Intracellular localization of DR5 and related regulatory pathways as a mechanism of resistance to TRAIL in cancer

TNF-related apoptosis-inducing ligand (TRAIL) is a prominent cytokine capable of inducing apoptosis. It can bind to five different cognate receptors, through which diverse intracellular pathways can be activated. TRAIL’s ability to preferentially kill transformed cells makes it a promising potential weapon for targeted tumor therapy. However, recognition of several resistance mechanisms to TRAIL-induced apoptosis has indicated that a thorough understanding of the details of TRAIL biology is still essential before this weapon can be confidently unleashed. Critical to this aim is revealing the functions and regulation mechanisms of TRAIL’s potent death receptor DR5. Although expression and signaling mechanisms of DR5 have been extensively studied, other aspects, such as its subcellular localization, non-signaling functions, and regulation of its membrane transport, have only recently attracted attention. Here, we discuss different aspects of TRAIL/DR5 biology, with a particular emphasis on the factors that seem to influence the cell surface expression pattern of DR5, along with factors that lead to its nuclear localization. Disturbance of this balance apparently affects the sensitivity of cancer cells to TRAIL-mediated apoptosis, thus constituting an eligible target for potential new therapeutic agents.     

Arboreality predicts Batrachochytrium dendrobatidis infection level in tropical direct-developing frogs

Pathogen-mediated changes in host behaviour can result from hosts altering their habitat preferences. Although infection risk with pathogenic fungus Batrachochytrium dendrobatidis in amphibians is associated with environments favouring its growth, the relationship with microhabitat use has not been examined. Here, we aim to determine if microhabitats used by frogs during their nocturnal activity predict B. dendrobatidis prevalence and infection intensity. Our focal host, Eleutherodactylus coqui, is a habitat generalist that uses multiple habitats from the forest floor to the canopy. We analysed data on B. dendrobatidis occurrence in 157 adults and 122 juveniles at El Yunque National forest in Puerto Rico. We categorized each individual’s nocturnal microhabitat as forest floor, curled palm fronds in the floor, arboreal bromeliads and foliage or tree trunks 50 cm to 2.5 m above ground. We found that frogs on the forest floor had the greatest B. dendrobatidis prevalence (73%), compared with those active in vegetation above ground (55%). Overall, the probability of B. dendrobatidis infection in frogs using microhabitats on the forest floor was twice as great as for those on arboreal substrates. Differences in B. dendrobatidis prevalence and intensity in E. coqui may be explained by specific abiotic conditions of microenvironments (temperature and humidity) affecting both pathogen and host, and by the age-specific ecological requirements of hosts. Adults were found to be most active in microhabitats where individuals had lower infection burdens, suggesting pathogen-modulated habitat choice. This work has important implications for the evolutionary dynamics of enzootic diseases and provides data that may inform potential mitigation strategies against a generalist amphibian pathogen.     

Citizenship and Voluntarism: A Meaningful Combination or the Basis for Exploitative Relationships?

The author starts from the observation that citizenship and voluntarism are contested terms with diverse meanings. They have also been appropriated by politicians of various persuasions and imbued with meanings associated with ‘feel good’ factors that emphasize serving in a community. Therefore, voluntarism has the potential to continue the exclusion of minority groups, marginalized individuals and collective groupings at the expense of their citizenship rights, particularly those identified by Hannah Arendt as the ‘right to have rights’ that have been endorsed through public policy but today are being undermined by the ‘age of austerity’ in publicly funded welfare states. Against the background of the political context of UK, and the public rhetoric on the ‘Big Society’, the author examines whether citizenship discourses allied with voluntarism support a meaningful endorsement of altruistic solidarity or whether they endorse exploitative relationships under the guise of meeting the public needs.     

A Hyper-Erlang Jump-Diffusion Process and Applications in Finance

This paper studies the first passage time problem for a reflected two-sided jump-diffusion risk model with the jumps having a hyper-Erlang distribution. The authors give the explicit closed-form expression for the joint Laplace transform of the first passage time and the overshoot for the reflected process. Finally, the formula is applied to the ruin problem under the barrier dividend strategy and the pricing of the Russian option.     

Deep cleaning of a metallurgical zinc leaching residue and recovery of valuable metals

Huge quantities of zinc leaching residues (ZLRs) generated from zinc production are dumped continuously around the world and pose a potential environmental threat because of their considerable amounts of entrained heavy metals (mainly lead). Most ZLRs have not been properly treated and the valuable metals in them have not yet been effectively recovered. Herein, the deep cleaning of a ZLR and recovery of valuable metals via a hydrometallurgical route were investigated. The cleaning process consists of two essential stages:acid leaching followed by calcium chloride leaching. The optimum conditions for extracting zinc, copper, and indium by acid leaching were a sulfuric acid concentration of 200 g·L-1, a liquid/solid ratio of 4:1 (mL/g), a leaching time of 2 h, and a temperature of 90℃. For lead and silver extractions, the optimum conditions were a calcium chloride concentration of 400 g·L-1, a pH value of 1.0, a leaching time of 1 h, and a temperature of 30℃. After calcium chloride leaching, silver and lead were extracted out and the lead was finally recovered as electrolytic lead by electrowinning. The anglesite phase, which poses the greatest potential environmental hazard, was removed from the ZLR after deep cleaning, thus reducing the cost of environmental management of ZLRs. The treatment of chlorine and spent electrolyte generated in the process was discussed.     

The Dynamics of Change in Everyday Life: Final Response

Due to Swedish history, to date there has been a common understanding of the meaning of volunteering in Sweden. However, it seems as if the meaning of volunteering is changing in Sweden, at least in some atypical hybrid organizations. However, this change presupposes that there is a conception of volunteering that has been institutionalized by tradition. Hence, to understand this change, one has to capture the institutionalized meaning of volunteering. In the academic debate there is sometimes an implied opposition between conceptual meaning and existential meaning. It is argued that this divide is unfortunate, the existential aspect presupposes the conceptual aspect of meaning. The study of the meaning of volunteering is an attempt to uncover existential meaning in everyday life. Neither the cognitive meaning nor the existential meaning of volunteering is an objective fact but fragile and dependent upon contextual factors.     

Inhibition of protein misfolding and aggregation by natural phenolic compounds

Protein misfolding and aggregation into fibrillar deposits is a common feature of a large group of degenerative diseases affecting the central nervous system or peripheral organs, termed protein misfolding disorders (PMDs). Despite their established toxic nature, clinical trials aiming to reduce misfolded aggregates have been unsuccessful in treating or curing PMDs. An interesting possibility for disease intervention is the regular intake of natural food or herbal extracts, which contain active molecules that inhibit aggregation or induce the disassembly of misfolded aggregates. Among natural compounds, phenolic molecules are of particular interest, since most have dual activity as amyloid aggregation inhibitors and antioxidants. In this article, we review many phenolic natural compounds which have been reported in diverse model systems to have the potential to delay or prevent the development of various PMDs, including Alzheimer’s and Parkinson’s diseases, prion diseases, amyotrophic lateral sclerosis, systemic amyloidosis, and type 2 diabetes. The lower toxicity of natural compounds compared to synthetic chemical molecules suggest that they could serve as a good starting point to discover protein misfolding inhibitors that might be useful for the treatment of various incurable diseases.