Exquisite Selectivity For Human Toll-like Receptor 8 in Substituted Furo[2,3-c]quinolines

Toll-like receptor (TLR)-8 agonists activate adaptive immune responses by inducing robust production of T helper 1-polarizing cytokines, suggesting that TLR8-active compounds may be promising candidate adjuvants. We synthesized and evaluated hitherto unexplored furo[2,3-c]quinolines and its regioisomeric furo[3,2-c]quinolines, derived via a tandem, one-pot Sonogashira coupling and intramolecular 5 endo-dig cyclization strategy, in a panel of primary screens. We observed a pure TLR8 agonistic activity profile in select furo[2,3-c]quinolines, with maximal potency conferred by a C2-butyl group (EC50: 1.6 µM); shorter, longer, or substituted homologues, as well as compounds bearing C1 substitutions were inactive, which was rationalized by docking studies using the recently-described crystal structure of human TLR8. The best-in-class compound displayed prominent proinflammatory cytokine induction (including interleukin-12 and interleukin-18), but was bereft of interferon-α inducing properties, confirming its high selectivity for human TLR8

Toll-like Receptor-8 Agonistic Activities in C2, C4, and C8 Modified Thiazolo[4,5-c]quinolines

Toll-like receptor (TLR)-8 agonists typified by the 2-alkylthiazolo[4,5-c]quinolin-4-amine (CL075) chemotype are uniquely potent in activating adaptive immune responses by inducing robust production of T helper 1-polarizing cytokines, suggesting that TLR8-active compounds could be promising candidate vaccine adjuvants, especially for neonatal vaccines. Alkylthiazoloquinolines with methyl, ethyl, propyl and butyl groups at C2 displayed comparable TLR8-agonistic potencies; activity diminished precipitously in the C2-pentyl compound, and higher homologues were inactive. The C2-butyl compound was unique in possessing substantial TLR7-agonistic activity. Analogues with branched alkyl groups at C2 displayed poor tolerance of terminal steric bulk. Virtually all modifications at C8 led to abrogation of agonistic activity. Alkylation on the C4-amine was not tolerated, whereas N-acyl analogues with short acyl groups (other than acetyl) retained TLR8 agonistic activity, but were substantially less water-soluble. Immunization in rabbits with a model subunit antigen adjuvanted with the lead C2-butyl thiazoloquinoline showed enhancements of antigen-specific antibody titers

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Global, regional, and national under-5 mortality, adult mortality, age-specific mortality, and life expectancy, 1970–2016: a systematic analysis for the Global Burden of Disease Study 2016

BACKGROUND: Detailed assessments of mortality patterns, particularly age-specific mortality, represent a crucial input that enables health systems to target interventions to specific populations. Understanding how all-cause mortality has changed with respect to development status can identify exemplars for best practice. To accomplish this, the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016) estimated age-specific and sex-specific all-cause mortality between 1970 and 2016 for 195 countries and territories and at the subnational level for the five countries with a population greater than 200 million in 2016. METHODS: We have evaluated how well civil registration systems captured deaths using a set of demographic methods called death distribution methods for adults and from consideration of survey and census data for children younger than 5 years. We generated an overall assessment of completeness of registration of deaths by dividing registered deaths in each location-year by our estimate of all-age deaths generated from our overall estimation process. For 163 locations, including subnational units in countries with a population greater than 200 million with complete vital registration (VR) systems, our estimates were largely driven by the observed data, with corrections for small fluctuations in numbers and estimation for recent years where there were lags in data reporting (lags were variable by location, generally between 1 year and 6 years). For other locations, we took advantage of different data sources available to measure under-5 mortality rates (U5MR) using complete birth histories, summary birth histories, and incomplete VR with adjustments; we measured adult mortality rate (the probability of death in individuals aged 15-60 years) using adjusted incomplete VR, sibling histories, and household death recall. We used the U5MR and adult mortality rate, together with crude death rate due to HIV in the GBD model life table system, to estimate age-specific and sex-specific death rates for each location-year. Using various international databases, we identified fatal discontinuities, which we defined as increases in the death rate of more than one death per million, resulting from conflict and terrorism, natural disasters, major transport or technological accidents, and a subset of epidemic infectious diseases; these were added to estimates in the relevant years. In 47 countries with an identified peak adult prevalence for HIV/AIDS of more than 0·5% and where VR systems were less than 65% complete, we informed our estimates of age-sex-specific mortality using the Estimation and Projection Package (EPP)-Spectrum model fitted to national HIV/AIDS prevalence surveys and antenatal clinic serosurveillance systems. We estimated stillbirths, early neonatal, late neonatal, and childhood mortality using both survey and VR data in spatiotemporal Gaussian process regression models. We estimated abridged life tables for all location-years using age-specific death rates. We grouped locations into development quintiles based on the Socio-demographic Index (SDI) and analysed mortality trends by quintile. Using spline regression, we estimated the expected mortality rate for each age-sex group as a function of SDI. We identified countries with higher life expectancy than expected by comparing observed life expectancy to anticipated life expectancy on the basis of development status alone. FINDINGS: Completeness in the registration of deaths increased from 28% in 1970 to a peak of 45% in 2013; completeness was lower after 2013 because of lags in reporting. Total deaths in children younger than 5 years decreased from 1970 to 2016, and slower decreases occurred at ages 5-24 years. By contrast, numbers of adult deaths increased in each 5-year age bracket above the age of 25 years. The distribution of annualised rates of change in age-specific mortality rate differed over the period 2000 to 2016 compared with earlier decades: increasing annualised rates of change were less frequent, although rising annualised rates of change still occurred in some locations, particularly for adolescent and younger adult age groups. Rates of stillbirths and under-5 mortality both decreased globally from 1970. Evidence for global convergence of death rates was mixed; although the absolute difference between age-standardised death rates narrowed between countries at the lowest and highest levels of SDI, the ratio of these death rates-a measure of relative inequality-increased slightly. There was a strong shift between 1970 and 2016 toward higher life expectancy, most noticeably at higher levels of SDI. Among countries with populations greater than 1 million in 2016, life expectancy at birth was highest for women in Japan, at 86·9 years (95% UI 86·7-87·2), and for men in Singapore, at 81·3 years (78·8-83·7) in 2016. Male life expectancy was generally lower than female life expectancy between 1970 and 2016, an

Study of multicomponent fluoro-phosphate based glasses: Ho3+ as a luminescence center

Sem informaçãoThe multicomponent 49.5P(2)O(5)-10AlF(3)-10BaF(2)-10SrF(2)-10PbO-10M (M=Li2O, Na2O, K2O, ZnO and Bi2O3) glasses doped with 0.5 mol% holmium were prepared by melt quenching technique. Their thermal behavior was examined from differential scanning calorimetry (DSC). It is found that bismuth fluorophosphate glass matrix has good thermal stability. Their structures were characterized by the X-ray diffraction with SEM analysis, fourier transform infrared (FTIR), Raman spectroscopy and magic angle spinning (MAS) nuclear magnetic resonance (NMR) techniques. It was found that the phosphate network of these glasses was composed mainly of Q(2) and Q(3) phosphate tetrahedral units. The Judd-Ofelt parameters (J-O) (Omega(2), Omega(4) and Omega(6)) were evaluated from the intensities of the energy levels through optical absorption spectra. The most intense transitions are observed in the visible region of the spectrum. It is observed that the transition I-5(8) -> (5)G(6) is the hypersensitive transition for Ho3+ ion. With these J-O parameters, various radiative properties like the probabilities of radiative transitions, radiative lifetimes and branching ratios have been calculated for different fluoro-phosphate glasses. The luminescence kinetics from excited holmium levels have been studied upon selective excitation through photoluminescence measurements. Holmium produces two visible laser emissions i.e. one is green (F-5(4)(S-5(2)) -> I-5(8)) and another one is red (F-5(5) -> I-5(8)). The lifetimes of these levels have been experimentally determined through decay profile studies. The above results suggest that the prepared bismuth fluorophosphate glass system could be a suitable candidate for using it as a green laser source (F-5(4)(S-5(2)) -> I-5(8)) in the visible region of the spectrum. (C) 2015 Elsevier B.V. All rights reserved.The multicomponent 49.5P(2)O(5)-10AlF(3)-10BaF(2)-10SrF(2)-10PbO-10M (M=Li2O, Na2O, K2O, ZnO and Bi2O3) glasses doped with 0.5 mol% holmium were prepared by melt quenching technique. Their thermal behavior was examined from differential scanning calorimetry (DSC). It is found that bismuth fluorophosphate glass matrix has good thermal stability. Their structures were characterized by the X-ray diffraction with SEM analysis, fourier transform infrared (FTIR), Raman spectroscopy and magic angle spinning (MAS) nuclear magnetic resonance (NMR) techniques. It was found that the phosphate network of these glasses was composed mainly of Q(2) and Q(3) phosphate tetrahedral units. The Judd-Ofelt parameters (J-O) (Omega(2), Omega(4) and Omega(6)) were evaluated from the intensities of the energy levels through optical absorption spectra. The most intense transitions are observed in the visible region of the spectrum. It is observed that the transition I-5(8) -> (5)G(6) is the hypersensitive transition for Ho3+ ion. With these J-O parameters, various radiative properties like the probabilities of radiative transitions, radiative lifetimes and branching ratios have been calculated for different fluoro-phosphate glasses. The luminescence kinetics from excited holmium levels have been studied upon selective excitation through photoluminescence measurements. Holmium produces two visible laser emissions i.e. one is green (F-5(4)(S-5(2)) -> I-5(8)) and another one is red (F-5(5) -> I-5(8)). The lifetimes of these levels have been experimentally determined through decay profile studies. The above results suggest that the prepared bismuth fluorophosphate glass system could be a suitable candidate for using it as a green laser source (F-5(4)(S-5(2)) -> I-5(8)) in the visible region of the spectrum.4792634Sem informaçãoSem informaçãoSem informaçãoOne of the authors S. Babu would like to thank University Grants Commission (UGC), New Delhi for the sanction of Senior Research Fellowship (SRF) under Research Fellowship in Sciences for Meritorious students (RFSMS) scheme. Also thanks to SAIF IISc, Bangalore for providing solid state NMR facilities

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Not AvailableShoot fly is one of the major pests of sorghum in India, which causes substantial economic losses in sorghum production. Levels of host plant resistance to sorghum shoot fly is low to moderate. Mutagenesis is a potential tool to induce new variation for crop improvement. Seeds of sorghum genotype IS 18551, a shoot fly resistant line, were mutated by irradiating with 500 Gy gamma rays. These mutants were evaluated under field condition for two seasons at four locations for resistance to shoot fly. Finally 30 mutant lines showed resistance to shoot fly across three hot spot locations over the resistance check (IS 18551) and three mutant lines showed break down of resistance and was on par with susceptible check (DJ 6514) were identified. Genetic analyses of these lines would throw light on the genes underlying resistance/susceptibility and facilitate development of genotypes with enhanced resistance.Not Availabl