An Interstellar Conduction Front Within a Wolf-Rayet Ring Nebula Observed with the GHRS

With the High Resolution Spectrograph aboard the Hubble Space Telescope we obtained high signal-to-noise (S/N > 200 - 600 per 17 km/s resolution element) spectra of narrow absorption lines toward the Wolf-Rayet star HD 50896. The ring nebula S308 that surrounds this star is thought to be caused by a pressure-driven bubble bounded by circumstellar gas (most likely from a red supergiant or luminous blue variable progenitor) pushed aside by a strong stellar wind. Our observation has shown for the first time that blueshifted (approximately 70 km/s relative to the star) absorption components of C IV and N V arise in a conduction front between the hot interior of the bubble and the cold shell of swept-up material. These lines set limits on models of the conduction front. Nitrogen in the shell appears to be overabundant by a factor ~10. The P Cygni profiles of N V and C IV are variable, possibly due to a suspected binary companion to HD 50896.Comment: 32 pages, Latex, to appear in the Astrophysical Journal, April, 199

Human candidate gene polymorphisms and risk of severe malaria in children in Kilifi, Kenya: a case-control association study

Background: Human genetic factors are important determinants of malaria risk. We investigated associations between multiple candidate polymorphisms—many related to the structure or function of red blood cells—and risk for severe Plasmodium falciparum malaria and its specific phenotypes, including cerebral malaria, severe malaria anaemia, and respiratory distress. Methods: We did a case-control study in Kilifi County, Kenya. We recruited as cases children presenting with severe malaria to the high-dependency ward of Kilifi County Hospital. We included as controls infants born in the local community between Aug 1, 2006, and Sept 30, 2010, who were part of a genetics study. We tested for associations between a range of candidate malaria-protective genes and risk for severe malaria and its specific phenotypes. We used a permutation approach to account for multiple comparisons between polymorphisms and severe malaria. We judged p values less than 0·005 significant for the primary analysis of the association between candidate genes and severe malaria. Findings: Between June 11, 1995, and June 12, 2008, 2244 children with severe malaria were recruited to the study, and 3949 infants were included as controls. Overall, 263 (12%) of 2244 children with severe malaria died in hospital, including 196 (16%) of 1233 with cerebral malaria. We investigated 121 polymorphisms in 70 candidate severe malaria-associated genes. We found significant associations between risk for severe malaria overall and polymorphisms in 15 genes or locations, of which most were related to red blood cells: ABO, ATP2B4, ARL14, CD40LG, FREM3, INPP4B, G6PD, HBA (both HBA1 and HBA2), HBB, IL10, LPHN2 (also known as ADGRL2), LOC727982, RPS6KL1, CAND1, and GNAS. Combined, these genetic associations accounted for 5·2% of the variance in risk for developing severe malaria among individuals in the general population. We confirmed established associations between severe malaria and sickle-cell trait (odds ratio [OR] 0·15, 95% CI 0·11–0·20; p=2·61 × 10−58), blood group O (0·74, 0·66–0·82; p=6·26 × 10−8), and –α3·7-thalassaemia (0·83, 0·76–0·90; p=2·06 × 10−6). We also found strong associations between overall risk of severe malaria and polymorphisms in both ATP2B4 (OR 0·76, 95% CI 0·63–0·92; p=0·001) and FREM3 (0·64, 0·53–0·79; p=3·18 × 10−14). The association with FREM3 could be accounted for by linkage disequilibrium with a complex structural mutation within the glycophorin gene region (comprising GYPA, GYPB, and GYPE) that encodes for the rare Dantu blood group antigen. Heterozygosity for Dantu was associated with risk for severe malaria (OR 0·57, 95% CI 0·49–0·68; p=3·22 × 10−11), as was homozygosity (0·26, 0·11–0·62; p=0·002). Interpretation: Both ATP2B4 and the Dantu blood group antigen are associated with the structure and function of red blood cells. ATP2B4 codes for plasma membrane calcium-transporting ATPase 4 (the major calcium pump on red blood cells) and the glycophorins are ligands for parasites to invade red blood cells. Future work should aim at uncovering the mechanisms by which these polymorphisms can result in severe malaria protection and investigate the implications of these associations for wider health. Funding: Wellcome Trust, UK Medical Research Council, European Union, and Foundation for the National Institutes of Health as part of the Bill & Melinda Gates Grand Challenges in Global Health Initiative

Pathways of pathogenicity:transcriptional stages of germination in the fatal fungal pathogen

ABSTRACT Rhizopus delemar is an invasive fungal pathogen responsible for the frequently fatal disease mucormycosis. Germination, a crucial mechanism by which infectious spores of Rhizopus delemar cause disease, is a key developmental process that transforms the dormant spore state into a vegetative one. The molecular mechanisms that underpin this transformation may be key to controlling mucormycosis; however, the regulation of germination remains poorly understood. This study describes the phenotypic and transcriptional changes that take place over the course of germination. This process is characterized by four distinct stages: dormancy, isotropic swelling, germ tube emergence, and hyphal growth. Dormant spores are shown to be transcriptionally unique, expressing a subset of transcripts absent in later developmental stages. A large shift in the expression profile is prompted by the initiation of germination, with genes involved in respiration, chitin, cytoskeleton, and actin regulation appearing to be important for this transition. A period of transcriptional consistency can be seen throughout isotropic swelling, before the transcriptional landscape shifts again at the onset of hyphal growth. This study provides a greater understanding of the regulation of germination and highlights processes involved in transforming Rhizopus delemar from a single-cellular to multicellular organism. IMPORTANCE Germination is key to the growth of many organisms, including fungal spores. Mucormycete spores exist abundantly within the environment and germinate to form hyphae. These spores are capable of infecting immunocompromised individuals, causing the disease mucormycosis. Germination from spore to hyphae within patients leads to angioinvasion, tissue necrosis, and often fatal infections. This study advances our understanding of how spore germination occurs in the mucormycetes, identifying processes we may be able to inhibit to help prevent or treat mucormycosis

Feasibility and acceptability of a technology-based, rural weight management int ervention in older adults with obesity

Background Older adults with obesity residing in rural areas have reduced access to weight management programs. We determined the feasibility, acceptability and preliminary outcomes of an integrated technology-based health promotion intervention in rural-living, older adults using remote monitoring and synchronous video-based technology. Methods A 6-month, non-randomized, non-blinded, single-arm study was conducted from October 2018 to May 2020 at a community-based aging center of adults aged ≥65 years with a body mass index (BMI) ≥30 kg/m2. Weekly dietitian visits focusing on behavior therapy and caloric restriction and twice-weekly physical therapist-led group strength, flexibility and balance training classes were delivered using video-conferencing to participants in their homes. Participants used a Fitbit Alta HR for remote monitoring with data feedback provided by the interventionists. An aerobic activity prescription was provided and monitored. Results Mean age was 72.9±3.9 years (82% female). Baseline anthropometric measures of weight, BMI, and waist circumference were 97.8±16.3 kg, 36.5±5.2 kg/m2, and 115.5±13.0 cm, respectively. A total of 142 participants were screened (n=27 ineligible), and 53 consented. There were nine dropouts (17%). Overall satisfaction with the trial (4.7+ 0.6, scale: 1 (low) to 5 (high)) and with Fitbit (4.2+ 0.9) were high. Fitbit was worn an average of 81.7±19.3% of intervention days. In completers, mean weight loss was 4.6±3.5 kg or 4.7±3.5% (p\u3c 0.001). Physical function measures of 30-s sit-to-stand repetitions increased from 13.5±5.7 to 16.7±5.9 (p\u3c 0.001), 6-min walk improved by 42.0±77.3 m (p=0.005) but no differences were observed in gait speed or grip strength. Subjective measures of late-life function improved (3.4±4.7 points, p\u3c 0.001). Conclusions A technology-based obesity intervention is feasible and acceptable to older adults with obesity and may lead to weight loss and improved physical function. Clinical trial registration Registered on Clinicaltrials.gov #NCT03104205. Registered on April 7, 2017. First participant enrolled on October 1st, 2018

Innovation and access to technologies for sustainable development: diagnosing weaknesses and identifying interventions in the Transnational Arena

Sustainable development – improving human well-being across present generations without compromising the ability of future generations to meet their own needs – is a central challenge for the 21st century. Technological innovation can play an important role in moving society toward sustainable development. However, poor, marginalized, and future populations often do not fully benefit from innovation due to their lack of market or political power to influence innovation processes. As a result, current innovation systems fail to contribute as much as they might to meeting sustainable development goals. This paper focuses on how actors and institutions operating in the transnational arena can mitigate such shortfalls. To identify the most important transnational functions required to meet sustainable development needs our analysis undertook three main steps. First, we developed a framework to diagnose blockages in the global innovation system for particular technologies. This framework was built on existing theory and new empirical analysis. On the theory side, we drew from the literatures of systems dynamics; technology and sectoral innovation systems, science and technology studies, the economics of innovation, and global governance. On the empirical front, we conducted eighteen detailed case studies of technology innovation in multiple sectors relevant to sustainable development: water, energy, health, food, and manufactured goods. We use the framework to analyze our case studies in the common language of (1) technology stocks, (2) non-linear flows between stocks substantiated by specific mechanisms, and (3) characteristics of actors and socio-technical conditions (STCs) which mediate the flows between stocks . We identify blockages in the innovation system for each of the cases, diagnosing where in the innovation system flows were hindered and which specific sets of STCs and actor characteristics were associated with these blockages. Figure E.1 displays the components of our framework and how they relate

Gender perspectives on views and preferences of older people on exercise to prevent falls: a systematic mixed studies review

Background: To offer fall prevention exercise programs that attract older people of both sexes there is a need to understand both womens and mens views and preferences regarding these programs. This paper aims to systematically review the literature to explore any underlying gender perspectives or gender interpretations on older peoples views or preferences regarding uptake and adherence to exercise to prevent falls. Methods: A review of the literature was carried out using a convergent qualitative design based on systematic searches of seven electronic databases (PubMed, CINAHL, Amed, PsycINFO, Scopus, PEDro, and OTseeker). Two investigators identified eligible studies. Each included article was read by at least two authors independently to extract data into tables. Views and preferences reported were coded and summarized in themes of facilitators and barriers using a thematic analysis approach. Results: Nine hundred and nine unique studies were identified. Twenty five studies met the criteria for inclusion. Only five of these contained a gender analysis of mens and womens views on fall prevention exercises. The results suggests that both women and men see women as more receptive to and in more need of fall prevention messages. The synthesis from all 25 studies identified six themes illustrating facilitators and six themes describing barriers for older people either starting or adhering to fall prevention exercise. The facilitators were: support from professionals or family; social interaction; perceived benefits; a supportive exercise context; feelings of commitment; and having fun. Barriers were: practical issues; concerns about exercise; unawareness; reduced health status; lack of support; and lack of interest. Considerably more women than men were included in the studies. Conclusion: Although there is plenty of information on the facilitators and barriers to falls prevention exercise in older people, there is a distinct lack of studies investigating differences or similarities in older womens and mens views regarding fall prevention exercise. In order to ensure that fall prevention exercise is appealing to both sexes and that the inclusion of both men and women are encouraged, more research is needed to find out whether gender differences exists and whether practitioners need to offer a range of opportunities and support strategies to attract both women and men to falls prevention exercise.Funding Agencies|Swedish Research Council [2015-03481]; Strategic Research Programme in Care Sciences, Umea University; Karolinska Institute, Sweden; Umea University</p

MicroRNA regulation of endothelial TREX1 reprograms the tumour microenvironment

Rather than targeting tumour cells directly, elements of the tumour microenvironment can be modulated to sensitize tumours to the effects of therapy. Here we report a unique mechanism by which ectopic microRNA-103 can manipulate tumour-associated endothelial cells to enhance tumour cell death. Using gain-and-loss of function approaches, we show that miR-103 exacerbates DNA damage and inhibits angiogenesis in vitro and in vivo. Local, systemic or vascular-targeted delivery of miR-103 in tumour-bearing mice decreased angiogenesis and tumour growth. Mechanistically, miR-103 regulation of its target gene TREX1 in endothelial cells governs the secretion of pro-inflammatory cytokines into the tumour microenvironment. Our data suggest that this inflammatory milieu may potentiate tumour cell death by supporting immune activation and inducing tumour expression of Fas and TRAIL receptors. Our findings reveal miR-mediated crosstalk between vasculature and tumour cells that can be exploited to improve the efficacy of chemotherapy and radiation.United States. National Institutes of Health (R00HL112962)United States. National Institutes of Health (R01 HL57900)Oregon Health & Science University. Knight Cancer Institute (2015-Dive-Knight-01