Deep lithospheric dynamics beneath the Sierra Nevada during the Mesozoic and Cenozoic as inferred from xenolith petrology

Peridotite xenoliths erupted in late Miocene basalts (~8 Ma) in the central Sierra Nevada sample a lithosphere that is vertically stratified in terms of age and thermal history. The deeper portions (~45-100 km) have asthenospheric osmium isotopic compositons and possess textural and chemical evidence for cooling from >1100° to 700-820°C. The shallower portions (<60 km) have unradiogenic Os isotopic compositions, which yield Proterozoic model ages, and contain orthopyroxenes that record temperatures as low as 670°C in their cores and heating up to 900°C on their rims. These observations suggest that the deeper xenoliths represent fragments of hot asthenosphere that upwelled to intrude and/or underplate the overlying Proterozoic lithosphere represented by the shallower xenoliths. The contrasting thermal histories between the shallow and deep xenoliths suggest that hot asthenosphere and cold lithosphere were suddenly juxtaposed, a feature consistent with the aftermath of rapid lithospheric removal or sudden intrusion of asthenospheric mantle into the lithosphere rather than passive extension. On the basis of regional tectonics and various time constraints, it is possible that this lithospheric removal event was associated with the generation of the Sierra Nevada granitic batholith during Mesozoic subduction of the Farallon plate beneath North America. Pleistocene basalt-hosted xenoliths record a different chapter in the geodynamic history of the Sierras. These xenoliths are relatively fertile, come from depths shallower than 45-60 km, are characterized by asthenospheric Os isotopic compositions, record hot equilibration temperatures (1000°-1100°C), and show no evidence for cooling. The strong contrast in composition and thermal history between the Pleistocene and late Miocene suites indicate that the post-Mesozoic lithospheric mantle, as represented by the latter, was entirely replaced by the former. The hot Pleistocene peridotites may thus represent new lithospheric additions associated with a post-Miocene lithospheric removal event or extension. High elevations, low sub-Moho seismic velocities, and the presence of fast velocity anomalies at 200 km depth may be manifestations of this event. If lithospheric removal occurred in the Mesozoic and Cenozoic, the observations presented here place constraints on the styles of lithospheric removal. In the Mesozoic, the lithospheric mantle was only partially removed, whereas in the Pliocene, the entire lithospheric mantle and probably the mafic lower crust were removed

Variability of the total ozone trend over Europe for the period 1950?2004 derived from reconstructed data

International audienceThe total ozone data over Europe are available for only few ground-based stations in the pre-satellite era disallowing examination of the spatial trend variability over the whole continent. A need of having gridded ozone data for a trend analysis and input to radiative transfer models stimulated a reconstruction of the daily ozone values since January 1950. Description of the reconstruction model and its validation were a subject of our previous paper. The data base used was built within the objectives of the COST action 726 "Long-term changes and climatology of UV radiation over Europe". Here we focus on trend analyses. The long-term variability of total ozone is discussed using results of a flexible trend model applied to the reconstructed total ozone data for the period 1950?2004. The trend pattern, which comprises both anthropogenic and "natural" component, is not a priori assumed but it comes from a smooth curve fit to the zonal monthly means and monthly grid values. The ozone long-term changes are calculated separately for cold (October?next year April) and warm (May?September) seasons. The confidence intervals for the estimated ozone changes are derived by the block bootstrapping. The statistically significant negative trends are found almost over the whole Europe only in the period 1985?1994. Negative trends up to ?3% per decade appeared over small areas in earlier periods when the anthropogenic forcing on the ozone layer was weak . The statistically positive trends are found only during warm seasons 1995?2004 over Svalbard archipelago. The reduction of ozone level in 2004 relative to that before the satellite era is not dramatic, i.e., up to ~?5% and ~?3.5% in the cold and warm subperiod, respectively. Present ozone level is still depleted over many popular resorts in southern Europe and northern Africa. For high latitude regions the trend overturning could be inferred in last decade (1995?2004) as the ozone depleted areas are not found there in 2004 in spite of substantial ozone depletion in the period 1985?1994

Precision medicine approaches for diabetic kidney disease:opportunities and challenges

The prevalence of end-stage kidney disease (ESKD) continuously increases worldwide. The increasing prevalence parallels the growth in the number of people with diabetes, which is the leading cause of ESKD. Early diagnosis of chronic kidney disease (CKD) in patients with diabetes and appropriate intervention is important to delay the progression of kidney function decline and prevent ESKD. Rate of CKD progression and response to treatment varies among patients with diabetes, highlighting the need to tailor individual treatment. In this review, we describe recent advances and areas for future studies with respect to precision medicine in diabetic kidney disease (DKD). DKD is a multi-factorial disease that is subject in part to genetic heritability, but is also influenced by various exogenous mediators, such as environmental or dietary factors. Genetic testing so far has limited utility to facilitate early diagnosis, classify progression or evaluate response to therapy. Various biomarker-based approaches are currently explored to identify patients at high risk of ESKD and to facilitate decision-making for targeted therapy. These studies have led to discovery and validation of a couple of inflammatory proteins such as circulating tumour necrosis factor receptors, which are strong predictors of kidney disease progression. Moreover, risk and drug-response scores based on multiple biomarkers are developed to predict kidney disease progression and long-term drug efficacy. These findings, if implemented in clinical practice, will pave the way to move from a one-size-fits-all to a one-fit-for-everyone approach

Preservation of ancient and fertile lithospheric mantle beneath the southwestern United States

Stable continental regions, free from tectonic activity, are generally found only within ancient cratons—the centres of continents which formed in the Archaean era, 4.0–2.5 Gyr ago. But in the Cordilleran mountain belt of western North America some younger (middle Proterozoic) regions have remained stable, whereas some older (late Archaean) regions have been tectonically disturbed, suggesting that age alone does not determine lithospheric strength and crustal stability. Here we report rhenium–osmium isotope and mineral compositions of peridotite xenoliths from two regions of the Cordilleran mountain belt. We found that the younger, undeformed Colorado plateau is underlain by lithospheric mantle that is 'depleted' (deficient in minerals extracted by partial melting of the rock), whereas the older (Archaean), yet deformed, southern Basin and Range province is underlain by 'fertile' lithospheric mantle (not depleted by melt extraction). We suggest that the apparent relationship between composition and lithospheric strength, inferred from different degrees of crustal deformation, occurs because depleted mantle is intrinsically less dense than fertile mantle (due to iron having been lost when melt was extracted from the rock). This allows the depleted mantle to form a thicker thermal boundary layer between the deep convecting mantle and the crust, thus reducing tectonic activity at the surface. The inference that not all Archaean crust developed a strong and thick thermal boundary layer leads to the possibility that such ancient crust may have been overlooked because of its intensive reworking or lost from the geological record owing to preferential recycling

Effects of Lactobacillus rhamnosus GG supplementation on cow's milk allergy in a mouse model

<p>Abstract</p> <p>Background</p> <p>Cow's milk allergy (CMA) is one of the most prevalent human food-borne allergies, particularly in infants and young children from developed countries. Our study aims to evaluate the effects of <it>Lactobacillus rhamnosus </it>GG (LGG) administration on CMA development using whole cow's milk proteins (CMP) sensitized Balb/C mice by two different sensitization methods.</p> <p>Methods</p> <p>LGG supplemented mice were either sensitized orally with CMP and cholera toxin B-subunit (CTB) as adjuvant, or intraperitoneally (IP) with CMP but without the adjuvant. Mice were then orally challenged with CMP and allergic responses were accessed by monitoring hypersensitivity scores, measuring the levels of CMP-specific immunoglobulins (IgG1, IgG2a and IgG) and total IgE from sera, and cytokines (IL-4 and IFN-γ) from spleen lysates.</p> <p>Results</p> <p>Sensitization to CMP was successful only in IP sensitized mice, but not in orally sensitized mice with CMP and CTB. Interestingly, LGG supplementation appeared to have reduced cow's milk allergy (CMA) in the IP group of mice, as indicated by lowered allergic responses.</p> <p>Conclusions</p> <p>Adjuvant-free IP sensitization with CMP was successful in inducing CMA in the Balb/C mice model. LGG supplementation favourably modulated immune reactions by shifting Th2-dominated trends toward Th1-dominated responses in CMP sensitized mice. Our results also suggest that oral sensitization by the co-administration of CMP and CTB, as adjuvant, might not be appropriate to induce CMA in mice.</p

A novel drug response score more accurately predicts renoprotective drug effects than existing renal risk scores

Background: Risk factor-based equations are used to predict risk of kidney disease progression in patients with type 2 diabetes order to guide treatment decisions. It is, however, unknown whether these models can also be used to predict the effects of drugs on clinical outcomes. Methods: The previously developed Parameter Response Efficacy (PRE) score, which integrates multiple short-term drug effects, was first compared with the existing risk scores, Kidney Failure Risk Equation (KFRE) and The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) renal risk score, in its performance to predict end-stage renal disease (ESRD; KFRE) and doubling of serum creatinine or ESRD (ADVANCE). Second, changes in the risk scores were compared after 6 months' treatment to predict the long-term effects of losartan on these renal outcomes in patients with type 2 diabetes and chronic kidney disease. Results: The KFRE, ADVANCE and PRE scores showed similarly good performance in predicting renal risk. However, for prediction of the effect of losartan, the KFRE risk score predicted a relative risk change in the occurrence of ESRD of 3.1% [95% confidence interval (CI) -5 to 12], whereas the observed risk change was -28.8% (95% CI -42.0 to -11.5). For the composite endpoint of doubling of serum creatinine or ESRD, the ADVANCE score predicted a risk change of -12.4% (95% CI -17 to -7), which underestimated the observed risk change -21.8% (95% CI -34 to -6). The PRE score predicted renal risk changes that were close to the observed risk changes with losartan treatment [-24.0% (95% CI -30 to -17) and -22.6% (95% CI -23 to -16) for ESRD and the composite renal outcome, respectively]. Conclusion: A drug response score such as the PRE score may assist in improving clinical decision making and implement precision medicine strategies

JAK-Inhibitors for the Treatment of Rheumatoid Arthritis : A Focus on the Present and an Outlook on the Future

Janus kinase inhibitors (JAKi) belong to a new class of oral targeted disease-modifying drugs which have recently revolutionized the therapeutic panorama of rheumatoid arthritis (RA) and other immune-mediated diseases, placing alongside or even replacing conventional and biological drugs. JAKi are characterized by a novel mechanism of action, consisting of the intracellular interruption of the JAK-STAT pathway crucially involved in the immune response. The aim of this narrative review is to globally report the most relevant pharmacological features and clinical outcomes of the developed and incoming JAKi for RA, based on the available preclinical and clinical evidence. A total of 219 papers, including narrative and systematic reviews, randomized controlled trials (RCTs), observational studies, case reports, guidelines, and drug factsheets, were selected. The efficacy and safety profile of both the first generation JAKi (baricitinib and tofacitinib) and the second generation JAKi (upadacitinib, filgotinib, peficitinib, decernotinib and itacitinib) were compared and discussed. Results from RCTs and real-life data are encouraging and outline a rapid onset of the pharmacologic effects, which are maintained during the time. Their efficacy and safety profile are comparable or superior to those of biologic agents and JAKi proved to be efficacious when given as monotherapy. Finally, the manufacturing of JAKi is relatively easier and cheaper than that of biologics, thus increasing the number of compounds being formulated and tested for clinical use

Prediction of the Effects of Liraglutide on Kidney and Cardiovascular Outcomes Based on Short-Term Changes in Multiple Risk Markers

Aims: The LEADER trial demonstrated that the glucagon-like peptide-1 receptor agonist (GLP1-RA) liraglutide reduces kidney and cardiovascular (CV) risk in patients with type 2 diabetes. We previously developed a Parameter Response Efficacy (PRE) score that translates multiple short-term risk marker changes, from baseline to first available follow-up measurement, into a predicted long-term drug effect on clinical outcomes. The objective of this study was to assess the accuracy of the PRE score in predicting the efficacy of liraglutide in reducing the risk of kidney and CV outcomes. Methods: Short-term changes in glycated hemoglobin (HbA1c), systolic blood pressure (BP), urinary-albumin-creatinine-ratio (UACR), hemoglobin, body weight, high-density-lipoprotein (HDL) cholesterol, low-density-lipoprotein (LDL) cholesterol, and potassium were monitored in the LEADER trial. Associations between risk markers and kidney or CV outcomes were established using a multivariable Cox proportional hazards model in a separate pooled database of 6,355 patients with type 2 diabetes. The regression coefficients were then applied to the short-term risk markers in the LEADER trial to predict the effects of liraglutide on kidney (defined as a composite of doubling of serum creatinine or end-stage kidney disease) and CV (defined as a composite of non-fatal myocardial infarction, non-fatal stroke, and CV death) outcomes. Results: Liraglutide compared to placebo reduced HbA1c (1.4%), systolic BP (3.0 mmHg), UACR (13.2%), body weight (2.3 kg), hemoglobin (2.6 g/L), and increased HDL-cholesterol (0.01 mmol/L) (all p-values <0.01). Integrating multiple risk marker changes in the PRE score resulted in a predicted relative risk reduction (RRR) of 16.2% (95% CI 13.7–18.6) on kidney outcomes which was close to the observed RRR of 15.5% (95% CI -9.0–34.6). For the CV outcome, the PRE score predicted a 7.6% (95% CI 6.8–8.3) RRR, which was less than the observed 13.2% (95% CI 3.2–22.2) RRR. Conclusion: Integrating multiple short-term risk markers using the PRE score adequately predicted the effect of liraglutide on the composite kidney outcome. However, the PRE score underestimated the effect of liraglutide for the composite CV outcome, suggesting that the risk markers included in the PRE score do not fully capture the CV benefit of liraglutide

FARMAPRICE: A Pharmacogenetic Clinical decision support system for precise and Cost-Effective Therapy

Pharmacogenetic (PGx) guidelines for the precise dosing and selection of drugs remain poorly implemented in current clinical practice. Among the barriers to the implementation process is the lack of clinical decision support system (CDSS) tools to aid health providers in managing PGx information in the clinical context. The present study aimed to describe the first Italian endeavor to develop a PGx CDSS, called FARMAPRICE. FARMAPRICE prototype was conceived for integration of patient molecular data into the clinical prescription process in the Italian Centro di Riferimento Oncologico (CRO)-Aviano Hospital. It was developed through a coordinated partnership between two high-tech companies active in the computerization of the Italian healthcare system. Introducing FARMAPRICE into the clinical setting can aid physicians in prescribing the most efficacious and cost-effective pharmacological therapy available