Genetic influences in self-reported symptoms of obstructive sleep apnoea and restless legs: a twin study.

Sleep disorders, such as obstructive sleep apnoea (OSA) and restless legs syndrome (RLS), are very common. The relative importance of genetic and nongenetic (environmental) influences on the symptomatology of these conditions has not been well studied. This study uses the twin design to examine this by evaluating OSA and RLS symptoms in monozygotic (MZ) and dizygotic (DZ) twins. Six thousand six hundred unselected female twin pairs, identified from a national volunteer twin register, were asked to complete a medical questionnaire. This questionnaire included questions on OSA and RLS symptoms, as well as questions on subject demographics, past medical history, smoking history and menopausal status. Responses were obtained from 4503 individuals (68% response rate). A total of 1937 twin pairs were evaluable: 933 MZ pairs (mean [range] age 51 [20-76] years) and 1004 DZ pairs (age 51 [20-80] years). Concordance rates were higher for MZ than DZ twins for OSA and RLS symptoms. Multifactorial liability threshold modeling suggests that additive genetic effects combined with unique environmental factors provide the best model for OSA and RLS symptoms. Heritability was estimated to be 52% (95% confidence interval 36% to 68%) for disruptive snoring, 48% (37% to 58%) for daytime sleepiness, 54% (44% to 63%) for restless legs, and 60% (51% to 69%) for legs jerking. These estimates dropped only slightly after adjustment for potential confounding influences on the symptoms of snoring and daytime sleepiness. These results suggest a substantial genetic contribution to the symptomatology of OSA and RLS. More research is needed to identify the genes responsible, and may ultimately lead to new therapies.     

Identification of a highly conserved domain in the EcoRII methyltransferase which can be photolabeled with S-adenosyl-L-[methyl-3H]methionine. Evidence for UV-induced transmethylation of cysteine 186

DNA methyltransferases can be photolabeled with S-adenosyl-L-methionine (AdoMet). Specific incorporation of radioactivity has been demonstrated after photolabeling with either [methyl-3H]AdoMet or [35S]AdoMet (Som, S., and Friedman, S. (1990) J. Biol. Chem. 265, 4278-4283). The labeling is believed to occur at the AdoMet binding site. With the purpose of localizing the site responsible for [methyl-3H]AdoMet photolabeling, we cleaved the labeled EcoRII methyltransferase by chemical and enzymatic reactions and isolated the radiolabeled peptides by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and high pressure liquid chromatography. The labeled peptides were identified by amino-terminal sequencing. A common region was localized which accounted for 65-70% of the total label. This region includes a highly conserved core sequence present in all DNA (cytosine 5)-methyltransferases. One such fragment was digested further with chymotrypsin, and amino acid analysis of the resulting 3H-labeled peptide was consistent with the sequence Ala-Gly-Phe-Pro-(Cys)-Gln-Pro-Phe-Ser-Leu. However, the cysteine residue was not recovered as carboxymethylcysteine. The Pro-Cys bond was found to be protected from cleavage at cysteine residues after cyanylation. These results suggest that the cysteine residue is modified by the labeling reaction. The chymotryptic fragment was hydrolyzed enzymatically to single amino acids, and the labeled amino acid was identified as S-methylcysteine by thin layer chromatography. These results indicate that the cysteine residue is located at or close to the AdoMet binding site of EcoRII methyltransferase.     

Genetic Identification of all Four Mangrove Mud Crab Species (genus Scylla) Using Multiple Molecular Markers

Biochemical Genetics - Misleading identification and subsequent publications on biological, molecular, and aquaculture data of mangrove mud crab (genus Scylla de Hann 1833) is a major concern in...     

Oligonucleotides Containing Pyrazolo[3,4-d]Pyrimidines: 8-Aza-7-deazaadenines With Bulky Substituents in the 2- or 7-Position

The synthesis of the 2′-deoxyadenosine analogues 1b, 2b, and 3c modified at the 7- and/or 2-position is described. The effect of 7-chloro and 2-methylthio groups on the duplex stability is evaluated. For that, the nucleosides 1b, 2b, and 3c were converted to the corresponding phosphoramidites 15, 19, and 22, which were employed in the solid-phase oligonucleotide synthesis. In oligonucleotide duplexes, compound 1b forms stable base pairs with dT, of which the separated 1b- dT base pairs contribute stronger than that of the consecutive base pairs. Compound 2b shows universal base pairing properties while its N8 isomer 3c forms duplexes with lower stability.     

A Hypomorphic Lsd1 Allele Results in Heart Development Defects in Mice

Lysine-specific demethylase 1 (Lsd1/Aof2/Kdm1a), the first enzyme with specific lysine demethylase activity to be described, demethylates histone and non-histone proteins and is essential for mouse embryogenesis. Lsd1 interacts with numerous proteins through several different domains, most notably the tower domain, an extended helical structure that protrudes from the core of the protein. While there is evidence that Lsd1-interacting proteins regulate the activity and specificity of Lsd1, the significance and roles of such interactions in developmental processes remain largely unknown. Here we describe a hypomorphic Lsd1 allele that contains two point mutations in the tower domain, resulting in a protein with reduced interaction with known binding partners and decreased enzymatic activity. Mice homozygous for this allele die perinatally due to heart defects, with the majority of animals suffering from ventricular septal defects. Molecular analyses revealed hyperphosphorylation of E-cadherin in the hearts of mutant animals. These results identify a previously unknown role for Lsd1 in heart development, perhaps partly through the control of E-cadherin phosphorylation.     

Reduction of nuclear Y654-p-β-catenin expression through SH3GL2-meditated downregulation of EGFR in chemotolerance TNBC: Clinical and prognostic importance

Triple negative breast cancer (TNBC) originates from a less differentiated ductal cell of breast, which is less sensitive to chemotherapy. The chemotolerance mechanism of TNBC has not yet been studied in detail. For this reason, molecular profiles (expression/genetic/epigenetic) of Y654-p-β-catenin (active) and its kinase epidermal growth factor receptor (EGFR) along with SH3GL2 (regulator of EGFR homeostasis) were compared between neoadjuvant chemotherapy treated (NACT) and pretherapeutic TNBC samples. Reduced nuclear expression of Y654-p-β-catenin protein with low proliferation index and CD44 prevalence showed concordance with reduced expression of EGFR/Y1045-p-EGFR proteins in the NACT samples than the pretherapeutic TNBC samples. Infrequent messenger RNA expression, gene amplification (10–32.5%), and mutation (1%) of EGFR were seen in the TNBC samples irrespective of therapy, suggesting the importance of EGFR protein stabilization in this tumor. The upregulation of SH3GL2 seen in the NACT samples in contrast to the pretherapeutic samples might be due to its promoter hypomethylation, as seen in the quantitative methylation assay. A similar trend of upregulation of SH3GL2 and downregulation of EGFR, Y1045-p-EGFR, Y654-p-β-catenin were seen in the MDA-MB-231 cell line using antharacycline antitumor drugs (doxorubicin/nogalamycin). The NACT patients with reduced expression of Y654-p-β-catenin and/or EGFR and high expression of SH3GL2 showed comparatively better prognosis than the pretherapeutic patients. Thus, our study showed that reduced nuclear expression of Y654-p-β-catenin in NACT samples due to downregulation of EGFR protein through promoter hypomethylation-mediated upregulation of SH3GL2, resulting in low proliferation index/CD44 prevalence with better prognosis of the NACT patients, might have an important role in the chemotolerance of TNBC.     

Cardiomyocyte-specific perilipin 5 overexpression leads to myocardial steatosis and modest cardiac dysfunction

Presence of ectopic lipid droplets (LDs) in cardiac muscle is associated to lipotoxicity and tissue dysfunction. However, presence of LDs in heart is also observed in physiological conditions, such as when cellular energy needs and energy production from mitochondria fatty acid β-oxidation are high (fasting). This suggests that development of tissue lipotoxicity and dysfunction is not simply due to the presence of LDs in cardiac muscle but due at least in part to alterations in LD function. To examine the function of cardiac LDs, we obtained transgenic mice with heart-specific perilipin 5 (Plin5) overexpression (MHC-Plin5), a member of the perilipin protein family. Hearts from MHC-Plin5 mice expressed at least 4-fold higher levels of plin5 and exhibited a 3.5-fold increase in triglyceride content versus nontransgenic littermates. Chronic cardiac excess of LDs was found to result in mild heart dysfunction with decreased expression of peroxisome proliferator-activated receptor (PPAR)α target genes, decreased mitochondria function, and left ventricular concentric hypertrophia. Lack of more severe heart function complications may have been prevented by a strong increased expression of oxidative-induced genes via NF-E2-related factor 2 antioxidative pathway. Perilipin 5 regulates the formation and stabilization of cardiac LDs, and it promotes cardiac steatosis without major heart function impairment.     

Predicting the distributions of predator (snow leopard) and prey (blue sheep) under climate change in the Himalaya

Future climate change is likely to affect distributions of species, disrupt biotic interactions, and cause spatial incongruity of predator–prey habitats. Understanding the impacts of future climate change on species distribution will help in the formulation of conservation policies to reduce the risks of future biodiversity losses. Using a species distribution modeling approach by MaxEnt, we modeled current and future distributions of snow leopard (Panthera uncia) and its common prey, blue sheep (Pseudois nayaur), and observed the changes in niche overlap in the Nepal Himalaya. Annual mean temperature is the major climatic factor responsible for the snow leopard and blue sheep distributions in the energy‐deficient environments of high altitudes. Currently, about 15.32% and 15.93% area of the Nepal Himalaya are suitable for snow leopard and blue sheep habitats, respectively. The bioclimatic models show that the current suitable habitats of both snow leopard and blue sheep will be reduced under future climate change. The predicted suitable habitat of the snow leopard is decreased when blue sheep habitats is incorporated in the model. Our climate‐only model shows that only 11.64% (17,190 km²) area of Nepal is suitable for the snow leopard under current climate and the suitable habitat reduces to 5,435 km² (reduced by 24.02%) after incorporating the predicted distribution of blue sheep. The predicted distribution of snow leopard reduces by 14.57% in 2030 and by 21.57% in 2050 when the predicted distribution of blue sheep is included as compared to 1.98% reduction in 2030 and 3.80% reduction in 2050 based on the climate‐only model. It is predicted that future climate may alter the predator–prey spatial interaction inducing a lower degree of overlap and a higher degree of mismatch between snow leopard and blue sheep niches. This suggests increased energetic costs of finding preferred prey for snow leopards – a species already facing energetic constraints due to the limited dietary resources in its alpine habitat. Our findings provide valuable information for extension of protected areas in future.