The diacylglycerol kinase α/Atypical PKC/β1 integrin pathway in SDF-1α mammary carcinoma invasiveness

Diacylglycerol kinase α (DGKα), by phosphorylating diacylglycerol into phosphatidic acid, provides a key signal driving cell migration and matrix invasion. We previously demonstrated that in epithelial cells activation of DGKα activity promotes cytoskeletal remodeling and matrix invasion by recruiting atypical PKC at ruffling sites and by promoting RCP-mediated recycling of α5β1 integrin to the tip of pseudopods. In here we investigate the signaling pathway by which DGKα mediates SDF-1α-induced matrix invasion of MDA-MB-231 invasive breast carcinoma cells. Indeed we showed that, following SDF-1α stimulation, DGKα is activated and localized at cell protrusion, thus promoting their elongation and mediating SDF-1α induced MMP-9 metalloproteinase secretion and matrix invasion. Phosphatidic acid generated by DGKα promotes localization at cell protrusions of atypical PKCs which play an essential role downstream of DGKα by promoting Rac-mediated protrusion elongation and localized recruitment of β1 integrin and MMP-9. We finally demonstrate that activation of DGKα, atypical PKCs signaling and β1 integrin are all essential for MDA-MB-231 invasiveness. These data indicates the existence of a SDF-1α induced DGKα - atypical PKC - β1 integrin signaling pathway, which is essential for matrix invasion of carcinoma cells

Bcl-2 protein family: Implications in vascular apoptosis and atherosclerosis

Apoptosis has been recognized as a central component in the pathogenesis of atherosclerosis, in addition to the other human pathologies such as cancer and diabetes. The pathophysiology of atherosclerosis is complex, involving both apoptosis and proliferation at different phases of its progression. Oxidative modification of lipids and inflammation differentially regulate the apoptotic and proliferative responses of vascular cells during progression of the atherosclerotic lesion. Bcl-2 proteins act as the major regulators of extrinsic and intrinsic apoptosis signalling pathways and more recently it has become evident that they mediate the apoptotic response of vascular cells in response to oxidation and inflammation either in a provocative or an inhibitory mode of action. Here we address Bcl-2 proteins as major therapeutic targets for the treatment of atherosclerosis and underscore the need for the novel preventive and therapeutic interventions against atherosclerosis, which should be designed in the light of molecular mechanisms regulating apoptosis of vascular cells in atherosclerotic lesions

The intensification of metallic layered phenomena above thunderstorms through the modulation of atmospheric tides

We present a multi-instrument experiment to study the effects of tropospheric thunderstorms on the mesopause region and the lower ionosphere. Sodium (Na) lidar and ionospheric observations by two digital ionospheric sounders are used to study the variation in the neutral metal atoms and metallic ions above thunderstorms. An enhanced ionospheric sporadic E layer with a downward tidal phase is observed followed by a subsequent intensification of neutral Na number density with an increase of 600 cm−3 in the mesosphere. In addition, the Na neutral chemistry and ion-molecule chemistry are considered in a Na chemistry model to simulate the dynamical and chemical coupling processes in the mesosphere and ionosphere above thunderstorms. The enhanced Na layer in the simulation obtained by using the ionospheric observation as input is in agreement with the Na lidar observation. We find that the intensification of metallic layered phenomena above thunderstorms is associated with the atmospheric tides, as a result of the troposphere-mesosphere-ionosphere coupling

Prostate cancer disparities in Black men of African descent: a comparative literature review of prostate cancer burden among Black men in the United States, Caribbean, United Kingdom, and West Africa

<p>Abstract</p> <p>Background</p> <p>African American men have the highest prostate cancer morbidity and mortality rates than any other racial or ethnic group in the US. Although the overall incidence of and mortality from prostate cancer has been declining in White men since 1991, the decline in African American men lags behind White men. Of particular concern is the growing literature on the disproportionate burden of prostate cancer among other Black men of West African ancestry in the Caribbean Islands, United Kingdom and West Africa. This higher incidence of prostate cancer observed in populations of African descent may be attributed to the fact that these populations share ancestral genetic factors. To better understand the burden of prostate cancer among men of West African Ancestry, we conducted a review of the literature on prostate cancer incidence, prevalence, and mortality in the countries connected by the Transatlantic Slave Trade.</p> <p>Results</p> <p>Several published studies indicate high prostate cancer burden in Nigeria and Ghana. There was no published literature for the countries Benin, Gambia and Senegal that met our review criteria. Prostate cancer morbidity and/or mortality data from the Caribbean Islands and the United Kingdom also provided comparable or worse prostate cancer burden to that of US Blacks.</p> <p>Conclusion</p> <p>The growing literature on the disproportionate burden of prostate cancer among other Black men of West African ancestry follows the path of the Transatlantic Slave Trade. To better understand and address the global prostate cancer disparities seen in Black men of West African ancestry, future studies should explore the genetic and environmental risk factors for prostate cancer among this group.</p

Leaching as a pretreatment process to complement torrefaction in improving co-firing characteristics of Jatropha curcas seed cake

The presence of certain inorganic elements in biomass causes issues such as slagging, fouling and corrosion when co-firing with coal for power generation. In this work, the efficacy of leaching to remove these elements from Jatropha curcas seed cake was investigated. Leaching of both untorrefied and torrefied seed cakes was carried out in Milli-Q water at temperatures of 20, 35 and 50 °C. At 20 °C, the two critical elements, potassium and chlorine, decreased by as much as 85 and 97 %, respectively. Leaching at higher temperatures was only beneficial for the more intensely torrefied biomass, since they were more resistant to leaching. The electrical conductivity and ion content of the leachates were measured, as were the inorganic elemental content, dry ash content, volatile matter content and higher heating value (HHV) of the solid seed cake. A secondary benefit of the leaching was an increase in the HHV by up to 10 %

MDCK Cystogenesis Driven by Cell Stabilization within Computational Analogues

The study of epithelial morphogenesis is fundamental to increasing our understanding of organ function and disease. Great progress has been made through study of culture systems such as Madin-Darby canine kidney (MDCK) cells, but many aspects of even simple morphogenesis remain unclear. For example, are specific cell actions tightly coupled to the characteristics of the cell's environment or are they more often cell state dependent? How does the single lumen, single cell layer cyst consistently emerge from a variety of cell actions? To improve insight, we instantiated in silico analogues that used hypothesized cell behavior mechanisms to mimic MDCK cystogenesis. We tested them through in vitro experimentation and quantitative validation. We observed novel growth patterns, including a cell behavior shift that began around day five of growth. We created agent-oriented analogues that used the cellular Potts model along with an Iterative Refinement protocol. Following several refinements, we achieved a degree of validation for two separate mechanisms. Both survived falsification and achieved prespecified measures of similarity to cell culture properties. In silico components and mechanisms mapped to in vitro counterparts. In silico, the axis of cell division significantly affects lumen number without changing cell number or cyst size. Reducing the amount of in silico luminal cell death had limited effect on cystogenesis. Simulations provide an observable theory for cystogenesis based on hypothesized, cell-level operating principles

Fibrocytes are associated with vascular and parenchymal remodelling in patients with obliterative bronchiolitis

<p>Abstract</p> <p>Background</p> <p>The aim of the present study was to explore the occurrence of fibrocytes in tissue and to investigate whether the appearance of fibrocytes may be linked to structural changes of the parenchyme and vasculature in the lungs of patients with obliterative bronchiolitis (OB) following lung or bone marrow transplantation.</p> <p>Methods</p> <p>Identification of parenchyme, vasculature, and fibrocytes was done by histological methods in lung tissue from bone marrow or lung-transplanted patients with obliterative bronchiolitis, and from controls.</p> <p>Results</p> <p>The transplanted patients had significantly higher amounts of tissue in the alveolar parenchyme (46.5 ± 17.6%) than the controls (21.7 ± 7.6%) (p < 0.05). The patients also had significantly increased numbers of fibrocytes identified by CXCR4/prolyl4-hydroxylase, CD45R0/prolyl4-hydroxylase, and CD34/prolyl4-hydroxylase compared to the controls (p < 0.01). There was a correlation between the number of fibrocytes and the area of alveolar parenchyma; CXCR4/prolyl 4-hydroxylase (p < 0.01), CD45R0/prolyl 4-hydroxylase (p < 0.05) and CD34/prolyl 4-hydroxylase (p < 0.05). In the pulmonary vessels, there was an increase in the endothelial layer in patients (0.31 ± 0.13%) relative to the controls (0.037 ± 0.02%) (p < 0.01). There was a significant correlation between the number of fibrocytes and the total area of the endothelial layer CXCR4/prolyl 4-hydroxylase (p < 0.001), CD45R0/prolyl 4-hydroxylase (p < 0.001) and CD34/prolyl 4-hydroxylase (p < 0.01). The percent areas of the lumen of the vessels were significant (p < 0.001) enlarged in the patient with OB compared to the controls. There was also a correlation between total area of the lumen and number of fibrocytes, CXCR4/prolyl 4-hydroxylase (p < 0.01), CD45R0/prolyl 4-hydroxylase (p < 0.001) and CD34/prolyl 4-hydroxylase (p < 0.01).</p> <p>Conclusion</p> <p>Our results indicate that fibrocytes are associated with pathological remodelling processes in patients with OB and that tissue fibrocytes might be a useful biomarker in these processes.</p

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015

SummaryBackground The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding Bill & Melinda Gates Foundation

Photobacterium profundum under Pressure:A MS-Based Label-Free Quantitative Proteomics Study

Photobacterium profundum SS9 is a Gram-negative bacterium, originally collected from the Sulu Sea. Its genome consists of two chromosomes and a 80 kb plasmid. Although it can grow under a wide range of pressures, P. profundum grows optimally at 28 MPa and 15°C. Its ability to grow at atmospheric pressure allows for both easy genetic manipulation and culture, making it a model organism to study piezophily. Here, we report a shotgun proteomic analysis of P. profundum grown at atmospheric compared to high pressure using label-free quantitation and mass spectrometry analysis. We have identified differentially expressed proteins involved in high pressure adaptation, which have been previously reported using other methods. Proteins involved in key metabolic pathways were also identified as being differentially expressed. Proteins involved in the glycolysis/gluconeogenesis pathway were up-regulated at high pressure. Conversely, several proteins involved in the oxidative phosphorylation pathway were up-regulated at atmospheric pressure. Some of the proteins that were differentially identified are regulated directly in response to the physical impact of pressure. The expression of some proteins involved in nutrient transport or assimilation, are likely to be directly regulated by pressure. In a natural environment, different hydrostatic pressures represent distinct ecosystems with their own particular nutrient limitations and abundances. However, the only variable considered in this study was atmospheric pressure

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente