Based on published prevalence studies, we used two different methodologies to project the number of individuals with Parkinson disease (PD) in Western Europe's 5 most and the world's 10 most populous ...nations. The number of individuals with PD over age 50 in these countries was between 4.1 and 4.6 million in 2005 and will double to between 8.7 and 9.3 million by 2030.
Climate variability in the high-latitude Southern Hemisphere (SH) is dominated by the SH annular mode, a large-scale pattern of variability characterized by fluctuations in the strength of the ...circumpolar vortex. We present evidence that recent trends in the SH tropospheric circulation can be interpreted as a bias toward the high-index polarity of this pattern, with stronger westerly flow encircling the polar cap. It is argued that the largest and most significant tropospheric trends can be traced to recent trends in the lower stratospheric polar vortex, which are due largely to photochemical ozone losses. During the summer-fall season, the trend toward stronger circumpolar flow has contributed substantially to the observed warming over the Antarctic Peninsula and Patagonia and to the cooling over eastern Antarctica and the Antarctic plateau.
Many tumors are dependent on de novo fatty acid synthesis to maintain cell growth. Fatty acid synthase (FASN) catalyzes the final synthetic step of this pathway, and its upregulation is correlated ...with tumor aggressiveness. The consequences and adaptive responses of acute or chronic inhibition of essential enzymes such as FASN are not fully understood. Herein we identify Fasnall, a thiophenopyrimidine selectively targeting FASN through its co-factor binding sites. Global lipidomics studies with Fasnall showed profound changes in cellular lipid profiles, sharply increasing ceramides, diacylglycerols, and unsaturated fatty acids as well as increasing exogenous palmitate uptake that is deviated more into neutral lipid formation rather than phospholipids. We also showed that the increase in ceramide levels contributes to some extent in the mediation of apoptosis. Consistent with this mechanism of action, Fasnall showed potent anti-tumor activity in the MMTV-Neu model of HER2+ breast cancer, particularly when combined with carboplatin.
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•Fasnall is a thiophenopyrimidine targeting fatty acid synthase•Fasnall has anti-proliferative activity and induces apoptosis in breast cancer cells•Fasnall promotes fatty acid uptake, ceramide and diacylglycerol accumulation•Fasnall is well tolerated and shows efficacy against HER2+ breast tumors in vivo
Many tumors are dependent on de novo fatty acid synthesis. Using a chemoproteomic screen, Alwarawrah et al. identified Fasnall, a thiophenopyrimidine fatty acid synthase inhibitor that displays anti-neoplastic activity against breast cancer in vitro and in vivo.
Besides being building blocks for protein synthesis, amino acids serve a wide variety of cellular functions, including acting as metabolic intermediates for ATP generation and for redox homeostasis. ...Upon amino acid deprivation, free uncharged tRNAs trigger GCN2-ATF4 to mediate the well-characterized transcriptional amino acid response (AAR). However, it is not clear whether the deprivation of different individual amino acids triggers identical or distinct AARs. Here, we characterized the global transcriptional response upon deprivation of one amino acid at a time. With the exception of glycine, which was not required for the proliferation of MCF7 cells, we found that the deprivation of most amino acids triggered a shared transcriptional response that included the activation of ATF4, p53 and TXNIP. However, there was also significant heterogeneity among different individual AARs. The most dramatic transcriptional response was triggered by methionine deprivation, which activated an extensive and unique response in different cell types. We uncovered that the specific methionine-deprived transcriptional response required creatine biosynthesis. This dependency on creatine biosynthesis was caused by the consumption of S-Adenosyl-L-methionine (SAM) during creatine biosynthesis that helps to deplete SAM under methionine deprivation and reduces histone methylations. As such, the simultaneous deprivation of methionine and sources of creatine biosynthesis (either arginine or glycine) abolished the reduction of histone methylation and the methionine-specific transcriptional response. Arginine-derived ornithine was also required for the complete induction of the methionine-deprived specific gene response. Collectively, our data identify a previously unknown set of heterogeneous amino acid responses and reveal a distinct methionine-deprived transcriptional response that results from the crosstalk of arginine, glycine and methionine metabolism via arginine/glycine-dependent creatine biosynthesis.
Overview of ocean power technology Wilberforce, Tabbi; El Hassan, Zaki; Durrant, A. ...
Energy (Oxford),
05/2019, Volume:
175
Journal Article
Peer reviewed
Open access
This work discusses and provides a critical expose of some of the newly emerging renewable energy technologies with special concentration on marine energy generation.
The work shows that there are ...several promising new developments in harvesting marine energy and it examines some of these technologies and discusses their advantages and some of the obstacles that are impeding the commercialization of these emerging technologies. This includes wave energy harvesting, tidal energy harvesting, ocean thermal energy and the utilisation of salinity gradients for electricity generation.
The work emphasises the fact that these new emerging technologies are currently at the developing stages and has a long way to go before successful commercialization and wide adoption become the norm.
The work stresses the need for more research and developmental work to address several of the technical issues that need to be addressed including devices designs, their installation and maintenance, the infrastructure which includes the grid and power transmission as well as losses, their use in arrays, and their longevity.
This work underlines the lack of reliable studies on the long term impacts of these technologies on both the marine environment and nearby habitations and highlights the need for proper environmental and social impact assessments of these technologies.
The work concludes that combination of technical, policy and economic advances will enable marine energy technologies to play a large role in combination with currently adopted non-pollution renewable energy resources to provide the world population with their energy needs and contribute to affecting significant reduction in the use of non-renewable and other polluting fuels worldwide.
Charpy test specimens were additively manufactured (AM) on a single stainless steel plate from a 17–4 class stainless steel using a powder-bed, laser melting technique on an EOS M280 direct metal ...laser sintering (DMLS) machine. Cross-hatched mesh support structures for the Charpy test specimens were varied in strut width and density to parametrically study their influence on the build stability and accuracy as the DMLS process has been known to generate parts with large amounts of residual stress. Neutron diffraction was used to profile the residual stresses in several of the AM samples before and after the samples were removed from the support structure for the purpose of determining residual stresses. The residual stresses were found to depend very little on the properties of the support structure over the limited range studied here. The largest stress component was in the long direction of each of the samples studied and was roughly 2/3 of the yield stress of the material. The stress field was altered considerably when the specimen was removed from the support structure. It was noted in this study that a single Charpy specimen developed a significant tear between the growth plate and support structure. The presence of the tear in the support structure strongly affected the observed stress field: the asymmetric tear resulted in a significantly asymmetric stress field that propagated through removal of the sample from the base plate. The altered final residual stress state of the sample as well as its observed final shape indicates that the tear initiated during the build and developed without disrupting the fabrication process, suggesting a need for in-situ monitoring.
The astrophysical sources of the extraterrestrial, very high-energy neutrinos detected by the IceCube collaboration remain to be identified. Gamma-ray (γ-ray) blazars have been predicted to yield a ...cumulative neutrino signal exceeding the atmospheric background above energies of 100 TeV, assuming that both the neutrinos and the γ-ray photons are produced by accelerated protons in relativistic jets. As the background spectrum falls steeply with increasing energy, the individual events with the clearest signature of being of extraterrestrial origin are those at petaelectronvolt energies. Inside the large positional-uncertainty fields of the first two petaelectronvolt neutrinos detected by IceCube, the integrated emission of the blazar population has a sufficiently high electromagnetic flux to explain the detected IceCube events, but fluences of individual objects are too low to make an unambiguous source association. Here, we report that a major outburst of the blazar PKS B1424-418 occurred in temporal and positional coincidence with a third petaelectronvolt-energy neutrino event (HESE-35) detected by IceCube. On the basis of an analysis of the full sample of γ-ray blazars in the HESE-35 field, we show that the long-term average γ-ray emission of blazars as a class is in agreement with both the measured all-sky flux of petaelectronvolt neutrinos and the spectral slope of the IceCube signal. The outburst of PKS B1424-418 provides an energy output high enough to explain the observed petaelectronvolt event, suggestive of a direct physical association.
Genetic cholestasis has been dissected through genetic investigation. The major PFIC genes are now described. ATP8B1 encodes FIC1, ABCB11 encodes BSEP, ABCB4 encodes MDR3, TJP2 encodes TJP2, NR1H4 ...encodes FXR, and MYO5B encodes MYO5B. The full spectra of phenotypes associated with mutations in each gene are discussed, along with our understanding of the disease mechanisms. Differences in treatment response and targets for future treatment are emerging.
Testosterone supplementation is commonly used for its effects on sexual function, bone health and body composition, yet its effects on disease outcomes are unknown. To better understand this, we ...identified genetic determinants of testosterone levels and related sex hormone traits in 425,097 UK Biobank study participants. Using 2,571 genome-wide significant associations, we demonstrate that the genetic determinants of testosterone levels are substantially different between sexes and that genetically higher testosterone is harmful for metabolic diseases in women but beneficial in men. For example, a genetically determined 1 s.d. higher testosterone increases the risks of type 2 diabetes (odds ratio (OR) = 1.37 (95% confidence interval (95% CI): 1.22-1.53)) and polycystic ovary syndrome (OR = 1.51 (95% CI: 1.33-1.72)) in women, but reduces type 2 diabetes risk in men (OR = 0.86 (95% CI: 0.76-0.98)). We also show adverse effects of higher testosterone on breast and endometrial cancers in women and prostate cancer in men. Our findings provide insights into the disease impacts of testosterone and highlight the importance of sex-specific genetic analyses.
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