We present the discovery of three new transiting giant planets, first detected with the WASP telescopes, and establish their planetary nature with follow up spectroscopy and ground-based photometric ...light curves. WASP-92 is an F7 star, with a moderately inflated planet orbiting with a period of 2.17 d, which has R sub( p) = 1.461 plus or minus 0.077R sub( J) and M sub( p) = 0.805 plus or minus 0.068M sub( J). WASP-93b orbits its F4 host star every 2.73 d and has R sub( p) = 1.597 plus or minus 0.077R sub( J) and M sub( p) = 1.47 plus or minus 0.029M sub( J). WASP-118b also has a hot host star (F6) and is moderately inflated, where R sub( p) = 1.440 plus or minus 0.036R sub( J) and M sub( p) = 0.514 plus or minus 0.020M sub( J) and the planet has an orbital period of 4.05 d. They are bright targets (V = 13.18, 10.97 and 11.07, respectively) ideal for further characterization work, particularly WASP-118b, which is being observed by K2 as part of campaign 8. The WASP-93 system has sufficient angular momentum to be tidally migrating outwards if the system is near spin-orbit alignment, which is divergent from the tidal behaviour of the majority of hot Jupiters discovered.
Abstract The dopamine transporter is a key protein responsible for regulating dopamine homeostasis. Its function is to transport dopamine from the extracellular space into the presynaptic neuron. ...Studies have suggested that accumulation of dopamine in the cytosol can trigger oxidative stress and neurotoxicity. Previously, ectopic expression of the dopamine transporter was shown to cause damage in non-dopaminergic neurons due to their inability to handle cytosolic dopamine. However, it is unknown whether increasing dopamine transporter activity will be detrimental to dopamine neurons that are inherently capable of storing and degrading dopamine. To address this issue, we characterized transgenic mice that over-express the dopamine transporter selectively in dopamine neurons. We report that dopamine transporter over-expressing (DAT-tg) mice display spontaneous loss of midbrain dopamine neurons that is accompanied by increases in oxidative stress markers, 5-S-cysteinyl-dopamine and 5-S-cysteinyl-DOPAC. In addition, metabolite-to-dopamine ratios are increased and VMAT2 protein expression is decreased in the striatum of these animals. Furthermore, DAT-tg mice also show fine motor deficits on challenging beam traversal that are reversed with l -DOPA treatment. Collectively, our findings demonstrate that even in neurons that routinely handle dopamine, increased uptake of this neurotransmitter through the dopamine transporter results in oxidative damage, neuronal loss and l -DOPA reversible motor deficits. In addition, DAT over-expressing animals are highly sensitive to MPTP-induced neurotoxicity. The effects of increased dopamine uptake in these transgenic mice could shed light on the unique vulnerability of dopamine neurons in Parkinson's disease.
Whaling has decimated North Atlantic right whales Eubalaena glacialis (NARW) since the 11th century and southern right whales E. australis (SRW) since the 19th century. Today, NARWs are Critically ...Endangered and decreasing, whereas SRWs are recovering. We review NARW health assessment literature, NARW Consortium databases, and efforts and limitations to monitor individual and species health, survival, and fecundity. Photographs are used to track individual movement and external signs of health such as evidence of vessel and entanglement trauma. Post-mortem examinations establish cause of death and determine organ pathology. Photogrammetry is used to assess growth rates and body condition. Samples of blow, skin, blubber, baleen and feces quantify hormones that provide information on stress, reproduction, and nutrition, identify microbiome changes, and assess evidence of infection. We also discuss models of the population consequences of multiple stressors, including the connection between human activities (e.g. entanglement) and health. Lethal and sublethal vessel and entanglement trauma have been identified as major threats to the species. There is a clear and immediate need for expanding trauma reduction measures. Beyond these major concerns, further study is needed to evaluate the impact of other stressors, such as pathogens, microbiome changes, and algal and industrial toxins, on NARW reproductive success and health. Current and new health assessment tools should be developed and used to monitor the effectiveness of management measures and will help determine whether they are sufficient for a substantive species recovery.
Women and men, female and male animals and cells are biologically different, and acknowledgement of this fact is critical to advancing medicine. However, incorporating concepts of sex-specific ...analysis in basic research is largely neglected, introducing bias into translational findings, clinical concepts and drug development. Research funding agencies recently approached these issues but implementation of policy changes in the scientific community is still limited, probably due to deficits in concepts, knowledge and proper methodology. This expert review is based on the EUGenMed project (www.eugenmed.eu) developing a roadmap for implementing sex and gender in biomedical and health research. For sake of clarity and conciseness, examples are mainly taken from the cardiovascular field that may serve as a paradigm for others, since a significant amount of knowledge how sex and oestrogen determine the manifestation of many cardiovascular diseases (CVD) has been accumulated. As main concepts for implementation of sex in basic research, the study of primary cell and animals of both sexes, the study of the influence of genetic vs. hormonal factors and the analysis of sex chromosomes and sex specific statistics in genome wide association studies (GWAS) are discussed. The review also discusses methodological issues, and analyses strength, weaknesses, opportunities and threats in implementing sex-sensitive aspects into basic research.
Postoperative acute kidney injury (PO-AKI) is a common complication of major surgery that is strongly associated with short-term surgical complications and long-term adverse outcomes, including ...increased risk of chronic kidney disease, cardiovascular events and death. Risk factors for PO-AKI include older age and comorbid diseases such as chronic kidney disease and diabetes mellitus. PO-AKI is best defined as AKI occurring within 7 days of an operative intervention using the Kidney Disease Improving Global Outcomes (KDIGO) definition of AKI; however, additional prognostic information may be gained from detailed clinical assessment and other diagnostic investigations in the form of a focused kidney health assessment (KHA). Prevention of PO-AKI is largely based on identification of high baseline risk, monitoring and reduction of nephrotoxic insults, whereas treatment involves the application of a bundle of interventions to avoid secondary kidney injury and mitigate the severity of AKI. As PO-AKI is strongly associated with long-term adverse outcomes, some form of follow-up KHA is essential; however, the form and location of this will be dictated by the nature and severity of the AKI. In this Consensus Statement, we provide graded recommendations for AKI after non-cardiac surgery and highlight priorities for future research.
The ENCODE (ENCyclopedia of DNA Elements) Project Feingold, E A; Good, P J; Guyer, M S ...
Science (American Association for the Advancement of Science),
10/2004, Letnik:
306, Številka:
5696
Journal Article
Recenzirano
The ENCyclopedia of DNA Elements (ENCODE) Project aims to identify all functional elements in the human genome sequence. The pilot phase of the Project is focused on a specified 30 megabases (~1%) of ...the human genome sequence and is organized as an international consortium of computational and laboratory-based scientists working to develop and apply high-throughput approaches for detecting all sequence elements that confer biological function. The results of this pilot phase will guide future efforts to analyze the entire human genome.
Summary Background In about 10% of patients worldwide and more than 50% of patients in Israel, cystic fibrosis results from nonsense mutations (premature stop codons) in the messenger RNA (mRNA) for ...the cystic fibrosis transmembrane conductance regulator (CFTR). PTC124 is an orally bioavailable small molecule that is designed to induce ribosomes to selectively read through premature stop codons during mRNA translation, to produce functional CFTR. Methods This phase II prospective trial recruited adults with cystic fibrosis who had at least one nonsense mutation in the CFTR gene. Patients were assessed in two 28-day cycles. During the first cycle, patients received PTC124 at 16 mg/kg per day in three doses every day for 14 days, followed by 14 days without treatment; in the second cycle, patients received 40 mg/kg of PTC124 in three doses every day for 14 days, followed by 14 days without treatment. The primary outcome had three components: change in CFTR-mediated total chloride transport; proportion of patients who responded to treatment; and normalisation of chloride transport, as assessed by transepithelial nasal potential difference (PD) at baseline, at the end of each 14-day treatment course, and after 14 days without treatment. The trial was registered with who.int/ictrp , and with clinicaltrials.gov , number NCT00237380. Findings Transepithelial nasal PD was evaluated in 23 patients in the first cycle and in 21 patients in the second cycle. Mean total chloride transport increased in the first treatment phase, with a change of −7·1 (SD 7·0) mV (p<0·0001), and in the second, with a change of −3·7 (SD 7·3) mV (p=0·032). We recorded a response in total chloride transport (defined as a change in nasal PD of −5 mV or more) in 16 of the 23 patients in the first cycle's treatment phase (p<0·0001) and in eight of the 21 patients in the second cycle (p<0·0001). Total chloride transport entered the normal range for 13 of 23 patients in the first cycle's treatment phase (p=0·0003) and for nine of 21 in the second cycle (p=0·02). Two patients given PTC124 had constipation without intestinal obstruction, and four had mild dysuria. No drug-related serious adverse events were recorded. Interpretation In patients with cystic fibrosis who have a premature stop codon in the CFTR gene, oral administration of PTC124 to suppress nonsense mutations reduces the epithelial electrophysiological abnormalities caused by CFTR dysfunction. Funding PTC Therapeutics, Cystic Fibrosis Foundation Therapeutics.
The addition of rituximab to combination chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), or R-CHOP, has significantly improved the survival of patients with ...diffuse large-B-cell lymphoma. Whether gene-expression signatures correlate with survival after treatment of diffuse large-B-cell lymphoma is unclear.
We profiled gene expression in pretreatment biopsy specimens from 181 patients with diffuse large-B-cell lymphoma who received CHOP and 233 patients with this disease who received R-CHOP. A multivariate gene-expression-based survival-predictor model derived from a training group was tested in a validation group.
A multivariate model created from three gene-expression signatures--termed "germinal-center B-cell," "stromal-1," and "stromal-2"--predicted survival both in patients who received CHOP and patients who received R-CHOP. The prognostically favorable stromal-1 signature reflected extracellular-matrix deposition and histiocytic infiltration. By contrast, the prognostically unfavorable stromal-2 signature reflected tumor blood-vessel density.
Survival after treatment of diffuse large-B-cell lymphoma is influenced by differences in immune cells, fibrosis, and angiogenesis in the tumor microenvironment.
Intelligence in childhood, as measured by psychometric cognitive tests, is a strong predictor of many important life outcomes, including educational attainment, income, health and lifespan. Results ...from twin, family and adoption studies are consistent with general intelligence being highly heritable and genetically stable throughout the life course. No robustly associated genetic loci or variants for childhood intelligence have been reported. Here, we report the first genome-wide association study (GWAS) on childhood intelligence (age range 6-18 years) from 17,989 individuals in six discovery and three replication samples. Although no individual single-nucleotide polymorphisms (SNPs) were detected with genome-wide significance, we show that the aggregate effects of common SNPs explain 22-46% of phenotypic variation in childhood intelligence in the three largest cohorts (P=3.9 × 10(-15), 0.014 and 0.028). FNBP1L, previously reported to be the most significantly associated gene for adult intelligence, was also significantly associated with childhood intelligence (P=0.003). Polygenic prediction analyses resulted in a significant correlation between predictor and outcome in all replication cohorts. The proportion of childhood intelligence explained by the predictor reached 1.2% (P=6 × 10(-5)), 3.5% (P=10(-3)) and 0.5% (P=6 × 10(-5)) in three independent validation cohorts. Given the sample sizes, these genetic prediction results are consistent with expectations if the genetic architecture of childhood intelligence is like that of body mass index or height. Our study provides molecular support for the heritability and polygenic nature of childhood intelligence. Larger sample sizes will be required to detect individual variants with genome-wide significance.
PDF
