Envelope protein dynamics in paramyxovirus entry.

Paramyxoviruses include major pathogens with significant global health and economic impact. This large family of enveloped RNA viruses infects cells by employing two surface glycoproteins that tightly cooperate to fuse their lipid envelopes with the target cell plasma membrane, an attachment and a fusion (F) protein. Membrane fusion is believed to depend on receptor-induced conformational changes within the attachment protein that lead to the activation and subsequent refolding of F. While structural and mechanistic studies have considerably advanced our insight into paramyxovirus cell adhesion and the structural basis of F refolding, how precisely the attachment protein links receptor engagement to F triggering remained poorly understood. Recent reports based on work with several paramyxovirus family members have transformed our understanding of the triggering mechanism of the membrane fusion machinery. Here, we review these recent findings, which (i) offer a broader mechanistic understanding of the paramyxovirus cell entry system, (ii) illuminate key similarities and differences between entry strategies of different paramyxovirus family members, and (iii) suggest new strategies for the development of novel therapeutics.

How HIV takes advantage of the cytoskeleton in entry and replication

The host cell cytoskeleton plays a key role in the life cycle of viral pathogens whose propagation depends on mandatory intracellular steps. Accordingly, also the human immunodeficiency virus type 1 (HIV-1) has evolved strategies to exploit and modulate in particular the actin cytoskeleton for its purposes. This review will recapitulate recent findings on how HIV-1 hijacks the cytoskeleton to facilitate entry into, transport within and egress from host cells as well as to commandeer communication of infected with uninfected bystander cells.

Chemotherapeutic strategies against Trypanosoma brucei: drug targets vs. drug targeting

Trypanosoma brucei rhodesiense and T. b. gambiense are the causative agents of sleeping sickness, a fatal disease that affects 36 countries in sub-Saharan Africa. Nevertheless, only a handful of clinically useful drugs are available. These drugs suffer from severe side-effects. The situation is further aggravated by the alarming incidence of treatment failures in several sleeping sickness foci, apparently indicating the occurrence of drug-resistant trypanosomes. Because of these reasons, and since vaccination does not appear to be feasible due to the trypanosomes' ever changing coat of variable surface glycoproteins (VSGs), new drugs are needed urgently. The entry of Trypanosoma brucei into the post-genomic age raises hopes for the identification of novel kinds of drug targets and in turn new treatments for sleeping sickness. The pragmatic definition of a drug target is, a protein that is essential for the parasite and does not have homologues in the host. Such proteins are identified by comparing the predicted proteomes of T. brucei and Homo sapiens, then validated by large-scale gene disruption or gene silencing experiments in trypanosomes. Once all proteins that are essential and unique to the parasite are identified, inhibitors may be found by high-throughput screening. However powerful, this functional genomics approach is going to miss a number of attractive targets. Several current, successful parasiticides attack proteins that have close homologues in the human proteome. Drugs like DFMO or pyrimethamine inhibit parasite and host enzymes alike--a therapeutic window is opened only by subtle differences in the regulation of the targets, which cannot be recognized in silico. Working against the post-genomic approach is also the fact that essential proteins tend to be more highly conserved between species than non-essential ones. Here we advocate drug targeting, i.e. uptake or activation of a drug via parasite-specific pathways, as a chemotherapeutic strategy to selectively inhibit enzymes that have equally sensitive counterparts in the host. The T. brucei purine salvage machinery offers opportunities for both metabolic and transport-based targeting: unusual nucleoside and nucleobase permeases may be exploited for selective import, salvage enzymes for selective activation of purine antimetabolites.

Deregulation strategies and its regulating effects: The case of the termination of Social Assistance for rejected asylum seekers in Switzerland

Deregulation strategies and their regulating effects: The case of the termination of Social Assistance for rejected asylum seekers in Switzerland. In Switzerland, rejected asylum seekers no longer have any residence rights. In 2003 the Swiss state decided to terminate the so far granted social assistance for people with a non-entry decision on their asylum request. In 2008 the termination of social assistance was expanded to all rejected asylum seekers. Nevertheless, facing the impossibility of deporting them, the Swiss state entitled this group of people to emergency assistance. It is a basic, which is stated in the Swiss Federal constitution. In this context, new structures were established specially for rejected asylum seekers. These structures had to be set up, financed, controlled, managed and legitimized. For example, collective centres were set up exclusively for rejected asylum seekers. In this speech, I want to analyze the political and bureaucratic process of terminating social assistance for rejected asylum seekers. The exclusion of rejected asylum seekers from social aid was embedded in a wider austerity program of the Federal State. The Federal Migration Office had been requested to save money. The main official goal was to reduce the support of these illegalized people, reduce any structures that would prolong their stay on Swiss ground and to set incentives so that they would leave the country on their own. But during the implementation, new regulating effects emerged. Drawing on ethnographic material, I will highlight these “messy procedures” (Sciortino 2004). First, I will analyze the means and goals developed by the Federal authorities while conceptualising the termination of social assistance. Second, I will focus on the new built structures and elaborate the practices and legitimating strategies of the authorities. As a conclusion, I will analyze the ambivalences of these processes which, at the end, established specific structures for the “unwanted”.

Conditions for the career entry of Swiss sports science graduates.

The differentiation and commercialisation of the sports domain means that graduates with sports science degrees have more and more occupational fields to choose from. On the other hand, formal admissions criteria are becoming less important in sports-related occupations. This means that graduates need to pursue specific strategies to successfully embark on a ca-reer. This article examines which factors determine the career entry of sports science graduates in Switzerland. Aside from the starting salary, non-monetary aspects such as appropriateness of the job for the level of education and job stability were also considered. The empirical study draws on data from a sample of n = 1,054 graduates from all Swiss universities, analys-ing the career entry of sports science graduates. The results show that education-related as-pects (e.g., university degree) lead to higher incomes and jobs that are appropriate to one’s academic education; however, differences exist between the diverse occupational domains of sport. Furthermore, additional qualifications obtained by sports science graduates and volun-tary activities in the field of sport are both associated with higher incomes, particularly in oc-cupations outside sport. However, other factors (e.g., social networks, internships) produce no relevant effects.

Overcoming Liability of Newness through Socialization : How Legitimation Strategies of a New Venture evolve

Liability of newness, the tendency of new ventures to die early after market entry, results from lacking legitimacy in their new cultural context and according failure to acquire resources. Based on a longitudinal case study on repeated resource acquisition attempts of a new venture, we found that overcoming liability of newness depended on the socialization of the new venture to the normative environment on which it depended on for resources. Over time and across repeated resource acquisition attempts, socialization - the process of learning the use of legitimate symbols and their culturally contingent meanings - enabled the new venture to become the skillful cultural operator on which legitimation and resource acquisition was contingent. From our data, 'Accumulating a repertoire of legitimate symbols' and 'Assimilating the evaluations of resource-holders' emerged as the two primary mechanisms for new venture socialization. The study's contributions to related literature and its broader theoretical implications are discussed