Variants in EMX2 and PTEN do not contribute to risk of endometriosis

Endometriosis has a genetic component, and significant linkage has been found to a region on chromosome 10q. Two candidate genes, EMX2 and PTEN, implicated in both endometriosis and endometrial cancer, lie on chromosome 10q. We hypothesized that variation in EMX2 and/or PTEN could contribute to the risk of endometriosis and may account for some of the linkage signal on 10q. We genotyped single nucleotide polymorphisms (SNPs) in a case-control design to evaluate association between endometriosis and common variations in these two genes. The genotyping and statistical analysis were based on samples collected from Australian volunteers. The cases were 768 unrelated women with surgically confirmed endometriosis selected from affected sister pair (ASP) families participating in the Australian Genes behind Endometriosis Study. The controls were 768 female participants in twin studies who, based on screening questions, did not have a diagnosis of endometriosis. Genotypes of 22 SNPs in the EMX2 gene and 15 SNPs in the PTEN gene were the main outcome measures. Statistical analysis provided measures of linkage disequilibrium and association. Permutation testing showed no globally significant association between any SNPs or haplotypes and endometriosis for either gene. It is unlikely that the EMX2 or PTEN gene variants investigated contribute to risk for initiation and/or development of endometriosis.

Voltage gated Na+ channels contribute to membrane voltage fluctuation in \alpha T3-1 pituitary gonadotroph cells

\alpha T3-1 cells showed a slope resistance of 1.8 G\omega. The cell membrane surface was not smooth and a scanning electron micrograph showed a complex structure with blebs and microvilli like projections. The cells showed spontaneous fluctuations at zero current resting membrane potential and hyperpolarization increased the amplitude of membrane potential fluctuations. The amplitude of membrane potential fluctuations at hyperpolarized membrane potential was attenuated on application of TTX to the bath solution. The potential at which half steady state inactivation of isolated sodium current occurred, was at a very hyperpolarized potential (-95.4 mV). The study presented in this paper shows that the voltage gated sodium channels contribute to the increase in the amplitude of electrical noise with hyperpolarization in \alpha T3-1 cells.

G-Quadruplex Structures Formed at the HOX11 Breakpoint Region Contribute to Its Fragility during t(10;14) Translocation in T-Cell Leukemia

The t(10;14) translocation involving the HOX11 gene is found in several T-cell leukemia patients. Previous efforts to determine the causes of HOX11 fragility were not successful. The role of non-B DNA structures is increasingly becoming an important cause of genomic instability. In the present study, bioinformatics analysis revealed two G-quadruplex-forming motifs at the HOX11 breakpoint cluster. Gel shift assays showed formation of both intra- and intermolecular G-quadruplexes, the latter being more predominant. The structure formation was dependent on four stretches of guanines, as revealed by mutagenesis. Circular dichroism analysis identified parallel conformations for both quadruplexes. The non-B DNA structure could block polymerization during replication on a plasmid, resulting in consistent K K+-dependent pause sites, which were abolished upon mutation of G-motifs, thereby demonstrating the role of the stretches of guanines even on double-stranded DNA. Extrachromosomal assays showed that the G-quadruplex motifs could block transcription, leading to reduced expression of green fluorescent protein (GFP) within cells. More importantly, sodium bisulfite modification assay showed the single-stranded character at regions I and II of HOX11 in the genome. Thus, our findings suggest the occurrence of G-quadruplex structures at the HOX11 breakpoint region, which could explain its fragility during the t(10;14) translocation.

Specific Sequence of a Beta Turn in Human La Protein May Contribute to Species Specificity of Hepatitis C Virus

Human La protein is known to be an essential host factor for translation and replication of hepatitis C virus (HCV) RNA. Previously, we have demonstrated that residues responsible for interaction of human La protein with the HCV internal ribosomal entry site (IRES) around the initiator AUG within stem-loop IV form a beta-turn in the RNA recognition motif (RRM) structure. In this study, sequence alignment and mutagenesis suggest that the HCV RNA-interacting beta-turn is conserved only in humans and chimpanzees, the species primarily known to be infected by HCV. A 7-mer peptide corresponding to the HCV RNA-interacting region of human La inhibits HCV translation, whereas another peptide corresponding to the mouse La sequence was unable to do so. Furthermore, IRES-mediated translation was found to be significantly high in the presence of recombinant human La protein in vitro in rabbit reticulocyte lysate. We observed enhanced replication with HCV subgenomic and full-length replicons upon overexpression of either human La protein or a chimeric mouse La protein harboring a human La beta-turn sequence in mouse cells. Taken together, our results raise the possibility of creating an immunocompetent HCV mouse model using human-specific cell entry factors and a humanized form of La protein.

DOPAMINE D2 RECEPTOR MECHANISMS CONTRIBUTE TO AGE-RELATED COGNITIVE DECLINE - THE EFFECTS OF QUINPIROLE ON MEMORY AND MOTOR-PERFORMANCE IN MONKEYS

The D2 dopamine (DA) receptor agonist, quinpirole, was characterized in young adult monkeys, young reserpine-treated monkeys and aged monkeys to assess the contribution of DA to age-related loss of prefrontal cortical (PFC) cognitive function, Monkeys were tested on a delayed response memory task that depends on the PFC, and a fine motor task that taps the functions of the motor cortex, In young adult monkeys, low quinpirole doses impaired performance of the PFC and fine motor tasks, while higher doses improved memory performance and induced dyskinesias and ''hallucinatory-like'' behaviors. The pattern of the quinpirole response in reserpine-treated monkeys suggested that the impairments in delayed response and fine motor performance resulted from drug actions at D2 autoreceptors, while the improvement in delayed response performance, dyskinesias and ''hallucinatory-like'' behaviors resulted from actions at postsynaptic receptors. In aged monkeys, low doses of quinpirole continued to impair fine motor performance, but lost their ability to impair delayed response performance. The magnitude of cognitive improvement and the incidence of ''hallucinatory-like'' behaviors were also reduced in the aged animals, suggesting some loss of postsynaptic D2 receptor function, The pattern of results is consistent with the greater loss of DA from the PFC than from motor areas in aged monkey brain (Goldman-Rakic and Brown, 1981; Wenk et al., 1989), and indicates that DA depletion contributes significantly to age-related cognitive decline.

Physiological advantages may contribute to successful invasion of the exotic Cyprinus carpio into the Xingyun Lake, China

Feeding and growth traits of Cyprinus carpio and Cyprinus pellegrini (both at age-0) were compared in three experiment, in an attempt to analyze potential causes for the displacement of the native C. pellegrini in the Xingyun Lake, Yuxi, Yunan, China. Experiment I was conducted in water which fluctuated between 15 and 20 degrees C. Experiment II and III were conducted in a laboratory and water temperature was maintained between 20 degrees C and 25 degrees C, respectively. Three common trends were noted for all three experiments: (1) feeding rate of C. carpio was lower than that of C. pellegrini, and this difference was found to be significant in experiment I; (2) growth rate of C. carpio was higher than C. pellegrini, and the difference was found to be significant in experiment II; (3) food conversion efficiency and energy retention efficiency for C. carpio were higher than those of C. pellegrini, and significant differences were noted in experiment I and II. Since the growth period for fish in the Xingyun Lake generally occurs when water temperatures are between 15 and 25 degrees C, it can be suggested that C. carpio has advantages over C. pellegrini in growth and food utilization efficiency, and lower food consumption than C. pellegrini. These physiological traits of C. carpio might allow this species to be more resistant to food shortage and predation, and may be partially responsible for the displacement of C. pellegrini by C. carpio.

Changes in biomechanical properties of the coronary artery wall contribute to maintained contractile responses to endothelin-1 in atherosclerosis.

AIMS: Our aim was to determine whether alterations in biomechanical properties of human diseased compared to normal coronary artery contribute to changes in artery responsiveness to endothelin-1 in atherosclerosis. MAIN METHODS: Concentration-response curves were constructed to endothelin-1 in normal and diseased coronary artery. The passive mechanical properties of arteries were determined using tensile ring tests from which finite element models of passive mechanical properties of both groups were created. Finite element modelling of artery endothelin-1 responses was then performed. KEY FINDINGS: Maximum responses to endothelin-1 were significantly attenuated in diseased (27±3 mN, n=55) compared to normal (38±2 mN, n=68) artery, although this remained over 70% of control. There was no difference in potency (pD2 control=8.03±0.06; pD2 diseased=7.98±0.06). Finite element modelling of tensile ring tests resulted in hyperelastic shear modulus μ=2004±410 Pa and hardening exponent α=22.8±2.2 for normal wall and μ=2464±1075 Pa and α=38.3±6.7 for plaque tissue and distensibility of diseased vessels was decreased. Finite element modelling of active properties of both groups resulted in higher muscle contractile strain (represented by thermal reactivity) of the atherosclerotic artery model than the normal artery model. The models suggest that a change in muscle response to endothelin-1 occurs in atherosclerotic artery to increase its distensibility towards that seen in normal artery. SIGNIFICANCE: Our data suggest that an adaptation occurs in medial smooth muscle of atherosclerotic coronary artery to maintain distensibility of the vessel wall in the presence of endothelin-1. This may contribute to the vasospastic effect of locally increased endothelin-1 production that is reported in this condition.

Multiple Dynamic Processes Contribute to the Complex Steady Shear Behavior of Cross-Linked Supramolecular Networks of Semidilute Entangled Polymer Solutions.

Molecular theories of shear thickening and shear thinning in associative polymer networks are typically united in that they involve a single kinetic parameter that describes the network -- a relaxation time that is related to the lifetime of the associative bonds. Here we report the steady-shear behavior of two structurally identical metallo-supramolecular polymer networks, for which single-relaxation parameter models break down in dramatic fashion. The networks are formed by the addition of reversible cross-linkers to semidilute entangled solutions of PVP in DMSO, and they differ only in the lifetime of the reversible cross-links. Shear thickening is observed for cross-linkers that have a slower dissociation rate (17 s(-1)), while shear thinning is observed for samples that have a faster dissociation rate (ca. 1400 s(-1)). The difference in the steady shear behavior of the unentangled vs. entangled regime reveals an unexpected, additional competing relaxation, ascribed to topological disentanglement in the semidilute entangled regime that contributes to the rheological properties.

Mechanosensitive neurons on the internal reproductive tract contribute to egg-laying-induced acetic acid attraction in Drosophila.

Selecting a suitable site to deposit their eggs is an important reproductive need of Drosophila females. Although their choosiness toward egg-laying sites is well documented, the specific neural mechanism that activates females' search for attractive egg-laying sites is not known. Here, we show that distention and contraction of females' internal reproductive tract triggered by egg delivery through the tract plays a critical role in activating such search. We found that females start to exhibit acetic acid (AA) attraction prior to depositing each egg but no attraction when they are not laying eggs. Artificially distending the reproductive tract triggers AA attraction in non-egg-laying females, whereas silencing the mechanosensitive neurons we identified that can sense the contractile status of the tract eliminates such attraction. Our work uncovers the circuit basis of an important reproductive need of Drosophila females and provides a simple model for dissecting the neural mechanism that underlies a reproductive need-induced behavioral modification.