Beginning With Pictures

This paper shows how simple drawings were used to teach English to a beginning-level language class. It contains a syllabus outlining the material covered in a ten-week course and reproductions of the pictures with commentary on how they were drawn and used. The main objective in using this type of drawing was to help students find the meaning of language within themselves, as they created it. The effectiveness of these pictures in teaching basic English led to the included in-depth analysis of how humans perceive, the elementary state of mind and viewpoint (as seen in the works of three groups of beginning artists: prehistoric man, children and the American Primitive), how art and language express and communicate, and the affirmation of the value of considering all of these in teaching beginning-level language students

Structural Variations in 3,4-Dihydro-2\u3ci\u3eH\u3c/i\u3e-pyran Ketals: Acyl and Aryl Warfarin Derivatives

The crystal structures of ( ± )-cis-2-methyl-5-oxo-4- phenyl-3,4-dihydro-2H,5H-pyrano[3,2-c][1]benzopyran-2-yl acetate [C21H18O5, Mr = 350·37, monoclinic, P21/n, a = 12·091 (4), b = 8·288 (3), c = 17·840 (5) Å, β = 106·34 (2)°, V = l715(2) Å3, Z = 4, Dx = 1·356 g cm-3, λ(Mo Kᾱ) = 0·7107 Å, μ = 0·904 cm-1, F(000) = 736, T = 295 K, R = 0·050 for 2767 observations with I ≥ 3σ(I)] and (6R,12S)-( — )-6,8-dimethyl-6, 12-methano-6H,l2H,l3H-[1] benzopyran[4,3-d][1,3]benzodioxocin-13-one [C20H16O4, Mr = 320·36, tetragonal, P43, a = 10·788 (4), c = 13·587 (9) Å, V = 1581 (2) Å3 , Z = 4, Dx = 1·345 g cm-3, λ(Mo Kᾱ) = 0·7107 Å, μ = 0·873 cm-1, F(000) = 672, T = 295 K, R = 0·049 for 1425 observations with I ≥ 2·5σ(I)] are described. They are acyl and aryl ketals of warfarin, respectively, and contain an embedded dihydropyran ring. The molecules were studied as part of a series of axial 2-O-substituted-2-methyl-3,4-dihydro-2H-pyran structures which show (hemi)ketal C—O bond-length variations indentified through factor analysis with the systematic geometrical changes associated with a spontaneous elimination (El-like) reaction from the ketal leading to 2-methyl-4H-pyran. As in α-tetrahydropyranyl acetals the C—0 lengths in dihydropyranyl ketals can be expressed as a function of the electron-withdrawing ability of the substituent conjugate base, and the slopes of the relat1onsh1ps for the two systems are similar. Corresponding endocyclic C—0 lengths are about 0·052 Å longer in these model dihydropyranyl ketals

Functional Analysis and Molecular Dynamics Simulation of LOX-1 K167N Polymorphism Reveal Alteration of Receptor Activity

The human lectin-like oxidized low density lipoprotein receptor 1 LOX-1, encoded by the ORL1 gene, is the major scavenger receptor for oxidized low density lipoprotein in endothelial cells. Here we report on the functional effects of a coding SNP, c.501G>C, which produces a single amino acid change (K>N at codon 167). Our study was aimed at elucidating whether the c.501G>C polymorphism changes the binding affinity of LOX-1 receptor altering its function. The presence of p.K167N mutation reduces ox-LDL binding and uptake. Ox-LDL activated extracellular signal-regulated kinases 1 and 2 (ERK 1/2) is inhibited. Furthermore, ox-LDL induced biosynthesis of LOX-1 receptors is dependent on the p.K167N variation. In human macrophages, derived from c.501G>C heterozygous individuals, the ox-LDL induced LOX-1 46 kDa band is markedly lower than in induced macrophages derived from c.501G>C controls. Investigation of p.K167N mutation through molecular dynamics simulation and electrostatic analysis suggests that the ox-LDL binding may be attributed to the coupling between the electrostatic potential distribution and the asymmetric flexibility of the basic spine residues. The N/N-LOX-1 mutant has either interrupted electrostatic potential and asymmetric fluctuations of the basic spine arginines

Enhancing Discovery of Genetic Variants for Posttraumatic Stress Disorder Through Integration of Quantitative Phenotypes and Trauma Exposure Information

Funding Information: This work was supported by the National Institute of Mental Health / U.S. Army Medical Research and Development Command (Grant No. R01MH106595 [to CMN, IL, MBS, KJRe, and KCK], National Institutes of Health (Grant No. 5U01MH109539 to the Psychiatric Genomics Consortium ), and Brain & Behavior Research Foundation (Young Investigator Grant [to KWC]). Genotyping of samples was provided in part through the Stanley Center for Psychiatric Genetics at the Broad Institute supported by Cohen Veterans Bioscience . Statistical analyses were carried out on the LISA/Genetic Cluster Computer ( https://userinfo.surfsara.nl/systems/lisa ) hosted by SURFsara. This research has been conducted using the UK Biobank resource (Application No. 41209). This work would have not been possible without the financial support provided by Cohen Veterans Bioscience, the Stanley Center for Psychiatric Genetics at the Broad Institute, and One Mind. Funding Information: MBS has in the past 3 years received consulting income from Actelion, Acadia Pharmaceuticals, Aptinyx, Bionomics, BioXcel Therapeutics, Clexio, EmpowerPharm, GW Pharmaceuticals, Janssen, Jazz Pharmaceuticals, and Roche/Genentech and has stock options in Oxeia Biopharmaceuticals and Epivario. In the past 3 years, NPD has held a part-time paid position at Cohen Veterans Bioscience, has been a consultant for Sunovion Pharmaceuticals, and is on the scientific advisory board for Sentio Solutions for unrelated work. In the past 3 years, KJRe has been a consultant for Datastat, Inc., RallyPoint Networks, Inc., Sage Pharmaceuticals, and Takeda. JLM-K has received funding and a speaking fee from COMPASS Pathways. MU has been a consultant for System Analytic. HRK is a member of the Dicerna scientific advisory board and a member of the American Society of Clinical Psychopharmacology Alcohol Clinical Trials Initiative, which during the past 3 years was supported by Alkermes, Amygdala Neurosciences, Arbor Pharmaceuticals, Dicerna, Ethypharm, Indivior, Lundbeck, Mitsubishi, and Otsuka. HRK and JG are named as inventors on Patent Cooperative Treaty patent application number 15/878,640, entitled “Genotype-guided dosing of opioid agonists,” filed January 24, 2018. RP and JG are paid for their editorial work on the journal Complex Psychiatry. OAA is a consultant to HealthLytix. All other authors report no biomedical financial interests or potential conflicts of interest. Funding Information: This work was supported by the National Institute of Mental Health/ U.S. Army Medical Research and Development Command (Grant No. R01MH106595 [to CMN, IL, MBS, KJRe, and KCK], National Institutes of Health (Grant No. 5U01MH109539 to the Psychiatric Genomics Consortium), and Brain & Behavior Research Foundation (Young Investigator Grant [to KWC]). Genotyping of samples was provided in part through the Stanley Center for Psychiatric Genetics at the Broad Institute supported by Cohen Veterans Bioscience. Statistical analyses were carried out on the LISA/Genetic Cluster Computer (https://userinfo.surfsara.nl/systems/lisa) hosted by SURFsara. This research has been conducted using the UK Biobank resource (Application No. 41209). This work would have not been possible without the financial support provided by Cohen Veterans Bioscience, the Stanley Center for Psychiatric Genetics at the Broad Institute, and One Mind. This material has been reviewed by the Walter Reed Army Institute of Research. There is no objection to its presentation and/or publication. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting true views of the U.S. Department of the Army or the Department of Defense. We thank the investigators who comprise the PGC-PTSD working group and especially the more than 206,000 research participants worldwide who shared their life experiences and biological samples with PGC-PTSD investigators. We thank Mark Zervas for his critical input. Full acknowledgments are in Supplement 1. MBS has in the past 3 years received consulting income from Actelion, Acadia Pharmaceuticals, Aptinyx, Bionomics, BioXcel Therapeutics, Clexio, EmpowerPharm, GW Pharmaceuticals, Janssen, Jazz Pharmaceuticals, and Roche/Genentech and has stock options in Oxeia Biopharmaceuticals and Epivario. In the past 3 years, NPD has held a part-time paid position at Cohen Veterans Bioscience, has been a consultant for Sunovion Pharmaceuticals, and is on the scientific advisory board for Sentio Solutions for unrelated work. In the past 3 years, KJRe has been a consultant for Datastat, Inc. RallyPoint Networks, Inc. Sage Pharmaceuticals, and Takeda. JLM-K has received funding and a speaking fee from COMPASS Pathways. MU has been a consultant for System Analytic. HRK is a member of the Dicerna scientific advisory board and a member of the American Society of Clinical Psychopharmacology Alcohol Clinical Trials Initiative, which during the past 3 years was supported by Alkermes, Amygdala Neurosciences, Arbor Pharmaceuticals, Dicerna, Ethypharm, Indivior, Lundbeck, Mitsubishi, and Otsuka. HRK and JG are named as inventors on Patent Cooperative Treaty patent application number 15/878,640, entitled ?Genotype-guided dosing of opioid agonists,? filed January 24, 2018. RP and JG are paid for their editorial work on the journal Complex Psychiatry. OAA is a consultant to HealthLytix. All other authors report no biomedical financial interests or potential conflicts of interest. Publisher Copyright: © 2021 Society of Biological PsychiatryBackground: Posttraumatic stress disorder (PTSD) is heritable and a potential consequence of exposure to traumatic stress. Evidence suggests that a quantitative approach to PTSD phenotype measurement and incorporation of lifetime trauma exposure (LTE) information could enhance the discovery power of PTSD genome-wide association studies (GWASs). Methods: A GWAS on PTSD symptoms was performed in 51 cohorts followed by a fixed-effects meta-analysis (N = 182,199 European ancestry participants). A GWAS of LTE burden was performed in the UK Biobank cohort (N = 132,988). Genetic correlations were evaluated with linkage disequilibrium score regression. Multivariate analysis was performed using Multi-Trait Analysis of GWAS. Functional mapping and annotation of leading loci was performed with FUMA. Replication was evaluated using the Million Veteran Program GWAS of PTSD total symptoms. Results: GWASs of PTSD symptoms and LTE burden identified 5 and 6 independent genome-wide significant loci, respectively. There was a 72% genetic correlation between PTSD and LTE. PTSD and LTE showed largely similar patterns of genetic correlation with other traits, albeit with some distinctions. Adjusting PTSD for LTE reduced PTSD heritability by 31%. Multivariate analysis of PTSD and LTE increased the effective sample size of the PTSD GWAS by 20% and identified 4 additional loci. Four of these 9 PTSD loci were independently replicated in the Million Veteran Program. Conclusions: Through using a quantitative trait measure of PTSD, we identified novel risk loci not previously identified using prior case-control analyses. PTSD and LTE have a high genetic overlap that can be leveraged to increase discovery power through multivariate methods.publishersversionpublishe

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Cardiometabolic Risk Factor Changes Observed in Diabetes Prevention Programs in US Settings: A Systematic Review and Meta-analysis

Background: The Diabetes Prevention Program (DPP) study showed that weight loss in high-risk adults lowered diabetes incidence and cardiovascular disease risk. No prior analyses have aggregated weight and cardiometabolic risk factor changes observed in studies implementing DPP interventions in nonresearch settings in the United States. Methods and Findings: In this systematic review and meta-analysis, we pooled data from studies in the United States implementing DPP lifestyle modification programs (focused on modest [5%–7%] weight loss through ≥150 min of moderate physical activity per week and restriction of fat intake) in clinical, community, and online settings. We reported aggregated pre- and post-intervention weight and cardiometabolic risk factor changes (fasting blood glucose [FBG], glycosylated hemoglobin [HbA1c], systolic or diastolic blood pressure [SBP/DBP], total [TC] or HDL-cholesterol). We searched the MEDLINE, EMBASE, Cochrane Library, and Clinicaltrials.gov databases from January 1, 2003, to May 1, 2016. Two reviewers independently evaluated article eligibility and extracted data on study designs, populations enrolled, intervention program characteristics (duration, number of core and maintenance sessions), and outcomes. We used a random effects model to calculate summary estimates for each outcome and associated 95% confidence intervals (CI). To examine sources of heterogeneity, results were stratified according to the presence of maintenance sessions, risk level of participants (prediabetes or other), and intervention delivery personnel (lay or professional). Forty-four studies that enrolled 8,995 participants met eligibility criteria. Participants had an average age of 50.8 years and body mass index (BMI) of 34.8 kg/m2, and 25.2% were male. On average, study follow-up was 9.3 mo (median 12.0) with a range of 1.5 to 36 months; programs offered a mean of 12.6 sessions, with mean participant attendance of 11.0 core sessions. Sixty percent of programs offered some form of post-core maintenance (either email or in person). Mean absolute changes observed were: weight -3.77 kg (95% CI: -4.55; -2.99), HbA1c -0.21% (-0.29; -0.13), FBG -2.40 mg/dL (-3.59; -1.21), SBP -4.29 mmHg (-5.73, -2.84), DBP -2.56 mmHg (-3.40, 1.71), HDL +0.85 mg/dL (-0.10, 1.60), and TC -5.34 mg/dL (-9.72, -0.97). Programs with a maintenance component achieved greater reductions in weight (additional -1.66kg) and FBG (additional -3.14 mg/dl). Findings are subject to incomplete reporting and heterogeneity of studies included, and confounding because most included studies used pre-post study designs. Conclusions: DPP lifestyle modification programs achieved clinically meaningful weight and cardiometabolic health improvements. Together, these data suggest that additional value is gained from these programs, reinforcing that they are likely very cost-effective

Genome-wide analysis in over 1 million individuals of European ancestry yields improved polygenic risk scores for blood pressure traits

Hypertension affects more than one billion people worldwide. Here we identify 113 novel loci, reporting a total of 2,103 independent genetic signals (P &lt; 5 × 10−8) from the largest single-stage blood pressure (BP) genome-wide association study to date (n = 1,028,980 European individuals). These associations explain more than 60% of single nucleotide polymorphism-based BP heritability. Comparing top versus bottom deciles of polygenic risk scores (PRSs) reveals clinically meaningful differences in BP (16.9 mmHg systolic BP, 95% CI, 15.5–18.2 mmHg, P = 2.22 × 10−126) and more than a sevenfold higher odds of hypertension risk (odds ratio, 7.33; 95% CI, 5.54–9.70; P = 4.13 × 10−44) in an independent dataset. Adding PRS into hypertension-prediction models increased the area under the receiver operating characteristic curve (AUROC) from 0.791 (95% CI, 0.781–0.801) to 0.826 (95% CI, 0.817–0.836, ∆AUROC, 0.035, P = 1.98 × 10−34). We compare the 2,103 loci results in non-European ancestries and show significant PRS associations in a large African-American sample. Secondary analyses implicate 500 genes previously unreported for BP. Our study highlights the role of increasingly large genomic studies for precision health research