Plasmodium falciparum metacaspase PfMCA-1 triggers a z-VAD-fmk inhibitable protease to promote cell death.

Activation of proteolytic cell death pathways may circumvent drug resistance in deadly protozoan parasites such as Plasmodium falciparum and Leishmania. To this end, it is important to define the cell death pathway(s) in parasites and thus characterize proteases such as metacaspases (MCA), which have been reported to induce cell death in plants and Leishmania parasites. We, therefore, investigated whether the cell death function of MCA is conserved in different protozoan parasite species such as Plasmodium falciparum and Leishmania major, focusing on the substrate specificity and functional role in cell survival as compared to Saccharomyces cerevisae. Our results show that, similarly to Leishmania, Plasmodium MCA exhibits a calcium-dependent, arginine-specific protease activity and its expression in yeast induced growth inhibition as well as an 82% increase in cell death under oxidative stress, a situation encountered by parasites during the host or when exposed to drugs such as artemisins. Furthermore, we show that MCA cell death pathways in both Plasmodium and Leishmania, involve a z-VAD-fmk inhibitable protease. Our data provide evidence that MCA from both Leishmania and Plasmodium falciparum is able to induce cell death in stress conditions, where it specifically activates a downstream enzyme as part of a cell death pathway. This enzymatic activity is also induced by the antimalarial drug chloroquine in erythrocytic stages of Plasmodium falciparum. Interestingly, we found that blocking parasite cell death influences their drug sensitivity, a result which could be used to create therapeutic strategies that by-pass drug resistance mechanisms by acting directly on the innate pathways of protozoan cell death

Tuberculosis lymphadenitis in a south-eastern region in Tunisia: Epidemiology, clinical features, diagnosis and treatment

Aim: To evaluate patients’ profiles, demographics, clinical and therapeutic approaches and strategies in patients with tuberculous lymphadenitis (TBG). Patients and methods: A retrospective study of all TBG-confirmed cases admitted in a tuberculosis specific health care facility between 1 January 2009 and 16 June 2013. Results: A total of 181 clinical files were examined. Mean age was 32 years old; the female/male ratio was 1.78 to 1. Raw milk consumption was noted in 1/3 of patients. Most cases involved the head and neck region (83.4%), nodes involvement, including axillary (12 cases), and mediastinal (9 cases). Clinical symptoms were present in only 55.2%. TST was conducted with 82.6% positive responses. Diagnostics confirmation was done with anatomical pathology in most of the patients; only 56 of them had any microbiology analysis done. Demonstration of acid-fast bacilli in microscopy from either fine-needle aspirates or biopsies was done in 17.5%, and cultures yielded positive results in 27%. Treatment duration was varied. Paradoxical reactions were noted in 12% and persistent lymphadenopathy after treatment completion was noted in 10% of cases. Conclusions: TBG remains a disease of interest. Today, its diagnosis and management is still a problem despite its increasing worldwide incidence, and especially in this study area. Disease control should be strengthened in this country

From Good Intentions to Behaviour Change: Probabilistic Feature Diagrams for Behaviour Support Agents

Behaviour support technology assists people in organising their daily activities and changing their behaviour. A fundamental notion underlying such supportive technology is that of compliance with behavioural norms: do people indeed perform the desired behaviour? Existing technology employs a rigid implementation of compliance: a norm is either satisfied or not. In practice however, behaviour change norms are less strict: E.g., is a new norm to do sports at least three times a week complied with if it is occasionally only done twice a week? To address this, in this paper we formally specify probabilistic norms through a variant of feature diagrams, enabling a hierarchical decomposition of the desired behaviour and its execution frequencies. Further, we define a new notion of probabilistic norm compliance using a formal hypothesis testing framework. We show that probabilistic norm compliance can be used in a real-world setting by implementing and evaluating our semantics with respect to an existing daily behaviour dataset

Semantic Heterogeneity in the Formal Development of Complex Systems: An Introduction

International audienceSystem engineering is a complex discipline[1], which is becoming more and more complicated by the heterogeneity of the subsystem components[2] and of the models involved in their design. This complexity can be managed only through the use of formal methods[3]. However, in general the engineering of software in such systems leads to a need for a mix of modelling languages and semantics; and this often leads to unexpected and undesirable interactions between components at all levels of abstraction[4]. There are currently no generally applicable tools for dealing with this heterogeneity of interactions in the engineering of complex systems