This publication addresses the broader issues of social cost-benefit analysis performed on options to invest in drinking-water supplies, with a focus on small community suppliers. It was written by a ...multi-disciplinary team, bases itself on experience on the ground and provides many practical examples of how to deal with economic issues of drinking-water supply in the context of the livelihood strategies and public health priorities of people living in small communities, from policy to practice.
NRG Oncology/RTOG 9802 (ClinicalTrials.gov Identifier: NCT00003375) is a practice-changing study for patients with WHO low-grade glioma (LGG, grade II), as it was the first to demonstrate a survival ...benefit of adjuvant chemoradiotherapy over radiotherapy. This post hoc study sought to determine the prognostic and predictive impact of the WHO-defined molecular subgroups and corresponding molecular alterations within NRG Oncology/RTOG 9802.
mutations were determined by immunohistochemistry and/or deep sequencing. A custom Ion AmpliSeq panel was used for mutation analysis. 1p/19q codeletion and
promoter methylation were determined by copy-number arrays and/or Illumina 450K array, respectively. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Hazard ratios (HRs) were calculated using the Cox proportional hazard model and tested using the log-rank test. Multivariable analyses (MVAs) were performed incorporating treatment and common prognostic factors as covariates.
Of the eligible patients successfully profiled for the WHO-defined molecular groups (n = 106/251), 26 (24%) were
wild type, 43 (41%) were
mutant/non-codeleted, and 37(35%) were
mutant/codeleted. MVAs demonstrated that WHO subgroup was a significant predictor of PFS after adjustment for clinical variables and treatment. Notably, treatment with postradiation chemotherapy (PCV; procarbazine, lomustine (CCNU), and vincristine) was associated with longer PFS (HR, 0.32;
= .003; HR, 0.13;
< .001) and OS (HR, 0.38;
= .013; HR, 0.21;
= .029) in the
mutant/non-codeleted and
mutant/codeleted subgroups, respectively. In contrast, no significant difference in either PFS or OS was observed with the addition of PCV in the
wild-type subgroup.
This study is the first to report the predictive value of the WHO-defined diagnostic classification in a set of uniformly treated patients with LGG in a clinical trial. Importantly, this post hoc analysis supports the notion that patients with
-mutant high-risk LGG regardless of codeletion status receive benefit from the addition of PCV.
Molecular biotechnology now makes it possible to build elaborate systems models, but the systems biology community needs information standards if models are to be shared, evaluated and developed ...cooperatively.
We summarize the Systems Biology Markup Language (SBML) Level 1, a free, open, XML-based format for representing biochemical reaction networks. SBML is a software-independent language for describing models common to research in many areas of computational biology, including cell signaling pathways, metabolic pathways, gene regulation, and others.
The specification of SBML Level 1 is freely available from http://www.sbml.org/
Establishing and maintaining protected areas (PAs) are key tools for biodiversity conservation. However, this approach is insufficient for many species, particularly those that are wide-ranging and ...sparse. The cheetah Acinonyx jubatus exemplifies such a species and faces extreme challenges to its survival. Here, we show that the global population is estimated at ∼7,100 individuals and confined to 9% of its historical distributional range. However, the majority of current range (77%) occurs outside of PAs, where the species faces multiple threats. Scenario modeling shows that, where growth rates are suppressed outside PAs, extinction rates increase rapidly as the proportion of population protected declines. Sensitivity analysis shows that growth rates within PAs have to be high if they are to compensate for declines outside. Susceptibility of cheetah to rapid decline is evidenced by recent rapid contraction in range, supporting an uplisting of the International Union for the Conservation of Nature (IUCN) Red List threat assessment to endangered. Our results are applicable to other protection-reliant species, which may be subject to systematic underestimation of threat when there is insufficient information outside PAs. Ultimately, conserving many of these species necessitates a paradigm shift in conservation toward a holistic approach that incentivizes protection and promotes sustainable human–wildlife coexistence across large multiple-use landscapes.
ERG (ETS-related gene) is a member of the ETS (Erythroblast-transformation specific) family of transcription factors abundantly present in vascular endothelial cells. Recent studies demonstrate that ...ERG has important roles in blood vessel stability and angiogenesis. However, it is unclear how ERG is potentially involved in microvascular barrier functions and permeability. A wide variety of diseases and clinical conditions including trauma-hemorrhagic shock and burn injury are associated with microvascular dysfunctions, which causes excessive microvascular permeability, tissue edema and eventually, multiple organ dysfunction and death. The main purpose of this study was to determine the specific role of ERG in regulating microvascular permeability in human lung microvascular endothelial cells (HLMEC) and to evaluate if exogenous ERG will protect the barrier. The HLMECs were grown on Transwell inserts as monolayers and were transfected with ERG CRISPR/cas9 knockdown plasmid, ERG CRISPR activation plasmid, recombinant ERG protein or their respective controls. Recombinant vascular endothelial growth factor (VEGF) was used as an inducer of permeability for evaluating the effect of ERG activation on permeability. Changes in barrier integrity and permeability were studied using monolayer permeability assay and immunofluorescence of adherens junction proteins (VE-cadherin and β-catenin) respectively. CRISPR/cas9-based ERG knockdown as well as VEGF treatment induced monolayer hyperpermeability, VE-cadherin, and β-catenin junctional relocation and cytoskeletal F-actin stress fiber formation. CRISPR based ERG activation and recombinant ERG transfection attenuated VEGF-induced monolayer hyperpermeability. ERG activation preserved the adherens junctions and cytoskeleton. These results demonstrate that ERG is a potent regulator of barrier integrity and permeability in human lung microvascular endothelial cells and endogenously or exogenously enhancing ERG provides protection against barrier dysfunction and hyperpermeability.
Smoke from wildland fires has been shown to produce neuroinflammation in preclinical models, characterized by neural infiltrations of neutrophils and monocytes, as well as altered neurovascular ...endothelial phenotypes. To address the longevity of such outcomes, the present study examined the temporal dynamics of neuroinflammation and metabolomics after inhalation exposures from biomass-derived smoke. 2-month-old female C57BL/6 J mice were exposed to wood smoke every other day for 2 weeks at an average exposure concentration of 0.5 mg/m
. Subsequent serial euthanasia occurred at 1-, 3-, 7-, 14-, and 28-day post-exposure. Flow cytometry of right hemispheres revealed two endothelial populations of CD31
and CD31
expressors, with wood smoke inhalation causing an increased proportion of CD31
. These populations of CD31
and CD31
were associated with an anti-inflammatory and pro-inflammatory response, respectively, and their inflammatory profiles were largely resolved by the 28-day mark. However, activated microglial populations (CD11b
/CD45
) remained higher in wood smoke-exposed mice than controls at day 28. Infiltrating neutrophil populations decreased to levels below controls by day 28. However, the MHC-II expression of the peripheral immune infiltrate remained high, and the population of neutrophils retained an increased expression of CD45, Ly6C, and MHC-II. Utilizing an unbiased approach examining the metabolomic alterations, we observed notable hippocampal perturbations in neurotransmitter and signaling molecules, such as glutamate, quinolinic acid, and 5-α-dihydroprogesterone. Utilizing a targeted panel designed to explore the aging-associated NAD
metabolic pathway, wood smoke exposure drove fluctuations and compensations across the 28-day time course, ending with decreased hippocampal NAD
abundance on day 28. Summarily, these results indicate a highly dynamic neuroinflammatory environment, with potential resolution extending past 28 days, the implications of which may include long-term behavioral changes, systemic and neurological sequalae directly associated with wildfire smoke exposure.
The endothelial transcription factor ETS (Erythroblast‐transformation specific)‐related gene (ERG) regulates canonical TGFβ‐SMAD signaling, by repressing SMAD3 activity. SMAD proteins function as ...important mediators of intracellular signal transduction of TGF‐β. Following their phosphorylation by TGF‐β receptor‐I, Receptor‐regulated SMADs (including SMAD2 and SMAD3 proteins) form a heteromeric complex with co‐SMAD and then translocate into the nucleus where they bind and regulate the expression of multiple target genes. Recent studies from our lab have demonstrated that ERG is a critical regulator of permeability in human lung microvascular endothelial cells (HLMECs) where ERG gene activation provided protection to the barrier. We have hypothesized that the protective effects of ERG on barrier integrity may be mediated via inhibiting TGF‐β/SMAD3 signaling pathway. To study the role of SMAD3 in microvascular endothelial barrier functions and permeability, HLMECs were grown on Transwell inserts and other cell culture platforms. Monolayer permeability was evaluated based on FITC‐albumin extravasation and measurement of its fluorescence intensity. TGF‐β (1‐50 ng/ml) induced a dose‐dependent increase in monolayer hyperpermeability. TGF‐β‐induced hyperpermeability was attenuated by a SMAD3 pharmacological inhibitor (SIS3) or CRISPR/cas9‐mediated knockdown of SMAD3. Immunoblot analysis demonstrated highly efficient SMAD3 knockdown by SMAD3 CRISPR/Cas9. TGF‐β treatment resulted in significant increase in matrixmetalloproteinase‐9 (MMP‐9) activity and the effect was decreased by SMAD3 inhibition. MMP‐9 is known to proteolytically breakdown the adherens junction proteins in microvascular endothelial cells, resulting in hyperpermeability. These results demonstrate that SMAD3 is a mediator of TGF‐β signaling‐induced loss of endothelial barrier integrity and permeability in microvascular endothelial cells. It also suggests that one of the downstream effects of TGFβ‐SMAD signaling is the activation of MMP‐9 which mediates loss of adherens junctional integrity.
Objective
One‐half of the 14 million persons in the US with knee osteoarthritis (OA) are not physically active, despite evidence that physical activity (PA) is associated with improved health. We ...undertook this study to estimate both the quality‐adjusted life‐year (QALY) losses in a US population with knee OA due to physical inactivity and the health benefits associated with higher PA levels.
Methods
We used data from the Osteoarthritis Initiative and the Centers for Disease Control and Prevention to estimate the proportions of a US population with knee OA ages ≥45 years that are inactive, insufficiently active, and active, and the likelihood of a shift in their PA level. We used the OA Policy Model, a computer simulation of knee OA, to determine QALYs lost due to inactivity and to measure potential benefits of increased PA (comorbidities averted and QALYs saved).
Results
Among 13.7 million persons with knee OA, a total of 7.5 million QALYs, or 0.55 QALYs per person, were lost due to inactivity or insufficient PA relative to activity over their remaining lifetimes. Black Hispanic women experienced the highest losses, at 0.76 QALYs per person. Women of all races/ethnicities had ~20% higher loss burdens than men. According to our model, if 20% of the inactive population were instead active, 95,920 cases of cancer, 222,413 of cardiovascular disease, and 214,725 of diabetes mellitus would potentially be averted, and 871,541 potential QALYs would be saved.
Conclusion
Physical inactivity leads to substantial QALY losses in a US population with knee OA. Increases in the activity levels in even a fraction of this population may have considerable collateral health benefits, potentially averting cases of cancer, cardiovascular disease, and diabetes mellitus.
Aims
To identify bacteria with high selenium tolerance and reduction capacity for bioremediation of wastewater and nanoselenium particle production.
Methods and Results
A bacterial endophyte was ...isolated from the selenium hyperaccumulator Stanleya pinnata (Brassicaceae) growing on seleniferous soils in Colorado, USA. Based on fatty acid methyl ester analysis and multi‐locus sequence analysis (MLSA) using 16S rRNA, gyrB, rpoB and rpoD genes, the isolate was identified as a subspecies of Pseudomonas moraviensis (97·3% nucleotide identity) and named P. moraviensis stanleyae. The isolate exhibited extreme tolerance to SeO32− (up to 120 mmol l−1) and SeO42− (>150 mmol l−1). Selenium oxyanion removal from growth medium was measured by microchip capillary electrophoresis (detection limit 95 nmol l−1 for SeO32− and 13 nmol l−1 for SeO42−). Within 48 h, P. moraviensis stanleyae aerobically reduced SeO32− to red Se(0) from 10 mmol l−1 to below the detection limit (removal rate 0·27 mmol h−1 at 30°C); anaerobic SeO32− removal was slower. No SeO42− removal was observed. Pseudomonas moraviensis stanleyae stimulated the growth of crop species Brassica juncea by 70% with no significant effect on Se accumulation.
Conclusions
Pseudomonas moraviensis stanleyae can tolerate extreme levels of selenate and selenite and can deplete high levels of selenite under aerobic and anaerobic conditions.
Significance and Impact of the Study
Pseudomonas moraviensis subsp. stanleyae may be useful for stimulating plant growth and for the treatment of Se‐laden wastewater.
Half of the 14 million persons in the US with knee osteoarthritis (OA) are not physically active, despite evidence that physical activity (PA) is associated with improved health. We estimated both ...the quality-adjusted life-year (QALY) losses in the US knee OA population due to physical inactivity and the health benefits associated with higher PA levels.
We used data from the Osteoarthritis Initiative and CDC to estimate the proportions of the US knee OA population aged 45+ that are inactive, insufficiently active, and active and their likelihoods of shifting PA level. We used the Osteoarthritis Policy (OAPol) Model, a computer simulation of knee OA, to determine QALYs lost due to inactivity and to measure potential benefits (comorbidities averted and QALYs saved) of increased PA.
Among 13.7 million persons living with knee OA, 7.5 million total QALYs, or 0.55 QALYs/person, were lost due to inactivity or insufficient PA relative to activity over their remaining lifetimes. Black Hispanic women experienced the highest losses, 0.76 QALYs/person. Females of all races/ethnicities had ~20% higher loss burdens than males. According to our model, if 20% of the inactive population were instead active, 95,920, 222,413, and 214,725 potential cases of cancer, cardiovascular disease, and diabetes would be averted, and 871,541 potential QALYs would be saved.
Physical inactivity leads to substantial QALY losses in the US knee OA population. Increasing activity level in even a fraction of this population may have considerable collateral health benefits, potentially averting cases of cancer, cardiovascular disease, and diabetes. This article is protected by copyright. All rights reserved.
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