Falstatin, a Cysteine Protease Inhibitor of Plasmodium falciparum, Facilitates Erythrocyte Invasion

Erythrocytic malaria parasites utilize proteases for a number of cellular processes, including hydrolysis of hemoglobin, rupture of erythrocytes by mature schizonts, and subsequent invasion of erythrocytes by free merozoites. However, mechanisms used by malaria parasites to control protease activity have not been established. We report here the identification of an endogenous cysteine protease inhibitor of Plasmodium falciparum, falstatin, based on modest homology with the Trypanosoma cruzi cysteine protease inhibitor chagasin. Falstatin, expressed in Escherichia coli, was a potent reversible inhibitor of the P. falciparum cysteine proteases falcipain-2 and falcipain-3, as well as other parasite- and nonparasite-derived cysteine proteases, but it was a relatively weak inhibitor of the P. falciparum cysteine proteases falcipain-1 and dipeptidyl aminopeptidase 1. Falstatin is present in schizonts, merozoites, and rings, but not in trophozoites, the stage at which the cysteine protease activity of P. falciparum is maximal. Falstatin localizes to the periphery of rings and early schizonts, is diffusely expressed in late schizonts and merozoites, and is released upon the rupture of mature schizonts. Treatment of late schizionts with antibodies that blocked the inhibitory activity of falstatin against native and recombinant falcipain-2 and falcipain-3 dose-dependently decreased the subsequent invasion of erythrocytes by merozoites. These results suggest that P. falciparum requires expression of falstatin to limit proteolysis by certain host or parasite cysteine proteases during erythrocyte invasion. This mechanism of regulation of proteolysis suggests new strategies for the development of antimalarial agents that specifically disrupt erythrocyte invasion

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

(Table 3) Geochemistry at DSDP Leg 79 Holes

Detailed mineralogical and geochemical studies were performed on samples from selected time intervals recovered during Leg 79 on the Mazagan Plateau. The uppermost Albian and Cenomanian sediments of Sites 545 and 547 can be correlated on the basis of mineralogy and geochemistry; these sediments illustrate differential settling processes and the existence of hot climates with alternating humid and dry seasons in the African coastal zone. The upper Aptian to Albian black shales of Site 545 point to an irregular alternation of tectonic activity and relaxation stages, allowing different behaviors in the reworking of soils, crystalline rocks, and sediments born in peri-marine basins. The barren lower Mesozoic reddish sediments and evaporitic series of Sites 546 and 547 are characterized by a strong physical erosion of sialic landscapes, without clear evidence of post-depositional metamorphic events. At Site 546 strong early diagenetic processes in a confined evaporitic environment affect both the mineralogy and the geochemistry of pre-Miocene rocks

Environnement du fossé hellénique d'après la minéralogie et la géochimie des dépôts superficiels (mission Cyanheat 1979)

Surficial deposits sampled in the Hellenic Trench by the diving saucer Cyana are studied from a mineralogical and geochemical point of view. The clayed-calcareous muds are very recent and express the detrital sources. The cemented deposits, chiefly post-Pliocene in age, correspond to the precipitation of middle-magnesian calcite on the sediment water oxidized interface. Locally occurs a precipitation of aragonite or dolomite, in a reduced or confined environment. Thin polymetallic deposits cover the lithified sediments in some areas characterized by temporarily very low rates of sedimentation.Les dépôts superficiels et indurés, recueillis au cours de plongées en submersible dans les Fosses Helléniques, sont étudiés d'un point de vue minéralogique et géochimique. Les vases calcaréo-argileuses sont sub-actuelles et reflètent les sources d'alluvionnement. Les sédiments indurés sont d'âges plus variés, essentiellement post-pliocènes. La cimentation est principalement déterminée par la précipitation de calcite moyennement magnésienne, en milieu oxydant et de faible dépôt ; localement des milieux réducteurs ou confinés déterminent la précipitation d'aragonite ou de dolomite. Des. enduits polymétalliques secondaires caractérisent les croûtes carbonatées demeurées le plus longtemps à l'interface.Debrabant Pierre, Chamley Hervé. Environnement du fossé hellénique d'après la minéralogie et la géochimie des dépôts superficiels (mission Cyanheat 1979). In: Géologie Méditerranéenne. Tome 9, numéro 1, 1982. pp. 11-21

(Appendix) Bulk inorganic chemistry at DSDP Leg 77 Holes

Clay mineralogic and inorganic geochemical investigations of Cretaceous and Cenozoic sediments of the western Gulf of Mexico lead to the following main conclusions. (1) Transition of lowermost Cretaceous continental to marine sedimentation is marked by a clay evaporitic stage, north of the Campeche Escarpment. (2) Existence of combined mineralogic and geochemical stratigraphy allows us to propose correlations between Sites 535 and 540, especially for the Albian. (3) Predominance of detrital clay assemblages is indicative of hot and variably humid continental climate until the early late Cenozoic. (4) Tectonic destabilization of the margins of Gulf of Mexico occurred at different periods, especially until the middle Cretaceous, with a mixed erosion of rocks and soils and temporary oxidized conditions of deposition. (5) Successive developments of confined perimarine basins occurred from the earliest Cretaceous until the Miocene, chiefly in the Florida area. The sources of inorganic materials were chiefly situated on the east of the studied area until the late Tertiary and after that in the Mississippi River basin. (6) Occasionally, volcanic activity influenced the clay mineralogy and mainly the geochemistry, and possibly contributed to the rather strong magnesian character of the deposition until the late Paleogene. (7) The argillaceous diagenesis is weak; variability of the carbonate diagenesis is marked by the relation Sr = f(CaO) and chiefly depends on the depth of burial, the clay content, the porosity, and the geologic age

Multiple seawater-derived geochemical signatures in Indian oceanic pelagic clays

This paper reports a geochemical study of oceanic clays. Major and trace elements were analyzed on smectite-rich, clay size (<2 mu m) samples, bulk sediments, and leachate residues from the Central Indian Basin. Sr-Nd isotopes were also studied to investigate their geochemical evolution during transport in the water column, sedimentation, and diagenesis. The region is of special interest because the sedimentation records the interaction between the detrital supply from the Bengal Fan in the north and the biosiliceous input associated with the equatorial divergence in the south. The clay size fractions display extremely variable trace element contents, e.g., [Ba] = 100-5000 ppm, [Sr] = 20-200 ppm, Ce/Ce* = 0.9-3.3, [Nd] = 10-50 ppm. Although in the argillaceous samples, clay size fractions have a similar trace element imprint to the bulk sediment, some major fractionations occur in the biosiliceous samples between the clay and the bulk sediment, especially for Sr and rare earth elements (REE). Three major components may account for the variable geochemical signatures of these pelagic clays. The first component (component A), already identified by Fagel et al. (1994), is characterized by a homogeneous geochemical signature (La-N/Yb-N = 1.03-1.05; Th/Ta = 12.8-21.1; Ba/Th similar to 28) and a nonradiogenic Nd isotopic composition (Nd-143/Nd-144 similar to 0.511880): it traces a detrital Himalayan-derived origin. The two other components display a seawater-derived isotopic composition with global Sr (Sr-87/Sr-86 similar to 0.709060) and regional Indian Ocean Nd(Nd-143/Nd-144 similar to 0.512200) signatures. Both components are enriched in Sr and Ba (Sr similar to 150 ppm, Ba/Th similar to 500), and they are either enriched in light rare earth elements (LREE, e.g., Nd similar to 50 ppm) in the argillaceous sediments (component B) or LREE-depleted (Nd < 20 ppm) in the biosiliceous sediments (component C). The frequent occurrence of micrometric (<5 mu m) Sr-REE-Th enriched barite grains showing three major habits (rhombic, rounded, dendritic) suggests that these biologically-derived mineral phases had a major role in the genesis of components B and C. A strong clay-barite equilibration is deduced from the Post Archean Australian Shales PAAS-like REE patterns of these barites and the Ba enrichment of the clays. We suggest that it results from two successive mechanisms of exchange. First, at the top of the oxygen minimum zone, the microbial-induced decay of organic matter is proposed to trigger a series of trace element transfers between the various particulate-forming components (clays, barites, and decaying organic coatings). This is proposed as the origin of the clay component B: the barite-derived components (Ba, Sr) and the organic-derived positive Ce anomaly are imported to the clay particles while the PAAS signature of the clays is retained by the remaining barite crystals. Second, after settling, the barites are believed to partly dissolve and recrystallize, especially in the anoxic part of the sedimentary column. This diagenetic barite dissolution is proposed as the origin of the clay component C. Copyright (C) 1997 Elsevier Science Ltd