Absence of the caspases 1/11 modulates liver global lipid profile and gut microbiota in high-fat-diet-induced obese mice

Obesity is a chronic disease with rising worldwide prevalence and largely associated with several other comorbidities, such as cancer, non-alcoholic fatty liver disease (NAFLD), and metabolic syndrome. Hepatic steatosis, a hallmark of NAFLD, is strongly correlated with obesity and has been correlated with changes in the gut microbiota, which can promote its development through the production of short-chain fatty acids (SCFAs) that regulate insulin resistance, bile acid, choline metabolism, and inflammation. Recent studies have suggested a controversial role for the inflammasome/caspase-1 in the development of obesity and non-alcoholic steatohepatitis (NASH). Here, we evaluated the role of inflammasome NLRP3 and caspases 1/11 in the establishment of obesity and hepatic steatosis in diet-induced obese mice, correlating them with the global lipid profile of the liver and gut microbiota diversity. After feeding wild-type, caspases 1/11, and NLRP3 knockout mice with a standard fat diet (SFD) or a high-fat diet (HFD), we found that the caspases 1/11 knockout mice, but not NLRP3 knockout mice, were more susceptible to HFD-induced obesity, and developed enhanced hepatic steatosis even under SFD conditions. Lipidomics analysis of the liver, assessed by MALDI-MS analysis, revealed that the HFD triggered a significant change in global lipid profile in the liver of WT mice compared to those fed an SFD, and this profile was modified by the lack of caspases 1/11 and NLRP3. The absence of caspases 1/11 was also correlated with an increased presence of triacylglycerol in the liver. Gut microbial diversity analysis, using 16S rRNA gene sequencing, showed that there was also an increase of Proteobacteria and a higher Firmicutes/Bacteroidetes ratio in the gut of caspases 1/11 knockout mice fed an HFD. Overall, mice without caspases 1/11 harbored gut bacterial phyla involved with weight gain, obesity, and hepatic steatosis. Taken together, our data suggest an important role for caspases 1/11 in the lipid composition of the liver and in the modulation of the gut microbial community composition. Our results further suggest that HFD-induced obesity and the absence of caspases 1/11 may regulate both lipid metabolism and gut microbial diversity, and therefore may be associated with NAFLD and obesity10CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP312359/2016-02016/22577-6This research was funded by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq -#312359/2016-0). CM was funded by the Canada Research Chair Program, the Canadian Foundation for Innovation, McGill University, and the Canadian Institutes for Health Research (PJT-149098). ME was funded by the São Paulo Research Foundation (FAPESP) (2016/22577-6)

Long-term effects of tafamidis for the treatment of transthyretin familial amyloid polyneuropathy

Tafamidis, a transthyretin (TTR) kinetic stabilizer, delayed neuropathic progression in patients with Val30Met TTR familial amyloid polyneuropathy (TTR-FAP) in an 18-month randomized controlled trial (study Fx-005). This 12-month, open-label extension study evaluated the long-term safety, tolerability, and efficacy of tafamidis 20 mg once daily in 86 patients who earlier received blinded treatment with tafamidis or placebo. Efficacy measures included the Neuropathy Impairment Score in the Lower Limbs (NIS-LL), Norfolk Quality of Life-Diabetic Neuropathy total quality of life (TQOL) score, and changes in neurologic function and nutritional status. We quantified the monthly rates of change in efficacy measures, and TTR stabilization, and monitored adverse events (AEs). Patients who continued on tafamidis had stable rates of change in NIS-LL (from 0.08 to 0.11/month; p = 0.60) and TQOL (from −0.03 to 0.25; p = 0.16). In patients switched from placebo, the monthly rate of change in NIS-LL declined (from 0.34 to 0.16/month; p = 0.01), as did TQOL score (from 0.61 to −0.16; p < 0.001). Patients treated with tafamidis for 30 months had 55.9 % greater preservation of neurologic function as measured by the NIS-LL than patients in whom tafamidis was initiated later. Plasma TTR was stabilized in 94.1 % of patients treated with tafamidis for 30 months. AEs were similar between groups; no patients discontinued because of an AE. Long-term tafamidis was well tolerated, with the reduced rate of neurologic deterioration sustained over 30 months. Tafamidis also slowed neurologic impairment in patients previously given placebo, but treatment benefits were greater when tafamidis was begun earlier

Chemotherapy with cisplatin and vinorelbine for elderly patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC)

BACKGROUND: Although modest improvements in the survival of patients with non-small cell lung cancer (NSCLC) can be achieved with cisplatin-based chemotherapy (CT), its value is disputed in the geriatric setting. In this study, we evaluate the feasibility of vinorelbine/cisplatin CT for elderly NSCLC patients. METHODS: In this pilot phase I/II trial, all patients received CT with vinorelbine 25 mg/m(2), on day 1 and 8, and cisplatin on day 1, in 28 days-cycles. After stratification for age (up to 75 years), younger patients were sequentially allocated to moderate cisplatin doses (80 mg/m(2 )or 90 mg/m(2)), and older patients were allocated to lower cisplatin doses (60 mg/m(2 )or 70 mg/m(2)). We recruited patients aged over 70 years with newly diagnosed NSCLC, clinical stage III or IV, Karnofsky performance status ≥ 70%, normal serum creatinine, peripheral neuropathy ≤ grade 1, and no prior cancer therapy. RESULTS: Analysis was by intention to treat. Main toxicities (grade 3–4) was as follows: neutropenia, 20%; anemia, 11%; and thrombocytopenia, 2%; alopecia, 55%; fatigue, 11%; and peripheral neurotoxicity, 2%. No grade 3–4 emesis or renal toxicity occurred. Global median time to progression (TTP) and overall survival (OS) were 27.0 (95% CI: 10.1 to 43.7) weeks and 30.1 (95% CI: 24.4 to 35.8) weeks; 1- and 2-year survival rates were 36.3% and 13.2%, respectively. Overall response rate was 50.0% (95% CI: 35.4% to 64.5%), with 1 complete response; no difference on response rate was noticed according to cisplatin dose. Median overall survival was 30.1 weeks, with 1- and 2-year survival rates of 36.3% and 13.2%, respectively. CONCLUSION: Age does not preclude assessment on the role of cisplatin-vinorelbine CT for elderly NSCLC patients with good performance status and adequate bodily functions

A <i>Herschel</i> and BIMA study of the sequential star formation near the W 48A H II region

We present the results of Herschel HOBYS (Herschel imaging survey of OB Young Stellar objects) photometric mapping combined with Berkeley Illinois Maryland Association (BIMA) observations and additional archival data, and perform an in-depth study of the evolutionary phases of the star-forming clumps in W 48A and their surroundings. Age estimates for the compact sources were derived from bolometric luminosities and envelope masses, which were obtained from the dust continuum emission, and agree within an order of magnitude with age estimates from molecular line and radio data. The clumps in W 48A are linearly aligned by age (east-old to west-young): we find a ultra-compact (UC) H II region, a young stellar object (YSO) with class II methanol maser emission, a YSO with a massive outflow and finally the NH2D prestellar cores from Pillai et al. This remarkable positioning reflects the (star) formation history of the region. We find that it is unlikely that the star formation in the W 48A molecular cloud was triggered by the UC H II region and discuss the Aquila supershell expansion as a major influence on the evolution of W 48A. We conclude that the combination of Herschel continuum data with interferometric molecular line and radio continuum data is important to derive trustworthy age estimates and interpret the origin of large-scale structures through kinematic information

Consensos em saúde bucal aprimorando a atenção básica, Ribeirão Preto, SP

Currently the development and use of protocols in the area of health as a tool has contributed to theOrganization and standardization of clinical practice. Model of the study: this study is to estimate qualitatively. Goal of the study: this research if proposed using the Delphi Technique to achieve a consensusamong the participants of the survey in the consolidation of the axles, concepts and categories that willcontribute to the creation and implementation of the Protocol in dental health Public health network of thecity of Ribeirão Preto. Methodology: Delphi Technique was used in the search for convergence of views.The initial sample of random character from sweepstakes between units of Health district west of Ribeirão Preto, was composed by 13 dentists and the method was described in 3 steps. Started with the Groupdental units selected, which responded to a series of questions and the results of this first phasecompiled and the summary of the results communicated again to members to reply again upon reconsideration of his replies. The end product was discussed in the workshop comprised dental practitionersinterviewed representatives of health teams, Secretary of health and of users of the service so that theinstrument could be built containing the views of all those involved in the process. Results: Showed thatthe technique Delphi favoured decision-making professionals and users about consolidation concepts,own the primary dental health for the development of dental health care, collaborating potentially forrational decisions and improving quality of care. Conclusion: Delphi technique proved effective instrument in seeking consensus on Dental public health.Atualmente, o desenvolvimento e utilização dos Protocolos clínicos e de regulação na área da saúde,como ferramenta para gestão, têm contribuído para a organização e padronização da prática clínica emdiversas áreas assistenciais, bem como conferido clareza quanto aos fluxos a serem percorridos pelospacientes, em busca do cuidado à saúde. Por meio de estudo de abordagem qualitativa e valendo-se daTécnica Delphi na busca da convergência de opiniões, objetivou-se obter um consenso entre os participantes da pesquisa para a adoção dos conceitos que pudessem subsidiar a criação e implantaçãode um Protocolo em Saúde Bucal a ser aplicado na Rede Pública de Saúde no município de RibeirãoPreto. A amostra inicial de caráter aleatório, a partir de sorteio entre as Unidades de Saúde do DistritoOeste de Ribeirão Preto foi composta por 13 dentistas e profissionais da equipe de saúde sendo que ametodologia foi desenvolvida em 3 etapas. A primeira iniciou-se com o grupo de dentistas das unidadessorteadas, que responderam a uma série de questões sendo os resultados dessa primeira fasecompilados e a síntese das tarefas reenviada aos membros para que respondessem novamente,reconsiderando as suas respostas. O produto final foi discutido em Oficina composta pelos dentistasentrevistados, representantes das equipes de saúde, da Secretaria de Saúde e dos usuários do serviçoa fim de que o instrumento pudesse ser construído contemplando o ponto de vista de todos os envolvidos no processo. Resultados: O trabalho identificou concordância final entre os participantes, pelo quese comprovou que a Técnica Delphi favoreceu a tomada de decisões dos profissionais e usuáriosacerca da consolidação de conceitos próprios da atenção básica em saúde bucal para o desenvolvimento dos cuidados nessa área, colaborando potencialmente para as decisões racionais e aprimoramento da qualidade da assistência. Mostrou-se  uma ferramenta com potência para a busca de consensos na área de Saúde Pública

Bacterial artificial chromosomes as analytical basis for gene transcriptional machineries

Bacterial Artificial Chromosomes (BACs) had been minimal components of various genome-sequencing projects, constituting perfect analytical basis for functional genomics. Here we describe an enhancer screening strategy in which BAC clones that cover any genomic segments of interest are modified to harbor a reporter cassette by transposon tagging, then processed to carry selected combinations of gene regulatory modules by homologous recombination mediated systematic deletions. Such engineered BAC-reporter constructs in bacterial cells are ready for efficient transgenesis in mice to evaluate activities of gene regulatory modules intact or absent in the constructs. By utilizing the strategy, we could speedily identify a critical genomic fragment for spatio-temporally regulated expression of a mouse cadherin gene whose structure is extraordinarily huge and intricate. This BAC-based methodology would hence provide a novel screening platform for gene transcriptional machineries that dynamically fluctuate during development, pathogenesis and/or evolution

Measurement of the t(t)over-bar production cross section in the dilepton channel in pp collisions at √s=8 TeV

The top-antitop quark (t (t) over bar) production cross section is measured in proton-proton collisions at root s = 8 TeV with the CMS experiment at the LHC, using a data sample corresponding to an integrated luminosity of 5.3 fb(-1). The measurement is performed by analysing events with a pair of electrons or muons, or one electron and one muon, and at least two jets, one of which is identified as originating from hadronisation of a bottom quark. The measured cross section is 239 +/- 2 (stat.) +/- 11 (syst.) +/- 6 (lum.) pb, for an assumed top-quark mass of 172.5 GeV, in agreement with the prediction of the standard model

Intermediate and extreme mass-ratio inspirals — astrophysics, science applications and detection using LISA

Black hole binaries with extreme (gtrsim104:1) or intermediate (~102–104:1) mass ratios are among the most interesting gravitational wave sources that are expected to be detected by the proposed laser interferometer space antenna (LISA). These sources have the potential to tell us much about astrophysics, but are also of unique importance for testing aspects of the general theory of relativity in the strong field regime. Here we discuss these sources from the perspectives of astrophysics, data analysis and applications to testing general relativity, providing both a description of the current state of knowledge and an outline of some of the outstanding questions that still need to be addressed. This review grew out of discussions at a workshop in September 2006 hosted by the Albert Einstein Institute in Golm, Germany

Measurements of Higgs boson production and couplings in diboson final states with the ATLAS detector at the LHC

Measurements are presented of production properties and couplings of the recently discovered Higgs boson using the decays into boson pairs, H →γ γ, H → Z Z∗ →4l and H →W W∗ →lνlν. The results are based on the complete pp collision data sample recorded by the ATLAS experiment at the CERN Large Hadron Collider at centre-of-mass energies of √s = 7 TeV and √s = 8 TeV, corresponding to an integrated luminosity of about 25 fb−1. Evidence for Higgs boson production through vector-boson fusion is reported. Results of combined fits probing Higgs boson couplings to fermions and bosons, as well as anomalous contributions to loop-induced production and decay modes, are presented. All measurements are consistent with expectations for the Standard Model Higgs boson

Standalone vertex finding in the ATLAS muon spectrometer

A dedicated reconstruction algorithm to find decay vertices in the ATLAS muon spectrometer is presented. The algorithm searches the region just upstream of or inside the muon spectrometer volume for multi-particle vertices that originate from the decay of particles with long decay paths. The performance of the algorithm is evaluated using both a sample of simulated Higgs boson events, in which the Higgs boson decays to long-lived neutral particles that in turn decay to bbar b final states, and pp collision data at √s = 7 TeV collected with the ATLAS detector at the LHC during 2011