Two novel factor V null mutations associated with activated protein C resistance phenotype/genotype discrepancy

Activated protein C (APC) resistance phenotype/genotype discrepancy is a very rare event. The objective of this study was to characterize the molecular mechanisms in two cases of APC phenotype/genotype discrepancy. An approach using direct sequencing of each exon and splicing junctions of the factor V gene showed that two novel factor V null mutations combined with heterozygous factor V Leiden mutation were responsible for this discrepancy. Our results suggest the necessity to use both phenotypic and genotypic analyses in some cases to determine an accurate diagnosis.     

Erythropoietin and IGF-1 signaling synchronize cell proliferation and maturation during erythropoiesis

Tight coordination of cell proliferation and differentiation is central to red blood cell formation. Erythropoietin controls the proliferation and survival of red blood cell precursors, while variations in GATA-1/FOG-1 complex composition and concentrations drive their maturation. However, clear evidence of cross-talk between molecular pathways is lacking. Here, we show that erythropoietin activates AKT, which phosphorylates GATA-1 at Ser310, thereby increasing GATA-1 affinity for FOG-1. In turn, FOG-1 displaces pRb/E2F-2 from GATA-1, ultimately releasing free, proproliferative E2F-2. Mice bearing a Gata-1^S310A mutation suffer from fatal anemia when a compensatory pathway for E2F-2 production involving insulin-like growth factor-1 (IGF-1) signaling is simultaneously abolished. In the context of the GATA-1^V205G mutation resulting in lethal anemia, we show that the Ser310 cannot be phosphorylated and that constitutive phosphorylation at this position restores partial erythroid differentiation. This study sheds light on the GATA-1 pathways that synchronize cell proliferation and differentiation for tissue homeostasis.     

Age-related functional reorganization,structural changes,and preserved cognition

Although healthy aging is associated with general cognitive decline, there is considerable variability in the extent to which cognitive functions decline or are preserved. Preserved cognitive function in the context of age-related neuroanatomical and functional changes, has been attributed to compensatory mechanisms. However, the existing sparse evidence is largely focused on functions associated with the frontal cortex, leaving open the question of how wider age-related brain changes relate to compensation. We evaluated relationships between age-related neural and functional changes in the context of preserved cognitive function by combining measures of structure, function, and cognitive performance during spoken language comprehension using a paradigm that does not involve an explicit task. We used a graph theoretical approach to derive cognitive activation-related functional magnetic resonance imaging networks. Correlating network properties with age, neuroanatomical variations, and behavioral data, we found that decreased gray matter integrity was associated with decreased connectivity within key language regions but increased overall functional connectivity. However, this network reorganization was less efficient, suggesting that engagement of a more distributed network in aging might be triggered by reduced connectivity within specialized networks.     

Sleep duration and sleep disturbances partly explain the association between depressive symptoms and cardiovascular mortality: the Whitehall II cohort study

Depressive symptoms are associated with an increased risk of death, but most of this association remains unexplained. Our aim was to explore the contribution of sleep duration and disturbances to the association between depressive symptoms, all‐cause and cardiovascular disease mortality. A total of 5813 (4220 men and 1593 women) aged 50–74 years at baseline, participants of the British Whitehall II prospective cohort study, were included. Depressive symptoms, sleep duration and disturbances were assessed in 2003–04. Mortality was ascertained through linkage to the national mortality register until August 2012, with a mean follow‐up of 8.8 years. Depressive symptoms were associated with an increased risk of mortality from all causes [hazard ratio (HR) = 1.51; 95% confidence interval (CI): 1.16–1.97)] and cardiovascular diseases (HR = 1.63; 95% CI: 1.01–2.64) after adjustment for sociodemographic characteristics. Further adjustment for sleep duration and disturbances reduced the association between depressive symptoms and cardiovascular mortality by 21% (HR = 1.53; 95% CI: 0.91–2.57). Sleep seems to have a role, as a mediator or confounder, in explaining the association between depressive symptoms and cardiovascular mortality. These findings need replication in larger studies with longer follow‐up.     

A high level of tetrasomy 9p mosaicism but no clinical manifestations other than moderate oligozoospermia with chromosomally balanced sperm: a case report

Journal of Assisted Reproduction and Genetics - Tetrasomy 9p (ORPHA: 3310) (i(9p)) is a rare chromosomal imbalance. It is characterized by the presence of a supernumerary chromosome incorporating...     

Evidence of Coulomb blockade behavior in a quasi-zero-dimensional quantum well on TiO2 surface

Line defects on the surface of rutile TiO₂(110) form in pairs separated by 1.2 nm creating a quantum well. The well is effectively closed by the presence of two charged structures at both ends separated by a distance in the 10–20 nm range. As expected for quantum confinement a long period oscillatory feature of the local density of states is observed and attributed to the formation of discrete quantum states inside the system. It is at first glance surprising that the lowest energy quantum state of the well can be observed at room temperature. The properties of the quantum state cannot be explained in an independent-electron, band-like theory. Instead, electron-electron correlation must be included to give a satisfactory picture of the spatial distribution of the charge density. Theory predicts charging energies of 1.30 eV and 1.14 eV for quantum well lengths of 14 nm and 16 nm, respectively, in good agreement with a classical calculation and the size dependence of the capacitance. This observation opens up the possibility of experimentally imaging the transition from a Coulomb blockade localized in a zero-dimensional system to an independent-particle or band-like behavior in an extended one-dimensional system.