Subcellular discharge of a serine protease mediates release of invasive malaria parasites from host erythrocytes.

The most virulent form of malaria is caused by waves of replication of blood stages of the protozoan pathogen Plasmodium falciparum. The parasite divides within an intraerythrocytic parasitophorous vacuole until rupture of the vacuole and host-cell membranes releases merozoites that invade fresh erythrocytes to repeat the cycle. Despite the importance of merozoite egress for disease progression, none of the molecular factors involved are known. We report that, just prior to egress, an essential serine protease called PfSUB1 is discharged from previously unrecognized parasite organelles (termed exonemes) into the parasitophorous vacuole space. There, PfSUB1 mediates the proteolytic maturation of at least two essential members of another enzyme family called SERA. Pharmacological blockade of PfSUB1 inhibits egress and ablates the invasive capacity of released merozoites. Our findings reveal the presence in the malarial parasitophorous vacuole of a regulated, PfSUB1-mediated proteolytic processing event required for release of viable parasites from the host erythrocyte

Constraint Oriented Specification with CSP and Real Time Temporal Logic

A popular specification style, particularly for the initial specification of a system, is the em constraint-oriented style, where the constraints are properties required to hold of the final system. One of the difficulties of using this style is that, for any particular notation, certain types of constraints are much harder to capture than others. In this paper we propose such a specification framework, which allows the specifier a choice of two languages: Communicating Sequential Processes (CSP) and a version of Propositional Temporal Logic (PTL). The components of a specification have to be checked for mutual consistency, to do this we present a common semantic framework for both PTL and CSP

Constraint Orientated Specification with CSP and Real Time Temporal Logic

this paper we propose such a specification framework, which allows the specifier a choice of two languages: Communicating Sequential Processes (CSP) [Hoa85] and a version of Propositional Temporal Logic (PTL), derived from [Eme90]. CSP is a process-algebraic language designed for the specification and analysis of parallel systems and (our version of) PTL is a real-time temporal logic designed to capture time-dependent constraints concisely. The behaviour of a CSP process is dependent on its environment; it is therefore difficult to assert global properties. PTL can be easily used to express global timing properties of systems, but it is less suited to describing the purely behavioural aspects. We will therefore develop a framework in which a specification is a pair (P ; OE), where P is a CSP process and OE is a formula of PTL. Global and timing constraints can be described within PTL, and behavioural constraints can be described within CSP. Both components of a specification have to be checked for mutual consistency, to do this we present a common semantic framework for both PTL and CSP. Since we wish to retain all the behavioural and all the timing information in this mapping, we choose to use a real-time CSP semantic model. However, the existing real-time CSP models [Ree88, Sch92, Dav93] insist that recursive processes must be time-guarded, that is some time must elapse between any instantiation of a process and its recursive invocation. This facilitates the task of semantically defining recursive processes, but goes against the philosophy of the dual language style which we develop here. We therefore present in Section 2 a novel denotational model for CSP (which we cal

Identification and In-Vitro ADME Assessment of a Series of Novel Anti-Malarial Agents Suitable for Hit-to-Lead Chemistry

Triage of a set of antimalaria hit compounds, identified through high throughput screening against the Chloroquine sensitive (3D7) and resistant (Dd2) parasite <i>Plasmodium falciparum</i> strains identified several novel chemotypes suitable for hit-to-lead chemistry investigation. The set was further refined through investigation of their <i>in vitro</i> ADME properties, which identified templates with good potential to be developed further as antimalarial agents. One example was profiled in an <i>in vivo</i> murine <i>Plasmodium berghei</i> model of malaria infection

Synthesis and structure-activity relationships of a novel series of pyrimidines as potent inhibitors of TBK1/IKKε kinases.

The design, synthesis and structure-activity relationships of a novel series of 2,4-diamino-5-cyclopropyl pyrimidines is described. Starting from BX795, originally reported to be a potent inhibitor of PDK1, we have developed compounds with improved selectivity and drug-like properties. These compounds have been evaluated in a range of cellular and in vivo assays, enabling us to probe the putative role of the TBK1/IKKε pathway in inflammatory diseases