The BCL-2 family member BOK promotes KRAS-driven lung cancer progression in a p53-dependent manner.

A variety of cancer entities are driven by KRAS mutations, which remain difficult to target clinically. Survival pathways, such as resistance to cell death, may represent a promising treatment approach in KRAS mutated cancers. Based on the frequently observed genomic deletions of BCL-2-related ovarian killer (BOK) in cancer patients, we explored the function of BOK in a mutant KrasG12D-driven murine model of lung cancer. Using KrasG12D/+ Bok-/- mice, we observed an overall tumor-promoting function of BOK in vivo. Specifically, loss of BOK reduced proliferation both in cell lines in vitro as well as in KrasG12D-driven tumor lesions in vivo. During tumor development in vivo, loss of BOK resulted in a lower tumor burden, with fewer, smaller, and less advanced tumors. Using KrasG12D/+ Tp53Δ/Δ Bok-/- mice, we identified that this phenotype was entirely dependent on the presence of functional p53. Furthermore, analysis of a human dataset of untreated early-stage lung tumors did not identify any common deletion of the BOK locus, independently of the TP53 status or the histopathological classification. Taken together our data indicate that BOK supports tumor progression in Kras-driven lung cancer

EC-Earth3-AerChem: a global climate model with interactive aerosols and atmospheric chemistry participating in CMIP6

This paper documents the global climate model EC-Earth3-AerChem, one of the members of the EC-Earth3 family of models participating in the Coupled Model Intercomparison Project Phase 6 (CMIP6). EC-Earth3-AerChem has interactive aerosols and atmospheric chemistry and contributes to the Aerosols and Chemistry Model Intercomparison Project (AerChemMIP). In this paper, we give an overview of the model, describe in detail how it differs from the other EC-Earth3 configurations, and outline the new features compared with the previously documented version of the model (EC-Earth 2.4). We explain how the model was tuned and spun up under preindustrial conditions and characterize the model's general performance on the basis of a selection of coupled simulations conducted for CMIP6. The net energy imbalance at the top of the atmosphere in the preindustrial control simulation is on average −0.09 W m−2 with a standard deviation due to interannual variability of 0.25 W m−2, showing no significant drift. The global surface air temperature in the simulation is on average 14.08 ∘C with an interannual standard deviation of 0.17 ∘C, exhibiting a small drift of 0.015 ± 0.005 ∘C per century. The model's effective equilibrium climate sensitivity is estimated at 3.9 ∘C, and its transient climate response is estimated at 2.1 ∘C. The CMIP6 historical simulation displays spurious interdecadal variability in Northern Hemisphere temperatures, resulting in a large spread across ensemble members and a tendency to underestimate observed annual surface temperature anomalies from the early 20th century onwards. The observed warming of the Southern Hemisphere is well reproduced by the model. Compared with the ECMWF (European Centre for Medium-Range Weather Forecasts) Reanalysis version 5 (ERA5), the surface air temperature climatology for 1995–2014 has an average bias of −0.86 ± 0.05 ∘C with a standard deviation across ensemble members of 0.35 ∘C in the Northern Hemisphere and 1.29 ± 0.02 ∘C with a corresponding standard deviation of 0.05 ∘C in the Southern Hemisphere. The Southern Hemisphere warm bias is largely caused by errors in shortwave cloud radiative effects over the Southern Ocean, a deficiency of many climate models. Changes in the emissions of near-term climate forcers (NTCFs) have significant effects on the global climate from the second half of the 20th century onwards. For the SSP3-7.0 Shared Socioeconomic Pathway, the model gives a global warming at the end of the 21st century (2091–2100) of 4.9 ∘C above the preindustrial mean. A 0.5 ∘C stronger warming is obtained for the AerChemMIP scenario with reduced emissions of NTCFs. With concurrent reductions of future methane concentrations, the warming is projected to be reduced by 0.5 ∘C

EC-Earth3-AerChem : a global climate model with interactive aerosols and atmospheric chemistry participating in CMIP6

This paper documents the global climate model EC-Earth3-AerChem, one of the members of the EC-Earth3 family of models participating in the Coupled Model Intercomparison Project Phase 6 (CMIP6). EC-Earth3-AerChem has interactive aerosols and atmospheric chemistry and contributes to the Aerosols and Chemistry Model Intercomparison Project (AerChemMIP). In this paper, we give an overview of the model, describe in detail how it differs from the other EC-Earth3 configurations, and outline the new features compared with the previously documented version of the model (EC-Earth 2.4). We explain how the model was tuned and spun up under preindustrial conditions and characterize the model's general performance on the basis of a selection of coupled simulations conducted for CMIP6. The net energy imbalance at the top of the atmosphere in the preindustrial control simulation is on average 0.09 Wm(-2) with a standard deviation due to interannual variability of 0.25 Wm(-2), showing no significant drift. The global surface air temperature in the simulation is on average 14.08 degrees C with an interannual standard deviation of 0.17 degrees C, exhibiting a small drift of 0.015 +/- 0.005 degrees C per century. The model's effective equilibrium climate sensitivity is estimated at 3.9 degrees C, and its transient climate response is estimated at 2.1 degrees C. The CMIP6 historical simulation displays spurious interdecadal variability in Northern Hemisphere temperatures, resulting in a large spread across ensemble members and a tendency to underestimate observed annual surface temperature anomalies from the early 20th century onwards. The observed warming of the Southern Hemisphere is well reproduced by the model. Compared with the ECMWF (European Centre for Medium-Range Weather Forecasts) Reanalysis version 5 (ERA5), the surface air temperature climatology for 1995-2014 has an average bias of -0.86 +/- 0.05 degrees C with a standard deviation across ensemble members of 0.35 degrees C in the North-ern Hemisphere and 1.29 +/- 0.02 degrees C with a corresponding standard deviation of 0.05 degrees C in the Southern Hemisphere. The Southern Hemisphere warm bias is largely caused by errors in shortwave cloud radiative effects over the Southern Ocean, a deficiency of many climate models. Changes in the emissions of near-term climate forcers (NTCFs) have significant effects on the global climate from the second half of the 20th century onwards. For the SSP3-7.0 Shared Socioeconomic Pathway, the model gives a global warming at the end of the 21st century (2091-2100) of 4.9 degrees C above the preindustrial mean. A 0.5 degrees C stronger warming is obtained for the AerChemMIP scenario with reduced emissions of NTCFs. With concurrent reductions of future methane concentrations, the warming is projected to be reduced by 0.5 degrees C.Peer reviewe

Secondary organic aerosols from anthropogenic volatile organic compounds contribute substantially to air pollution mortality

Anthropogenic secondary organic aerosol (ASOA), formed from anthropogenic emissions of organic compounds, constitutes a substantial fraction of the mass of submicron aerosol in populated areas around the world and contributes to poor air quality and premature mortality. However, the precursor sources of ASOA are poorly understood, and there are large uncertainties in the health benefits that might accrue from reducing anthropogenic organic emissions. We show that the production of ASOA in 11 urban areas on three continents is strongly correlated with the reactivity of specific anthropogenic volatile organic compounds. The differences in ASOA production across different cities can be explained by differences in the emissions of aromatics and intermediate- and semi-volatile organic compounds, indicating the importance of controlling these ASOA precursors. With an improved model representation of ASOA driven by the observations, we attribute 340&thinsp;000&nbsp;PM2.5-related premature deaths per year to ASOA, which is over an order of magnitude higher than prior studies. A sensitivity case with a more recently proposed model for attributing mortality to PM2.5 (the Global Exposure Mortality Model) results in up to 900&thinsp;000 deaths. A limitation of this study is the extrapolation from cities with detailed studies and regions where detailed emission inventories are available to other regions where uncertainties in emissions are larger. In addition to further development of institutional air quality management infrastructure, comprehensive air quality campaigns in the countries in South and Central America, Africa, South Asia, and the Middle East are needed for further progress in this area. &nbsp;</p

Partial hepatectomy accelerates colorectal metastasis by priming an inflammatory premetastatic niche in the liver

BackgroundResection of colorectal liver metastasis is the standard of care for patients with Stage IV CRC. Despite undoubtedly improving the overall survival of patients, pHx for colorectal liver metastasis frequently leads to disease recurrence. The contribution of this procedure to metastatic colorectal cancer at a molecular level is poorly understood. We designed a mouse model of orthograde metastatic colorectal cancer (CRC) to investigate the effect of partial hepatectomy (pHx) on tumor progression.MethodsCRC organoids were implanted into the cecal walls of wild type mice, and animals were screened for liver metastasis. At the time of metastasis, 1/3 partial hepatectomy was performed and the tumor burden was assessed longitudinally using MRI. After euthanasia, different tissues were analyzed for immunological and transcriptional changes using FACS, qPCR, RNA sequencing, and immunohistochemistry.ResultsMice that underwent pHx presented significant liver hypertrophy and an increased overall metastatic load compared with SHAM operated mice in MRI. Elevation in the metastatic volume was defined by an increase in de novo liver metastasis without any effect on the growth of each metastasis. Concordantly, the livers of pHx mice were characterized by neutrophil and bacterial infiltration, inflammatory response, extracellular remodeling, and an increased abundance of tight junctions, resulting in the formation of a premetastatic niche, thus facilitating metastatic seeding.ConclusionsRegenerative pathways following pHx accelerate colorectal metastasis to the liver by priming a premetastatic niche

Profound Depletion of HIV-1 Transcription in Patients Initiating Antiretroviral Therapy during Acute Infection

Early intervention resulted in profound depletion of PBMC expressing HIV-1 RNA. This is contrary to chronically infected patients who predominantly showed continuous UsRNA expression on cART. Thus, antiretroviral treatment initiated during the acute phase of infection prevented establishment or expansion of long-lived transcriptionally active viral cellular reservoirs in peripheral blood

Global, regional, and national burden of osteoarthritis, 1990–2020 and projections to 2050: a systematic analysis for the Global Burden of Disease Study 2021

Background Osteoarthritis is the most common form of arthritis in adults, characterised by chronic pain and loss of mobility. Osteoarthritis most frequently occurs after age 40 years and prevalence increases steeply with age. WHO has designated 2021–30 the decade of healthy ageing, which highlights the need to address diseases such as osteoarthritis, which strongly affect functional ability and quality of life. Osteoarthritis can coexist with, and negatively effect, other chronic conditions. Here we estimate the burden of hand, hip, knee, and other sites of osteoarthritis across geographies, age, sex, and time, with forecasts of prevalence to 2050. Methods In this systematic analysis for the Global Burden of Disease Study, osteoarthritis prevalence in 204 countries and territories from 1990 to 2020 was estimated using data from population-based surveys from 26 countries for knee osteoarthritis, 23 countries for hip osteoarthritis, 42 countries for hand osteoarthritis, and US insurance claims for all of the osteoarthritis sites, including the other types of osteoarthritis category. The reference case definition was symptomatic, radiographically confirmed osteoarthritis. Studies using alternative definitions from the reference case definition (for example self-reported osteoarthritis) were adjusted to reference using regression models. Osteoarthritis severity distribution was obtained from a pooled meta-analysis of sources using the Western Ontario and McMaster Universities Arthritis Index. Final prevalence estimates were multiplied by disability weights to calculate years lived with disability (YLDs). Prevalence was forecast to 2050 using a mixed-effects model. Findings Globally, 595 million (95% uncertainty interval 535–656) people had osteoarthritis in 2020, equal to 7·6% (95% UI 6·8–8·4) of the global population, and an increase of 132·2% (130·3–134·1) in total cases since 1990. Compared with 2020, cases of osteoarthritis are projected to increase 74·9% (59·4–89·9) for knee, 48·6% (35·9–67·1) for hand, 78·6% (57·7–105·3) for hip, and 95·1% (68·1–135·0) for other types of osteoarthritis by 2050. The global age-standardised rate of YLDs for total osteoarthritis was 255·0 YLDs (119·7–557·2) per 100 000 in 2020, a 9·5% (8·6–10·1) increase from 1990 (233·0 YLDs per 100 000, 109·3–510·8). For adults aged 70 years and older, osteoarthritis was the seventh ranked cause of YLDs. Age-standardised prevalence in 2020 was more than 5·5% in all world regions, ranging from 5677·4 (5029·8–6318·1) per 100 000 in southeast Asia to 8632·7 (7852·0–9469·1) per 100 000 in high-income Asia Pacific. Knee was the most common site for osteoarthritis. High BMI contributed to 20·4% (95% UI –1·7 to 36·6) of osteoarthritis. Potentially modifiable risk factors for osteoarthritis such as recreational injury prevention and occupational hazards have not yet been explored in GBD modelling. Interpretation Age-standardised YLDs attributable to osteoarthritis are continuing to rise and will lead to substantial increases in case numbers because of population growth and ageing, and because there is no effective cure for osteoarthritis. The demand on health systems for care of patients with osteoarthritis, including joint replacements, which are highly effective for late stage osteoarthritis in hips and knees, will rise in all regions, but might be out of reach and lead to further health inequity for individuals and countries unable to afford them. Much more can and should be done to prevent people getting to that late stage

Les droits disciplinaires des fonctions publiques : « unification », « harmonisation » ou « distanciation ». A propos de la loi du 26 avril 2016 relative à la déontologie et aux droits et obligations des fonctionnaires

The production of tt‾ , W+bb‾ and W+cc‾ is studied in the forward region of proton–proton collisions collected at a centre-of-mass energy of 8 TeV by the LHCb experiment, corresponding to an integrated luminosity of 1.98±0.02 fb−1 . The W bosons are reconstructed in the decays W→ℓν , where ℓ denotes muon or electron, while the b and c quarks are reconstructed as jets. All measured cross-sections are in agreement with next-to-leading-order Standard Model predictions.The production of $t\overline{t}$, $W+b\overline{b}$ and $W+c\overline{c}$ is studied in the forward region of proton-proton collisions collected at a centre-of-mass energy of 8 TeV by the LHCb experiment, corresponding to an integrated luminosity of 1.98 $\pm$ 0.02 \mbox{fb}^{-1}. The $W$ bosons are reconstructed in the decays $W\rightarrow\ell\nu$, where $\ell$ denotes muon or electron, while the $b$ and $c$ quarks are reconstructed as jets. All measured cross-sections are in agreement with next-to-leading-order Standard Model predictions

Physics case for an LHCb Upgrade II - Opportunities in flavour physics, and beyond, in the HL-LHC era

The LHCb Upgrade II will fully exploit the flavour-physics opportunities of the HL-LHC, and study additional physics topics that take advantage of the forward acceptance of the LHCb spectrometer. The LHCb Upgrade I will begin operation in 2020. Consolidation will occur, and modest enhancements of the Upgrade I detector will be installed, in Long Shutdown 3 of the LHC (2025) and these are discussed here. The main Upgrade II detector will be installed in long shutdown 4 of the LHC (2030) and will build on the strengths of the current LHCb experiment and the Upgrade I. It will operate at a luminosity up to 2×1034 cm−2s−1, ten times that of the Upgrade I detector. New detector components will improve the intrinsic performance of the experiment in certain key areas. An Expression Of Interest proposing Upgrade II was submitted in February 2017. The physics case for the Upgrade II is presented here in more depth. CP-violating phases will be measured with precisions unattainable at any other envisaged facility. The experiment will probe b → sl+l−and b → dl+l− transitions in both muon and electron decays in modes not accessible at Upgrade I. Minimal flavour violation will be tested with a precision measurement of the ratio of B(B0 → μ+μ−)/B(Bs → μ+μ−). Probing charm CP violation at the 10−5 level may result in its long sought discovery. Major advances in hadron spectroscopy will be possible, which will be powerful probes of low energy QCD. Upgrade II potentially will have the highest sensitivity of all the LHC experiments on the Higgs to charm-quark couplings. Generically, the new physics mass scale probed, for fixed couplings, will almost double compared with the pre-HL-LHC era; this extended reach for flavour physics is similar to that which would be achieved by the HE-LHC proposal for the energy frontier