Dating protracted fault activities: microstructures, microchemistry and geochronology of the Vaikrita Thrust, Main Central Thrust zone, Garhwal Himalaya, NW India

The timing of shearing along the Vaikrita Thrust, the structurally upper boundary of the Main Central Thrust zone (MCTz), was constrained by combined microstructural, microchemical and geochronological investigations. Three different biotite-muscovite growth and recrystallisation episodes were observed: a relict mica-1; mica-2 along the main mylonitic foliation; mica-3 in coronitic structures around garnet during its breakdown. Analyses of biotite by electron microprobe show chloritization, and bimodal composition of biotite- 2 in one sample. Muscovite-2 and muscovite-3 differ in composition from each other. Biotite and muscovite 39Ar-40Ar age spectra from all samples give both inter-sample and intra- sample discrepancies. Biotite step ages range between 8.6 and 16 Ma, muscovite step ages between 3.6 and 7.8 Ma. These ages cannot be interpreted as "cooling ages", as samples from the same outcrop cooled simultaneously. Instead, Ar systematics reflect sample-specific recrystallisation markers. Intergrown impurities were diagnosed by Ca/K ratios. Age data of biotite were interpreted as a mixture of true biotite-2 (9.00±0.10 Ma) and two alteration products. The negative Cl/K-age correlation identifies a Cl-poor muscovite-2 (>7 Ma) and a Cl-rich, post-deformational, coronitic muscovite-3 grown at ≤5.88±0.03 Ma. The Vaikrita Thrust was active at least from 9 to 6 Ma around 600 °C; its movement ceased by 6 Ma

Energy-Dependent Timing of Thermal Emission in Solar Flares

We report solar flare plasma to be multi-thermal in nature based on the theoretical model and study of the energy-dependent timing of thermal emission in ten M-class flares. We employ high-resolution X-ray spectra observed by the Si detector of the "Solar X-ray Spectrometer" (SOXS). The SOXS onboard the Indian GSAT-2 spacecraft was launched by the GSLV-D2 rocket on 8 May 2003. Firstly we model the spectral evolution of the X-ray line and continuum emission flux F(\epsilon) from the flare by integrating a series of isothermal plasma flux. We find that multi-temperature integrated flux F(\epsilon) is a power-law function of \epsilon with a spectral index (\gamma) \approx -4.65. Next, based on spectral-temporal evolution of the flares we find that the emission in the energy range E= 4 - 15 keV is dominated by temperatures of T= 12 - 50 MK, while the multi-thermal power-law DEM index (\gamma) varies in the range of -4.4 and -5.7. The temporal evolution of the X-ray flux F(\epsilon,t) assuming a multi-temperature plasma governed by thermal conduction cooling reveals that the temperature-dependent cooling time varies between 296 and 4640 s and the electron density (n_e) varies in the range of n_e= (1.77-29.3)*10^10 cm-3. Employing temporal evolution technique in the current study as an alternative method for separating thermal from non-thermal components in the energy spectra, we measure the break-energy point ranging between 14 and 21\pm1.0 keV.Comment: Solar Physics, in pres

Development of A Method To Quantify The DNA Content in Cationic Peptide-DNA Nanoparticles

Gene therapy has the potential to provide safe and targeted therapies for a variety of diseases. A range of intracellular gene delivery vehicles have been proposed for this purpose. Non-viral vectors are a particularly attractive option and among them cationic peptides have emerged as promising candidates. For the pharmaceutical formulation and application to clinical studies it is necessary to quantify the amount of pDNA condensed with the delivery system. There is a severe deficiency in this area, thus far no methods have been reported specifically for pDNA condensed with cationic peptide to form nanoparticles. The current study seeks to address this and describes the evaluation of a range of disruption agents to extract DNA from nanoparticles formed by condensation with cationic fusogenic peptides RALA and KALA. Only proteinase K exhibited efficient and reproducible results and compatibility with the PicoGreen reagent based quantification assay. Thus we report for the first time a simple and reliable method that can quantify the pDNA content in pDNA cationic peptide nanoparticles

International Review and Advisory Committee

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Lysyl-tRNA synthetase as a drug target in malaria and cryptosporidiosis

Malaria and cryptosporidiosis, caused by apicomplexan parasites, remain major drivers of global child mortality. New drugs for the treatment of malaria and cryptosporidiosis, in particular, are of high priority; however, there are few chemically validated targets. The natural product cladosporin is active against blood- and liver-stage; Plasmodium falciparum; and; Cryptosporidium parvum; in cell-culture studies. Target deconvolution in; P. falciparum; has shown that cladosporin inhibits lysyl-tRNA synthetase (; Pf; KRS1). Here, we report the identification of a series of selective inhibitors of apicomplexan KRSs. Following a biochemical screen, a small-molecule hit was identified and then optimized by using a structure-based approach, supported by structures of both; Pf; KRS1 and; C. parvum; KRS (; Cp; KRS). In vivo proof of concept was established in an SCID mouse model of malaria, after oral administration (ED; 90; = 1.5 mg/kg, once a day for 4 d). Furthermore, we successfully identified an opportunity for pathogen hopping based on the structural homology between; Pf; KRS1 and; Cp; KRS. This series of compounds inhibit; Cp; KRS and; C. parvum; and; Cryptosporidium hominis; in culture, and our lead compound shows oral efficacy in two cryptosporidiosis mouse models. X-ray crystallography and molecular dynamics simulations have provided a model to rationalize the selectivity of our compounds for; Pf; KRS1 and; Cp; KRS vs. (human); Hs; KRS. Our work validates apicomplexan KRSs as promising targets for the development of drugs for malaria and cryptosporidiosis

Measuring the predictability of life outcomes with a scientific mass collaboration.

How predictable are life trajectories? We investigated this question with a scientific mass collaboration using the common task method; 160 teams built predictive models for six life outcomes using data from the Fragile Families and Child Wellbeing Study, a high-quality birth cohort study. Despite using a rich dataset and applying machine-learning methods optimized for prediction, the best predictions were not very accurate and were only slightly better than those from a simple benchmark model. Within each outcome, prediction error was strongly associated with the family being predicted and weakly associated with the technique used to generate the prediction. Overall, these results suggest practical limits to the predictability of life outcomes in some settings and illustrate the value of mass collaborations in the social sciences

Effect of SGLT2 inhibitors on stroke and atrial fibrillation in diabetic kidney disease: Results from the CREDENCE trial and meta-analysis

BACKGROUND AND PURPOSE: Chronic kidney disease with reduced estimated glomerular filtration rate or elevated albuminuria increases risk for ischemic and hemorrhagic stroke. This study assessed the effects of sodium glucose cotransporter 2 inhibitors (SGLT2i) on stroke and atrial fibrillation/flutter (AF/AFL) from CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) and a meta-Analysis of large cardiovascular outcome trials (CVOTs) of SGLT2i in type 2 diabetes mellitus. METHODS: CREDENCE randomized 4401 participants with type 2 diabetes mellitus and chronic kidney disease to canagliflozin or placebo. Post hoc, we estimated effects on fatal or nonfatal stroke, stroke subtypes, and intermediate markers of stroke risk including AF/AFL. Stroke and AF/AFL data from 3 other completed large CVOTs and CREDENCE were pooled using random-effects meta-Analysis. RESULTS: In CREDENCE, 142 participants experienced a stroke during follow-up (10.9/1000 patient-years with canagliflozin, 14.2/1000 patient-years with placebo; hazard ratio [HR], 0.77 [95% CI, 0.55-1.08]). Effects by stroke subtypes were: ischemic (HR, 0.88 [95% CI, 0.61-1.28]; n=111), hemorrhagic (HR, 0.50 [95% CI, 0.19-1.32]; n=18), and undetermined (HR, 0.54 [95% CI, 0.20-1.46]; n=17). There was no clear effect on AF/AFL (HR, 0.76 [95% CI, 0.53-1.10]; n=115). The overall effects in the 4 CVOTs combined were: Total stroke (HRpooled, 0.96 [95% CI, 0.82-1.12]), ischemic stroke (HRpooled, 1.01 [95% CI, 0.89-1.14]), hemorrhagic stroke (HRpooled, 0.50 [95% CI, 0.30-0.83]), undetermined stroke (HRpooled, 0.86 [95% CI, 0.49-1.51]), and AF/AFL (HRpooled, 0.81 [95% CI, 0.71-0.93]). There was evidence that SGLT2i effects on total stroke varied by baseline estimated glomerular filtration rate (P=0.01), with protection in the lowest estimated glomerular filtration rate (45 mL/min/1.73 m2]) subgroup (HRpooled, 0.50 [95% CI, 0.31-0.79]). CONCLUSIONS: Although we found no clear effect of SGLT2i on total stroke in CREDENCE or across trials combined, there was some evidence of benefit in preventing hemorrhagic stroke and AF/AFL, as well as total stroke for those with lowest estimated glomerular filtration rate. Future research should focus on confirming these data and exploring potential mechanisms

Large vessel vasculitis

Takayasu arteritis is a chronic granulomatous disease of the aorta and its major branches that usually affects women during the second and third decades of life, but it has been reported in young children. This review details the clinical, pathological and radiological features, differential diagnoses and management of the condition, focusing chiefly on the disease in children. The recent definition of Takayasu arteritis is discussed. The condition should be considered in patients with unexplained arterial hypertension or unexplained inflammatory syndromes without signs of localization. Since the disease may be life-threatening and progressive, early recognition is necessary to initiate appropriate therapy. Patients with persistent ischaemic symptoms including hypertension might benefit from revascularization procedures