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The assembly of nitrogen-rich building blocks determines the energy storage capacity and affects the stability of energetic materials. Owing to the environmentally harmful properties of the propellant, ammonium perchlorate (AP), much research has explored halogen-free replacements which often suffer from poor thermal stability. In our goal of balancing performance and stability, we report access to an energetic molecule (3) by smart assembly of an azo bridge into trinitromethyl triazoles. Compound 3 exhibits a decomposition temperature of 175 °C, which approaches the highest among reported trinitromethyl derivatives. The density (1.91 g cm −3 ) and oxygen balance (+29%) for 3 exceed other candidates, suggesting it as a high energy dense oxidizer (HEDO) replacement for AP in rocket propellants. One-step azo-involved cyclization of 3 give two fused nitro triazolones, (FNTO) 4 and its N -oxide 5, having thermal stabilities and energies superior to the analogous derivatives of 5-nitro-2,4-dihydro-3 H -1,2,4-triazole-3-one (NTO). The comparison of properties of the fused triazolones 4 and 8 and their N -oxide derivatives 5 and 9 shows that formation of an N -oxide is an effective strategy which results in an increase of the decomposition temperature, oxygen balance, specific impulse, and detonation properties and in a decrease of the sensitivity of the corresponding energetic material. This work highlights bridged and fused triazolic energetic frameworks with an azo building block providing an alternative structural motif for seeking an applicable high-energy ingredient. 

Genome‐wide association studies (GWAS) have led to rapid growth in detecting genetic variants associated with various phenotypes. Owing to a great number of publicly accessible GWAS summary statistics, and the difficulty in obtaining individual‐level genotype data, many existing gene‐based association tests have been adapted to require only GWAS summary statistics rather than individual‐level data. However, these association tests are restricted to unrelated individuals and thus do not apply to family samples directly. Moreover, due to its flexibility and effectiveness, the linear mixed model has been increasingly utilized in GWAS to handle correlated data, such as family samples. However, it remains unknown how to perform gene‐based association tests in family samples using the GWAS summary statistics estimated from the linear mixed model. In this study, we show that, when family size is negligible compared to the total sample size, the diagonal block structure of the kinship matrix makes it possible to approximate the correlation matrix of marginalZscores by linkage disequilibrium matrix. Based on this result, current methods utilizing summary statistics for unrelated individuals can be directly applied to family data without any modifications. Our simulation results demonstrate that this proposed strategy controls the type 1 error rate well in various situations. Finally, we exemplify the usefulness of the proposed approach with a dental caries GWAS data set.

 

Aldosterone-producing adenomas (APAs) are the commonest curable cause of hypertension. Most have gain-of-function somatic mutations of ion channels or transporters. Herein we report the discovery, replication and phenotype of mutations in the neuronal cell adhesion geneCADM1. Independent whole exome sequencing of 40 and 81 APAs found intramembranous p.Val380Asp or p.Gly379Asp variants in two patients whose hypertension and periodic primary aldosteronism were cured by adrenalectomy. Replication identified two more APAs with each variant (total,n = 6). The most upregulated gene (10- to 25-fold) in human adrenocortical H295R cells transduced with the mutations (compared to wildtype) was CYP11B2 (aldosterone synthase), and biological rhythms were the most differentially expressed process. CADM1 knockdown or mutation inhibited gap junction (GJ)-permeable dye transfer. GJ blockade by Gap27 increased CYP11B2 similarly to CADM1 mutation. Human adrenal zona glomerulosa (ZG) expression of GJA1 (the main GJ protein) was patchy, and annular GJs (sequelae of GJ communication) were less prominent in CYP11B2-positive micronodules than adjacent ZG. Somatic mutations ofCADM1cause reversible hypertension and reveal a role for GJ communication in suppressing physiological aldosterone production.