Global precipitation response to changing forcings since 1870

Predicting and adapting to changes in the hydrological cycle is one of the major challenges for the 21st century. To better estimate how it will respond to future changes in climate forcings, it is crucial to understand how the hydrological cycle has evolved in the past and why. In our study, we use an atmospheric global climate model with prescribed sea surface temperatures (SSTs) to investigate how, in the period 1870–2005, changing climate forcings have affected the global land temperature and precipitation. We show that between 1870 and 2005, prescribed SSTs (encapsulating other forcings and internal variability) determine the decadal and interannual variabilities of the global land temperature and precipitation, mostly via their influence in the tropics (25° S–25° N). In addition, using simulations with prescribed SSTs and considering the atmospheric response alone, we find that between 1930 and 2005 increasing aerosol emissions have reduced the global land temperature and precipitation by up to 0.4 °C and 30 mm yr<sup>−1</sup>, respectively, and that between about 1950 and 2005 increasing greenhouse gas concentrations have increased them by up to 0.25 °C and 10 mm yr<sup>−1</sup>, respectively. Finally, we suggest that between about 1950 and 1970, increasing aerosol emissions had a larger impact on the hydrological cycle than increasing greenhouse gas concentrations

The effect of manipulated prenatal conditions on growth, survival, and reproduction throughout the complete life course of a precocial bird

This is the final version. Available on open access from Frontiers Media via the DOI in this record. Data Availability Statement: The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The quality of the environment individuals experience during development is commonly regarded as very influential on performance in later life. However, studies that have experimentally manipulated the early-life environment and subsequently measured individual performance in all components of fitness over the complete life course are scarce. In this study, we incubated fertile eggs of Japanese quail (Coturnix japonica) at substandard and standard incubation temperature, and monitored growth, survival, and reproduction throughout the complete life course. While embryonic development was slower and hatching success tended to be lower under substandard incubation temperature, the prenatal treatment had no effect on post-hatching growth, survival to sexual maturity, or age at first reproduction. In adulthood, body mass and investment in individual egg mass peaked at middle age, irrespective of the prenatal treatment. Individual reproduction rate declined soon after its onset, and was higher in females that lived longer. Yet, reproduction, and its senescence, were independent of the prenatal treatment. Similarly, adult survival over the complete lifespan was not affected. Hence, we did not find evidence for effects on performance beyond the developmental period that was manipulated. Our results suggest that effects of unfavorable developmental conditions on individual performance later in life could be negligible in some circumstances.Deutsche Forschungsgemeinschaft (DFG

Impact of Holocene climate variability on lacustrine records and human settlements in South Greenland

International audienceDue to its sensitivity to climate changes, south Greenland is a particularly suitable area to study past global climate changes and their influence on locale Human settlements. A paleohydrological investigation was therefore carried out on two river-fed lakes: Lake Qallimiut and Little Kangerluluup, both located close to the Labrador Sea in the historic 5 farming center of Greenland. Two sediment cores (QAL-2011 and LKG-2011), spanning the last four millennia, were retrieved and showed similar thin laminae, described by high magnetic susceptibility and density, high titanium and TOC / TN atomic ratio, and coarse grain size. They are also characterized either by inverse grading followed by normal grading or by normal grading only and a prevalence of red amorphous particles 10 and lignocellulosic fragments, typical of flood deposits. Flood events showed similar trend in both records: they mainly occurred during cooler and wetter periods characterized by weaker Greenlandic paleo-temperatures, substantial glacier advances, and a high precipitation on the Greenlandic Ice Sheet and North Atlantic ice-rafting events. They can therefore be interpreted as a result of ice and 15 snow-melting episodes. They occurred especially during rapid climate changes (RCC) such as the Middle to Late Holocene transition around 2250 BC, the Sub-boreal/Sub-atlantic transition around 700 BC and the Little Ice Age (LIA) between AD 1300 and AD 1900, separated by cycles of 1500 years and driven by solar forcing. These global RCC revealed by QAL-2011 and LKG-2011 flood events may have influenced Human 20 settlements in south Greenland, especially the paleo-Eskimo cultures and the Norse settlement, and have been mainly responsible for their demise

Characterization of early disease status in treatment-naive male paediatric patients with Fabry disease enrolled in a randomized clinical trial.

Trial designThis analysis characterizes the degree of early organ involvement in a cohort of oligo-symptomatic untreated young patients with Fabry disease enrolled in an ongoing randomized, open-label, parallel-group, phase 3B clinical trial.MethodsMales aged 5-18 years with complete α-galactosidase A deficiency, without symptoms of major organ damage, were enrolled in a phase 3B trial evaluating two doses of agalsidase beta. Baseline disease characteristics of 31 eligible patients (median age 12 years) were studied, including cellular globotriaosylceramide (GL-3) accumulation in skin (n = 31) and kidney biopsy (n = 6; median age 15 years; range 13-17 years), renal function, and glycolipid levels (plasma, urine).ResultsPlasma and urinary GL-3 levels were abnormal in 25 of 30 and 31 of 31 patients, respectively. Plasma lyso-GL-3 was elevated in all patients. GL-3 accumulation was documented in superficial skin capillary endothelial cells (23/31 patients) and deep vessel endothelial cells (23/29 patients). The mean glomerular filtration rate (GFR), measured by plasma disappearance of iohexol, was 118.1 mL/min/1.73 m(2) (range 90.4-161.0 mL/min/1.73 m(2)) and the median urinary albumin/creatinine ratio was 10 mg/g (range 4.0-27.0 mg/g). On electron microscopy, renal biopsy revealed GL-3 accumulation in all glomerular cell types (podocytes and parietal, endothelial, and mesangial cells), as well as in peritubular capillary and non-capillary endothelial, interstitial, vascular smooth muscle, and distal tubules/collecting duct cells. Lesions indicative of early Fabry arteriopathy and segmental effacement of podocyte foot processes were found in all 6 patients.ConclusionsThese data reveal that in this small cohort of children with Fabry disease, histological evidence of GL-3 accumulation, and cellular and vascular injury are present in renal tissues at very early stages of the disease, and are noted before onset of microalbuminuria and development of clinically significant renal events (e.g. reduced GFR). These data give additional support to the consideration of early initiation of enzyme replacement therapy, potentially improving long-term outcome.Trial registrationClinicalTrials.gov NCT00701415

Determinants of the voltage dependence of G protein modulation within calcium channel β subunits

CaVβ subunits of voltage-gated calcium channels contain two conserved domains, a src-homology-3 (SH3) domain and a guanylate kinase-like (GK) domain with an intervening HOOK domain. We have shown in a previous study that, although Gβγ-mediated inhibitory modulation of CaV2.2 channels did not require the interaction of a CaVβ subunit with the CaVα1 subunit, when such interaction was prevented by a mutation in the α1 subunit, G protein modulation could not be removed by a large depolarization and showed voltage-independent properties (Leroy et al., J Neurosci 25:6984–6996, 2005). In this study, we have investigated the ability of mutant and truncated CaVβ subunits to support voltage-dependent G protein modulation in order to determine the minimal domain of the CaVβ subunit that is required for this process. We have coexpressed the CaVβ subunit constructs with CaV2.2 and α2δ-2, studied modulation by the activation of the dopamine D2 receptor, and also examined basal tonic modulation. Our main finding is that the CaVβ subunit GK domains, from either β1b or β2, are sufficient to restore voltage dependence to G protein modulation. We also found that the removal of the variable HOOK region from β2a promotes tonic voltage-dependent G protein modulation. We propose that the absence of the HOOK region enhances Gβγ binding affinity, leading to greater tonic modulation by basal levels of Gβγ. This tonic modulation requires the presence of an SH3 domain, as tonic modulation is not supported by any of the CaVβ subunit GK domains alone

Agalsidase alfa versus agalsidase beta for the treatment of Fabry disease: an international cohort study

BACKGROUND: Two recombinant enzymes (agalsidase alfa 0.2 mg/kg/every other week and agalsidase beta 1.0 mg/kg/every other week) have been registered for the treatment of Fabry disease (FD), at equal high costs. An independent international initiative compared clinical and biochemical outcomes of the two enzymes. METHODS: In this multicentre retrospective cohort study, clinical event rate, left ventricular mass index (LVMI), estimated glomerular filtration rate (eGFR), antibody formation and globotriaosylsphingosine (lysoGb3) levels were compared between patients with FD treated with agalsidase alfa and beta at their registered dose after correction for phenotype and sex. RESULTS: 387 patients (192 women) were included, 248 patients received agalsidase alfa. Mean age at start of enzyme replacement therapy was 46 (±15) years. Propensity score matched analysis revealed a similar event rate for both enzymes (HR 0.96, P=0.87). The decrease in plasma lysoGb3 was more robust following treatment with agalsidase beta, specifically in men with classical FD (β: -18 nmol/L, P<0.001), persisting in the presence of antibodies. The risk to develop antibodies was higher for patients treated with agalsidase beta (OR 2.8, P=0.04). LVMI decreased in a higher proportion following the first year of agalsidase beta treatment (OR 2.27, P=0.03), while eGFR slopes were similar. CONCLUSIONS: Treatment with agalsidase beta at higher dose compared with agalsidase alfa does not result in a difference in clinical events, which occurred especially in those with more advanced disease. A greater biochemical response, also in the presence of antibodies, and better reduction in left ventricular mass was observed with agalsidase beta

Consensus recommendations for the treatment and management of patients with Fabry disease on migalastat: a modified Delphi study

Objective: Fabry disease is a progressive disorder caused by deficiency of the α-galactosidase A enzyme (α-Gal A), leading to multisystemic organ damage with heterogenous clinical presentation. The addition of the oral chaperone therapy migalastat to the available treatment options for Fabry disease is not yet universally reflected in all treatment guidelines. These consensus recommendations are intended to provide guidance for the treatment and monitoring of patients with Fabry disease receiving migalastat. Methods: A modified Delphi process was conducted to determine consensus on treatment decisions and monitoring of patients with Fabry disease receiving migalastat. The multidisciplinary panel comprised 14 expert physicians across nine specialties and two patients with Fabry disease. Two rounds of Delphi surveys were completed and recommendations on the use of biomarkers, multidisciplinary monitoring, and treatment decisions were generated based on statements that reached consensus. Results: The expert panel reached consensus agreement on 49 of 54 statements, including 16 that reached consensus in round 1. Statements that reached consensus agreement are summarized in recommendations for migalastat treatment and monitoring, including baseline and follow-up assessments and frequency. All patients with Fabry disease and an amenable mutation may initiate migalastat treatment if they have evidence of Fabry-related symptoms and/or organ involvement. Treatment decisions should include holistic assessment of the patient, considering clinical symptoms and organ involvement as well as patient-reported outcomes and patient preference. The reliability of α-Gal A and globotriaosylsphingosine as pharmacodynamic response biomarkers remains unclear. Conclusion: These recommendations build on previously published guidelines to highlight the importance of holistic, multidisciplinary monitoring for patients with Fabry disease receiving migalastat, in addition to shared decision-making regarding treatments and monitoring throughout the patient journey. (Figure presented.)

Assessment of plasma lyso-Gb(3)for clinical monitoring of treatment response in migalastat-treated patients with Fabry disease

Purpose To assess the utility of globotriaosylsphingosine (lyso-Gb(3)) for clinical monitoring of treatment response in patients with Fabry disease receiving migalastat. Methods A post hoc analysis evaluated data from 97 treatment-naive and enzyme replacement therapy (ERT)-experienced patients with migalastat-amenableGLAvariants from FACETS (NCT00925301) and ATTRACT (NCT01218659) and subsequent open-label extension studies. The relationship between plasma lyso-Gb(3)and measures of Fabry disease progression (left ventricular mass index [LVMi], estimated glomerular filtration rate [eGFR], and pain) and the relationship between lyso-Gb(3)and incidence of Fabry-associated clinical events (FACEs) were assessed in both groups. The relationship between changes in lyso-Gb(3)and kidney interstitial capillary (KIC) globotriaosylceramide (Gb(3)) inclusions was assessed in treatment-naive patients. Results No significant correlations were identified between changes in lyso-Gb(3)and changes in LVMi, eGFR, or pain. Neither baseline lyso-Gb(3)levels nor the rate of change in lyso-Gb(3)levels during treatment predicted FACE occurrences in all patients or those receiving migalastat for >= 24 months. Changes in lyso-Gb(3)correlated with changes in KIC Gb(3)inclusions in treatment-naive patients. Conclusions Although used as a pharmacodynamic biomarker in research and clinical studies, plasma lyso-Gb(3)may not be a suitable biomarker for monitoring treatment response in migalastat-treated patients.Medical Biochemistr