We provide major updates to the ‘top down’ Fire Radiative Energy Emissions (FREM) approach to biomass burning emissions calculations, bypassing the estimation of fuel consumption that is a major ...source of uncertainty in widely used ‘bottom up’ approaches. The FREM approach links satellite observations of fire radiative power (FRP) to emission rates of total particulate matter (TPM) via spatially varying smoke emissions coefficients (g.MJ−1) – each derived from matchups of FRP and smoke plume aerosol optical depth (AOD). In the original FREMv1 approach, FRP data came from the geostationary Meteosat satellite and AOD data from the 10 km spatial resolution MODIS MOD04 aerosol product. However, the latter often performs quite poorly close to biomass burning sources due to its large 10 km pixels, bias at high MODIS view zenith angles, and saturation and/or removal of areas of high AOD - limitations introducing bias and uncertainty into the final FREM-derived smoke emissions estimates. We address each of these issues through a series of significant methodological and input data improvements, including exploitation of the 1 km MODIS MAIAC AOD product that performs far better close to fire sources. We use our FREMv2 methodology to generate a new pan-African fire emissions inventory for TPM and the carbonaceous gases CO2, CO and CH4, and our annual mean TPM emissions are within 11% of those of the MODIS-based FEER top-down approach, but significantly higher than those of GFASv1.2 and GFEDv4.1s (by 114% and 69% respectively) - agreeing with independent assessments that aerosol emissions of GFASv1.2 require upscaling by a factor of 2 to 3.4 to deliver matching magnitudes between modelled and observed AODs. From our carbonaceous emissions totals we map dry matter consumed (DMC) across Africa, and dividing this by the FireCCISFD11 20 m burned area product we provide one of the first data-driven pan-African maps of fuel consumption per unit area (kg.m−2) which in many areas is higher than in GFEDv4.1s. Our estimates represent the highest spatio-temporal resolution biomass burning emissions data yet available over Africa, and significantly advance the aim of a pan-tropical and mid-latitude inventory based on FRP from the global geostationary satellite network (Meteosat, Meteosat IOD, GOES and Himawari).
•New top-down smoke emission coefficients using high-resolution MAIAC AOD.•Improved biome stratification using CCI Landcover and 30 m Landsat Tree Cover data.•Presents a 6-year fire inventory of TPM, CO2, CO and CH4 emissions for Africa.•Highest spatio-temporal resolution emissions estimates yet available over Africa.•We find similar emissions to FEER, but much higher emissions than GFED and GFAS.
The human proteome is a major source of therapeutic targets. Recent genetic association analyses of the plasma proteome enable systematic evaluation of the causal consequences of variation in plasma ...protein levels. Here we estimated the effects of 1,002 proteins on 225 phenotypes using two-sample Mendelian randomization (MR) and colocalization. Of 413 associations supported by evidence from MR, 130 (31.5%) were not supported by results of colocalization analyses, suggesting that genetic confounding due to linkage disequilibrium is widespread in naïve phenome-wide association studies of proteins. Combining MR and colocalization evidence in cis-only analyses, we identified 111 putatively causal effects between 65 proteins and 52 disease-related phenotypes ( https://www.epigraphdb.org/pqtl/ ). Evaluation of data from historic drug development programs showed that target-indication pairs with MR and colocalization support were more likely to be approved, evidencing the value of this approach in identifying and prioritizing potential therapeutic targets.
The biology of color Cuthill, Innes C.; Allen, William L.; Arbuckle, Kevin ...
Science (American Association for the Advancement of Science),
08/2017, Letnik:
357, Številka:
6350
Journal Article
Recenzirano
Odprti dostop
Coloration mediates the relationship between an organism and its environment in important ways, including social signaling, antipredator defenses, parasitic exploitation, thermoregulation, and ...protection from ultraviolet light, microbes, and abrasion. Methodological breakthroughs are accelerating knowledge of the processes underlying both the production of animal coloration and its perception, experiments are advancing understanding of mechanism and function, and measurements of color collected noninvasively and at a global scale are opening windows to evolutionary dynamics more generally. Here we provide a roadmap of these advances and identify hitherto unrecognized challenges for this multi- and interdisciplinary field.
Antilipoperoxidant protein dysfunction is associated with many human diseases, suggesting that bilayer lipid peroxidation may contribute broadly to pathogenesis. Small molecule inhibitors of this ...membrane-localized chemistry could in theory enable better understanding and/or treatment of such diseases, but currently available compounds have important limitations. Many biological questions thus remain unanswered, and clinical trials have largely been disappointing. Enabled by efficient, building block-based syntheses of three atypical carotenoid natural products produced by microorganisms that thrive in environments of extreme oxidative stress, we found that peridinin is a potent inhibitor of nonenzymatic bilayer lipid peroxidation in liposomes and in primary human endothelial cells. We also found that peridinin blocks monocyte-endothelial cell adhesion, a key step in atherogenesis. A series of frontier solid-state NMR experiments with a site-specifically
C-labeled isotopolog synthesized using the same MIDA boronate building block-based total synthesis approach revealed that peridinin is completely embedded within and physically spans the hydrophobic core of POPC membranes, maximizing its effective molarity at the site of the targeted lipid peroxidation reactions. Alternatively, the widely used carotenoid astaxanthin is significantly less potent and was found to primarily localize extramembranously. Peridinin thus represents a promising and biophysically well-characterized starting point for the development of small molecule antilipoperoxidants that serve as more effective biological probes and/or therapeutics.
Abstract
Background
Although people living with human immunodeficiency virus (PLWH) are at increased risk of invasive pneumococcal disease (IPD) and community-acquired pneumonia (CAP), it is unclear ...whether this remains the case in the setting of early initiation of combination antiretroviral therapy (cART), at high CD4 cell counts. This is important, as pneumococcal vaccination coverage in PLWH is low in Europe and the United States, despite longstanding international recommendations.
Methods
We identified all CAP and IPD cases between 2008 and 2017 in a cohort of PLWH in a Dutch HIV referral center. We calculated incidence rates stratified by CD4 count and cART status and conducted a case-control study to identify risk factors for CAP in PLWH receiving cART.
Results
Incidence rates of IPD and CAP in PLWH were 111 and 1529 per 100 000 patient-years of follow-up (PYFU). Although IPD and CAP occurred more frequently in patients with CD4 counts <500 cells/μL (incidence rate ratio IRR, 6.1 95% confidence interval, 2.2–17 and IRR, 2.4 95% confidence interval, 1.9–3.0), the incidence rate in patients with CD4 counts >500 cells/μL remained higher compared with the general population (946 vs 188 per 100 000 PYFU). All IPD isolates were vaccine serotypes. Risk factors for CAP were older age, CD4 counts <500 cells/μL, smoking, drug use, and chronic obstructive pulmonary disease.
Conclusions
The incidence of IPD and CAP among PLWH remains higher compared with the general population, even in those who are virally suppressed and have high CD4 counts. With all serotyped IPD isolates covered by pneumococcal vaccines, our study provides additional argumentation against the poor current adherence to international recommendations to vaccinate PLWH.
The incidence of pneumococcal disease and pneumonia among people living with HIV (PLWH) remains higher compared with the general population, even in those who are virally suppressed, and have high CD4 cell counts. Pneumococcal vaccination should be considered in all PLWH.
Preserving energy homeostasis in the presence of stressors such as proinflammatory cytokines and nutrient overload is crucial to maintaining normal cellular function. Six transmembrane epithelial ...antigen of the prostate 4 (STEAP4), a metalloreductase involved in iron and copper homeostasis, is thought to play a potentially important role in the cellular response to inflammatory stress. Genome-wide association studies have linked various mutations in
with the development of metabolic disorders such as obesity, metabolic syndrome and type 2 diabetes. Several studies have shown that expression of
is modulated by inflammatory cytokines, hormones and other indicators of cellular stress and that STEAP4 may protect cells from damage, helping to maintain normal metabolic function. STEAP4 appears to be particularly relevant in metabolically oriented cells, such as adipocytes, hepatocytes and pancreatic islet cells. These cells struggle to maintain their function in iron or copper overloaded states, presumably due to increased oxidative stress, suggesting STEAP4's role in metal homeostasis is critical to the maintenance of cellular homeostasis in general, and in preventing the onset of metabolic disease. In this review, we explore genetic associations of
with metabolic disorders, and we examine STEAP4 tissue expression, subcellular localization, regulation, structure and function as it relates to metabolic diseases. We then examine how STEAP4's role as a regulator of cellular iron and copper may relate to type 2 diabetes.
Abstract
Background
Patients with hematological cancers (HC) are at high risk of infections, in particular community-acquired pneumonia (CAP). Recent data on incidence and predictors of CAP among ...patients with HC are scarce.
Methods
We performed a cohort study (2016–2019) in 2 hospitals in the Netherlands among adults with HC to calculate incidence rates (IRs) of CAP. In addition, we performed a nested case-control study to identify predictors of CAP.
Results
We identified 275 CAP cases during 6264 patient-years of follow-up. The IR of CAP was 4390/100 000 patient-years of follow-up. Compared with the general population, IR ratios ranged from 5.4 to 55.3 for the different HCs. The case fatality and intensive care unit (ICU) admission rates were 5.5% and 9.8%, respectively. Predictors for CAP in patients with HC were male sex, anemia, lymphocytopenia, chronic kidney disease, cardiovascular disease, autologous and allogeneic stem cell transplantation, treatment with immunosuppressive medication for graft-vs-host disease, treatment with rituximab in the past year, and treatment with immunomodulators (lenalidomide, thalidomide, pomalidomide and/or methotrexate) in the past month. Independent predictors of a severe disease course (death or ICU admission) included neutropenia (odds ratio, 4.14 95% confidence interval, 1.63–10.2), pneumococcal pneumonia (10.24 3.48–30.1), chronic obstructive pulmonary disease (6.90 2.07–23.0), and the use of antibacterial prophylaxis (2.53 1.05–6.08).
Conclusions
The burden of CAP in patients with HC is high, with significant morbidity and mortality rates. Therefore, vaccination against respiratory pathogens early in the disease course is recommended, in particular before starting certain immunosuppressive therapies.
A high burden of community-acquired pneumonia (CAP) was observed in oncohematological patients. Use of rituximab, immunomodulators, and immunosuppressive agents for graft-vs-host disease were the strongest predictors of CAP, highlighting the importance of vaccination against respiratory pathogens before treatment initiation.
Prospective data on the efficacy of a watch-and-wait strategy to achieve organ preservation in patients with locally advanced rectal cancer treated with total neoadjuvant therapy are limited.
In this ...prospective, randomized phase II trial, we assessed the outcomes of 324 patients with stage II or III rectal adenocarcinoma treated with induction chemotherapy followed by chemoradiotherapy (INCT-CRT) or chemoradiotherapy followed by consolidation chemotherapy (CRT-CNCT) and either total mesorectal excision (TME) or watch-and-wait on the basis of tumor response. Patients in both groups received 4 months of infusional fluorouracil-leucovorin-oxaliplatin or capecitabine-oxaliplatin and 5,000 to 5,600 cGy of radiation combined with either continuous infusion fluorouracil or capecitabine during radiotherapy. The trial was designed as two stand-alone studies with disease-free survival (DFS) as the primary end point for both groups, with a comparison to a null hypothesis on the basis of historical data. The secondary end point was TME-free survival.
Median follow-up was 3 years. Three-year DFS was 76% (95% CI, 69 to 84) for the INCT-CRT group and 76% (95% CI, 69 to 83) for the CRT-CNCT group, in line with the 3-year DFS rate (75%) observed historically. Three-year TME-free survival was 41% (95% CI, 33 to 50) in the INCT-CRT group and 53% (95% CI, 45 to 62) in the CRT-CNCT group. No differences were found between groups in local recurrence-free survival, distant metastasis-free survival, or overall survival. Patients who underwent TME after restaging and patients who underwent TME after regrowth had similar DFS rates.
Organ preservation is achievable in half of the patients with rectal cancer treated with total neoadjuvant therapy, without an apparent detriment in survival, compared with historical controls treated with chemoradiotherapy, TME, and postoperative chemotherapy.
Psilocybin is being studied for use in treatment-resistant depression.
In this phase 2 double-blind trial, we randomly assigned adults with treatment-resistant depression to receive a single dose of ...a proprietary, synthetic formulation of psilocybin at a dose of 25 mg, 10 mg, or 1 mg (control), along with psychological support. The primary end point was the change from baseline to week 3 in the total score on the Montgomery-Åsberg Depression Rating Scale (MADRS; range, 0 to 60, with higher scores indicating more severe depression). Secondary end points included response at week 3 (≥50% decrease from baseline in the MADRS total score), remission at week 3 (MADRS total score ≤10), and sustained response at 12 weeks (meeting response criteria at week 3 and all subsequent visits).
A total of 79 participants were in the 25-mg group, 75 in the 10-mg group, and 79 in the 1-mg group. The mean MADRS total score at baseline was 32 or 33 in each group. Least-squares mean changes from baseline to week 3 in the score were -12.0 for 25 mg, -7.9 for 10 mg, and -5.4 for 1 mg; the difference between the 25-mg group and 1-mg group was -6.6 (95% confidence interval CI, -10.2 to -2.9; P<0.001) and between the 10-mg group and 1-mg group was -2.5 (95% CI, -6.2 to 1.2; P = 0.18). In the 25-mg group, the incidences of response and remission at 3 weeks, but not sustained response at 12 weeks, were generally supportive of the primary results. Adverse events occurred in 179 of 233 participants (77%) and included headache, nausea, and dizziness. Suicidal ideation or behavior or self-injury occurred in all dose groups.
In this phase 2 trial involving participants with treatment-resistant depression, psilocybin at a single dose of 25 mg, but not 10 mg, reduced depression scores significantly more than a 1-mg dose over a period of 3 weeks but was associated with adverse effects. Larger and longer trials, including comparison with existing treatments, are required to determine the efficacy and safety of psilocybin for this disorder. (Funded by COMPASS Pathfinder; EudraCT number, 2017-003288-36; ClinicalTrials.gov number, NCT03775200.).
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