Synthesis and DPPH scavenging assay of reserpine analogues, computational studies and in silico docking studies in AChE and BChE responsible for Alzheimer's disease

Alzheimer's disease (AD) is a fast growing neurodegenerative disorder of the central nervous system and anti-oxidants can be used to help suppress the oxidative stress caused by the free radicals that are responsible for AD. A series of selected synthetic indole derivatives were biologically evaluated to identify potent new antioxidants. Most of the evaluated compounds showed significant to modest antioxidant properties (IC50 value 399.07 140.0±50 µM). Density Functional Theory (DFT) studies were carried out on the compounds and their corresponding free radicals. Differences in the energy of the parent compounds and their corresponding free radicals provided a good justification for the trend found in their IC50 values. In silico, docking of compounds into the proteins acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), which are well known for contributing in AD disease, was also performed to predict anti-AD potential

The SPTPoL extended cluster survey

We describe the observations and resultant galaxy cluster catalog from the 2770 deg2 SPTpol Extended Cluster Survey (SPT-ECS). Clusters are identified via the Sunyaev-Zel'dovich (SZ) effect and confirmed with a combination of archival and targeted follow-up data, making particular use of data from the Dark Energy Survey (DES). With incomplete follow-up we have confirmed as clusters 244 of 266 candidates at a detection significance ξ ≥ 5 and an additional 204 systems at 4 4 threshold, and 10% of their measured SZ flux. We associate SZ-selected clusters, from both SPT-ECS and the SPT-SZ survey, with clusters from the DES redMaPPer sample, and we find an offset distribution between the SZ center and central galaxy in general agreement with previous work, though with a larger fraction of clusters with significant offsets. Adopting a fixed Planck-like cosmology, we measure the optical richness-SZ mass (l - M) relation and find it to be 28% shallower than that from a weak-lensing analysis of the DES data-a difference significant at the 4σ level-with the relations intersecting at λ = 60. The SPT-ECS cluster sample will be particularly useful for studying the evolution of massive clusters and, in combination with DES lensing observations and the SPT-SZ cluster sample, will be an important component of future cosmological analyses

Solar parameters for modeling interplanetary background

The goal of the Fully Online Datacenter of Ultraviolet Emissions (FONDUE) Working Team of the International Space Science Institute in Bern, Switzerland, was to establish a common calibration of various UV and EUV heliospheric observations, both spectroscopic and photometric. Realization of this goal required an up-to-date model of spatial distribution of neutral interstellar hydrogen in the heliosphere, and to that end, a credible model of the radiation pressure and ionization processes was needed. This chapter describes the solar factors shaping the distribution of neutral interstellar H in the heliosphere. Presented are the solar Lyman-alpha flux and the solar Lyman-alpha resonant radiation pressure force acting on neutral H atoms in the heliosphere, solar EUV radiation and the photoionization of heliospheric hydrogen, and their evolution in time and the still hypothetical variation with heliolatitude. Further, solar wind and its evolution with solar activity is presented in the context of the charge exchange ionization of heliospheric hydrogen, and in the context of dynamic pressure variations. Also the electron ionization and its variation with time, heliolatitude, and solar distance is presented. After a review of all of those topics, we present an interim model of solar wind and the other solar factors based on up-to-date in situ and remote sensing observations of solar wind. Results of this effort will further be utilised to improve on the model of solar wind evolution, which will be an invaluable asset in all heliospheric measurements, including, among others, the observations of Energetic Neutral Atoms by the Interstellar Boundary Explorer (IBEX).Comment: Chapter 2 in the planned "Cross-Calibration of Past and Present Far UV Spectra of Solar System Objects and the Heliosphere", ISSI Scientific Report No 12, ed. R.M. Bonnet, E. Quemerais, M. Snow, Springe

Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls

Protein-coding genetic variants that strongly affect disease risk can yield relevant clues to disease pathogenesis. Here we report exome-sequencing analyses of 20,791 individuals with type 2 diabetes (T2D) and 24,440 non-diabetic control participants from 5 ancestries. We identify gene-level associations of rare variants (with minor allele frequencies of less than 0.5%) in 4 genes at exome-wide significance, including a series of more than 30 SLC30A8 alleles that conveys protection against T2D, and in 12 gene sets, including those corresponding to T2D drug targets (P = 6.1 × 10−3) and candidate genes from knockout mice (P = 5.2 × 10−3). Within our study, the strongest T2D gene-level signals for rare variants explain at most 25% of the heritability of the strongest common single-variant signals, and the gene-level effect sizes of the rare variants that we observed in established T2D drug targets will require 75,000–185,000 sequenced cases to achieve exome-wide significance. We propose a method to interpret these modest rare-variant associations and to incorporate these associations into future target or gene prioritization efforts

Clonal hematopoiesis of indeterminate potential, DNA methylation, and risk for coronary artery disease

Age-related changes to the genome-wide DNA methylation (DNAm) pattern observed in blood are well-documented. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by the age-related acquisition and expansion of leukemogenic mutations in hematopoietic stem cells (HSCs), is associated with blood cancer and coronary artery disease (CAD). Epigenetic regulators DNMT3A and TET2 are the two most frequently mutated CHIP genes. Here, we present results from an epigenome-wide association study for CHIP in 582 Cardiovascular Health Study (CHS) participants, with replication in 2655 Atherosclerosis Risk in Communities (ARIC) Study participants. We show that DNMT3A and TET2 CHIP have distinct and directionally opposing genome-wide DNAm association patterns consistent with their regulatory roles, albeit both promoting self-renewal of HSCs. Mendelian randomization analyses indicate that a subset of DNAm alterations associated with these two leading CHIP genes may promote the risk for CAD

A factor analysis of the SSQ (Speech, Spatial, and Qualities of Hearing Scale)

OBJECTIVE: The speech, spatial, and qualities of hearing questionnaire (SSQ) is a self-report test of auditory disability. The 49 items ask how well a listener would do in many complex listening situations illustrative of real life. The scores on the items are often combined into the three main sections or into 10 pragmatic subscales. We report here a factor analysis of the SSQ that we conducted to further investigate its statistical properties and to determine its structure. DESIGN: Statistical factor analysis of questionnaire data, using parallel analysis to determine the number of factors to retain, oblique rotation of factors, and a bootstrap method to estimate the confidence intervals. STUDY SAMPLE: 1220 people who have attended MRC IHR over the last decade. RESULTS: We found three clear factors, essentially corresponding to the three main sections of the SSQ. They are termed "speech understanding", "spatial perception", and "clarity, separation, and identification". Thirty-five of the SSQ questions were included in the three factors. There was partial evidence for a fourth factor, "effort and concentration", representing two more questions. CONCLUSIONS: These results aid in the interpretation and application of the SSQ and indicate potential methods for generating average scores

Whole genome sequence association analysis of fasting glucose and fasting insulin levels in diverse cohorts from the NHLBI TOPMed program

The genetic determinants of fasting glucose (FG) and fasting insulin (FI) have been studied mostly through genome arrays, resulting in over 100 associated variants. We extended this work with high-coverage whole genome sequencing analyses from fifteen cohorts in NHLBI’s Trans-Omics for Precision Medicine (TOPMed) program. Over 23,000 non-diabetic individuals from five race-ethnicities/populations (African, Asian, European, Hispanic and Samoan) were included. Eight variants were significantly associated with FG or FI across previously identified regions MTNR1B, G6PC2, GCK, GCKR and FOXA2. We additionally characterize suggestive associations with FG or FI near previously identified SLC30A8, TCF7L2, and ADCY5 regions as well as APOB, PTPRT, and ROBO1. Functional annotation resources including the Diabetes Epigenome Atlas were compiled for each signal (chromatin states, annotation principal components, and others) to elucidate variant-to-function hypotheses. We provide a catalog of nucleotide-resolution genomic variation spanning intergenic and intronic regions creating a foundation for future sequencing-based investigations of glycemic traits

Multi-ancestry genome-wide gene–smoking interaction study of 387,272 individuals identifies new loci associated with serum lipids

The concentrations of high- and low-density-lipoprotein cholesterol and triglycerides are influenced by smoking, but it is unknown whether genetic associations with lipids may be modified by smoking. We conducted a multi-ancestry genome-wide gene–smoking interaction study in 133,805 individuals with follow-up in an additional 253,467 individuals. Combined meta-analyses identified 13 new loci associated with lipids, some of which were detected only because association differed by smoking status. Additionally, we demonstrate the importance of including diverse populations, particularly in studies of interactions with lifestyle factors, where genomic and lifestyle differences by ancestry may contribute to novel findings