The molecular basis of social behavior: models, methods and advances.

Elucidating the molecular and neural basis of complex social behaviors such as communal living, division of labor and warfare requires model organisms that exhibit these multi-faceted behavioral phenotypes. Social insects, such as ants, bees, wasps and termites, are attractive models to address this problem, with rich ecological and ethological foundations. However, their atypical systems of reproduction have hindered application of classical genetic approaches. In this review, we discuss how recent advances in social insect genomics, transcriptomics, and functional manipulations have enhanced our ability to observe and perturb gene expression, physiology and behavior in these species. Such developments begin to provide an integrated view of the molecular and cellular underpinnings of complex social behavior.

Reduction of connexin36 content by ICER-1 contributes to insulin-secreting cells apoptosis induced by oxidized LDL particles.

Connexin36 (Cx36), a trans-membrane protein that forms gap junctions between insulin-secreting beta-cells in the Langerhans islets, contributes to the proper control of insulin secretion and beta-cell survival. Hypercholesterolemia and pro-atherogenic low density lipoproteins (LDL) contribute to beta-cell dysfunction and apoptosis in the context of Type 2 diabetes. We investigated the impact of LDL-cholesterol on Cx36 levels in beta-cells. As compared to WT mice, the Cx36 content was reduced in islets from hypercholesterolemic ApoE-/- mice. Prolonged exposure to human native (nLDL) or oxidized LDL (oxLDL) particles decreased the expression of Cx36 in insulin secreting cell-lines and isolated rodent islets. Cx36 down-regulation was associated with overexpression of the inducible cAMP early repressor (ICER-1) and the selective disruption of ICER-1 prevented the effects of oxLDL on Cx36 expression. Oil red O staining and Plin1 expression levels suggested that oxLDL were less stored as neutral lipid droplets than nLDL in INS-1E cells. The lipid beta-oxidation inhibitor etomoxir enhanced oxLDL-induced apoptosis whereas the ceramide synthesis inhibitor myriocin partially protected INS-1E cells, suggesting that oxLDL toxicity was due to impaired metabolism of the lipids. ICER-1 and Cx36 expressions were closely correlated with oxLDL toxicity. Cx36 knock-down in INS-1E cells or knock-out in primary islets sensitized beta-cells to oxLDL-induced apoptosis. In contrast, overexpression of Cx36 partially protected INS-1E cells against apoptosis. These data demonstrate that the reduction of Cx36 content in beta-cells by oxLDL particles is mediated by ICER-1 and contributes to oxLDL-induced beta-cell apoptosis.

Risk reduction practices in men who have sex with men in Switzerland: serosorting, strategic positioning, and withdrawal before ejaculation.

The aim of this study was to identify predictors of intentional use of the HIV risk reduction practices of serosorting, strategic positioning, and withdrawal before ejaculation during unprotected anal intercourse (UAI) with casual partners. A cross-sectional survey pertaining to the Swiss HIV behavioral surveillance system, using an anonymous self-administered questionnaire, was conducted in 2007 in a self-selected sample of men having sex with other men (MSM). Analysis was restricted to participants with UAI with casual partner(s) (N = 410). Logistic regression was used to estimate factors associated with intentional use of serosorting, strategic positioning, and withdrawal before ejaculation. In the previous 12 months, 71% of participants reported having UAI with a casual partner of different or unknown HIV-status. Of these, 47% reported practicing withdrawal, 38% serosorting, and 25% strategic positioning. In the 319 participants with known HIV-status, serosorting was associated with frequent Internet use to find partners (OR = 2.32), STI (OR = 2.07), and HIV testing in the past 12 months (OR = 1.81). Strategic positioning was associated with HIV-status (OR = 0.13) and having UAI with a partner of different or unknown HIV-status (OR = 3.57). Withdrawal was more frequently practiced by HIV-negative participants or participants reporting high numbers of sexual partners (OR = 2.48) and having UAI with a partner of unknown or different serostatus (OR = 2.08). Risk reduction practices are widely used by MSM, each practice having its own specificities. Further research is needed to determine the contextual factors surrounding harm reduction practices, particularly the strategic or opportunistic nature of their use.

Reduction of Helicobacter infection in IL-10-/- mice is dependent on CD4+ T cells but not on mast cells.

BACKGROUND: In contrast to wild type, interleukin-10-deficient (IL-10(-/-)) mice are able to clear Helicobacter infection. In this study, we investigated the immune response of IL-10(-/-) mice leading to the reduction of Helicobacter infection. MATERIALS AND METHODS: We characterized the immune responses of Helicobacter felis-infected IL-10(-/-) mice by studying the systemic antibody and cellular responses toward Helicobacter. We investigated the role of CD4(+) T cells in the Helicobacter clearance by injecting H. felis-infected IL-10(-/-) mice with anti-CD4 depleting antibodies. To examine the role of mast cells in Helicobacter clearance, we constructed and infected mast cells and IL-10 double-deficient mice. RESULTS: Reduction of Helicobacter infection in IL-10(-/-) mice is associated with strong humoral (fivefold higher serum antiurease antibody titers were measured in IL-10(-/-) in comparison to wild-type mice, p < .008) and cellular (urease-stimulated splenic CD4(+) T cells isolated from infected IL-10(-/-) mice produce 150-fold more interferon-gamma in comparison to wild-type counterparts, p < .008) immune responses directed toward Helicobacter. Depletion of CD4(+) cells from Helicobacter-infected IL-10(-/-) mice lead to the loss of bacterial clearance (rapid urease tests are threefold higher in CD4(+) depleted IL-10(-/-) in comparison to nondepleted IL-10(-/-) mice, p < .02). Mast cell IL-10(-/-) double-deficient mice clear H. felis infection, indicating that mast cells are unnecessary for the bacterial eradication in IL-10(-/-) mice. CONCLUSION: Taken together, these results suggest that CD4(+) cells are required for Helicobacter clearance in IL-10(-/-) mice. This reduction of Helicobacter infection is, however, not dependent on the mast cell population.

Fanconi-Bickel syndrome and autosomal recessive proximal tubulopathy with hypercalciuria (ARPTH) are allelic variants caused by GLUT2 mutations.

CONTEXT: Many inherited disorders of calcium and phosphate homeostasis are unexplained at the molecular level. OBJECTIVE: The objective of the study was to identify the molecular basis of phosphate and calcium abnormalities in two unrelated, consanguineous families. PATIENTS: The affected members in family 1 presented with rickets due to profound urinary phosphate-wasting and hypophosphatemic rickets. In the previously reported family 2, patients presented with proximal renal tubulopathy and hypercalciuria yet normal or only mildly increased urinary phosphate excretion. METHODS: Genome-wide linkage scans and direct nucleotide sequence analyses of candidate genes were performed. Transport of glucose and phosphate by glucose transporter 2 (GLUT2) was assessed using Xenopus oocytes. Renal sodium-phosphate cotransporter 2a and 2c (Npt2a and Npt2c) expressions were evaluated in transgenically rescued Glut2-null mice (tgGlut2-/-). RESULTS: In both families, genetic mapping and sequence analysis of candidate genes led to the identification of two novel homozygous mutations (IVS4-2A>G and R124S, respectively) in GLUT2, the gene mutated in Fanconi-Bickel syndrome, a rare disease usually characterized by renal tubulopathy, impaired glucose homeostasis, and hepatomegaly. Xenopus oocytes expressing the [R124S]GLUT2 mutant showed a significant reduction in glucose transport, but neither wild-type nor mutant GLUT2 facilitated phosphate import or export; tgGlut2-/- mice demonstrated a profound reduction of Npt2c expression in the proximal renal tubules. CONCLUSIONS: Homozygous mutations in the facilitative glucose transporter GLUT2, which cause Fanconi-Bickel syndrome, can lead to very different clinical and biochemical findings that are not limited to mild proximal renal tubulopathy but can include significant hypercalciuria and highly variable degrees of urinary phosphate-wasting and hypophosphatemia, possibly because of the impaired proximal tubular expression of Npt2c.

On landslide risk, resilience and vulnerability of mountain communities in Central-Eastern Nepal

Executive SummaryIn Nepal, landslides are one of the major natural hazards after epidemics, killing over 100 persons per year. However, this figure is an underreported reflection of the actual impact that landslides have on livelihoods and food security in rural Nepal. With predictions of more intense rainfall patterns, landslide occurrence in the Himalayas is likely to increase and continue to be one of the major impediments to development. Due to the remoteness of many localities and lack of resources, responsibilities for disaster preparedness and response in mountain areas usually lie with the communities themselves. Everyday life is full of risk in mountains of Nepal. This is why mountain populations, as well as other populations living in harsh conditions have developed a number of coping strategies for dealing with adverse situations. Perhaps due to the dispersed and remote nature of landslides in Nepal, there have been few studies on vulnerability, coping- and mitigation strategies of landslide affected populations. There are also few recommendations available to guide authorities and populations how to reduce losses due to landslides in Nepal, and even less so, how to operationalize resilience and vulnerability.Many policy makers, international donors, NGOs and national authorities are currently asking what investments are needed to increase the so-called 'resilience' of mountain populations to deal with climate risks. However, mountain populations are already quite resilient to seasonal fluctuations, temperature variations, rainfall patterns and market prices. In spite of their resilience, they continue to live in places at risk due to high vulnerability caused by structural inequalities: access to land, resources, markets, education. This interdisciplinary thesis examines the concept of resilience by questioning its usefulness and validity as the current goal of international development and disaster risk reduction policies, its conceptual limitations and its possible scope of action. The goal of this study is two-fold: to better define and distinguish factors and relationships between resilience, vulnerability, capacities and risk; and to test and improve a participatory methodology for evaluating landslide risk that can serve as a guidance tool for improving community-based disaster risk reduction. The objective is to develop a simple methodology that can be used by NGOs, local authorities and communities to reduce losses from landslides.Through its six case studies in Central-Eastern Nepal, this study explores the relation between resilience, vulnerability and landslide risk based on interdisciplinary methods, including geological assessments of landslides, semi-structured interviews, focus groups and participatory risk mapping. For comparison, the study sites were chosen in Tehrathum, Sunsari and Dolakha Districts of Central/Eastern Nepal, to reflect a variety of landslide types, from chronic to acute, and a variety of communities, from very marginalized to very high status. The study uses the Sustainable Livelihoods Approach as its conceptual basis, which is based on the notion that access and rights to resources (natural, human/institutional, economic, environmental, physical) are the basis for coping with adversity, such as landslides. The study is also intended as a contribution to the growing literature and practices on Community Based Disaster Risk Reduction specifically adapted to landslide- prone areas.In addition to the six case studies, results include an indicator based methodology for assessing and measuring vulnerability and resilience, a composite risk assessment methodology, a typology of coping strategies and risk perceptions and a thorough analysis of the relation between risk, vulnerability and resilience. The methodology forassessing vulnerability, resilience and risk is relatively cost-effective and replicable in a low-data environment. Perhaps the major finding is that resilience is a process that defines a community's (or system's) capacity to rebound following adversity but it does not necessarily reduce vulnerability or risk, which requires addressing more structural issues related to poverty. Therefore, conclusions include a critical view of resilience as a main goal of international development and disaster risk reduction policies. It is a useful concept in the context of recovery after a disaster but it needs to be addressed in parallel with vulnerability and risk.This research was funded by an interdisciplinary grant (#26083591) from the Swiss National Science Foundation for the period 2009-2011 and a seed grant from the Faculty of Geosciences and Environment at the University of Lausanne in 2008.Résumé en françaisAu Népal, les glissements de terrain sont un des aléas les plus dévastateurs après les épidémies, causant 100 morts par an. Pourtant, ce chiffre est une sous-estimation de l'impact réel de l'effet des glissements sur les moyens de subsistance et la sécurité alimentaire au Népal. Avec des prévisions de pluies plus intenses, l'occurrence des glissements dans les Himalayas augmente et présente un obstacle au développement. Du fait de l'éloignement et du manque de ressources dans les montagnes au Népal, la responsabilité de la préparation et la réponse aux catastrophes se trouve chez les communautés elles-mêmes. Le risque fait partie de la vie quotidienne dans les montagnes du Népal. C'est pourquoi les populations montagnardes, comme d'autres populations vivant dans des milieux contraignants, ont développé des stratégies pour faire face aux situations défavorables. Peu d'études existent sur la vulnérabilité, ceci étant probablement dû à l'éloignement et pourtant, les stratégies d'adaptation et de mitigation des populations touchées par des glissements au Népal existent.Beaucoup de décideurs politiques, bailleurs de fonds, ONG et autorités nationales se demandent quels investissements sont nécessaires afin d'augmenter la 'resilience' des populations de montagne pour faire face aux changements climatiques. Pourtant, ces populations sont déjà résilientes aux fluctuations des saisons, des variations de température, des pluies et des prix des marchés. En dépit de leur résilience, ils continuent de vivre dans des endroits à fort risque à cause des vulnérabilités créées par les inégalités structurelles : l'accès à la terre, aux ressources, aux marchés et à l'éducation. Cette thèse interdisciplinaire examine le concept de la résilience en mettant en cause son utilité et sa validité en tant que but actuel des politiques internationales de développement et de réduction des risques, ainsi que ses limitations conceptuelles et ses possibles champs d'action. Le but de cette étude est double : mieux définir et distinguer les facteurs et relations entre la résilience, la vulnérabilité, les capacités et le risque ; Et tester et améliorer une méthode participative pour évaluer le risque des glissements qui peut servir en tant qu'outil indicatif pour améliorer la réduction des risques des communautés. Le but est de développer une méthodologie simple qui peut être utilisée par des ONG, autorités locales et communautés pour réduire les pertes dues aux glissements.A travers les études de cas au centre-est du Népal, cette étude explore le rapport entre la résilience, la vulnérabilité et les glissements basée sur des méthodes interdisciplinaires ; Y sont inclus des évaluations géologiques des glissements, des entretiens semi-dirigés, des discussions de groupes et des cartes de risques participatives. Pour la comparaison, les zones d'études ont été sélectionnées dans les districts de Tehrathum, Sunsari et Dolakha dans le centre-est du Népal, afin de refléter différents types de glissements, de chroniques à urgents, ainsi que différentes communautés, variant de très marginalisées à très haut statut. Pour son cadre conceptuel, cette étude s'appuie sur l'approche de moyens de subsistance durable, qui est basée sur les notions d'accès et de droit aux ressources (naturelles, humaines/institutionnelles, économiques, environnementales, physiques) et qui sont le minimum pour faire face à des situations difficiles, comme des glissements. Cette étude se veut aussi une contribution à la littérature et aux pratiques en croissantes sur la réduction des risques communautaires, spécifiquement adaptées aux zones affectées par des glissements.En plus des six études de cas, les résultats incluent une méthodologie basée sur des indicateurs pour évaluer et mesurer la vulnérabilité et la résilience, une méthodologie sur le risque composé, une typologie de stratégies d'adaptation et perceptions des risques ainsi qu'une analyse fondamentale de la relation entre risque, vulnérabilité et résilience. Les méthodologies pour l'évaluation de la vulnérabilité, de la résilience et du risque sont relativement peu coûteuses et reproductibles dans des endroits avec peu de données disponibles. Le résultat probablement le plus pertinent est que la résilience est un processus qui définit la capacité d'une communauté (ou d'un système) à rebondir suite à une situation défavorable, mais qui ne réduit pas forcement la vulnérabilité ou le risque, et qui requiert une approche plus fondamentale s'adressant aux questions de pauvreté. Les conclusions incluent une vue critique de la résilience comme but principal des politiques internationales de développement et de réduction des risques. C'est un concept utile dans le contexte de la récupération après une catastrophe mais il doit être pris en compte au même titre que la vulnérabilité et le risque.Cette recherche a été financée par un fonds interdisciplinaire (#26083591) du Fonds National Suisse pour la période 2009-2011 et un fonds de préparation de recherches par la Faculté des Géosciences et Environnement à l'Université de Lausanne en 2008.

Vitamin C requirements in parenteral nutrition.

Some biochemical functions of vitamin C make it an essential component of parenteral nutrition (PN) and an important therapeutic supplement in other acute conditions. Ascorbic acid is a strong aqueous antioxidant and is a cofactor for several enzymes. The average body pool of vitamin C is 1.5 g, of which 3%-4% (40-60 mg) is used daily. Steady state is maintained with 60 mg/d in nonsmokers and 140 mg/d in smokers. Shocked surgical, trauma, and septic patients have a drastic reduction of circulating plasma ascorbate concentrations. These low concentrations require 3-g doses/d to restore normal plasma ascorbate concentrations, questioning the recommended PN dose of 100 mg/d. Determination of intravenous requirements is usually based on plasma concentrations, which are altered during the inflammatory response. There is no clear indicator of deficiency: serum or plasma ascorbate concentrations <0.3 mg/dL (20 micromol/L) indicates inadequate vitamin C status. On the basis of available pharmacokinetic data the 100 mg/d dose for patients receiving home PN and 200 mg/d for stable adult patients receiving PN are adequate, but requirements have been shown to be higher in perioperative, trauma, burn, and critically ill patients, paralleling oxidative stress. One recommendation cannot fit all categories of patients. Large vitamin C supplements may be considered in severe critical illness, major trauma, and burns because of increased requirements resulting from oxidative stress and wound healing. Future research should distinguish therapeutic use of high-dose ascorbic acid antioxidant therapy from nutritional PN requirements.

Molecular basis of odor detection in insects.

Olfactory systems are evolutionarily ancient, underlying the common requirement for all animals to sense and respond to diverse volatile chemical signals in their environment. Odor detection is mediated by odorant receptors (ORs) that, in most olfactory systems, comprise large families of divergent G protein-coupled receptors. Here, I discuss our and others' recent investigations of ORs in the fruit fly, Drosophila melanogaster, which have revealed insights into the distinct evolutionary origin and molecular function of insect ORs. I also describe a bioinformatics strategy that we developed to identify molecules that function with these insect-specific receptors in odor detection.

Dispersion of natural arsenic in the Malcantone watershed, Southern Switzerland: field evidence for repeated sorption-desorption and oxidation-reduction processes

In recent years, elevated arsenic concentrations have been found in waters and soils of many, countries, often resulting in a health threat for the local population. Switzerland is not an exception and this paper deals with the release and subsequent fate of arsenic in a 200-km(2) mountainous watershed, characterized by crystalline silicate rocks (gneisses, schists, amphibolites) that contain abundant As-bearing sulfide ore deposits, some of which have been mined for iron and gold in the past. Using analytical methods common for mineralogical, ground water and soil studies (XRD, XRF, XAS-XANES and -EXAFS, electron microprobe, extraction, ICP, AAS with hydride generator, ion chromatography), seven different field situations and related dispersion processes of natural arsenic have been studied: (1) release by rock weathering, (2) transport and deposition by water and ice; (3) release of As to the ground and surface water due to increasing pH; (4) accumulation in humic soil horizons; (5) remobilization by reduction in water-saturated soils and stagnant ground waters; (6) remobilization by using P-rich fertilizers or dung and (7) oxidation, precipitation and dilution in surface waters. Comparison of the results with experimental adsorption studies and speciation diagrams from the literature allows us to reconstruct and identify the typical behavior of arsenic in a natural environment under temperate climatic conditions. The main parameters identified are: (a) once liberated from the primary minerals, sorption processes on Fe-oxy-hydroxides dominate over Al-phases, such as Al-hydroxides or clay minerals and limit the As concentrations in the spring and well waters between 20 and 300 mug/l. (b) Precipitation as secondary minerals is limited to the weathering domain, where the As concentrations are still high and not yet too diluted by rain and soils waters. (c) Although neutral and alkaline pH conditions clearly increase the mobility of As, the main factor to mobilize As is a low redox potential (Eh close or below 0 mV), which favors the dissolution of the Fe-oxy-hydroxides on which the As is sorbed. (d) X-ray absorption spectroscopy (XAS) of As in water-logged humic forest soils indicates that the reduction to As III only occurs at the solid-water interface and that the solid contains As as As V (e) A and Bh horizons of humic cambisols can effectively capture As when As-rich waters flow through them. Complex spatial and temporal variation of the various parameters in a watershed results in repeated mobilization and immobilization of As, which continuously transports As from the upper to the lower part of a watershed and ultimately to the ocean. (C) 2004 Elsevier B.V. All rights reserved.

Cis-trans interactions of cell surface receptors: biological roles and structural basis.

Cell surface receptors bind ligands expressed on other cells (in trans) in order to communicate with neighboring cells. However, an increasing number of cell surface receptors are found to also interact with ligands expressed on the same cell (in cis). These observations raise questions regarding the biological role of such cis interactions. Specifically, it is important to know whether cis and trans binding have distinct functional effects and, if so, how a single cell discriminates between interactions in cis versus trans. Further, what are the structural features that allow certain cell surface receptors to engage ligand both on the same as well as on an apposed cell membrane? Here, we summarize known examples of receptors that display cis-trans binding and discuss the emerging diversity of biological roles played by these unconventional two-way interactions, along with their structural basis.

Fetal dose reduction in head and neck radiotherapy of a pregnant woman.

BACKGROUND AND PURPOSE: A pregnant woman was referred for post-operative radiotherapy of a malignant schwannoma in the head and neck region. A best-treatment plan was devised in order to minimize the fetal dose. MATERIAL AND METHODS: The fetal dose resulting from radiological examinations was determined according to international protocols, that resulting from radiotherapy was calculated according to Recommendation 36 of the American Association of Physicists in Medicine (AAPM) Task Group. Pre-treatment dosimetry was performed with an anthropomorphic phantom. Several alternative treatment plans were evaluated. The use of a multileaf collimator (MLC) and a virtual wedge (VW) was compared to cerrobend blocks (CB) and physical wedge (PW). In-vivo dosimetry was performed using a vaginal probe containing thermoluminescent dosimeters (TLD). RESULTS: The total fetal dose resulting from diagnostic and radiotherapy procedures was estimated to be 36 mGy. The technique based on MLC and VW was elected for patient treatment. Measurements for this configuration resulted in afetal dose reduction of 82%. The shielding of the patient's abdomen further reduced the fetal dose by 42%. CONCLUSION: The use of VW and MLC for the treatment of a pregnant woman is highly recommended. Each case should be individually studied with pre-treatment and in-vivo dosimetry.

New insights into the molecular basis of desmoplakin- and desmin-related cardiomyopathies.

Desmosomes are intercellular adhesive complexes that anchor the intermediate filament cytoskeleton to the cell membrane in epithelia and cardiac muscle cells. The desmosomal component desmoplakin plays a key role in tethering various intermediate filament networks through its C-terminal plakin repeat domain. To gain better insight into the cytoskeletal organization of cardiomyocytes, we investigated the association of desmoplakin with desmin by cell transfection, yeast two-hybrid, and/or in vitro binding assays. The results indicate that the association of desmoplakin with desmin depends on sequences within the linker region and C-terminal extremity of desmoplakin, where the B and C subdomains contribute to efficient binding; a potentially phosphorylatable serine residue in the C-terminal extremity of desmoplakin affects its association with desmin; the interaction of desmoplakin with non-filamentous desmin requires sequences contained within the desmin C-terminal rod portion and tail domain in yeast, whereas in in vitro binding studies the desmin tail is dispensable for association; and mutations in either the C-terminus of desmoplakin or the desmin tail linked to inherited cardiomyopathy seem to impair desmoplakindesmin interaction. These studies increase our understanding of desmoplakin-intermediate filament interactions, which are important for maintenance of cytoarchitecture in cardiomyocytes, and give new insights into the molecular basis of desmoplakin- and desmin-related human diseases.