The meaning of marriage for men during the transition to fatherhood : the Swiss context

In Europe, Switzerland presents an unusual pattern of marriage with a very high proportion of couples who begin to cohabit without being married, but with a very low proportion of nonmarital births. A lot of couples marry before the conception of the child or during the pregnancy. In this article we focus on the point of view of men vis-agrave-vis the marriage and its meanings. Qualitative investigations show that men strongly desire marriage for several reasons, from their desire to participate in child rearing to the fear of having their paternity denied by Swiss institutions

Transition from hemifusion to pore opening is rate limiting for vacuole membrane fusion.

Fusion pore opening and expansion are considered the most energy-demanding steps in viral fusion. Whether this also applies to soluble N-ethyl-maleimide sensitive fusion protein attachment protein receptor (SNARE)- and Rab-dependent fusion events has been unknown. We have addressed the problem by characterizing the effects of lysophosphatidylcholine (LPC) and other late-stage inhibitors on lipid mixing and pore opening during vacuole fusion. LPC inhibits fusion by inducing positive curvature in the bilayer and changing its biophysical properties. The LPC block reversibly prevented formation of the hemifusion intermediate that allows lipid, but not content, mixing. Transition from hemifusion to pore opening was sensitive to guanosine-5'-(gamma-thio)triphosphate. It required the vacuolar adenosine triphosphatase V0 sector and coincided with its transformation. Pore opening was rate limiting for the reaction. As with viral fusion, opening the fusion pore may be the most energy-demanding step for intracellular, SNARE-dependent fusion reactions, suggesting that fundamental aspects of lipid mixing and pore opening are related for both systems.

International union of basic and clinical pharmacology. XCI. structure, function, and pharmacology of acid-sensing ion channels and the epithelial Na+ channel.

The epithelial Na(+) channel (ENaC) and the acid-sensing ion channels (ASICs) form subfamilies within the ENaC/degenerin family of Na(+) channels. ENaC mediates transepithelial Na(+) transport, thereby contributing to Na(+) homeostasis and the maintenance of blood pressure and the airway surface liquid level. ASICs are H(+)-activated channels found in central and peripheral neurons, where their activation induces neuronal depolarization. ASICs are involved in pain sensation, the expression of fear, and neurodegeneration after ischemia, making them potentially interesting drug targets. This review summarizes the biophysical properties, cellular functions, and physiologic and pathologic roles of the ASIC and ENaC subfamilies. The analysis of the homologies between ENaC and ASICs and the relation between functional and structural information shows many parallels between these channels, suggesting that some mechanisms that control channel activity are shared between ASICs and ENaC. The available crystal structures and the discovery of animal toxins acting on ASICs provide a unique opportunity to address the molecular mechanisms of ENaC and ASIC function to identify novel strategies for the modulation of these channels by pharmacologic ligands.

Thermal and magnetic field-induced martensite-austenite transition in Ni50.3Mn35.3Sn14.4 ribbons

Thermal and field-induced martensite-austenite transition was studied in melt spun Ni50.3Mn35.3Sn14.4 ribbons. Its distinct highly ordered columnarlike microstructure normal to ribbon plane allows the direct observation of critical fields at which field-induced and highly hysteretic reverse transformation starts (H=17kOe at 240K), and easy magnetization direction for austenite and martensite phases with respect to the rolling direction. Single phase L21 bcc austenite with TC of 313K transforms into a 7M orthorhombic martensite with thermal hysteresis of 21K and transformation temperatures of MS=226K, Mf=218K, AS=237K, and Af=244K

Citrobacter rodentium Requires Intestinal Neural Wiskott-Aldrich Syndrome Protein (N-WASp) for Actin Pedestal Formation, Colonization and Epithelial Barrier Disruption In Vivo

Background: Citrobacter rodentium is a natural mouse pathogen that is genetically closelyrelated to the human enteric pathogens enteropathogenic and enterohemorrhagic E. coli.Among the repertoire of conserved virulence factors that these pathogens deliver via typeIII secretion, Tir and EspF are responsible for the formation of characteristic actin-richpedestals and disruption of tight junction integrity, respectively. There is evidence In Vitrothese effectors accomplish this, at least in part, by subverting the normal host cellularfunctions of N-WASP, a critical regulator of branched chain actin assembly. Although NWASPhas been shown to be involved in pedestal formation In Vitro, the requirements ofN-WASP-mediated actin pedestals for intestinal colonization by attaching/effacing (A/E)pathogens In Vivo is not known. Furthermore, it is not known whether N-WASP is requiredfor EspF-mediated tight junction disruption. Methods: To investigate the role of N-WASPin the gut epithelium, we generated mice with intestine-specific deletion of N-WASP(iNWKO), by mating mice homozygous for a floxed N-WASP allele (N-WASPL2L/L2L) tomice expressing Cre recombinase under the villin promoter. Separately housed groups ofWT and iNWKO mice were inoculated with 5x108 GFP-expressing C. rodentium by intragastriclavage. Stool was collected 2, 4, 7, and 12 days after infection, and recoverablecolony forming units (CFUs) of C. rodentium were quantified by plating serial dilutions ofhomogenized stool on MacConkey's agar. GFP+ colonies were counted after 24 hoursincubation at 37°C. The presence of actin pedestals was investigated by electron microscopy(EM), and tight junction morphology was assessed by immunofluorescence staining ofoccludin, ZO-1 and claudin-2. Results: C. rodentium infection did not result in mortalityin WT or iNWKO mice. Compared to controls, iNWKO mice exhibited higher levels ofbacterial shedding during the first 4 days of infection (day 4 average: WT 5.2x104 CFU/gvs. iNWKO 4.7x105 CFU/g, p=0.08), followed by a more rapid clearance of C. rodentium, (day7-12 average: WT 2x106 CFU/g vs. iNWKO 2.7x105, p=0.01). EM and immunofluorescencerevealed the complete lack of actin pedestals in iNWKO mice and no mucosa-associatedGFP+ C. rodentium by day 7. WT controls exhibited tight junction disruption, reflected byaltered distribution of ZO-1, whereas iNWKO mice had no change in the pattern of ZO-1.Conclusion: Intestinal N-WASP is required for actin pedestal formation by C. rodentium InVivo, and ablation of N-WASP is associated with more rapid bacterial clearance and decreasedability of C. rodentium to disrupt intercellular junctions.

Space Competition and Time Delays in Human Range Expansions. Application to the Neolithic Transition

Space competition effects are well-known in many microbiological and ecological systems. Here we analyze such an effectin human populations. The Neolithic transition (change from foraging to farming) was mainly the outcome of a demographic process that spread gradually throughout Europe from the Near East. In Northern Europe, archaeological data show a slowdown on the Neolithic rate of spread that can be related to a high indigenous (Mesolithic) population density hindering the advance as a result of the space competition between the two populations. We measure this slowdown from a database of 902 Early Neolithic sites and develop a time-delayed reaction-diffusion model with space competition between Neolithic and Mesolithic populations, to predict the observed speeds. The comparison of the predicted speed with the observations and with a previous non-delayed model show that both effects, the time delay effect due to the generation lag and the space competition between populations, are crucial in order to understand the observations

Bone marrow mesenchymal stem cells stabilize already-formed aortic aneurysms more efficiently than vascular smooth muscle cells in a rat model.

PURPOSE: Abdominal aortic aneurysms (AAAs) expand because of aortic wall destruction. Enrichment in Vascular Smooth Muscle Cells (VSMCs) stabilizes expanding AAAs in rats. Mesenchymal Stem Cells (MSCs) can differentiate into VSMCs. We have tested the hypothesis that bone marrow-derived MSCs (BM-MSCs) stabilizes AAAs in a rat model. MATERIAL AND METHODS: Rat Fischer 344 BM-MSCs were isolated by plastic adhesion and seeded endovascularly in experimental AAAs using xenograft obtained from guinea pig. Culture medium without cells was used as control group. The main criteria was the variation of the aortic diameter at one week and four weeks. We evaluated the impact of cells seeding on inflammatory response by immunohistochemistry combined with RT-PCR on MMP9 and TIMP1 at one week. We evaluated the healing process by immunohistochemistry at 4 weeks. RESULTS: The endovascular seeding of BM-MSCs decreased AAA diameter expansion more powerfully than VSMCs or culture medium infusion (6.5% ± 9.7, 25.5% ± 17.2 and 53.4% ± 14.4; p = .007, respectively). This result was sustained at 4 weeks. BM-MSCs decreased expression of MMP-9 and infiltration by macrophages (4.7 ± 2.3 vs. 14.6 ± 6.4 mm(2) respectively; p = .015), increased Tissue Inhibitor Metallo Proteinase-1 (TIMP-1), compared to culture medium infusion. BM-MSCs induced formation of a neo-aortic tissue rich in SM-alpha active positive cells (22.2 ± 2.7 vs. 115.6 ± 30.4 cells/surface units, p = .007) surrounded by a dense collagen and elastin network covered by luminal endothelial cells. CONCLUSIONS: We have shown in this rat model of AAA that BM-MSCs exert a specialized function in arterial regeneration that transcends that of mature mesenchymal cells. Our observation identifies a population of cells easy to isolate and to expand for therapeutic interventions based on catheter-driven cell therapy.

EWS-FLI-1 modulates miRNA145 and SOX2 expression to initiate mesenchymal stem cell reprogramming toward Ewing sarcoma cancer stem cells

Introduction: Cancer stem cells (CSC) display plasticity and self renewal properties reminiscent of normal tissue stem cells but the events responsible for their emergence remain obscure. We have recently identified CSC in Ewing sarcoma family tumors (ESFT) and shown that they arise from mesenchymal stem cells from the bone marrow. Objective of the study: To analyze the mechanisms underlying cancer stem cell development in ESFT. Methods: Primary human mesenchymal stem cells (MSC) isolation from adult and pediatric bone marrow. Retroviral delivery of fusion protein (EWS-FLI1) to primary MSC, and transcriptional and phenotypical analysis. Results: We show that the EWS-FLI-1 fusion gene, associated wit 85-90% of ESFT and believed to initiate their pathogenesis, induces expression of the embryonic stem cell (ESC) genes OCT4, SOX2 and NANOG in human pediatric MSC (hpMSC) but not in their adult counterparts. Moreover, under appropriate culture conditions, hpMSC expressing EWS-FLI-1 generate a cell subpopulation displaying ESFT CSC features in vitro. We further demonstrate that induction of the ESFT CSC phenotype is the result of the combined effect of EWSFLI- 1 on its target gene expression and repression of microRNA-145 (miRNA145) promoter activity. Finally, we provide evidence that EWS-FLI-1 and miRNA-145 function in a mutually repressive feedback loop and identify their common target gene SOX2, in addition to miRNA145 itself, as key players in ESFT cell differentiation and tumorigenicity. Conclusion: Our observations provide insight for the first time into the mechanisms whereby a single oncogene can reprogram primary cells to display a cancer stem cell phenotype.

Antirotavirus immunoglobulin A neutralizes virus in vitro after transcytosis through epithelial cells and protects infant mice from diarrhea.

Rotaviruses are the major cause of severe diarrhea in infants and young children worldwide. Due to their restricted site of replication, i.e., mature enterocytes, local intestinal antibodies have been proposed to play a major role in protective immunity. Whether secretory immunoglobulin A (IgA) antibodies alone can provide protection against rotavirus diarrhea has not been fully established. To address this question, a library of IgA monoclonal antibodies (MAbs) previously developed against different proteins of rhesus rotavirus was used. A murine hybridoma "backpack tumor" model was established to examine if a single MAb secreted onto mucosal surfaces via the normal epithelial transport pathway was capable of protecting mice against diarrhea upon oral challenge with rotavirus. Of several IgA and IgG MAbs directed against VP8 and VP6 of rotavirus, only IgA VP8 MAbs (four of four) were found to protect newborn mice from diarrhea. An IgG MAb recognizing the same epitope as one of the IgA MAbs tested failed to protect mice from diarrhea. We also investigated if antibodies could be transcytosed in a biologically active form from the basolateral domain to the apical domain through filter-grown Madin-Darby canine kidney (MDCK) cells expressing the polymeric immunoglobulin receptor. Only IgA antibodies with VP8 specificity (four of four) neutralized apically administered virus. The results support the hypothesis that secretory IgA antibodies play a major role in preventing rotavirus diarrhea. Furthermore, the results show that the in vivo and in vitro methods described are useful tools for exploring the mechanisms of viral mucosal immunity.

Development of MASH TL-3 Transition Between Guardrail and Portable Concrete Barriers, TPF-5(081), 2014

Often, road construction causes the need to create a work zone. In these scenarios, portable concrete barriers (PCBs) are typically installed to shield workers and equipment from errant vehicles as well as prevent motorists from striking other roadside hazards. For an existing W-beam guardrail system installed adjacent to the roadway and near the work zone, guardrail sections are removed in order to place the portable concrete barrier system. The focus of this research study was to develop a proper stiffness transition between W-beam guardrail and portable concrete barrier systems. This research effort was accomplished through development and refinement of design concepts using computer simulation with LS-DYNA. Several design concepts were simulated, and design metrics were used to evaluate and refine each concept. These concepts were then analyzed and ranked based on feasibility, likelihood of success, and ease of installation. The rankings were presented to the Technical Advisory Committee (TAC) for selection of a preferred design alternative. Next, a Critical Impact Point (CIP) study was conducted, while additional analyses were performed to determine the critical attachment location and a reduced installation length for the portable concrete barriers. Finally, an additional simulation effort was conducted in order to evaluate the safety performance of the transition system under reverse-direction impact scenarios as well as to select the CIP. Recommendations were also provided for conducting a Phase II study and evaluating the nested Midwest Guardrail System (MGS) configuration using three Test Level 3 (TL-3) full-scale crash tests according to the criteria provided in the Manual for Assessing Safety Hardware, as published by the American Association of Safety Highway and Transportation Officials (AASHTO).

Distribution of metals exposure and associations with cardiometabolic risk factors in the "Modeling the Epidemiologic Transition Study".

BACKGROUND: Metals are known endocrine disruptors and have been linked to cardiometabolic diseases via multiple potential mechanisms, yet few human studies have both the exposure variability and biologically-relevant phenotype data available. We sought to examine the distribution of metals exposure and potential associations with cardiometabolic risk factors in the "Modeling the Epidemiologic Transition Study" (METS), a prospective cohort study designed to assess energy balance and change in body weight, diabetes and cardiovascular disease risk in five countries at different stages of social and economic development. METHODS: Young adults (25-45 years) of African descent were enrolled (N = 500 from each site) in: Ghana, South Africa, Seychelles, Jamaica and the U.S.A. We randomly selected 150 blood samples (N = 30 from each site) to determine concentrations of selected metals (arsenic, cadmium, lead, mercury) in a subset of participants at baseline and to examine associations with cardiometabolic risk factors. RESULTS: Median (interquartile range) metal concentrations (μg/L) were: arsenic 8.5 (7.7); cadmium 0.01 (0.8); lead 16.6 (16.1); and mercury 1.5 (5.0). There were significant differences in metals concentrations by: site location, paid employment status, education, marital status, smoking, alcohol use, and fish intake. After adjusting for these covariates plus age and sex, arsenic (OR 4.1, 95% C.I. 1.2, 14.6) and lead (OR 4.0, 95% C.I. 1.6, 9.6) above the median values were significantly associated with elevated fasting glucose. These associations increased when models were further adjusted for percent body fat: arsenic (OR 5.6, 95% C.I. 1.5, 21.2) and lead (OR 5.0, 95% C.I. 2.0, 12.7). Cadmium and mercury were also related with increased odds of elevated fasting glucose, but the associations were not statistically significant. Arsenic was significantly associated with increased odds of low HDL cholesterol both with (OR 8.0, 95% C.I. 1.8, 35.0) and without (OR 5.9, 95% C.I. 1.5, 23.1) adjustment for percent body fat. CONCLUSIONS: While not consistent for all cardiometabolic disease markers, these results are suggestive of potentially important associations between metals exposure and cardiometabolic risk. Future studies will examine these associations in the larger cohort over time.