The human metallothionein gene cluster is not disrupted in myelomonocytic leukemia

The human metallothionein gene complex on chromosome 16 has been remapped to 16q13 using high-resolution in situ hybridization. The complex is not disrupted by the rearrangement breakpoint on the long arm of chromosome 16 in patients with myelomonocytic leukemia with abnormal eosinophils, as had been previously reported. The locus order on 16q is cen-MT-FRA16B-D16S4-inversion breakpoint-HP-tel.     

Isolation of intact polysomes from mechanically dehulled developing grain

A rapid method for obtaining large quantities of developing groats suitable for the isolation of highly intact polysomes has been developed. Developing spikelets were harvested directly from oat panicles into liquid nitrogen and then quickly passed through a dehuller. Chaff was removed by air aspiration and the resultant groats were collected directly back into liquid nitrogen. Approximately 250 g of groats could be isolated each man-hour by the above method. In comparison, only 10 g of endosperm could be collected by squeezing it out of spikelets using an endosperm mangle. Membrane-bound polysomes extracted from the immature groats were compared to those extracted from endosperm. The largest polysomes discernable as unique peaks on sucrose gradients were ten-mers and nine-mers for groats and endosperm, respectively. Polysomes isolated from both starting materials stimulated similar incorporations of [³⁵S]methionine into trichloroacetic acid-insoluble products during in vitro translations in wheat germ extract. Both polysome preparations directed the synthesis of similar high-molecular-weight proteins. Based on these criteria, polysomes from both preparations were found to be of similar intactness, although the groat starting material was much more readily obtained. The polysome classes having the maximum absorbance peak for endosperm and groat polysomes were six-mers and eight-mers, respectively.     

ABLATIVE TECHNIQUES FOR SURGICAL TREATMENT OF PAROXYSMAL TACHYCARDIA

In this report, the collaborative efforts of cardiologists and surgeons to provide optimal treatment of patients with rhythm disturbances are discussed, along with definitive advances in new surgical techniques to relieve supraventricular tachycardia and paroxysmal ventricular tachycardia. Some of the techniques described are destined to find a permanent place in the surgeon's armamentarium.     

Association of 25-Hydroxyvitamin D status and genetic variation in the vitamin D metabolic pathway with FEV1 in the Framingham Heart Study

Background

Vitamin D is associated with lung function in cross-sectional studies, and vitamin D inadequacy is hypothesized to play a role in the pathogenesis of chronic obstructive pulmonary disease. Further data are needed to clarify the relation between vitamin D status, genetic variation in vitamin D metabolic genes, and cross-sectional and longitudinal changes in lung function in healthy adults.

Methods

We estimated the association between serum 25-hydroxyvitamin D [25(OH)D] and cross-sectional forced expiratory volume in the first second (FEV₁) in Framingham Heart Study (FHS) Offspring and Third Generation participants and the association between serum 25(OH)D and longitudinal change in FEV₁ in Third Generation participants using linear mixed-effects models. Using a gene-based approach, we investigated the association between 241 SNPs in 6 select vitamin D metabolic genes in relation to longitudinal change in FEV₁ in Offspring participants and pursued replication of these findings in a meta-analyzed set of 4 independent cohorts.

Results

We found a positive cross-sectional association between 25(OH)D and FEV₁ in FHS Offspring and Third Generation participants (P = 0.004). There was little or no association between 25(OH)D and longitudinal change in FEV₁ in Third Generation participants (P = 0.97). In Offspring participants, the CYP2R1 gene, hypothesized to influence usual serum 25(OH)D status, was associated with longitudinal change in FEV₁ (gene-based P < 0.05). The most significantly associated SNP from CYP2R1 had a consistent direction of association with FEV₁ in the meta-analyzed set of replication cohorts, but the association did not reach statistical significance thresholds (P = 0.09).

Conclusions

Serum 25(OH)D status was associated with cross-sectional FEV₁, but not longitudinal change in FEV₁. The inconsistent associations may be driven by differences in the groups studied. CYP2R1 demonstrated a gene-based association with longitudinal change in FEV₁ and is a promising candidate gene for further studies.

Electronic supplementary material

The online version of this article (doi:10.1186/s12931-015-0238-y) contains supplementary material, which is available to authorized users.     

Discovery of 2,5-diarylnicotinamides as selective orexin-2 receptor antagonists (2-SORAs)

The orexin (or hypocretin) system has been identified as a novel target for the treatment of insomnia due to the wealth of biological and genetic data discovered over the past decade. Recently, clinical proof-of-concept was achieved for the treatment of primary insomnia using dual (OX₁R/OX₂R) orexin receptor antagonists. However, elucidation of the pharmacology associated with selective orexin-2 receptor antagonists (2-SORAs) has been hampered by the lack of orally bioavailable, highly selective small molecule probes. Herein, the discovery and optimization of a novel series of 2,5-diarylnicotinamides as potent and orally bioavailable orexin-2 receptor selective antagonists is described. A compound from this series demonstrated potent sleep promotion when dosed orally to EEG telemetrized rats.     

Methylated DNA/RNA in Body Fluids as Biomarkers for Lung Cancer

DNA/RNA methylation plays an important role in lung cancer initiation and progression. Liquid biopsy makes use of cells, nucleotides and proteins released from tumor cells into body fluids to help with cancer diagnosis and prognosis. Methylation of circulating tumor DNA (ctDNA) has gained increasing attention as biomarkers for lung cancer. Here we briefly introduce the biological basis and detection method of ctDNA methylation, and review various applications of methylated DNA in body fluids in lung cancer screening, diagnosis, prognosis, monitoring and treatment prediction. We also discuss the emerging role of RNA methylation as biomarkers for cancer.     

Histological structure of human nail as studied by synchrotron X-ray microdiffraction.

Three layers (characterized by different orientations of the keratin molecules) from the outer to the inner side of human nail were observed by synchrotron X-ray microdiffraction. These layers are associated with the histological dorsal, intermediate and ventral plates. The hair-like type alpha-keratin filaments (81 A in diameter), are only present in the intermediate layer (accounting for approximately 2/3 of the nail width) and are perfectly oriented perpendicular to the growth axis, in the nail plane. Keratin filaments of stratum corneum (epidermis) type, found in the dorsal and ventral cells, are oriented in two privileged directions; parallel and perpendicular to the growth axis. This "sandwich" structure in the corneocytes and the strong intercellular junctions, gives the nail high mechanical rigidity and hardness, both in the curvature direction and in the growth direction. Lipid bilayers (49 A thick) parallel to the nail surface fill certain ampullar dilations of the dorsal plate and intercellular spaces in the ventral plate. Using X-ray micro-diffraction, we show that onychomycosis disrupts the keratin structure, probably during the synthesis phase.     

Out of Africa and back again: nested cladistic analysis of human Y chromosome variation

We surveyed nine diallelic polymorphic sites on the Y chromosomes of 1,544 individuals from Africa, Asia, Europe, Oceania, and the New World. Phylogenetic analyses of these nine sites resulted in a tree for 10 distinct Y haplotypes with a coalescence time of approximately 150,000 years. The 10 haplotypes were unevenly distributed among human populations: 5 were restricted to a particular continent, 2 were shared between Africa and Europe, 1 was present only in the Old World, and 2 were found in all geographic regions surveyed. The ancestral haplotype was limited to African populations. Random permutation procedures revealed statistically significant patterns of geographical structuring of this paternal genetic variation. The results of a nested cladistic analysis indicated that these geographical associations arose through a combination of processes, including restricted, recurrent gene flow (isolation by distance) and range expansions. We inferred that one of the oldest events in the nested cladistic analysis was a range expansion out of Africa which resulted in the complete replacement of Y chromosomes throughout the Old World, a finding consistent with many versions of the Out of Africa Replacement Model. A second and more recent range expansion brought Asian Y chromosomes back to Africa without replacing the indigenous African male gene pool. Thus, the previously observed high levels of Y chromosomal genetic diversity in Africa may be due in part to bidirectional population movements. Finally, a comparison of our results with those from nested cladistic analyses of human mtDNA and beta-globin data revealed different patterns of inferences for males and females concerning the relative roles of population history (range expansions) and population structure (recurrent gene flow), thereby adding a new sex-specific component to models of human evolution.