Alum Activates the Bovine NLRP3 Inflammasome

peer-reviewedThere has been a move away from vaccines composed of whole or inactivated antigens toward subunit-based vaccines, which although safe, provide less immunological protection. As a result, the use of adjuvants to enhance and direct adaptive immune responses has become the focus of much targeted bovine vaccine research. However, the mechanisms by which adjuvants work to enhance immunological protection in many cases remains unclear, although this knowledge is critical to the rational design of effective next generation vaccines. This study aimed to investigate the mechanisms by which alum, a commonly used adjuvant in bovine vaccines, enhances IL-1β secretion in bovine peripheral blood mononuclear cells (PBMCs). Unlike the case with human PBMCs, alum promoted IL-1β secretion in a subset of bovine PBMCs without priming with a toll-like receptor agonist. This suggests that PBMCs from some cattle are primed to produce this potent inflammatory cytokine and western blotting confirmed the presence of preexisting pro-IL-1β in PBMCs from a subset of 8-month-old cattle. To address the mechanism underlying alum-induced IL-1β secretion, specific inhibitors identified that alum mediates lysosomal disruption which subsequently activates the assembly of an NLRP3, ASC, caspase-1, and potentially caspase-8 containing complex. These components form an inflammasome, which mediates alum-induced IL-1β secretion in bovine PBMCs. Given the demonstrated role of the NLRP3 inflammasome in regulating adaptive immunity in murine systems, these results will inform further targeted research into the potential of inflammasome activation for rational vaccine design in cattle

Near-Surface Density Currents Observed in the Southeast Pacific Stratocumulus-Topped Marine Boundary Layer

Density currents (i.e., cold pools or outflows) beneath marine stratocumulus clouds are characterized using 30 days of ship-based observations obtained during the 2008 Variability of American Monsoon Systems (VAMOS) Ocean–Cloud–Atmosphere–Land Study Regional Experiment (VOCALS-REx) in the southeast Pacific. An air density increase criterion applied to the Improved Meteorological (IMET) sensor data identified 71 density current front, core (peak density), and tail (dissipating) zones. The similarity in speeds of the mean density current propagation speed (1.8 m s⁻¹) and the mean cloud-level advection relative to the surface layer wind (1.9 m s⁻¹) allowed drizzle cells to deposit elongated density currents in their wakes. Scanning Doppler lidar captured prefrontal updrafts with a mean intensity of 0.91 m s⁻¹ and an average vertical extent of 800 m. Updrafts were often surmounted by low-lying shelf clouds not connected to the overlying stratocumulus cloud. The observed density currents were 5–10 times thinner and weaker than typical continental thunderstorm cold pools. Nearly 90% of density currents were identified when C-band radar estimated areal average rain rates exceeded 1 mm day⁻¹ over a 30-km diameter. Rather than peaking when rain rates were highest overnight, density current occurrence peaks between 0600 and 0800 local solar time when enhanced local drizzle co-occurred with shallow subcloud dry and stable layers. The dry layers may have contributed to density current formation by enhancing subcloud evaporation of drizzle. Density currents preferentially occurred in a large region of predominantly open cells but also occurred in regions of closed cells.This is the publisher’s final pdf. The published article is copyrighted by American Meteorological Society and can be found at: https://www2.ametsoc.org/ams/index.cfm/publications/journals/monthly-weather-review/Keywords: Density currents, Boundary layer, Drizzle, In situ atmospheric observations, Lidars/Lidar observations, Subtropic

Recommendations for a national agenda to substantially reduce cervical cancer

PURPOSE: Prophylactic human papillomavirus (HPV) vaccines and new HPV screening tests, combined with traditional Pap test screening, provide an unprecedented opportunity to greatly reduce cervical cancer in the USA. Despite these advances, thousands of women continue to be diagnosed with and die of this highly preventable disease each year. This paper describes the initiatives and recommendations of national cervical cancer experts toward preventing and possibly eliminating this disease. METHODS: In May 2011, Cervical Cancer-Free America, a national initiative, convened a cervical cancer summit in Washington, DC. Over 120 experts from the public and private sector met to develop a national agenda for reducing cervical cancer morbidity and mortality in the USA. RESULTS: Summit participants evaluated four broad challenges to reducing cervical cancer: (1) low use of HPV vaccines, (2) low use of cervical cancer screening, (3) screening errors, and (4) lack of continuity of care for women diagnosed with cervical cancer. The summit offered 12 concrete recommendations to guide future national and local efforts toward this goal. CONCLUSIONS: Cervical cancer incidence and mortality can be greatly reduced by better deploying existing methods and systems. The challenge lies in ensuring that the array of available prevention options are accessible and utilized by all age-appropriate women-particularly minority and underserved women who are disproportionately affected by this disease. The consensus was that cervical cancer can be greatly reduced and that prevention efforts can lead the way towards a dramatic reduction in this preventable disease in our country

Making sense of frailty: An ethnographic study of the experience of older people living with complex health problems

Aim: To explore how older people with complex health problems experience frailty in their daily lives. Background: A better understanding of the personal experience of frailty in the context of fluctuating ill-health has the potential to contribute to the development of personalised approaches to care planning and delivery. Design: An ethnographic study of older people, living at home, receiving support from a community matron service in a large city in the North of England. Methods: Up to six care encounters with each of ten older people, and their community matron, were observed at monthly intervals, over a period of time ranging from four to eleven months. Semi-structured interviews were conducted with the older participants in their own homes. Fieldwork took place over a four-year period. Data analysis was undertaken using the constant comparative method. Findings: The experience of frailty was understood through the construction of four themes: Fluctuating ill-health and the disruption of daily living; Changes to the management of daily living; Frailty as fear, anxiety and uncertainty; Making sense of changes to health and daily living. Conclusions: Older people work hard to shape and maintain daily routines in the context of complicated and enduring transitions in health and illness. However, they experience episodic moments of frailty, often articulated as uncertainty, where daily living becomes precarious and their resilience is threatened. Developing an understanding of the personal experiences of frail older people in the context of transition has the potential to inform nursing practice in person centred care

Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD.

BACKGROUND: Germline pathogenic variants in SDHB/SDHC/SDHD are the most frequent causes of inherited phaeochromocytomas/paragangliomas. Insufficient information regarding penetrance and phenotypic variability hinders optimum management of mutation carriers. We estimate penetrance for symptomatic tumours and elucidate genotype-phenotype correlations in a large cohort of SDHB/SDHC/SDHD mutation carriers. METHODS: A retrospective survey of 1832 individuals referred for genetic testing due to a personal or family history of phaeochromocytoma/paraganglioma. 876 patients (401 previously reported) had a germline mutation in SDHB/SDHC/SDHD (n=673/43/160). Tumour risks were correlated with in silico structural prediction analyses. RESULTS: Tumour risks analysis provided novel penetrance estimates and genotype-phenotype correlations. In addition to tumour type susceptibility differences for individual genes, we confirmed that the SDHD:p.Pro81Leu mutation has a distinct phenotype and identified increased age-related tumour risks with highly destabilising SDHB missense mutations. By Kaplan-Meier analysis, the penetrance (cumulative risk of clinically apparent tumours) in SDHB and (paternally inherited) SDHD mutation-positive non-probands (n=371/67 with detailed clinical information) by age 60 years was 21.8% (95% CI 15.2% to 27.9%) and 43.2% (95% CI 25.4% to 56.7%), respectively. Risk of malignant disease at age 60 years in non-proband SDHB mutation carriers was 4.2%(95% CI 1.1% to 7.2%). With retrospective cohort analysis to adjust for ascertainment, cumulative tumour risks for SDHB mutation carriers at ages 60 years and 80 years were 23.9% (95% CI 20.9% to 27.4%) and 30.6% (95% CI 26.8% to 34.7%). CONCLUSIONS: Overall risks of clinically apparent tumours for SDHB mutation carriers are substantially lower than initially estimated and will improve counselling of affected families. Specific genotype-tumour risk associations provides a basis for novel investigative strategies into succinate dehydrogenase-related mechanisms of tumourigenesis and the development of personalised management for SDHB/SDHC/SDHD mutation carriers

Methodological Issues in Ethnic and Racial Identity Research With Ethnic Minority Populations: Theoretical Precision, Measurement Issues, and Research Designs

This article takes stock of research methods employed in the study of racial and ethnic identity with ethnic minority populations. The article is presented in three parts. The first section reviews theories, conceptualizations, and measurement of ethnic and racial identity (ERI) development. The second section reviews theories, conceptualizations, and measurement of ERI content. The final section reviews key methodological and analytic principles that are important to consider for both ERI development and content. The article concludes with suggestions for future research addressing key methodological limitations when studying ERI

Bone marrow niche trafficking of miR-126 controls the self-renewal of leukemia stem cells in chronic myelogenous leukemia

Leukemia stem cells (LSCs) in individuals with chronic myelogenous leukemia (CML) (hereafter referred to as CML LSCs) are responsible for initiating and maintaining clonal hematopoiesis. These cells persist in the bone marrow (BM) despite effective inhibition of BCR–ABL kinase activity by tyrosine kinase inhibitors (TKIs). Here we show that although the microRNA (miRNA) miR-126 supported the quiescence, self-renewal and engraftment capacity of CML LSCs, miR-126 levels were lower in CML LSCs than in long-term hematopoietic stem cells (LT-HSCs) from healthy individuals. Downregulation of miR-126 levels in CML LSCs was due to phosphorylation of Sprouty-related EVH1-domain-containing 1 (SPRED1) by BCR–ABL, which led to inhibition of the RAN–exportin-5–RCC1 complex that mediates miRNA maturation. Endothelial cells (ECs) in the BM supply miR-126 to CML LSCs to support quiescence and leukemia growth, as shown using mouse models of CML in which Mir126a (encoding miR-126) was conditionally knocked out in ECs and/or LSCs. Inhibition of BCR–ABL by TKI treatment caused an undesired increase in endogenous miR-126 levels, which enhanced LSC quiescence and persistence. Mir126a knockout in LSCs and/or ECs, or treatment with a miR-126 inhibitor that targets miR-126 expression in both LSCs and ECs, enhanced the in vivo anti-leukemic effects of TKI treatment and strongly diminished LSC leukemia-initiating capacity, providing a new strategy for the elimination of LSCs in individuals with CML

Exploring Predictors of Outcome in the Psychosis Prodrome: Implications for Early Identification and Intervention

Functional disability is a key component of many psychiatric illnesses, particularly schizophrenia. Impairments in social and role functioning are linked to cognitive deficits, a core feature of psychosis. Retrospective analyses demonstrate that substantial functional decline precedes the onset of psychosis. Recent investigations reveal that individuals at clinical-high-risk (CHR) for psychosis show impairments in social relationships, work/school functioning and daily living skills. CHR youth also demonstrate a pattern of impairment across a range of cognitive domains, including social cognition, which is qualitatively similar to that of individuals with schizophrenia. While many studies have sought to elucidate predictors of clinical deterioration, specifically the development of schizophrenia, in such CHR samples, few have investigated factors relevant to psychosocial outcome. This review integrates recent findings regarding cognitive and social-cognitive predictors of outcome in CHR individuals, and proposes potential directions for future research that will contribute to targeted interventions and improved outcome for at-risk youth