It is recognized now that intrinsically disordered proteins (IDPs), which do not have unique 3D structures as a whole or in noticeable parts, constitute a significant fraction of any given proteome. ...IDPs are characterized by an astonishing structural and functional diversity that defines their ability to be universal regulators of various cellular pathways. Programmed cell death (PCD) is one of the most intricate cellular processes where the cell uses specialized cellular machinery and intracellular programs to kill itself. This cell-suicide mechanism enables metazoans to control cell numbers and to eliminate cells that threaten the animal's survival. PCD includes several specific modules, such as apoptosis, autophagy, and programmed necrosis (necroptosis). These modules are not only tightly regulated but also intimately interconnected and are jointly controlled via a complex set of protein-protein interactions. To understand the role of the intrinsic disorder in controlling and regulating the PCD, several large sets of PCD-related proteins across 28 species were analyzed using a wide array of modern bioinformatics tools. This study indicates that the intrinsic disorder phenomenon has to be taken into consideration to generate a complete picture of the interconnected processes, pathways, and modules that determine the essence of the PCD. We demonstrate that proteins involved in regulation and execution of PCD possess substantial amount of intrinsic disorder. We annotate functional roles of disorder across and within apoptosis, autophagy, and necroptosis processes. Disordered regions are shown to be implemented in a number of crucial functions, such as protein-protein interactions, interactions with other partners including nucleic acids and other ligands, are enriched in post-translational modification sites, and are characterized by specific evolutionary patterns. We mapped the disorder into an integrated network of PCD pathways and into the interactomes of selected proteins that are involved in the p53-mediated apoptotic signaling pathway.
Improved limit on the muon electric dipole moment Bennett, G. W.; Bousquet, B.; Brown, H. N. ...
Physical review. D, Particles, fields, gravitation, and cosmology,
09/2009, Letnik:
80, Številka:
5
Journal Article
By applying the principles of real-time biopsy, biomarker-based, adaptively randomized studies in non-small-cell lung cancer (NSCLC) established by the Biomarker-Integrated Approaches of Targeted ...Therapy for Lung Cancer Elimination (BATTLE) trial, we conducted BATTLE-2 (BATTLE-2 Program: A Biomarker-Integrated Targeted Therapy Study in Previously Treated Patients With Advanced Non-Small Cell Lung Cancer), an umbrella study to evaluate the effects of targeted therapies focusing on KRAS-mutated cancers.
Patients with advanced NSCLC (excluding sensitizing EGFR mutations and ALK gene fusions) refractory to more than one prior therapy were randomly assigned, stratified by KRAS status, to four arms: (1) erlotinib, (2) erlotinib plus MK-2206, (3) MK-2206 plus AZD6244, or (4) sorafenib. Tumor gene expression profiling-targeted next-generation sequencing was performed to evaluate predictive and prognostic biomarkers.
Two hundred patients, 27% with KRAS-mutated (KRAS mut+) tumors, were adaptively randomly assigned to erlotinib (n = 22), erlotinib plus MK-2206 (n = 42), MK-2206 plus AZD6244 (n = 75), or sorafenib (n = 61). In all, 186 patients were evaluable, and the primary end point of an 8-week disease control rate (DCR) was 48% (arm 1, 32%; arm 2, 50%; arm 3, 53%; and arm 4, 46%). For KRAS mut+ patients, DCR was 20%, 25%, 62%, and 44% whereas for KRAS wild-type patients, DCR was 36%, 57%, 49%, and 47% for arms 1, 2, 3, and 4, respectively. Median progression-free survival was 2.0 months, not different by KRAS status, 1.8 months for arm 1, and 2.5 months for arms 2 versus arms 3 and 4 in KRAS mut+ patients (P = .04). Median overall survival was 6.5 months, 9.0 and 5.1 months for arms 1 and 2 versus arms 3 and 4 in KRAS wild-type patients (P = .03). Median overall survival was 7.5 months in mesenchymal versus 5 months in epithelial tumors (P = .02).
Despite improved progression-free survival on therapy that did not contain erlotinib for KRAS mut+ patients and improved prognosis for mesenchymal tumors, better biomarker-driven treatment strategies are still needed.
A numerical model including 29 reactions and 11 species is developed to investigate the spatial-temporal distributions of species and electric field in oxygen parallel-plate positive pulsed ...dielectric barrier discharge for ozone generation. Electron energy conservation equation is coupled to electron continuity equation, heavy species continuity equation and Poisson's equation. The spatial-temporal distributions of species and electric field are obtained at electron avalanche and during streamer propagation. The results show the dominant positive ion, negative ion and excited species are O2+, O3− and O2(∑g+1), respectively. The average streamer propagation velocity is about 5.56 × 104 m/s. Overall electron density almost increases exponentially but with a violent oscillation in the vicinity of anode at electron avalanche. Electron density increases at first and then declines in the vicinity of anode and streamer channel during streamer propagation, and increases gradually in streamer head with the development of streamer, as well as reduces sharply to almost zero near cathode. Electron density almost remains constant in whole streamer channel at any one moment. Other species have a similar spatial-temporal distribution.
•A plasma fluid and chemical model coupling electron energy conservation is developed.•Spatial-temporal distribution of species and electric field were obtained in oxygen pulsed DBD.•Obvious oscillations present near anode and the streamer propagation velocity is about 5.56 × 104 m/s.
Our understanding and quantification of global soil nitrous oxide (N2O) emissions and the underlying processes remain largely uncertain. Here, we assessed the effects of multiple anthropogenic and ...natural factors, including nitrogen fertilizer (N) application, atmospheric N deposition, manure N application, land cover change, climate change, and rising atmospheric CO2 concentration, on global soil N2O emissions for the period 1861–2016 using a standard simulation protocol with seven process‐based terrestrial biosphere models. Results suggest global soil N2O emissions have increased from 6.3 ± 1.1 Tg N2O‐N/year in the preindustrial period (the 1860s) to 10.0 ± 2.0 Tg N2O‐N/year in the recent decade (2007–2016). Cropland soil emissions increased from 0.3 Tg N2O‐N/year to 3.3 Tg N2O‐N/year over the same period, accounting for 82% of the total increase. Regionally, China, South Asia, and Southeast Asia underwent rapid increases in cropland N2O emissions since the 1970s. However, US cropland N2O emissions had been relatively flat in magnitude since the 1980s, and EU cropland N2O emissions appear to have decreased by 14%. Soil N2O emissions from predominantly natural ecosystems accounted for 67% of the global soil emissions in the recent decade but showed only a relatively small increase of 0.7 ± 0.5 Tg N2O‐N/year (11%) since the 1860s. In the recent decade, N fertilizer application, N deposition, manure N application, and climate change contributed 54%, 26%, 15%, and 24%, respectively, to the total increase. Rising atmospheric CO2 concentration reduced soil N2O emissions by 10% through the enhanced plant N uptake, while land cover change played a minor role. Our estimation here does not account for indirect emissions from soils and the directed emissions from excreta of grazing livestock. To address uncertainties in estimating regional and global soil N2O emissions, this study recommends several critical strategies for improving the process‐based simulations.
The ensemble of terrestrial biosphere models indicates that global soil N2O emissions have increased from 6.3 ± 1.1 Tg N2O‐N/year in the preindustrial period (the 1860s) to 10.0 ± 2.0 Tg N2O‐N/year in the recent decade (2007–2016). Cropland soil emissions increased from 0.3 Tg N2O‐N/year to 3.3 Tg N2O‐N/year over the same period, accounting for 82% of the total increase, among which 54% attributes to nitrogen fertilizer application. Regionally, China, South Asia, and Southeast Asia underwent rapid increases in cropland N2O emissions since the 1970s. However, European cropland N2O emissions appear to have decreased by 14%.
Chest CT is emerging as a valuable diagnostic tool for clinical management of COVID-19 associated lung disease. Artificial intelligence (AI) has the potential to aid in rapid evaluation of CT scans ...for differentiation of COVID-19 findings from other clinical entities. Here we show that a series of deep learning algorithms, trained in a diverse multinational cohort of 1280 patients to localize parietal pleura/lung parenchyma followed by classification of COVID-19 pneumonia, can achieve up to 90.8% accuracy, with 84% sensitivity and 93% specificity, as evaluated in an independent test set (not included in training and validation) of 1337 patients. Normal controls included chest CTs from oncology, emergency, and pneumonia-related indications. The false positive rate in 140 patients with laboratory confirmed other (non COVID-19) pneumonias was 10%. AI-based algorithms can readily identify CT scans with COVID-19 associated pneumonia, as well as distinguish non-COVID related pneumonias with high specificity in diverse patient populations.
A trial involving patients with various types of acute stroke and in a variety of health care settings compared a lying-flat position with a sitting-up position (with head elevated to ≥30 degrees) ...for 24 hours. Results showed no between-group difference in disability outcomes.
The prognosis in patients with acute ischemic stroke is determined according to the location and size of the occluded cerebral vessel,
1
the extent of collateral blood flow,
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and the time to reperfusion therapy.
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Small, nonrandomized studies have indicated that the lying-flat position (i.e., fully supine with the back horizontal and the face upwards) increases blood flow in major arteries
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and improves oxygenation of the brain,
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,
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whereas a sitting-up body position with the head elevated (hereafter referred to as the “sitting-up position”) may reduce intracranial pressure in patients with large hemispheric ischemic stroke.
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Uncertainty over the role of . . .
The association between intake of fruits, vegetables, and legumes with cardiovascular disease and deaths has been investigated extensively in Europe, the USA, Japan, and China, but little or no data ...are available from the Middle East, South America, Africa, or south Asia.
We did a prospective cohort study (Prospective Urban Rural Epidemiology PURE in 135 335 individuals aged 35 to 70 years without cardiovascular disease from 613 communities in 18 low-income, middle-income, and high-income countries in seven geographical regions: North America and Europe, South America, the Middle East, south Asia, China, southeast Asia, and Africa. We documented their diet using country-specific food frequency questionnaires at baseline. Standardised questionnaires were used to collect information about demographic factors, socioeconomic status (education, income, and employment), lifestyle (smoking, physical activity, and alcohol intake), health history and medication use, and family history of cardiovascular disease. The follow-up period varied based on the date when recruitment began at each site or country. The main clinical outcomes were major cardiovascular disease (defined as death from cardiovascular causes and non-fatal myocardial infarction, stroke, and heart failure), fatal and non-fatal myocardial infarction, fatal and non-fatal strokes, cardiovascular mortality, non-cardiovascular mortality, and total mortality. Cox frailty models with random effects were used to assess associations between fruit, vegetable, and legume consumption with risk of cardiovascular disease events and mortality.
Participants were enrolled into the study between Jan 1, 2003, and March 31, 2013. For the current analysis, we included all unrefuted outcome events in the PURE study database through March 31, 2017. Overall, combined mean fruit, vegetable and legume intake was 3·91 (SD 2·77) servings per day. During a median 7·4 years (5·5–9·3) of follow-up, 4784 major cardiovascular disease events, 1649 cardiovascular deaths, and 5796 total deaths were documented. Higher total fruit, vegetable, and legume intake was inversely associated with major cardiovascular disease, myocardial infarction, cardiovascular mortality, non-cardiovascular mortality, and total mortality in the models adjusted for age, sex, and centre (random effect). The estimates were substantially attenuated in the multivariable adjusted models for major cardiovascular disease (hazard ratio HR 0·90, 95% CI 0·74–1·10, ptrend=0·1301), myocardial infarction (0·99, 0·74–1·31; ptrend=0·2033), stroke (0·92, 0·67–1·25; ptrend=0·7092), cardiovascular mortality (0·73, 0·53–1·02; ptrend=0·0568), non-cardiovascular mortality (0·84, 0·68–1·04; ptrend =0·0038), and total mortality (0·81, 0·68–0·96; ptrend<0·0001). The HR for total mortality was lowest for three to four servings per day (0·78, 95% CI 0·69–0·88) compared with the reference group, with no further apparent decrease in HR with higher consumption. When examined separately, fruit intake was associated with lower risk of cardiovascular, non-cardiovascular, and total mortality, while legume intake was inversely associated with non-cardiovascular death and total mortality (in fully adjusted models). For vegetables, raw vegetable intake was strongly associated with a lower risk of total mortality, whereas cooked vegetable intake showed a modest benefit against mortality.
Higher fruit, vegetable, and legume consumption was associated with a lower risk of non-cardiovascular, and total mortality. Benefits appear to be maximum for both non-cardiovascular mortality and total mortality at three to four servings per day (equivalent to 375–500 g/day).
Full funding sources listed at the end of the paper (see Acknowledgments).
This paper presents a novel micro end-milling cutting forces prediction methodology including the edge radius, material strengthening, varying sliding friction coefficient and run-out together. A new ...iterative algorithm is proposed to evaluate the effective rake angle, shear angle and friction angle, which takes into account the effects of edge radius as well as varying sliding friction coefficient. A modified Johnson–Cook constitutive model is introduced to estimate the shear flow stress. This model considers not only the strain-hardening, strain-rate and temperature but also the material strengthening. Furthermore, a generalized algorithm is presented to calculate uncut chip thickness considering run-out. The cutting forces model is calibrated and validated by NAK80 steel, and the relevant micro slot end-milling experiments are carried out on a 3-axis ultra-precision micro-milling machine. The comparison of the predicted and measured cutting forces shows that the proposed model can provide very accurate predicted results. Finally, the effects of material strengthening, edge radius and cutting speed on the cutting forces are investigated by the proposed model and some conclusions are given as follows: (1) the material strengthening behavior has significant effect on micro end-milling process at the micron level. (2) Cutting forces predicted increase with the increase of edge radius. (3) Considering varying sliding friction coefficient can enhance the sensitivity of the predicted cutting forces to cutting speed.
•A novel micro end-milling cutting forces prediction methodology was presented.•Edge radius, material strengthening and sliding friction coefficient were considered.•Material strengthening has a significant effect on cutting forces at micron level.•Cutting forces predicted increase with the increase of edge radius.•Varying sliding friction coefficient affects the predicted cutting forces.
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