•The climate system is complex but with a simple core, the laws of radiative transfer.•These laws are incorporated in Earth System Models (ESMs), with climate feedbacks.•The core physics leads to ...projected global warming, amplified by climate feedbacks.•ESMs provide a compelling case that ongoing CO2 emissions cause global warming.
Climate warming during the course of the twenty-first century is projected to be between 1.0 and 3.7°C depending on future greenhouse gas emissions, based on the ensemble-mean results of state-of-the-art Earth System Models (ESMs). Just how reliable are these projections, given the complexity of the climate system? The early history of climate research provides insight into the understanding and science needed to answer this question. We examine the mathematical quantifications of planetary energy budget developed by Svante Arrhenius (1859–1927) and Guy Stewart Callendar (1898–1964) and construct an empirical approximation of the latter, which we show to be successful at retrospectively predicting global warming over the course of the twentieth century. This approximation is then used to calculate warming in response to increasing atmospheric greenhouse gases during the twenty-first century, projecting a temperature increase at the lower bound of results generated by an ensemble of ESMs (as presented in the latest assessment by the Intergovernmental Panel on Climate Change). This result can be interpreted as follows. The climate system is conceptually complex but has at its heart the physical laws of radiative transfer. This basic, or “core” physics is relatively straightforward to compute mathematically, as exemplified by Callendar's calculations, leading to quantitatively robust projections of baseline warming. The ESMs include not only the physical core but also climate feedbacks that introduce uncertainty into the projections in terms of magnitude, but not sign: positive (amplification of warming). As such, the projections of end-of-century global warming by ESMs are fundamentally trustworthy: quantitatively robust baseline warming based on the well-understood physics of radiative transfer, with extra warming due to climate feedbacks. These projections thus provide a compelling case that global climate will continue to undergo significant warming in response to ongoing emissions of CO2 and other greenhouse gases to the atmosphere.
Global tropical cyclone (TC) activity is simulated by the Geophysical Fluid Dynamics Laboratory (GFDL) Climate Model, version 2.5 (CM2.5), which is a fully coupled global climate model with a ...horizontal resolution of about 50 km for the atmosphere and 25 km for the ocean. The present climate simulation shows a fairly realistic global TC frequency, seasonal cycle, and geographical distribution. The model has some notable biases in regional TC activity, including simulating too few TCs in the North Atlantic. The regional biases in TC activity are associated with simulation biases in the large-scale environment such as sea surface temperature, vertical wind shear, and vertical velocity. Despite these biases, the model simulates the large-scale variations of TC activity induced by El Niño–Southern Oscillation fairly realistically. The response of TC activity in the model to global warming is investigated by comparing the present climate with a CO₂ doubling experiment. Globally, TC frequency decreases (−19%) while the intensity increases (+2.7%) in response to CO₂ doubling, consistent with previous studies. The average TC lifetime decreases by −4.6%, while the TC size and rainfall increase by about 3% and 12%, respectively. These changes are generally reproduced across the different basins in terms of the sign of the change, although the percent changes vary from basin to basin and within individual basins. For the Atlantic basin, although there is an overall reduction in frequency from CO₂ doubling, the warmed climate exhibits increased interannual hurricane frequency variability so that the simulated Atlantic TC activity is enhanced more during unusually warm years in the CO₂-warmed climate relative to that in unusually warm years in the control climate.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A newly developed microwave (MW) land surface temperature (LST) product is used to substitute thermal infrared (TIR) based LST in the Atmosphere Land Exchange Inverse (ALEXI) modelling framework for ...estimating ET from space. ALEXI implements a two-source energy balance (TSEB) land surface scheme in a time-differential approach, designed to minimize sensitivity to absolute biases in input records of LST through the analysis of the rate of temperature change in the morning. Thermal infrared (TIR) retrievals of the diurnal LST curve, traditionally from geostationary platforms, are hindered by cloud cover, reducing model coverage on any given day. This study tests the utility of diurnal temperature information retrieved from a constellation of satellites with microwave radiometers that together provide 6-8 observations of Ka-band brightness temperature per location per day. This represents the first ever attempt at a global implementation of ALEXI with MW-based LST and is intended as the first step towards providing all-weather capability to the ALEXI framework. The analysis is based on 9-year long, global records of ALEXI ET generated using both MW and TIR based diurnal LST information as input. In this study, the MW-LST sampling is restricted to the same clear sky days as in the IR-based implementation to be able to analyse the impact of changing the LST dataset separately from the impact of sampling all-sky conditions. The results show that long-term bulk ET estimates from both LST sources agree well, with a spatial correlation of 92% for total ET in the Europe/Africa domain and agreement in seasonal (3-month) totals of 83-97 % depending on the time of year. Most importantly, the ALEXI-MW also matches ALEXI-IR very closely in terms of 3-month inter-annual anomalies, demonstrating its ability to capture the development and extent of drought conditions. Weekly ET output from the two parallel ALEXI implementations is further compared to a common ground measured reference provided by the FLUXNET consortium. Overall, the two model implementations generate similar performance metrics (correlation and RMSE) for all but the most challenging sites in terms of spatial heterogeneity and level of aridity. It is concluded that a constellation of MW satellites can effectively be used to provide LST for estimating ET through ALEXI, which is an important step towards all-sky satellite-based retrieval of ET using an energy balance framework.
CONTEXT Streptococcus pneumoniae is a serious infection in young infants. A heptavalent pneumococcal conjugate vaccine (PCV7) was licensed in 2000 and recommended for all children aged 2 to 23 ...months. OBJECTIVE To determine the rates of invasive pneumococcal disease (IPD) in young infants before and after PCV7 was incorporated into the childhood immunization schedule in June 2000. DESIGN, SETTING, AND PARTICIPANTS A prospective, population-based study of infants aged 0 to 90 days who resided in areas in 8 US states with active laboratory surveillance for invasive S pneumoniae infections from July 1, 1997, to June 30, 2004. MAIN OUTCOME MEASURES Rates of laboratory-confirmed IPD before (July 1, 1997-June 30, 2000) and after (July 1, 2001-June 30, 2004) PCV7 introduction, excluding a transition year (July 1, 2000-June 30, 2001). RESULTS There were 146 cases of IPD, 89 before and 57 after PCV7 introduction. Isolated bacteremia occurred in 94 cases (64%), pneumonia in 27 (18%), meningitis in 22 (15%), and septic arthritis and/or osteomyelitis in 3 (2%). Mean rates of IPD for infants aged 0 to 90 days decreased 40% from 11.8 (95% confidence interval CI, 9.6-14.5) to 7.2 (95% CI, 5.6-9.4; P = .004) per 100 000 live births following PCV7 introduction. Among black infants, mean rates of IPD decreased significantly from 17.1 (95% CI, 11.9-24.6) to 5.3 (95% CI, 2.8-10.1; P = .001) per 100 000 live births, with a nonsignificant decrease from 9.6 (95% CI, 7.3-12.7) to 6.8 (95% CI, 4.9-9.4) per 100 000 live births for white infants. Rates of PCV7-serotype isolates decreased significantly from 7.3 (95% CI, 5.3-10.1) to 2.4 (95% CI, 1.6-3.8; P<.001) per 100 000 live births, while rates of non-PCV7 serotypes remained stable (P = .55). CONCLUSIONS Since PCV7 introduction, rates of IPD in young infants have decreased significantly, providing evidence that vaccinating children aged 2 to 23 months has led to changes in pneumococcal carriage in infants too young to receive PCV7. With a significant decrease in rates of IPD among black infants, the previous racial difference has been eliminated.
Responses of tropical cyclones (TCs) to CO
2
doubling are explored using coupled global climate models (GCMs) with increasingly refined atmospheric/land horizontal grids (~ 200 km, ~ 50 km and ~ ...25 km). The three models exhibit similar changes in background climate fields thought to regulate TC activity, such as relative sea surface temperature (SST), potential intensity, and wind shear. However, global TC frequency decreases substantially in the 50 km model, while the 25 km model shows no significant change. The ~ 25 km model also has a substantial and spatially-ubiquitous increase of Category 3–4–5 hurricanes. Idealized perturbation experiments are performed to understand the TC response. Each model’s transient fully-coupled 2 × CO
2
TC activity response is largely recovered by “time-slice” experiments using time-invariant SST perturbations added to each model’s own SST climatology. The TC response to SST forcing depends on each model’s background climatological SST biases: removing these biases leads to a global TC intensity increase in the ~ 50 km model, and a global TC frequency increase in the ~ 25 km model, in response to CO
2
-induced warming patterns and CO
2
doubling. Isolated CO
2
doubling leads to a significant TC frequency decrease, while isolated uniform SST warming leads to a significant global TC frequency increase; the ~ 25 km model has a greater tendency for frequency increase. Global TC frequency responds to both (1) changes in TC “seeds”, which increase due to warming (more so in the ~ 25 km model) and decrease due to higher CO
2
concentrations, and (2) less efficient development of these“seeds” into TCs, largely due to the nonlinear relation between temperature and saturation specific humidity.
Targetable NOTCH1 rearrangements in reninoma Treger, Taryn D; Lawrence, John E G; Anderson, Nathaniel D ...
Nature communications,
09/2023, Letnik:
14, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Reninomas are exceedingly rare renin-secreting kidney tumours that derive from juxtaglomerular cells, specialised smooth muscle cells that reside at the vascular inlet of glomeruli. They are the ...central component of the juxtaglomerular apparatus which controls systemic blood pressure through the secretion of renin. We assess somatic changes in reninoma and find structural variants that generate canonical activating rearrangements of, NOTCH1 whilst removing its negative regulator, NRARP. Accordingly, in single reninoma nuclei we observe excessive renin and NOTCH1 signalling mRNAs, with a concomitant non-excess of NRARP expression. Re-analysis of previously published reninoma bulk transcriptomes further corroborates our observation of dysregulated Notch pathway signalling in reninoma. Our findings reveal NOTCH1 rearrangements in reninoma, therapeutically targetable through existing NOTCH1 inhibitors, and indicate that unscheduled Notch signalling may be a disease-defining feature of reninoma.
High rates of unintended pregnancies worldwide indicate a need for more accessible and acceptable methods of contraception. We have developed a monoclonal antibody, the Human Contraception Antibody ...(HCA), for use by women in vaginal films and rings for contraception. The divalent F(ab')2 region of HCA binds to an abundant male reproductive tract-specific antigen, CD52g, and potently agglutinates sperm. Certain other antibody activities mediated by the Fc region such as mucus trapping, complement-dependent cytotoxicity (CDC) and antibody-dependent cellular phagocytosis (ADCP) could have beneficial or negative effects. The purpose of this study was to document HCA Fc effector functions and determine whether an engineered variant of HCA with a modified Fc region, HCA-LALAPG, retains desirable contraceptive activity while minimizing Fc-mediated effects. Fab and Fc functions were compared between HCA and HCA-LALAPG. Fab activity was assessed using sperm agglutination and modified swim-up ("sperm escape") assays. Fc functions were assessed by CDC (sperm immobilization), ADCP, and cervical mucus penetration assays. HCA and HCA-LALAPG showed equivalent activity in assays of Fab function. In the assays of Fc function, HCA supported strong CDC, ADCP, and sperm trapping in cervical mucus whereas HCA-LALAPG demonstrated little to no activity. HCA and the HCA-LALAPG variant were both highly effective in the sperm agglutination assays but differed in Fc mediated functions. Use of the HCA-LALAPG variant for contraception in women could reduce antibody-mediated inflammation and antigen presentation but may have reduced contraceptive efficacy due to much weaker sperm trapping in mucus and complement-dependent sperm immobilization activity.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Acute respiratory distress syndrome (ARDS) lacks known causal biomarkers. Plasma concentrations of sRAGE (soluble receptor for advanced glycation end products) strongly associate with ARDS risk. ...However, whether plasma sRAGE contributes causally to ARDS remains unknown.
Evaluate plasma sRAGE as a causal intermediate in ARDS by Mendelian randomization (MR), a statistical method to infer causality using observational data.
We measured early plasma sRAGE in two critically ill populations with sepsis. The cohorts were whole-genome genotyped and phenotyped for ARDS. To select validated genetic instruments for MR, we regressed plasma sRAGE on genome-wide genotypes in both cohorts. The causal effect of plasma sRAGE on ARDS was inferred using the top variants with significant associations in both populations (
< 0.01,
> 0.02). We applied the inverse variance-weighted method to obtain consistent estimates of the causal effect of plasma sRAGE on ARDS risk.
There were 393 European and 266 African ancestry patients in the first cohort and 843 European ancestry patients in the second cohort. Plasma sRAGE was strongly associated with ARDS risk in both populations (odds ratio, 1.86; 95% confidence interval 1.54-2.25; 2.56 2.14-3.06 per log increase). Using genetic instruments common to both populations, plasma sRAGE had a consistent causal effect on ARDS risk with a β estimate of 0.50 (95% confidence interval 0.09-0.91 per log increase).
Plasma sRAGE is genetically regulated during sepsis, and MR analysis indicates that increased plasma sRAGE leads to increased ARDS risk, suggesting plasma sRAGE acts as a causal intermediate in sepsis-related ARDS.
Purpose
A causal biomarker for acute respiratory distress syndrome (ARDS) could fuel precision therapy options. Plasma angiopoietin-2 (ANG2), a vascular permeability marker, is a strong candidate on ...the basis of experimental and observational evidence. We used genetic causal inference methods—Mendelian randomization and mediation—to infer potential effects of plasma ANG2.
Methods
We genotyped 703 septic subjects, measured ICU admission plasma ANG2, and performed a quantitative trait loci (QTL) analysis to determine variants in the
ANGPT2
gene associated with plasma ANG2 (
p
< 0.005). We then used linear regression and post-estimation analysis to genetically predict plasma ANG2 and tested genetically predicted ANG2 for ARDS association using logistic regression. We estimated the proportion of the genetic effect explained by plasma ANG2 using mediation analysis.
Results
Plasma ANG2 was strongly associated with ARDS (OR 1.59 (95% CI 1.35, 1.88) per log). Five
ANGPT2
variants were associated with ANG2 in European ancestry subjects (
n
= 404). Rs2442608C, the most extreme
cis
QTL (coefficient 0.22, 95% CI 0.09–0.36,
p
= 0.001), was associated with higher ARDS risk: adjusted OR 1.38 (95% CI 1.01, 1.87)
, p
= 0.042. No significant QTL were identified in African ancestry subjects. Genetically predicted plasma ANG2 was associated with ARDS risk: adjusted OR 2.25 (95% CI 1.06–4.78),
p
= 0.035. Plasma ANG2 mediated 34% of the rs2442608C-related ARDS risk.
Conclusions
In septic European ancestry subjects, the strongest ANG2-determining
ANGPT2
genetic variant is associated with higher ARDS risk. Plasma ANG2 may be a causal factor in ARDS development. Strategies to reduce plasma ANG2 warrant testing to prevent or treat sepsis-associated ARDS.
MB66 film is a multipurpose prevention technology (MPT) product with monoclonal antibodies (mAbs) against HIV-1 (VRC01-N) and HSV-1 and 2 (HSV8-N). The mAbs were produced by transient expression in ...Nicotiana benthamiana (N). We conducted a Phase I clinical trial to assess the safety, pharmacokinetics (PK), and ex vivo efficacy of single and repeated doses of MB66 when used intravaginally.
The clinical trial enrolled healthy reproductive-aged, sexually abstinent women. In Segment A, 9 women received a single MB66 film which was inserted into the vaginal posterior fornix by a clinician. In Segment B, 29 women were randomly assigned to MB66 (Active) or Placebo film groups and were instructed to insert 1 film vaginally for 7 consecutive days. Visits and clinical sampling occurred predose and at various time points after single and repeated film doses. The primary endpoint was number of adverse events (AEs) Grade 2 or higher related to product use. Secondary endpoints included film dissolution rate, Nugent score (a Gram stain scoring system to diagnose bacterial vaginosis), vaginal pH, post-use survey results, cytokine concentrations in cervicovaginal lavage (CVL) specimens (assessed by Luminex assay), mAb concentrations in vaginal fluid collected from 4 sites (assessed by ELISA), and HIV and HSV neutralization activity of CVL samples ex vivo (assessed by TZM-bl and plaque reduction assay, respectively). The product was generally safe and well tolerated, with no serious AEs recorded in either segment. The AEs in this study were primarily genitourinary in nature with the most commonly reported AE being asymptomatic microscopic hematuria. There were no differences in vaginal pH or Nugent scores or significant increases in levels of proinflammatory cytokines for up to 7 days after film insertion in either segment or between Active and Placebo groups. Acceptability and willingness to use the product were judged to be high by post-use surveys. Concentrations of VRC01-N and HSV8-N in vaginal secretions were assessed over time to generate pharmacokinetic curves. Antibody levels peaked 1 hour postdosing with Active film (median: 35 μg/mL) and remained significantly elevated at 24 hours post first and seventh film (median: 1.8 μg/mL). Correcting for sample dilution (1:20), VRC01-N concentrations ranged from 36 to 700 μg/mL at the 24-hour time point, greater than 100-fold the IC50 for VRC01 (0.32 μg/mL); HSV8-N concentrations ranged from 80 to 601 μg/mL, well above the IC50 of 0.1 μg/m. CVL samples collected 24 hours after MB66 insertion significantly neutralized both HIV-1 and HSV-2 ex vivo. Study limitations include the small size of the study cohort, and the fact that no samples were collected between 24 hours and 7 days for pharmacokinetic evaluation.
Single and repeated intravaginal applications of MB66 film were safe, well tolerated, and acceptable. Concentrations and ex vivo bioactivity of both mAbs in vaginal secretions were significantly elevated and thus could provide protection for at least 24 hours postdose. However, further research is needed to evaluate the efficacy of MB66 film in women at risk for HIV and HSV infection. Additional antibodies could be added to this platform to provide protection against other sexually transmitted infections (STIs) and contraception.
ClinicalTrials.gov NCT02579083.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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