsibilities of a disaster nurse encompass wider community health promotion, critical decision-making beyond the individual patient, resilience and ethical challenges. Whilst significant advancements have emerged in the last 30 years, further research, and representation of the profession at a strategic and political level could enhance the effectiveness of nurses’ roles in the 4 phases of disaster response: mitigation, preparation, response and recovery

Advancing a National Agenda to Eliminate Disparities in Pain Care: Directions for Health Policy, Education, Practice, and Research

Abstract available at publisher's web site

Prevalence of Mycobacterium tuberculosis infection as measured by the QuantiFERON-TB Gold assay and ESAT-6 free IGRA among adolescents in Mwanza, Tanzania

Background The prevalence of latent tuberculosis infection (LTBI) is vastly higher than that of tuberculosis (TB) disease and this enormous reservoir of individuals with LTBI impacts the global TB control strategy. Adolescents are at greatest risk of TB infection and are thus an ideal target population for a potential effective TB vaccine to be added to the current BCG programme as it could reduce the number of latent infections and consequently the number of adults with TB disease. However, LTBI rates are often unknown for this population. This study aims to estimate the magnitude of LTBI and to determine if Tanzanian adolescents would be a good population for a prevention of TB infection trial. Methods This was a descriptive cross-sectional study that recruited 193 adolescents aged 12 and 16 years from government schools and directly from the community in Mwanza Region, Tanzania. Socio-demographic characteristics were collected for all enrolled participants. Blood was drawn and tested using QuantiFERON-TB Gold In-Tube (QFT-GIT), and Early Secretory Antigenic Target-6–Free Interferon-gamma Release Assay (ESAT-6 free IGRA). Concordance between QFT-GIT and ESAT-6 free IGRA was evaluated using the McNemar’s test. Results Overall estimates of LTBI prevalence were 19.2% [95%CI, 14.1; 25.2] and 18.6% [95%CI, 13.6; 24.6] as measured by QFT-GIT IGRA and ESAT-6 free IGRA, respectively. The 16-year-old cohort had a higher LTBI prevalence (23.7% [95%CI, 16.1; 32.9]) as compared to 12-year-old cohort (14.6% [95%CI, 8.6; 22.7]) as measured by QFT-GIT IGRA. When measured by ESAT-6 Free IGRA, LTBI prevalence was 24.7% (95%CI, 16.9; 34.0) for the 16-year-old cohort and 12.5% (95%CI, 7.0; 20.3) among the 12-year-old cohort. According to both tests the prevalence of TB infection and the corresponding annual risk of tuberculosis infection (ARTI) and force of infection were high and increased with age. Of all enrolled participants, 97.4% had concordant results for QFT-GIT IGRA and ESAT-6 free IGRA (p = 0.65). Conclusions The prevalence of LTBI and the associated ARTI and force of infection among adolescents is high and increases with age in Mwanza Region. There was a high concordance between the QFT-GIT and the novel ESAT-6 free IGRA assays. These findings suggest Mwanza is a promising area to conduct novel TB vaccine research prevention of infection (POI) studies targeting adolescents.publishedVersio

Development and Piloting of a Novel Evaluation Tool for Childhood Obesity Prevention Programs

Childhood obesity remains chronic and high in the U.S., driven by factors including poor dietary habits and lack of physical activity. Interventions that address multiple causal factors may be the most appropriate strategy to address rising childhood obesity rates. The Cooperative Extension Service offers programs across the country to address causal factors of childhood obesity, but few coordinated or concerted efforts have been made to determine overlap, reduce duplication, or identify best practices in programming. To fill this gap, the National Institute of Food and Agriculture Multistate Project W3005 Extension Workgroup sought to develop a novel tool to compare programs with components related to childhood obesity prevention. This manuscript details the iterative process used to develop the Childhood Obesity Prevention Program in Extension Rubric (COPPER), provides findings from the pilot process, and reveals the broad application and potential of this tool within Extension and nutrition education. The newly developed COPPER tool is multi-functional and may be beneficial in program development, implementation, adoption, and/or adaptation of programs in new settings. This tool will be useful for Extension, public health, and other community organizations focused on issues central to childhood obesity targeting children, parents, and/or caregivers

Mitotic stress is an integral part of the oncogene-induced senescence program that promotes multinucleation and cell cycle arrest

Oncogene-induced senescence (OIS) is a tumor suppression mechanism that blocks cell proliferation in response to oncogenic signaling. OIS is frequently accompanied by multinucleation; however, the origin of this is unknown. Here, we show that multinucleate OIS cells originate mostly from failed mitosis. Prior to senescence, mutant H-RasV12 activation in primary human fibroblasts compromised mitosis, concordant with abnormal expression of mitotic genes functionally linked to the observed mitotic spindle and chromatin defects. Simultaneously, H-RasV12 activation enhanced survival of cells with damaged mitoses, culminating in extended mitotic arrest and aberrant exit from mitosis via mitotic slippage. ERK-dependent transcriptional upregulation of Mcl1 was, at least in part, responsible for enhanced survival and slippage of cells with mitotic defects. Importantly, mitotic slippage and oncogene signaling cooperatively induced senescence and key senescence effectors p21 and p16. In summary, activated Ras coordinately triggers mitotic disruption and enhanced cell survival to promote formation of multinucleate senescent cells

Mitochondrial permeabilization engages NF-κB-dependent anti-tumour activity under caspase deficiency

Apoptosis represents a key anti-cancer therapeutic effector mechanism. During apoptosis, mitochondrial outer membrane permeabilization (MOMP) typically kills cells even in the absence of caspase activity. Caspase activity can also have a variety of unwanted consequences that include DNA damage. We therefore investigated whether MOMP-induced caspase-independent cell death (CICD) might be a better way to kill cancer cells. We find that cells undergoing CICD display potent pro-inflammatory effects relative to apoptosis. Underlying this, MOMP was found to stimulate NF-κB activity through the downregulation of inhibitor of apoptosis proteins. Strikingly, engagement of CICD displays potent anti-tumorigenic effects, often promoting complete tumour regression in a manner dependent on intact immunity. Our data demonstrate that by activating NF-κB, MOMP can exert additional signalling functions besides triggering cell death. Moreover, they support a rationale for engaging caspase-independent cell death in cell-killing anti-cancer therapies