Climate strongly influences global wildfire activity, and recent wildfire surges may signal fire weather-induced pyrogeographic shifts. Here we use three daily global climate data sets and three fire ...danger indices to develop a simple annual metric of fire weather season length, and map spatio-temporal trends from 1979 to 2013. We show that fire weather seasons have lengthened across 29.6 million km(2) (25.3%) of the Earth's vegetated surface, resulting in an 18.7% increase in global mean fire weather season length. We also show a doubling (108.1% increase) of global burnable area affected by long fire weather seasons (>1.0 σ above the historical mean) and an increased global frequency of long fire weather seasons across 62.4 million km(2) (53.4%) during the second half of the study period. If these fire weather changes are coupled with ignition sources and available fuel, they could markedly impact global ecosystems, societies, economies and climate.
Five years after the last prostatic carcinoma grading consensus conference of the International Society of Urological Pathology (ISUP), accrual of new data and modification of clinical practice ...require an update of current pathologic grading guidelines. This manuscript summarizes the proceedings of the ISUP consensus meeting for grading of prostatic carcinoma held in September 2019, in Nice, France. Topics brought to consensus included the following: (1) approaches to reporting of Gleason patterns 4 and 5 quantities, and minor/tertiary patterns, (2) an agreement to report the presence of invasive cribriform carcinoma, (3) an agreement to incorporate intraductal carcinoma into grading, and (4) individual versus aggregate grading of systematic and multiparametric magnetic resonance imaging-targeted biopsies. Finally, developments in the field of artificial intelligence in the grading of prostatic carcinoma and future research perspectives were discussed.
Influence of Triplet Instabilities in TDDFT Peach, Michael J. G; Williamson, Matthew J; Tozer, David J
Journal of chemical theory and computation,
11/2011, Volume:
7, Issue:
11
Journal Article
Peer reviewed
Open access
Singlet and triplet vertical excitation energies from time-dependent density functional theory (TDDFT) can be affected in different ways by the inclusion of exact exchange in hybrid or ...Coulomb-attenuated/range-separated exchange–correlation functionals; in particular, triplet excitation energies can become significantly too low. To investigate these issues, the explicit dependence of excitation energies on exact exchange is quantified for four representative molecules, paying attention to the effect of constant, short-range, and long-range contributions. A stability analysis is used to verify that the problematic TDDFT triplet excitations can be understood in terms of the ground state triplet instability problem, and it is proposed that a Hartree–Fock stability analysis should be used to identify triplet excitations for which the presence of exact exchange in the TDDFT functional is undesirable. The use of the Tamm–Dancoff approximation (TDA) significantly improves the problematic triplet excitation energies, recovering the correct state ordering in benzoquinone; it also affects the corresponding singlet states, recovering the correct state ordering in naphthalene. The impressive performance of the TDA is maintained for a wide range of molecules across representative functionals.
Super-resolution microscopy has revealed that immune cell receptors are organized in nanoscale clusters at cell surfaces and immune synapses. However, mechanisms and functions for this nanoscale ...organization remain unclear. Here, we used super-resolution microscopy to compare the surface organization of paired killer Ig-like receptors (KIR), KIR2DL1 and KIR2DS1, on human primary natural killer cells and cell lines. Activating KIR2DS1 assembled in clusters two-fold larger than its inhibitory counterpart KIR2DL1. Site-directed mutagenesis established that the size of nanoclusters is controlled by transmembrane amino acid 233, a lysine in KIR2DS1. Super-resolution microscopy also revealed two ways in which the nanoscale clustering of KIR affects signaling. First, KIR2DS1 and DAP12 nanoclusters are juxtaposed in the resting cell state but coalesce upon receptor ligation. Second, quantitative super-resolution microscopy revealed that phosphorylation of the kinase ZAP-70 or phosphatase SHP-1 is favored in larger KIR nanoclusters. Thus, the size of KIR nanoclusters depends on the transmembrane sequence and affects downstream signaling.
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•Activating and inhibitory NK cell receptors have a distinct nanoscale organization•The transmembrane sequence of KIR controls their nanoscale organization•Nanoclusters of KIR2DS1 and its adaptor are juxtaposed but mix upon activation•Phosphorylation of ZAP-70 or SHP-1 is favored in larger receptor nanoclusters
Oszmiana et al. use different super-resolution microscopy techniques to compare the nanoscale organization of paired activating and inhibitory receptors at the human NK cell surface. They show that the size of receptor nanoclusters is controlled by the transmembrane sequence and establish that nanocluster size affects the strength of receptor signaling.
There is mounting concern that global wildfire activity is shifting in frequency, intensity, and seasonality in response to climate change. Fuel moisture provides a powerful means of detecting ...changing fire potential. Here, we use global burned area, weather reanalysis data, and the Canadian fire weather index system to calculate fuel moisture trends for multiscale biogeographic regions across a gradient in vegetation productivity. We quantify the proportion of days in the local fire season between 1979 and 2019, where fuel moisture content is below a critical threshold indicating extreme fire potential. We then associate fuel moisture trends over that period to vegetation productivity and comment on its implications for projected anthropogenic climate change. Overall, there is a strong drying trend across realms, biomes, and the productivity gradient. Even where a wetting trend is observed, this often indicates a trend toward increasing fire activity due to an expected increase in fuel production. The detected trends across the productivity gradient lead us to conclude global fire activity will increase with anthropogenic climate change.
The last 40 years have seen a strong drying trend across wildfire fuels worldwide. Even where a wetting trend is observed, this often indicates a trend toward increasing fire activity due to an expected increase in fuel production. These detected trends lead us to conclude global fire activity will increase with anthropogenic climate change.
Lipid microdomains are postulated to regulate many membrane-associated processes but have remained highly controversial. Here we provide the first direct evidence that the plasma membrane of intact, ...live cells is comprised of a sub-resolution mixture of approximately 76% ordered and 24% disordered lipid domains, which correspond to liquid-ordered and -disordered model membranes. These measurements were based on the unmixing of fluorescence lifetime decays (phasor analysis) obtained from environmentally sensitive membrane dyes that report the degree of lipid packing. Using the transmembrane protein Linker for Activation of T cells (LAT) as an example, we demonstrate that association with ordered domains retarded LAT diffusion and decreased clustering in meso-scaled protein domains as analysed by super-resolution microscopy. Our data therefore propose a membrane model in which the majority of the plasma membrane is covered by cholesterol-dependent, ordered lipid domains that contribute to the non-random distribution and diffusion of membrane constituents.
Solution-processed organic photovoltaic cells (OPVs) hold great promise to enable roll-to-roll printing of environmentally friendly, mechanically flexible and cost-effective photovoltaic devices. ...Nevertheless, many high-performing systems show best power conversion efficiencies (PCEs) with a thin active layer (thickness is ~100 nm) that is difficult to translate to roll-to-roll processing with high reproducibility. Here we report a new molecular donor, benzodithiophene terthiophene rhodanine (BTR), which exhibits good processability, nematic liquid crystalline behaviour and excellent optoelectronic properties. A maximum PCE of 9.3% is achieved under AM 1.5G solar irradiation, with fill factor reaching 77%, rarely achieved in solution-processed OPVs. Particularly promising is the fact that BTR-based devices with active layer thicknesses up to 400 nm can still afford high fill factor of ~70% and high PCE of ~8%. Together, the results suggest, with better device architectures for longer device lifetime, BTR is an ideal candidate for mass production of OPVs.
Pirfenidone is an antifibrotic agent that has been evaluated in three multinational phase 3 trials in patients with idiopathic pulmonary fibrosis (IPF). We analysed pooled data from the multinational ...trials to obtain the most precise estimates of the magnitude of treatment effect on measures of disease progression.All patients randomised to pirfenidone 2403 mg·day(-1) or placebo in the CAPACITY or ASCEND studies were included in the analysis. Pooled analyses of outcomes at 1 year were based on the pre-specified end-points and analytic methods described in the ASCEND study protocol.A total of 1247 patients were included in the analysis. At 1 year, pirfenidone reduced the proportion of patients with a ≥10% decline in per cent predicted forced vital capacity or death by 43.8% (95% CI 29.3-55.4%) and increased the proportion of patients with no decline by 59.3% (95% CI 29.0-96.8%). A treatment benefit was also observed for progression-free survival, 6-min walk distance and dyspnoea. Gastrointestinal and skin-related adverse events were more common in the pirfenidone group, but rarely led to discontinuation.Analysis of data from three phase 3 trials demonstrated that treatment with pirfenidone for 1 year resulted in clinically meaningful reductions in disease progression in patients with IPF.
In clinical trials of idiopathic pulmonary fibrosis, rates of all-cause mortality are low. Thus prospective mortality trials are logistically very challenging, justifying the use of pooled analyses ...or meta-analyses. We did pooled analyses and meta-analyses of clinical trials of pirfenidone versus placebo to determine the effect of pirfenidone on mortality outcomes over 120 weeks.
We did a pooled analysis of the combined patient populations of the three global randomised phase 3 trials of pirfenidone versus placebo-Clinical Studies Assessing Pirfenidone in Idiopathic Pulmonary Fibrosis: Research of Efficacy and Safety Outcomes (CAPACITY 004 and 006; trial durations 72-120 weeks) and Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis (ASCEND 016; 52 weeks)-for all-cause mortality, treatment-emergent all-cause mortality, idiopathic-pulmonary-fibrosis-related mortality, and treatment-emergent idiopathic-pulmonary-fibrosis-related mortality at weeks 52, 72, and 120. We also did meta-analyses of these data and data from two Japanese trials of pirfenidone versus placebo-Shionogi Phase 2 (SP2) and Shionogi Phase 3 (SP3; trial durations 36-52 weeks).
At week 52, the relative risk of death for all four mortality outcomes was significantly lower in the pirfenidone group than in the placebo group in the pooled population (all-cause mortality hazard ratio HR 0·52 95% CI 0·31-0·87; p=0·0107; treatment-emergent all-cause mortality 0·45 0·24-0·83; 0·0094; idiopathic-pulmonary-fibrosis-related mortality 0·35 0·17-0·72; 0·0029; treatment-emergent idiopathic-pulmonary-fibrosis-related mortality 0·32 0·14-0·76; 0·0061). Consistent with the pooled analysis, meta-analyses for all-cause mortality at week 52 also showed a clinically relevant and significant risk reduction in the pirfenidone group compared with the placebo group. Over 120 weeks, we noted significant differences in the pooled analysis favouring pirfenidone therapy compared with placebo for treatment-emergent all-cause mortality (p=0·0420), idiopathic-pulmonary-fibrosis-related mortality (0·0237), and treatment-emergent idiopathic-pulmonary-fibrosis-related (0·0132) mortality; similar results were shown by meta-analyses.
Several analytic approaches demonstrated that pirfenidone therapy is associated with a reduction in the relative risk of mortality compared with placebo over 120 weeks.
F Hoffmann-La Roche/Genentech.
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