Protection from lethal gram-negative bacterial sepsis by targeting Toll-like receptor 4.

Toll-like receptor 4 (TLR4), the signal-transducing molecule of the LPS receptor complex, plays a fundamental role in the sensing of LPS from gram-negative bacteria. Activation of TLR4 signaling pathways by LPS is a critical upstream event in the pathogenesis of gram-negative sepsis, making TLR4 an attractive target for novel antisepsis therapy. To validate the concept of TLR4-targeted treatment strategies in gram-negative sepsis, we first showed that TLR4(-/-) and myeloid differentiation primary response gene 88 (MyD88)(-/-) mice were fully resistant to Escherichia coli-induced septic shock, whereas TLR2(-/-) and wild-type mice rapidly died of fulminant sepsis. Neutralizing anti-TLR4 antibodies were then generated using a soluble chimeric fusion protein composed of the N-terminal domain of mouse TLR4 (amino acids 1-334) and the Fc portion of human IgG1. Anti-TLR4 antibodies inhibited intracellular signaling, markedly reduced cytokine production, and protected mice from lethal endotoxic shock and E. coli sepsis when administered in a prophylactic and therapeutic manner up to 13 h after the onset of bacterial sepsis. These experimental data provide strong support for the concept of TLR4-targeted therapy for gram-negative sepsis.

Prediction of postnatal outcome in fetuses with pulmonary hypoplasia by fetal-MRI: Comparison between lung volumetry and pulmonary signal intensity values

Purpose: Pulmonary hypoplasia is a determinant parameter for extra-uterine life. In the last years, MRI appears as a complement to US in order to evaluate the degree of pulmonary hypoplasia in foetuses with congenital anomalies, by using different methods - fetal lung volumetry (FLV), lung-to-liver signal intensity ratio (LLSIR)-. But until now, information about the correlation between the MRI prediction and the real postnatal outcome is limited. Methods and materials: We retrospectively reviewed the fetal MRI performed at our Institution in the last 8 years and selected the cases with suspicion of fetal pulmonary hypoplasia (n = 30). The pulmonary volumetry data of these foetuses were collected and the lung-to-liver signal intensity ratio (LLSIR) measures performed. These data were compared with those obtained from a control group of 25 foetuses considered as normal at MRI. The data of the study group were also correlated with the autopsy records or the post-natal clinical information of the patients. Results: As expected, the control group showed higher FLV and LLSIR values than the problem group at all gestational ages. Higher values of FLV and LLSIR were associated with a better post-natal outcome. Sensitivity, specificity, positive and negative predictive values and accuracy for the relative LLSIR and the relative FLV showed no significant differences. Conclusion: Our data show that not only the FLV but also the relative LLSIR inform about the degree of fetal lung development. This information may help to predict the fetal outcome and to evaluate the need for neonatal intensive care.

Balance Between Investment Protection and Sustainable Development in BITs: the Example of Switzerland

The objective of this article is to examine how substantive and procedural rights granted to foreign investors by Swiss bits are gradually being balanced with social and environmental provisions. Switzerland has enjoyed a long bit practice, as it signed its first treaty with Tunisia fifty years ago. Swiss bits rely on the post-establishment model and include usual standards of treatment. From 1981, they also systematically provide for a dispute settlement mechanism for disputes arising between an investor and a host State. Since the Switzerland - El Salvador bit in 1994, sustainable development concerns have been expressly inserted in some Swiss bits, as well as in several recent free trade agreements. Provisions on this theme are however far from being systematic in Switzerland's bit practice and essentially remain declaratory in nature. The trend towards wider inclusion of sustainable development provisions in bits still faces several practical and political challenges.

Protection of pancreatic beta-cells by high density lipoproteins

SUMMARYThe incidence of type 2 diabetes (T2D) is increasing worldwide and is linked to the enhancement of obesity. The principal cause of T2D development is insulin resistance, which lead to the increase of insulin production by the pancreatic beta-cells. In a pathological environment, namely dyslipidaemia, hyperglycaemia and inflammation, beta-cell compensation will fail in more vulnerable cells and diabetes will occur. High Density Lipoproteins (HDLs), commonly named "good cholesterol" are known to be atheroprotective. Low levels of HDLs are associated with increased prevalence of cardiovascular disease but are also an independent risk factor for the development of T2D. HDLs were demonstrated to protect pancreatic beta-cells against several stresses. However the molecular mechanisms of the protection are unknown and the objectives of this work were to try to elucidate the way how HDLs protect. The first approach was a broad screening of genes regulated by the stress and HDLs. A microarray analysis was performed on beta-cells stressed by serum deprivation and rescued by HDLs. Among the genes regulated, we focused on 4E-BP1, a cap-dependent translational inhibitor. In addition, HDLs were also found to protect against several other stresses.Endoplasmic reticulum (ER) stress is a mechanism that may play a role in the onset of T2D. The unfolded protein response (UPR) is a physiological process that aims at maintaining ER homeostasis in conditions where the protein folding and secretion is perturbed. Specific signalling pathways are involved in the increase of folding, export and degradation capacity of the ER. However, in case where the stress is prolonged, this mechanism turns to be pathological, by inducing cell death effector pathways, leading to beta-cell apoptosis. In our study, we discovered that HDLs were protective against ER stress induced by drugs and physiological stresses such as saturated free fatty acids. HDLs protected beta-cells by promoting ER homeostasis via the improvement of the folding and trafficking od proteins from the ER to the Golgi apparatus.Altogether our results suggest that HDLs are important for beta-cell function and survival, by protecting them from several stresses and acting on ER homeostasis. This suggests that attempt in keeping normal HDLs levels or function in patients is crucial to lessen the development of T2D.RÉSUMÉL'incidence du diabète de type 2 est en constante augmentation et est fortement liée à l'accroissement du taux d'obésité. La cause principale du diabète de type 2 est la résistance à l'insuline, qui entraîne une surproduction d'insuline par les cellules bêta pancréatiques. Dans un environnement pathologique associé à l'obésité (dyslipidémie, hyperglycémie et inflammation), les cellules bêta les plus vulnérables ne sont plus capables de compenser en augmentant leur production d'insuline, dysfonctionnent, ce qui conduit à leur mort par apoptose. Les lipoprotéines de hautes densités (HDLs), communément appelées (( bon cholestérol », sont connues pour leurs propriétés protectrices contre l'athérosclérose. Des niveaux bas de HDLs sanguins sont associés au risque de développer un diabète de type 2. Les HDLs ont également montré des propriétés protectrices contre divers stresses dans la cellule bêta. Cependant, les mécanismes de protection restent encore inconnus et l'objectif de ce travail a été d'investiguer les mécanismes moléculaires de protection des HDLs. La première approche choisie a été une étude du profil d'expression génique par puce à ADN afin d'identifier les gènes régulés par le stress et les HDLs. Parmi les gènes régulés, notre intérêt s'est porté sur 4E-BP1, un inhibiteur de la traduction coiffe- dépendante, dont l'induction par le stress était corrélée avec une augmentation de l'apoptose. Suite à cette étude, les HDLs ont également montrés un rôle protecteur contre d'autres stresses. Il s'agit particulièrement du stress du réticulum endoplasmique (RE), qui est un mécanisme qui semble jouer un rôle clé dans le développement du diabète. L'UPR (« Unfolded Protein Response ») est un processus physiologique tendant à maintenir l'homéostasie du réticulum endoplasmique, organelle prépondérante pour la fonction des cellules sécrétrices, notamment lorsqu'elle est soumise à des conditions extrêmes telles que des perturbations de la conformation tertiaire des protéines ou de la sécrétion. Dans ces cas, des voies de signalisation moléculaires sont activées, ce qui mène à l'exportation des protéines mal repliées, à leur dégradation et à l'augmentation de l'expression de chaperonnes capables d'améliorer le repliement des protéines mal formées. Toutefois, en cas de stress persistant, ce mécanisme de protection s'avère être pathologique. En induisant des voies de signalisation effectrices de l'apoptose, il conduit finalement au développement du diabète. Dans cette étude, nous avons démontré que les HDLs étaient capables de protéger la cellule bêta contre le stress du RE induits par des inhibiteurs (thapsigargine, tunicamycine) ou des stresses physiologiques tels que les acides gras libres. Les HDLs ont la capacité d'améliorer l'homéostasie du RE, notamment en favorisant le repliement et le transfert des protéines du RE à l'appareil de Golgi.En résumé, ces données suggèrent que les HDLs sont bénéfiques pour la survie des cellules bêta soumises à des stresses impliqués dans le développement du diabète, notamment en restaurant l'homéostasie du RE. Ces résultats conduisent à soutenir que le maintien des taux de cholestérol joue un rôle important dans la limitation de l'incidence du diabète.

Effects of employment protection and product market regulations on the Italian labor market

Labor market regulations have often being blamed for high and persistentunemployment in Europe, but evidence on their impact remains mixed. Morerecently, attention has turned to the impact of product market regulationson employment growth. This paper analyzes how labor and product marketregulations interact to affect turnover and employment. We present a matchingmodel which illustrates how barriers to entry in the product market mitigatethe impact of labor market deregulation. We, then, use the Italian SocialSecurity employer-employee panel to study the interaction between barriersto entry and dismissal costs. We exploit the fact that costs for unjustdismissals in Italy increased for firms below 15 employees relative to biggerfirms after 1990. We find that the increase in dismissal costs after 1990decreased accessions and separations in small relative to big firms,especially for women. Moreover, consistent with our model, we find evidencethat the increase in dismissal costs had smaller effects on turnover for womenin sectors faced with strict product market regulations.

The political economy of employment protection

This paper develops a model of job creation and job destruction in agrowing economy with embodied technical progress, that we use toanalyze the political support for employment protection legislationssuch as the ones that are observed in most European countries.We analyze the possibility of Condorcet cycles due to the fact thatworkers about to become unemployed prefer both an increase and areduction in firing costs over the status quo. Despite this problem, we show the existence of local, and sometimes global majority winners.In voting in favour of employment protection, incumbent employeestrade off lower living standards (because employment protectionmaintains workers in less productive activities) against longer job duration. We show that the gains from, and consequently the politicalsupport for employment protection (as defined by maximunjob tenure) are larger, the lower the rate of creative destruction and the largerthe worker's bargaining power. Numerical simulations suggest a hump-shaped response of firing costs to these variables, as well as negative impact of exogeneous turnover on employment protection.

Work values as predictors of entrepreneurial career intentions: A longitudinal analysis of gender effects

Purpose - Work values are an important characteristic to understand gender differences in career intentions, but how gender affects the relationship between values and career intentions is not well established. The purpose of this paper is to investigate whether gender moderates the effects of work values on level and change of entrepreneurial intentions (EI). Design/methodology/approach - In total, 218 German university students were sampled regarding work values and with EI assessed three times over the course of 12 months. Data were analysed with latent growth modelling. Findings - Self-enhancement and openness to change values predicted higher levels and conservation values lower levels of EI. Gender moderated the effects of enhancement and conservation values on change in EI. Research limitations/implications - The authors relied on self-reported measures and the sample was restricted to university students. Future research needs to verify to what extent these results generalize to other samples and different career fields, such as science or nursing. Practical implications - The results imply that men and women are interested in an entrepreneurial career based on the same work values but that values have different effects for men and women regarding individual changes in EI. The results suggest that the prototypical work values of a career domain seem important regarding increasing the career intent for the gender that is underrepresented in that domain. Originality/value - The results enhance understanding of how gender affects the relation of work values and a specific career intention, such as entrepreneurship.

Iowa Values Fund and Business Assistance Programs 2007 Annual Report, 2007

Following is the 2007 Annual Report of the Iowa Values Fund (IVF 2005) and Business Assistance Programs covering activity during Fiscal Year 2007 (FY ‘07) and cumulative for the first four years of the Iowa Values Fund Programs. The IVF (2005) is the primary funding source for a menu of financial assistance programs the Iowa Department of Economic Development (IDED) offers as incentives to Iowa companies to expand here, to recruit new companies into Iowa and assist new entrepreneurial ventures. In addition to IDED the law appropriates IVF (2005) funds for economic development activities to the Board of Regents, the Departments of Cultural Affairs and Natural Resources and to Community Colleges for certain workforce training programs. In addition to the IVF (2005), IDED allocates a portion of Community Development Block Grant and Federal Emergency Stimulus funds and several tax credit programs, all of which are included in this report.

An experimental study of discharge partitioning and flow structure at symmetrical bifurcations

Recent research has examined the factors controlling the geometrical configuration of bifurcations, determined the range of stability conditions for a number of bifurcation types and assessed the impact of perturbations on bifurcation evolution. However, the flow division process and the parameters that influence flow and sediment partitioning are still poorly characterized. To identify and isolate these parameters, three-dimensional velocities were measured at 11 cross-sections in a fixed-walled experimental bifurcation. Water surface gradients were controlled, and systematically varied, using a weir in each distributary. As may be expected, the steepest distributary conveyed the most discharge ( was dominant) while the mildest distributary conveyed the least discharge ( was subordinate). A zone of water surface super-elevation was co-located with the bifurcation in symmetric cases or displaced into the subordinate branch in asymmetric cases. Downstream of a relatively acute-angled bifurcation, primary velocity cores were near to the water surface and against the inner banks, with near-bed zones of lower primary velocity at the outer banks. Downstream of an obtuse-angled bifurcation, velocity cores were initially at the outer banks, with near-bed zones of lower velocities at the inner banks, but patterns soon reverted to match the acute-angled case. A single secondary flow cell was generated in each distributary, with water flowing inwards at the water surface and outwards at the bed. Circulation was relatively enhanced within the subordinate branch, which may help explain why subordinate distributaries remain open, may play a role in determining the size of commonly-observed topographic features, and may thus exert some control on the stability of asymmetric bifurcations. Further, because larger values of circulation result from larger gradient disadvantages, the length of confluence-diffluence units in braided rivers or between diffluences within delta distributary networks may vary depending upon flow structures inherited from upstream and whether, and how, they are fed by dominant or subordinate distributaries. Copyright (C) 2011 John Wiley & Sons, Ltd.

Managing by values in the next milenium: Cultural redesign for strategic organizational change

The system of beliefs and values, that shaped the model for management and organizations during the 20th century, is just not good enough today. In order to keep a business functioning well and competing successfully in markets that are increasingly more global, complex, professionally demanding, constantly changing and oriented towards quality and customer satisfaction a new model is needed. In this paper, we will propose that both Management by Instructions (MBI) and Management by Objectives (MBO) today give notoriously inadequate results. By contrast, description of a new approach labeled: Management by Values (MBV), seem to be emerging as a strategic leadership tool. The paper outlines this approach and discusses the implementation of MBV as a tool to redesign culture in organizations and prepare them for the next millenium.

A community survey of sun exposure, sunburn and sun protection.

AIM: To describe outdoor activities, sun protection behaviours and the experience of sunburn in a sample of New Zealanders during summer weekends of 1994. METHODS: 1243 respondents to a telephone survey provided information regarding their outdoor activities for the 5 hour period around midday of the previous Saturday and Sunday. The sample was drawn from those aged 15 to 65 years in the five centres of Auckland, Hamilton, Wellington, Christchurch and Dunedin. Respondents provided information on sun exposure, sunburn, sun protection and beliefs about tanning, as well as background demographic information, skin type and previous experience of sunburn. RESULTS: 12% of the sample (or 17% of all those outdoors) reported being sunburned on the preceding weekend, and those sunburned tended to be men, and to be under age 35 years. The face, neck and limbs were the areas most frequently reported as burned. Sporting activities and beach or water activities were associated with the highest number of episodes of burning. Overall 38% of those outside reported wearing a hat and 32% reported the use of a sunscreen. Positive attitudes to tanning were quite common and probably present the main target for change in the community. CONCLUSION: On any sunny weekend in summer about three-quarters of adult New Zealanders will be out in the sun for relatively long periods of time, and many will get sunburned. The reduction of such harmful sun exposures remains an important public health goal.

Employment protection, international specialization and innovation

We develop a model to analyse the implications of firing costs on incentivesfor R&D and international specialization. The Key idea is paying the firingcost, the country with a rigid labor market will tend to produce relativelysecure goods, at a late stage of their product life cycle.Under international trade, an international product cycle emerges where,roughly, new goods are first produced in the low firing cost country willspecialize in 'secondary innovations', that is, improvements in existinggoods, while the low firing cost country will more specialize in 'primaryinnovation', that is, invention of new goods.

c-Myc acts downstream of IL-15 in the regulation of memory CD8 T-cell homeostasis.

A subset of CD8 T cells in normal mice, expressing high levels of activation markers such as CD44, shares many properties with antigen-specific memory CD8 T cells. Homeostasis of CD44(high) CD8 T cells depends upon cytokines such as interleukin-15 (IL-15); however, the downstream signaling pathways regulating IL-15-dependent homeostatic proliferation are poorly defined. Surprisingly, we show here that haploinsufficiency of the protooncogene c-myc leads to a highly selective decrease in CD44(high) CD8 T cells in mice. Although steady-state proliferation and survival of CD44(high) CD8 T cells appeared not to be dependent on c-Myc, homeostatic proliferation of c-myc(+/-) CD44(high) CD8 T cells in lymphopenic hosts was strongly reduced, and the residual homeostatic proliferation of these cells appeared to occur independently of IL-15. Moreover, c-myc(+/-) CD44(high) CD8 T cells responded very poorly to purified IL-15 in vitro. Backcrossing of c-myc(+/-) mice to IL-15(-/-) mice revealed that the number of CD44(high) CD8 T cells decreased in an additive fashion in mice heterozygous for c-myc and IL-15. Finally homeostatic proliferation of antigen-specific memory CD44(high) CD8 T cells was also impaired in c-myc(+/-) mice. Collectively, our data identify c-Myc as a novel downstream component of the IL-15-dependent pathway controlling homeostatic proliferation of memory CD44(high) CD8 T cells.