Urochordate Histoincompatible Interactions Activate Vertebrate-Like Coagulation System Components

The colonial ascidian Botryllus schlosseri expresses a unique allorecognition system. When two histoincompatible Botryllus colonies come into direct contact, they develop an inflammatory-like rejection response. A surprising high number of vertebrates' coagulation genes and coagulation-related domains were disclosed in a cDNA library of differentially expressed sequence tags (ESTs), prepared for this allorejection process. Serine proteases, especially from the trypsin family, were highly represented among Botryllus library ortholgues and its “molecular function” gene ontology analysis. These, together with the built-up clot-like lesions in the interaction area, led us to further test whether a vertebrate-like clotting system participates in Botryllus innate immunity. Three morphologically distinct clot types (points of rejection; POR) were followed. We demonstrated the specific expression of nine coagulation orthologue transcripts in Botryllus rejection processes and effects of the anti-coagulant heparin on POR formation and heartbeats. In situ hybridization of fibrinogen and von Willebrand factor orthologues elucidated enhanced expression patterns specific to histoincompatible reactions as well as common expressions not augmented by innate immunity. Immunohistochemistry for fibrinogen revealed, in naïve and immune challenged colonies alike, specific antibody binding to a small population of Botryllus compartment cells. Altogether, molecular, physiological and morphological outcomes suggest the involvement of vertebrates-like coagulation elements in urochordate immunity, not assigned with vasculature injury

Identification of GSK3186899/DDD853651 as a Preclinical Development Candidate for the Treatment of Visceral Leishmaniasis

The leishmaniases are diseases that affect millions of people across the world, in particular visceral leishmaniasis (VL) which is fatal unless treated. Current standard of care for VL suffers from multiple issues and there is a limited pipeline of new candidate drugs. As such, there is a clear unmet medical need to identify new treatments. This paper describes the optimization of a phenotypic hit against Leishmania donovani, the major causative organism of VL. The key challenges were to balance solubility and metabolic stability while maintaining potency. Herein, strategies to address these shortcomings and enhance efficacy are discussed, culminating in the discovery of preclinical development candidate GSK3186899/DDD853651 (<b>1</b>) for VL

Constraining sediment provenance for tsunami deposits using distributions of grain size and foraminifera from the Kujukuri coastline and shelf, Japan

Tsunami deposits preserved in the geological record provide a more comprehensive understanding of their patterns of frequency and intensity over longer timescales; but recognizing tsunami deposits can prove challenging due to post-depositional changes, lack of contrast between the deposits and surrounding sedimentary layers, and differentiating between tsunami and storm deposition. Modern baseline studies address these challenges by providing insight into modern spatial distributions that can be compared with palaeotsunami deposits. This study documents the spatial fingerprint of grain size and foraminifera from Hasunuma Beach and the Kujukuri shelf to provide a basis from which tsunami deposits can be interpreted. At Hasunuma Beach, approximately 50 km east of Tokyo, the spatial distribution of three common proxies (foraminiferal taxonomy, foraminiferal taphonomy and sediment grain size) for tsunami identification were mapped and clustered using Partitioning Around Medoids cluster analysis. Partitioning Around Medoids cluster analysis objectively discriminated two coastal zones corresponding to onshore and offshore sample locations. Results show that onshore samples are characterized by coarser grain sizes (medium to coarse sand) and higher abundances of Pararotalia nipponica (27 to 63%) than offshore samples, which are characterized by finer grain sizes (fine to medium sand), lower abundances of Pararotalia nipponica (2 to 19%) and Ammonia parkinsoniana (0 to 10%), higher abundances of planktonics (15 to 58%) and species with fragile tests including Uvigerinella glabra. When compared to grain-size and foraminiferal taxonomy, foraminiferal taphonomy; i.e. surface condition of foraminifera, a proxy not commonly used to identify tsunami deposits, was most effective in discriminating modern coastal zones (identified supratidal, intertidal and offshore environments) and determining sediment provenance for tsunami deposits at Kujukuri. This modern baseline study assists the interpretation of tsunami deposits in the geological record because it provides a basis for sediment provenance to be determined.NRF (Natl Research Foundation, S’pore)MOE (Min. of Education, S’pore)Published versio