HNF1B variants associate with promoter methylation and regulate gene networks activated in prostate and ovarian cancer

Two independent regions within HNF1B are consistently identified in prostate and ovarian cancer genome-wide association studies (GWAS); their functional roles are unclear. We link prostate cancer (PC) risk SNPs rs11649743 and rs3760511 with elevated HNF1B gene expression and allele-specific epigenetic silencing, and outline a mechanism by which common risk variants could effect functional changes that increase disease risk: functional assays suggest that HNF1B is a pro-differentiation factor that suppresses epithelial-to-mesenchymal transition (EMT) in unmethylated, healthy tissues. This tumor-suppressor activity is lost when HNF1B is silenced by promoter methylation in the progression to PC. Epigenetic inactivation of HNF1B in ovarian cancer also associates with known risk SNPs, with a similar impact on EMT. This represents one of the first comprehensive studies into the pleiotropic role of a GWAS-associated transcription factor across distinct cancer types, and is the first to describe a conserved role for a multi-cancer genetic risk factor

The first view of δ Scuti and γ Doradus stars with the TESS mission

We present the first asteroseismic results for δ Scuti and γ Doradus stars observed in Sectors 1 and 2 of the TESS mission. We utilize the 2-min cadence TESS data for a sample of 117 stars to classify their behaviour regarding variability and place them in the Hertzsprung-Russell diagram using Gaia DR2 data. Included within our sample are the eponymous members of two pulsator classes, γ Doradus and SX Phoenicis. Our sample of pulsating intermediate-mass stars observed by TESS also allows us to confront theoretical models of pulsation driving in the classical instability strip for the first time and show that mixing processes in the outer envelope play an important role. We derive an empirical estimate of 74 per cent for the relative amplitude suppression factor as a result of the redder TESS passband compared to the Kepler mission using a pulsating eclipsing binary system. Furthermore, our sample contains many high-frequency pulsators, allowing us to probe the frequency variability of hot young δ Scuti stars, which were lacking in the Kepler mission data set, and identify promising targets for future asteroseismic modelling. The TESS data also allow us to refine the stellar parameters of SX Phoenicis, which is believed to be a blue straggler.Fil: Antoci, Victoria. Stellar Astrophysics Centre; DinamarcaFil: Cunha, M. S.. Universidad de Porto; PortugalFil: Bowman, D. M.. Institute of Astronomy; BélgicaFil: Murphy, S. J.. Stellar Astrophysics Centre; Dinamarca. University of Sydney; AustraliaFil: Kurtz, D. W.. University of Central Lancashire; Reino UnidoFil: Bedding, T. R.. Stellar Astrophysics Centre; Dinamarca. University of Sydney; AustraliaFil: Borre, C. C.. Stellar Astrophysics Centre; DinamarcaFil: Christophe, S.. Universite de Paris I Pantheon - Sorbonne; Francia. Centre National de la Recherche Scientifique. Observatoire de Paris; FranciaFil: Daszynska Daszkiewicz, J.. Instytut Astronomiczny; PoloniaFil: Fox Machado, L.. Universidad Nacional Autónoma de México; MéxicoFil: García Hernández, A.. Universidad de Granada; EspañaFil: Ghasemi, Hamed. Institute For Advanced Studies In Basic Sciences; IránFil: Handberg, R.. Stellar Astrophysics Centre; DinamarcaFil: Hansen, Ted H.. Stellar Astrophysics Centre; DinamarcaFil: Hasanzadeh, A.. University Of Zanjan; IránFil: Houdek, G.. Stellar Astrophysics Centre; DinamarcaFil: Johnston, C.. Katholikie Universiteit Leuven; BélgicaFil: Justesen, A. B.. Stellar Astrophysics Centre; DinamarcaFil: Kahraman Alicavus, F.. Nicolaus Copernicus Astronomical Center Of The Polish Academy Of Sciences; PoloniaFil: Kotysz, K.. Instytut Astronomiczny, Uniwersytet Wrocławski; PoloniaFil: Latham, D.. Harvard-Smithsonian Center for Astrophysics; Estados UnidosFil: Matthews, J. M.. University of British Columbia; CanadáFil: Mønster, J.. Stellar Astrophysics Centre; DinamarcaFil: Niemczura, E.. Uniwersytet Wrocławski; PoloniaFil: Paunzen, E.. Masaryk University; República ChecaFil: Sánchez Arias, Julieta Paz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Astrofísica La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Astronómicas y Geofísicas. Instituto de Astrofísica La Plata; ArgentinaFil: Pigulski, A.. Uniwersytet Wrocławski; PoloniaFil: Pepper, J.. Lehigh University; Estados UnidosFil: Richey Yowell, T.. Lehigh University; Estados UnidosFil: Safari, H.. University of Zanjan; Irá

PLoS One

INTRODUCTION: The Temprano and START trials provided evidence to support early ART initiation recommendations. We projected long-term clinical and economic outcomes of immediate ART initiation in Cote d'Ivoire. METHODS: We used a mathematical model to compare three potential ART initiation criteria: 1) CD4 <350/muL (ART<350/muL); 2) CD4 <500/muL (ART<500/muL); and 3) ART at presentation (Immediate ART). Outcomes from the model included life expectancy, 10-year medical resource use, incremental cost-effectiveness ratios (ICERs) in $/year of life saved (YLS), and 5-year budget impact. We simulated people with HIV (PWH) in care (mean CD4: 259/muL, SD 198/muL) and transmitted cases. Key input parameters to the analysis included first-line ART efficacy (80$90/person-year). We assessed cost-effectiveness relative to Cote d'Ivoire's 2017 per capita annual gross domestic product ($1,600). RESULTS: Immediate ART increased life expectancy by 0.34 years compared to ART<350/muL and 0.17 years compared to ART<500/muL. Immediate ART resulted in 4,500 fewer 10-year transmissions per 170,000 PWH compared to ART<350/muL. In cost-effectiveness analysis, Immediate ART had a 10-year ICER of$680/YLS compared to ART<350/muL, ranging from cost-saving to an ICER of $1,440/YLS as transmission rates varied. ART<500/muL was "dominated" (an inefficient use of resources), compared with Immediate ART. Immediate ART increased the 5-year HIV care budget from$801.9M to $812.6M compared to ART<350/muL. CONCLUSIONS: In Cote d'Ivoire, immediate compared to later ART initiation will increase life expectancy, decrease HIV transmission, and be cost-effective over the long-term, with modest budget impact. Immediate ART initiation is an appropriate, high-value standard of care in Cote d'Ivoire and similar settings

Trust in the public sector: Is there any evidence for a long-term decline?

Concerns with declining public trust in government have become a permanent element of the contemporary political discourse. This concern also extends to levels of citizens’ trust in the public administration and public services. Trust is said to be declining, and this decline is generally seen as detrimental to public service delivery. In this article, we examine the main elements in this discussion, review the existing international survey data and summarise the main findings for OECD countries. Citizens’ trust in the public sector is found to fluctuate, and the data generally do not show consistently declining levels of trust. Furthermore, in some countries there simply is insufficient data to come to any conclusions at all about time trends in citizen trust in the public sector. Points for practitioners This article summarises some of the survey material on citizens’ trust in the public administration. It allows practitioners to compare trends in public trust in their country across time and space. The findings lead us to reject the hypothesis of a universal decline of trust in the public sector. The article warns against using opinion poll results without considering context. The long-term and comparative perspective on citizens’ trust in the public sector is all too often absent from the policy discourse that is frequently based on assumptions and ad-hoc approaches

Enduring Behavioral Effects Induced by Birth by Caesarean Section in the Mouse

Birth by Caesarean (C)-section impacts early gut microbiota colonization and is associated with an increased risk of developing immune and metabolic disorders. Moreover, alterations of the microbiome have been shown to affect neurodevelopmental trajectories. However, the long-term effects of C-section on neurobehavioral processes remain unknown. Here, we demonstrated that birth by C-section results in marked but transient changes in microbiome composition in the mouse, in particular, the abundance of Bifidobacterium spp. was depleted in early life. Mice born by C-section had enduring social, cognitive, and anxiety deficits in early life and adulthood. Interestingly, we found that these specific behavioral alterations induced by the mode of birth were also partially corrected by co-housing with vaginally born mice. Finally, we showed that supplementation from birth with a Bifidobacterium breve strain, or with a dietary prebiotic mixture that stimulates the growth of bifidobacteria, reverses selective behavioral alterations in C-section mice. Taken together, our data link the gut microbiota to behavioral alterations in C-section-born mice and suggest the possibility of developing adjunctive microbiota-targeted therapies that may help to avert long-term negative consequences on behavior associated with C-section birth mode

Simple Parameters from Complete Blood Count Predict In-Hospital Mortality in COVID-19

The clinical course of Coronavirus Disease 2019 (COVID-19) is highly heterogenous, ranging from asymptomatic to fatal forms. The identification of clinical and laboratory predictors of poor prognosis may assist clinicians in monitoring strategies and therapeutic decisions

Using fish models to investigate the links between microbiome and social behaviour: the next step for translational microbiome research?

Recent research has revealed surprisingly important connections between animals’ microbiome and social behaviour. Social interactions can affect the composition and function of the microbiome; conversely, the microbiome affects social communication by influencing the hosts’ central nervous system and peripheral chemical communication. These discoveries set the stage for novel research focusing on the evolution and physiology of animal social behaviour in relation to microbial transmission strategies. Here, we discuss the emerging roles of teleost fish models and their potential for advancing research fields, linked to sociality and microbial regulation. We argue that fish models, such as the zebrafish (Danio rerio, Cyprinidae), sticklebacks (‎Gasterosteidae), guppies (Poeciliidae) and cleaner–client dyads (e.g., obligate cleaner fish from the Labridae and Gobiidae families and their visiting clientele), will provide valuable insights into the roles of microbiome in shaping social behaviour and vice versa, while also being of direct relevance to the food and ornamental fish trades. The diversity of fish behaviour warrants more interdisciplinary research, including microbiome studies, which should have a strong ecological (field‐derived) approach, together with laboratory‐based cognitive and neurobiological experimentation. The implications of such integrated approaches may be of translational relevance, opening new avenues for future investigation using fish models

Contrasting Population Structures of the Genes Encoding Ten Leading Vaccine-Candidate Antigens of the Human Malaria Parasite, Plasmodium falciparum

The extensive diversity of Plasmodium falciparum antigens is a major obstacle to a broadly effective malaria vaccine but population genetics has rarely been used to guide vaccine design. We have completed a meta-population genetic analysis of the genes encoding ten leading P. falciparum vaccine antigens, including the pre-erythrocytic antigens csp, trap, lsa1 and glurp; the merozoite antigens eba175, ama1, msp's 1, 3 and 4, and the gametocyte antigen pfs48/45. A total of 4553 antigen sequences were assembled from published data and we estimated the range and distribution of diversity worldwide using traditional population genetics, Bayesian clustering and network analysis. Although a large number of distinct haplotypes were identified for each antigen, they were organized into a limited number of discrete subgroups. While the non-merozoite antigens showed geographically variable levels of diversity and geographic restriction of specific subgroups, the merozoite antigens had high levels of diversity globally, and a worldwide distribution of each subgroup. This shows that the diversity of the non-merozoite antigens is organized by physical or other location-specific barriers to gene flow and that of merozoite antigens by features intrinsic to all populations, one important possibility being the immune response of the human host. We also show that current malaria vaccine formulations are based upon low prevalence haplotypes from a single subgroup and thus may represent only a small proportion of the global parasite population. This study demonstrates significant contrasts in the population structure of P. falciparum vaccine candidates that are consistent with the merozoite antigens being under stronger balancing selection than non-merozoite antigens and suggesting that unique approaches to vaccine design will be required. The results of this study also provide a realistic framework for the diversity of these antigens to be incorporated into the design of next-generation malaria vaccines

Thymidine phosphorylase expression in normal, hyperplastic and neoplastic prostates: correlation with tumour associated macrophages, infiltrating lymphocytes, and angiogenesis

Thymidine phosphorylase is an angiogenic factor primarily expressed by cancer cells, stromal cells and tumour-associated macrophages in many human malignancies. These different types of thymidine phosphorylase-expressing cells, however, may have a distinct place in the angiogenic process, and this question was addressed in the present study. A series of 20 normal/hyperplastic prostate glands and 60 prostate carcinomas was investigated by immunohistochemistry, using specific antibodies for thymidine phosphorylase (P-GF.44C), tumour-associated macrophages (CD68), endothelium (CD31) and prostate specific antigen (ER-PR8). Thymidine phosphorylase expression by normal and hyperplastic epithelial or stromal cells occurred almost exclusively in the context of an intense lymphocytic infiltrate. High thymidine phosphorylase cancer cells and thymidine phosphorylase stromal cells expression was associated with high angiogenesis in prostate carcinomas, and this significant association was extended to include both tumour-associated macrophages and tumour-infiltrating lymphocytes. Thymidine phosphorylase expression and tumour-infiltrating lymphocytes were related inversely with prostate specific antigen reactivity. In conclusion, thymidine phosphorylase is a major angiogenic factor in prostate carcinomas and its up-regulation is likely to occur in the context of a host immune response