2-Oxaadamantane-1-N,N,N-trimethylmethanaminium Iodide: Synthesis and Potential for Muscarinic Activity

The synthesis of the title compound from adamantanone is described. The series of steps include ring expansion and hydrolysis to endo-7-hydroxy-exo-3-bicyclo(3.3.1)nonane carboxylic acid, followed by oxidative ring closure using lead tetraacetate. The final, substituted oxaadamantane incorporates the key functional group elements known to be necessary for useful muscarinic activity into a molecular geometry not present in acetylcholine agonists or antagonists previously prepared

The Nixon shocks : implications for Japan\u27s foreign policy in the 1970\u27s

This thesis examines the implications that the Nixon “shocks” may have on Japan’s foreign policy. The data used consisted of books, articles, periodicals, government publications and newspapers. Examined were such important factors as: the attitudes of the political parties in Japan on foreign policy questions, the rapid rise of the Japanese economy and the implications this has had on Japan\u27s relations with other countries, and the question of Japan\u27s possible remilitarization, both in conventional and nuclear terms. In addition, Japan\u27s relations with the other three Great Powers in Asia, (China, the Soviet Union and the United States), are also studied. From about 1945 until the close of the 1960\u27s, Japan\u27s foreign policy had been based on a close relationship with the United States. From about the end of 1970 to the end of 1971, Japan was stung by a series of “shocks” in the course of American foreign policy. These included tile sudden and last minute announcement of Nixon\u27s visit to China, severe economic measures, the imposition of\u27 textile quotas, and the failure of Japan\u27s co-sponsoring of the United Nations motion allowing Taiwan to keep its membership. The period of 1969 to 1972 is critical to the future alignment of Japan’s foreign policy. One conclusion from this re-alignment is that it is now clear that Japan will no longer serve as the American junior partner in Asia. Japan now shows a new independent attitude in its relations with other countries, quite apart from American desire. Also in 1972 following the Nixon “shocks,” both China and the Soviet Union competed against the other to draw Japan away from its American alliance. It is the shift in Japan\u27s foreign policy that this thesis is concerned with

\u3cem\u3eABCC9\u3c/em\u3e Gene Polymorphism Is Associated with Hippocampal Sclerosis of Aging Pathology

Hippocampal sclerosis of aging (HS-Aging) is a high-morbidity brain disease in the elderly but risk factors are largely unknown. We report the first genome-wide association study (GWAS) with HS-Aging pathology as an endophenotype. In collaboration with the Alzheimer\u27s Disease Genetics Consortium, data were analyzed from large autopsy cohorts: (#1) National Alzheimer\u27s Coordinating Center (NACC); (#2) Rush University Religious Orders Study and Memory and Aging Project; (#3) Group Health Research Institute Adult Changes in Thought study; (#4) University of California at Irvine 90+ Study; and (#5) University of Kentucky Alzheimer\u27s Disease Center. Altogether, 363 HS-Aging cases and 2,303 controls, all pathologically confirmed, provided statistical power to test for risk alleles with large effect size. A two-tier study design included GWAS from cohorts #1-3 (Stage I) to identify promising SNP candidates, followed by focused evaluation of particular SNPs in cohorts #4-5 (Stage II). Polymorphism in the ATP-binding cassette, sub-family C member 9 (ABCC9) gene, also known as sulfonylurea receptor 2, was associated with HS-Aging pathology. In the meta-analyzed Stage I GWAS, ABCC9 polymorphisms yielded the lowest p values, and factoring in the Stage II results, the meta-analyzed risk SNP (rs704178:G) attained genome-wide statistical significance (p = 1.4 × 10-9), with odds ratio (OR) of 2.13 (recessive mode of inheritance). For SNPs previously linked to hippocampal sclerosis, meta-analyses of Stage I results show OR = 1.16 for rs5848 (GRN) and OR = 1.22 rs1990622 (TMEM106B), with the risk alleles as previously described. Sulfonylureas, a widely prescribed drug class used to treat diabetes, also modify human ABCC9 protein function. A subsample of patients from the NACC database (n = 624) were identified who were older than age 85 at death with known drug history. Controlling for important confounders such as diabetes itself, exposure to a sulfonylurea drug was associated with risk for HS-Aging pathology (p = 0.03). Thus, we describe a novel and targetable dementia risk factor

Genome-wide linkage analyses of non-Hispanic white families identify novel loci for familial late-onset Alzheimer's disease

INTRODUCTION: Few high penetrance variants that explain risk in late-onset Alzheimer's disease (LOAD) families have been found. METHODS: We performed genome-wide linkage and identity-by-descent (IBD) analyses on 41 non-Hispanic white families exhibiting likely dominant inheritance of LOAD, and having no mutations at known familial Alzheimer's disease (AD) loci, and a low burden of APOE ε4 alleles. RESULTS: Two-point parametric linkage analysis identified 14 significantly linked regions, including three novel linkage regions for LOAD (5q32, 11q12.2-11q14.1, and 14q13.3), one of which replicates a genome-wide association LOAD locus, the MS4A6A-MS4A4E gene cluster at 11q12.2. Five of the 14 regions (3q25.31, 4q34.1, 8q22.3, 11q12.2-14.1, and 19q13.41) are supported by strong multipoint results (logarithm of odds [LOD*] ≥1.5). Nonparametric multipoint analyses produced an additional significant locus at 14q32.2 (LOD* = 4.18). The 1-LOD confidence interval for this region contains one gene, C14orf177, and the microRNA Mir_320, whereas IBD analyses implicates an additional gene BCL11B, a regulator of brain-derived neurotrophic signaling, a pathway associated with pathogenesis of several neurodegenerative diseases. DISCUSSION: Examination of these regions after whole-genome sequencing may identify highly penetrant variants for familial LOAD

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

Toward a Spatial Theory of Intra-Nation Modernization in Advanced Societies: The West German Case 1965-1969

Die Wiederkehr politischer Konflikte in westlichen Demokratien hat das wachsende Interesse hervorgerufen, die räumlichen Bedingungen (spatial patternings) der sozialökonomischen Entwicklung und ihren Einfluß auf das Wahlsystem in Massengesellschaften näher zu untersuchen. Die vorliegende Studie unternimmt es, einen Theorieansatz zur Diskussion zu stellen, der in der Lage ist, die räumliche Komplexität der Beziehungsverhältnisse, die die entwickelten Gesellschaften heute aufweisen, auf nationaler Ebene angemessen zu erfassen, wobei sie zugleich versucht, am Beispiel Westdeutschland Daten zur empirischen Überprüfung vorzulegen. Ist der theoretische Ansatz primär darum bemüht, die Implikationen räumlicher Art, die die Beziehungsverhältnisse in Gesellschaften prägen, für die entwickelten Nationen generell anzugeben, bezieht sich der empirische Teil der Studie auf aggregierte sozialökonomische Daten sowie Daten von Wahlergebnissen, die auf Wahlkreisebene für Westdeutschland ermittelt wurden.

Silver coating of spindle-and filament-type magnetic particles for conductive adhesive applications

Spindle-type hematite and magnetite particles and nickel filaments have been coated uniformly with silver by using chemical reduction. The effects of the reaction time and the concentration and nature of the reducing agent on the particle coatings were investigated at constant temperature. The reaction time had a pronounced effect on the nature of the coated surface layer. Coated and core particles were examined by scanning electron microscopy (SEM) and energy-dispersive X-ray analysis (EDAX). The electrical properties of the particles were also characterized. The conductivity of nickel filaments which can be oriented under a magnetic field for anisotropic electric conduction increased from 302 to 877 S/cm at 3.5 kPa pressure when coated with silver