Sodium channel slow inactivation interferes with open channel block

Mutations in the voltage-gated sodium channel Nav1.7 are linked to inherited pain syndromes such as erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD). PEPD mutations impair Nav1.7 fast inactivation and increase persistent currents. PEPD mutations also increase resurgent currents, which involve the voltage-dependent release of an open channel blocker. In contrast, IEM mutations, whenever tested, leave resurgent currents unchanged. Accordingly, the IEM deletion mutation L955 (ΔL955) fails to produce resurgent currents despite enhanced persistent currents, which have hitherto been considered a prerequisite for resurgent currents. Additionally, ΔL955 exhibits a prominent enhancement of slow inactivation (SI). We introduced mutations into Nav1.7 and Nav1.6 that either enhance or impair SI in order to investigate their effects on resurgent currents. Our results show that enhanced SI is accompanied by impaired resurgent currents, which suggests that SI may interfere with open-channel block

Children’s perspectives on scale response options of subjective well-being measures: A comparison between numerical and verbal-response formats

It is crucial to establish the validity of existing measures of children’s subjective well-being (SWB) for use within specific contexts. Two important measurement issues that implicate the validly of SWB scales are ‘question framing’ and ‘response options’. Fundamental to the latter is the concept of scale granularity, which refers to the number of response options imposed on a scale. However, the majority of studies on the topic have used adult and not child samples. The overarching aim of the study was to explore how children from three different contexts (Catalonia, Cape Town and North-Western Romania) perceive, understand, and make sense of SWB instruments, using focus group interviews and thematic analysis. A key finding of the study was the similarities in children’s understandings of the response options across these contexts. While this does not represent a claim for a ‘universal understanding’ of measurement scale response formats, it is suggesting that there are similar cognitive processes that children across the contexts apply when making sense of and deciding on which response option to endorse (for both verbal and numerical formats)

Solid state quantum memory using the 31P nuclear spin

The transfer of information between different physical forms is a central theme in communication and computation, for example between processing entities and memory. Nowhere is this more crucial than in quantum computation, where great effort must be taken to protect the integrity of a fragile quantum bit. Nuclear spins are known to benefit from long coherence times compared to electron spins, but are slow to manipulate and suffer from weak thermal polarisation. A powerful model for quantum computation is thus one in which electron spins are used for processing and readout while nuclear spins are used for storage. Here we demonstrate the coherent transfer of a superposition state in an electron spin 'processing' qubit to a nuclear spin 'memory' qubit, using a combination of microwave and radiofrequency pulses applied to 31P donors in an isotopically pure 28Si crystal. The electron spin state can be stored in the nuclear spin on a timescale that is long compared with the electron decoherence time and then coherently transferred back to the electron spin, thus demonstrating the 31P nuclear spin as a solid-state quantum memory. The overall store/readout fidelity is about 90%, attributed to systematic imperfections in radiofrequency pulses which can be improved through the use of composite pulses. We apply dynamic decoupling to protect the nuclear spin quantum memory element from sources of decoherence. The coherence lifetime of the quantum memory element is found to exceed one second at 5.5K.Comment: v2: Tomography added and storage of general initial state

Synergistic Anticancer Effects of the 9.2.27PE Immunotoxin and ABT-737 in Melanoma

In cancer, combinations of drugs targeting different cellular functions is well accepted to improve tumor control. We studied the effects of a Pseudomonas exotoxin A (PE) - based immunotoxin, the 9.2.27PE, and the BH-3 mimetic compound ABT-737 in a panel of melanoma cell lines. The drug combination resulted in synergistic cytotoxicity, and the cell death observed was associated with apoptosis, as activation of caspase-3, inactivation of Poly (ADP-ribose) polymerase (PARP) and increased DNA fragmentation could be prevented by pre-treatment with caspase and cathepsin inhibitors. We further show that ABT-737 caused endoplasmic reticulum (ER) stress with increased GRP78 and phosphorylated eIF2α protein levels. Moreover, treatment with ABT-737 increased the intracellular calcium levels, an effect which was enhanced by 9.2.27PE, which as a single entity drug had minimal effect on calcium release from the ER. In addition, silencing of Mcl-1 by short hairpin RNA (shRNA) enhanced the intracellular calcium levels and cytotoxicity caused by ABT-737. Notably, the combination of 9.2.27PE and ABT-737 caused growth delay in a human melanoma xenograft mice model, supporting further investigations of this particular drug combination

Wellbeing indicators affecting female entrepreneurship in OECD countries

[EN] The objective of this research is to know which wellbeing indicators, such as work-life balance, educational level, income or job security, are related to the rate of female entrepreneurship in 29 OECD countries. In addition, these countries have been classified according to the motivation of the entrepreneur either by necessity or by opportunity. The empiric study is focused on 29 OECD countries covering the different geographic areas (Western Europe, Central and Eastern Europe, Middle East, etc.) Due to the fact that the sample is relatively small, it is essential to use a selective approach when selecting the causal conditions. To this end, fsQCA is the most appropriate methodology for such a small data set. A total of 5 variables have been used: an independent variable (female TEA ratio), and four dependent variables (work life balance, educational level, sustainable household income and job security). Data measuring female TEA ratio have been obtained from Global Entrepreneur Monitor (GEM in Global report, 2015) data base, while data measuring wellbeing dimensions were taken from the Better Life Index (OECD in How¿s life? Measuring wellbeing, 2015. http://www.oecdbetterlifeindex.org). The results of this piece of research show that countries with high sustainable household income together with high level of education achieves high female entrepreneurship ratio with both, a good work-life balance (despite of a high unemployment probability), or a high labour-personal imbalance (in this latter, with a low probability of unemployment).This work has been funded by the R + D project for emerging research groups with reference (GVA) GV/2016/078.Ribes-Giner, G.; Moya Clemente, I.; Cervelló Royo, RE.; Perelló Marín, MR. (2019). Wellbeing indicators affecting female entrepreneurship in OECD countries. 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Geographic and Racial Variation in Premature Mortality in the U.S.: Analyzing the Disparities

Life expectancy at birth, estimated from United States period life tables, has been shown to vary systematically and widely by region and race. We use the same tables to estimate the probability of survival from birth to age 70 (S70), a measure of mortality more sensitive to disparities and more reliably calculated for small populations, to describe the variation and identify its sources in greater detail to assess the patterns of this variation. Examination of the unadjusted probability of S70 for each US county with a sufficient population of whites and blacks reveals large geographic differences for each race-sex group. For example, white males born in the ten percent healthiest counties have a 77 percent probability of survival to age 70, but only a 61 percent chance if born in the ten percent least healthy counties. Similar geographical disparities face white women and blacks of each sex. Moreover, within each county, large differences in S70 prevail between blacks and whites, on average 17 percentage points for men and 12 percentage points for women. In linear regressions for each race-sex group, nearly all of the geographic variation is accounted for by a common set of 22 socio-economic and environmental variables, selected for previously suspected impact on mortality; R2 ranges from 0.86 for white males to 0.72 for black females. Analysis of black-white survival chances within each county reveals that the same variables account for most of the race gap in S70 as well. When actual white male values for each explanatory variable are substituted for black in the black male prediction equation to assess the role explanatory variables play in the black-white survival difference, residual black-white differences at the county level shrink markedly to a mean of −2.4% (+/−2.4); for women the mean difference is −3.7% (+/−2.3)

REST is a hypoxia-responsive transcriptional repressor

Cellular exposure to hypoxia results in altered gene expression in a range of physiologic and pathophysiologic states. Discrete cohorts of genes can be either up- or down-regulated in response to hypoxia. While the Hypoxia-Inducible Factor (HIF) is the primary driver of hypoxia-induced adaptive gene expression, less is known about the signalling mechanisms regulating hypoxia-dependent gene repression. Using RNA-seq, we demonstrate that equivalent numbers of genes are induced and repressed in human embryonic kidney (HEK293) cells. We demonstrate that nuclear localization of the Repressor Element 1-Silencing Transcription factor (REST) is induced in hypoxia and that REST is responsible for regulating approximately 20% of the hypoxia-repressed genes. Using chromatin immunoprecipitation assays we demonstrate that REST-dependent gene repression is at least in part mediated by direct binding to the promoters of target genes. Based on these data, we propose that REST is a key mediator of gene repression in hypoxia

An exploration into the impact of exposure to community violence and hope on children's perceptions of well-being: a South African perspective

The study aims to explore the relationship between exposure to community violence, hope, and well-being. More specifically, the study aims to ascertain whether hope is a stronger predictor of well-being than exposure to violence. Stratified random sampling was used to select a sample of 566 adolescents aged 14–17 years, from both high violence and low violence areas in Cape Town, South Africa. A questionnaire consisting of Snyder’s Children’s Hope Scale, the Recent Exposure to Violence Scale and the KIDSCREEN-52 was used. Data analysis techniques included descriptive statistics, correlations, and multiple regression. A positive, significant relationship was found between children’s hope and their well-being. Although exposure to community violence was found to be significantly correlated with wellbeing, the relationship was negligible.While exposure to community violence and hope were found to be significant predictors of well-being, hope emerged as a stronger predictor of child well-being than exposure to community violence.Department of HE and Training approved lis

Novel SMAC-mimetics synergistically stimulate melanoma cell death in combination with TRAIL and Bortezomib

BACKGROUND: XIAP (X-linked inhibitor of apoptosis protein) is an anti-apoptotic protein exerting its activity by binding and suppressing caspases. As XIAP is overexpressed in several tumours, in which it apparently contributes to chemoresistance, and because its activity in vivo is antagonised by second mitochondria-derived activator of caspase (SMAC)/direct inhibitor of apoptosis-binding protein with low pI, small molecules mimicking SMAC (so called SMAC-mimetics) can potentially overcome tumour resistance by promoting apoptosis. METHODS: Three homodimeric compounds were synthesised tethering a monomeric SMAC-mimetic with different linkers and their affinity binding for the baculoviral inhibitor repeats domains of XIAP measured by fluorescent polarisation assay. The apoptotic activity of these molecules, alone or in combination with tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) and/or Bortezomib, was tested in melanoma cell lines by MTT viability assays and western blot analysis of activated caspases. RESULTS: We show that in melanoma cell lines, which are typically resistant to chemotherapeutic agents, XIAP knock-down sensitises cells to TRAIL treatment in vitro, also favouring the accumulation of cleaved caspase-8. We also describe a new series of 4-substituted azabicyclo[5.3.0] alkane monomeric and dimeric SMAC-mimetics that target various members of the IAP family and powerfully synergise at submicromolar concentrations with TRAIL in inducing cell death. Finally, we show that the simultaneous administration of newly developed SMAC-mimetics with Bortezomib potently triggers apoptosis in a melanoma cell line resistant to the combined effect of SMAC-mimetics and TRAIL. CONCLUSION: Hence, the newly developed SMAC-mimetics effectively synergise with TRAIL and Bortezomib in inducing cell death. These findings warrant further preclinical studies in vivo to verify the anticancer effectiveness of the combination of these agents