Killing of Trypanozoon Parasites by the Equine Cathelicidin eCATH1.

Trypanozoon parasites infect both humans, causing sleeping sickness, and animals, causing nagana, surra, and dourine. Control of nagana and surra depends to a great extent on chemotherapy. However, drug resistance to several of the front-line drugs is rising. Furthermore, there is no official treatment for dourine. Therefore, there is an urgent need to develop antiparasitic agents with novel modes of action. Host defense peptides have recently gained attention as promising candidates. We have previously reported that one such peptide, the equine antimicrobial peptide eCATH1, is highly active against equine Gram-positive and Gram-negative bacteria, without cytotoxicity against mammalian cells at bacteriolytic concentrations. In the present study, we show that eCATH1 exhibits an in vitro 50% inhibitory concentration (IC50) of 9.5 µM against Trypanosoma brucei brucei, Trypanosoma evansi, and Trypanosoma equiperdum Its trypanocidal mechanism involves plasma membrane permeabilization and mitochondrial alteration based on the following data: (i) eCATH1 induces the rapid influx of the vital dye SYTOX Green; (ii) it rapidly disrupts mitochondrial membrane potential, as revealed by immunofluorescence microscopy using the fluorescent dye rhodamine 123; (iii) it severely damages the membrane and intracellular structures of the parasites as early as 15 min after exposure at 9.5 µM and 5 min after exposure at higher concentrations (19 µM), as evidenced by scanning and transmission electron microscopy. We also demonstrate that administration of eCATH1 at a dose of 10 mg/kg to T. equiperdum-infected mice delays mortality. Taken together, our findings suggest that eCATH1 is an interesting template for the development of novel therapeutic agents in the treatment of trypanosome infections.

Oxidation of the Ediacaran ocean.

Oxygenation of the Earth's surface is increasingly thought to have occurred in two steps. The first step, which occurred approximately 2,300 million years (Myr) ago, involved a significant increase in atmospheric oxygen concentrations and oxygenation of the surface ocean. A further increase in atmospheric oxygen appears to have taken place during the late Neoproterozoic period ( approximately 800-542 Myr ago). This increase may have stimulated the evolution of macroscopic multicellular animals and the subsequent radiation of calcified invertebrates, and may have led to oxygenation of the deep ocean. However, the nature and timing of Neoproterozoic oxidation remain uncertain. Here we present high-resolution carbon isotope and sulphur isotope records from the Huqf Supergroup, Sultanate of Oman, that cover most of the Ediacaran period (approximately 635 to approximately 548 Myr ago). These records indicate that the ocean became increasingly oxygenated after the end of the Marinoan glaciation, and they allow us to identify three distinct stages of oxidation. When considered in the context of other records from this period, our data indicate that certain groups of eukaryotic organisms appeared and diversified during the second and third stages of oxygenation. The second stage corresponds with the Shuram excursion in the carbon isotope record and seems to have involved the oxidation of a large reservoir of organic carbon suspended in the deep ocean, indicating that this event may have had a key role in the evolution of eukaryotic organisms. Our data thus provide new insights into the oxygenation of the Ediacaran ocean and the stepwise restructuring of the carbon and sulphur cycles that occurred during this significant period of Earth's history.

Planetary science: bedrock formation at Meridiani Planum.

The Mars Exploration Rover Opportunity discovered sulphate-rich sedimentary rocks at Meridiani Planum on Mars, which are interpreted by McCollom and Hynek as altered volcanic rocks. However, their conclusions are derived from an incorrect representation of our depositional model, which is upheld by more recent Rover data. We contend that all the available data still support an aeolian and aqueous sedimentary origin for Meridiani bedrock.

Canyon Wall and Floor Debris Deposits in Aeolis Mons, Mars.

Aeolis Mons (informally, Mount Sharp) exhibits a number of canyons, including Gediz and Sakarya Valles. Poorly sorted debris deposits are evident on both canyon floors and connect with debris extending down the walls for canyon segments that cut through sulphate-bearing strata. On the floor of Gediz Vallis, debris overfills a central channel and merges with a massive debris ridge located at the canyon terminus. One wall-based debris ridge is evident. In comparison, the floor of Sakarya Vallis exhibits a complex array of debris deposits. Debris deposits on wall segments within Sakarya Vallis are mainly contained within chutes that extend downhill from scarps. Lateral debris ridges are also evident on chute margins. We interpret the debris deposits in the two canyons to be a consequence of one or more late-stage hydrogeomorphic events that increased the probability of landslides, assembled and channelized debris on the canyon floors, and moved materials down-canyon. The highly soluble nature of the sulphate-bearing rocks likely contributed to enhanced debris generation by concurrent aqueous weathering to produce blocky regolith for transport downslope by fluvial activity and landslides, including some landslides that became debris flows. Subsequent wind erosion in Gediz Vallis removed most of the debris deposits within that canyon and partially eroded the deposits within Sakarya Vallis. The enhanced wind erosion within Gediz Vallis was a consequence of the canyon's alignment with prevailing slope winds.

An olivine cumulate outcrop on the floor of Jezero crater, Mars.

The geological units on the floor of Jezero crater, Mars, are part of a wider regional stratigraphy of olivine-rich rocks, which extends well beyond the crater. We investigated the petrology of olivine and carbonate-bearing rocks of the Séítah formation in the floor of Jezero. Using multispectral images and x-ray fluorescence data, acquired by the Perseverance rover, we performed a petrographic analysis of the Bastide and Brac outcrops within this unit. We found that these outcrops are composed of igneous rock, moderately altered by aqueous fluid. The igneous rocks are mainly made of coarse-grained olivine, similar to some martian meteorites. We interpret them as an olivine cumulate, formed by settling and enrichment of olivine through multistage cooling of a thick magma body.

Functional expression of NOD2 in freshly isolated human peripheral blood γδ T cells.

γδ T cells play an important role in anti-infective immunity. The major subset of human γδ T cells selectively recognizes phosphorylated bacterial metabolites of the isoprenoid biosynthesis pathway, so-called phosphoantigens. The activation of γδ T cells is modulated by functionally expressed innate immune receptors, notably Toll-like receptor 2 and 3. It was also reported that in vitro expanded γδ T cells respond to muramyl dipeptide (MDP), the minimal peptidoglycan motif activating the nucleotide-binding oligomerization domain containing 2 (NOD2) receptor, although it is unknown whether ex vivo isolated human γδ T cells express functional NOD2. Here, we report that freshly isolated, highly purified peripheral blood γδ T cells express NOD2 mRNA and detectable amounts of NOD2 protein. The biologically active MDP L-D isomer but not the inactive D-D isomer augmented the interferon-γ (IFN-γ) secretion in phosphoantigen-stimulated peripheral blood mononuclear cells. Moreover, a moderate but reproducible and statistically significant increase in IFN-γ secretion was also observed when highly purified peripheral blood γδ T cells were activated by T cell receptor cross-linking in the presence of MDP. Taken together, our results indicate that in addition to the T cell receptor and Toll-like receptors, circulating human γδ T cells express NOD2 as a third class of pattern recognition receptor for sensing bacterial products.

Aeolian processes at the Mars Exploration Rover Meridiani Planum landing site.

The martian surface is a natural laboratory for testing our understanding of the physics of aeolian (wind-related) processes in an environment different from that of Earth. Martian surface markings and atmospheric opacity are time-variable, indicating that fine particles at the surface are mobilized regularly by wind. Regolith (unconsolidated surface material) at the Mars Exploration Rover Opportunity's landing site has been affected greatly by wind, which has created and reoriented bedforms, sorted grains, and eroded bedrock. Aeolian features here preserve a unique record of changing wind direction and wind strength. Here we present an in situ examination of a martian bright wind streak, which provides evidence consistent with a previously proposed formational model for such features. We also show that a widely used criterion for distinguishing between aeolian saltation- and suspension-dominated grain behaviour is different on Mars, and that estimated wind friction speeds between 2 and 3 m s(-1), most recently from the northwest, are associated with recent global dust storms, providing ground truth for climate model predictions.

The Mars 2020 Perseverance Rover Mast Camera Zoom (Mastcam-Z) Multispectral, Stereoscopic Imaging Investigation.

Mastcam-Z is a multispectral, stereoscopic imaging investigation on the Mars 2020 mission's Perseverance rover. Mastcam-Z consists of a pair of focusable, 4:1 zoomable cameras that provide broadband red/green/blue and narrowband 400-1000 nm color imaging with fields of view from 25.6° × 19.2° (26 mm focal length at 283 µrad/pixel) to 6.2° × 4.6° (110 mm focal length at 67.4 µrad/pixel). The cameras can resolve (≥ 5 pixels) ∼0.7 mm features at 2 m and ∼3.3 cm features at 100 m distance. Mastcam-Z shares significant heritage with the Mastcam instruments on the Mars Science Laboratory Curiosity rover. Each Mastcam-Z camera consists of zoom, focus, and filter wheel mechanisms and a 1648 × 1214 pixel charge-coupled device detector and electronics. The two Mastcam-Z cameras are mounted with a 24.4 cm stereo baseline and 2.3° total toe-in on a camera plate ∼2 m above the surface on the rover's Remote Sensing Mast, which provides azimuth and elevation actuation. A separate digital electronics assembly inside the rover provides power, data processing and storage, and the interface to the rover computer. Primary and secondary Mastcam-Z calibration targets mounted on the rover top deck enable tactical reflectance calibration. Mastcam-Z multispectral, stereo, and panoramic images will be used to provide detailed morphology, topography, and geologic context along the rover's traverse; constrain mineralogic, photometric, and physical properties of surface materials; monitor and characterize atmospheric and astronomical phenomena; and document the rover's sample extraction and caching locations. Mastcam-Z images will also provide key engineering information to support sample selection and other rover driving and tool/instrument operations decisions.

Brine-driven destruction of clay minerals in Gale crater, Mars.

Mars' sedimentary rock record preserves information on geological (and potential astrobiological) processes that occurred on the planet billions of years ago. The Curiosity rover is exploring the lower reaches of Mount Sharp, in Gale crater on Mars. A traverse from Vera Rubin ridge to Glen Torridon has allowed Curiosity to examine a lateral transect of rock strata laid down in a martian lake ~3.5 billion years ago. We report spatial differences in the mineralogy of time-equivalent sedimentary rocks <400 meters apart. These differences indicate localized infiltration of silica-poor brines, generated during deposition of overlying magnesium sulfate-bearing strata. We propose that destabilization of silicate minerals driven by silica-poor brines (rarely observed on Earth) was widespread on ancient Mars, because sulfate deposits are globally distributed.

Perseverance rover reveals an ancient delta-lake system and flood deposits at Jezero crater, Mars.

Observations from orbital spacecraft have shown that Jezero crater on Mars contains a prominent fan-shaped body of sedimentary rock deposited at its western margin. The Perseverance rover landed in Jezero crater in February 2021. We analyze images taken by the rover in the 3 months after landing. The fan has outcrop faces, which were invisible from orbit, that record the hydrological evolution of Jezero crater. We interpret the presence of inclined strata in these outcrops as evidence of deltas that advanced into a lake. In contrast, the uppermost fan strata are composed of boulder conglomerates, which imply deposition by episodic high-energy floods. This sedimentary succession indicates a transition from sustained hydrologic activity in a persistent lake environment to highly energetic short-duration fluvial flows.

Allergen IgE-isotype-specific suppression by maternally derived monoclonal anti-IgG-idiotype.

BACKGROUND: The dramatic increase of IgE-mediated allergic diseases in western countries demonstrates the urgent need for new therapeutic or prophylactic approaches. In mice, a prophylactic long-lasting allergen-specific suppression of IgE responsiveness is induced by maternal IgG antibodies to allergens like ovalbumin, phospholipase A(2) (bvPLA(2)) or ovomucoid. As neonatal application or maternally derived pathogen-reactive antibodies (idiotypes) as well as corresponding anti-idiotypes can induce anti-microbial protection, we probed the transgenerational IgE-suppressive mechanism with a syngeneic monoclonal anti-idiotypic antibody. METHODS: The monoclonal bee-venom-phospholipase A(2) (bvPLA(2))-reactive IgG antibody MS613 (idiotype) or the corresponding syngeneic anti-idiotype II/2-19 were injected during the first 2 days postpartum to the dams. Immunization of offspring with minute doses of IgE-inducing bvPLA(2) was started at an adult age of 3(1/2) months. RESULTS: The postnatal transfer of the anti-bvPLA(2) idiotype MS613 or the corresponding anti-idiotype II/2-19 induced long-lasting allergen-specific IgE suppression in a dose-dependent manner, while the IgG response to the allergen developed normally. Quantitatively, the anti-idiotype was more effective than idiotype. Molecular modeling of the idiotype-anti-idiotype complex and its comparison with the bvPLA(2) structure revealed that the anti-idiotype does not mimic bvPLA(2) epitopes and thus can not be regarded as an internal image antibody and, consequently, does not function as a surrogate antigen. CONCLUSIONS: Idiotypic network reactivity is at least one major factor for induction of transgenerational IgE suppression by maternal IgG antibodies. If applicable to humans, these data suggest the possibility of a prophylactic and possibly therapeutic treatment of IgE-mediated allergic diseases with anti-idiotypic antibodies.

Evidence for Multiple Diagenetic Episodes in Ancient Fluvial-Lacustrine Sedimentary Rocks in Gale Crater, Mars.

The Curiosity rover's exploration of rocks and soils in Gale crater has provided diverse geochemical and mineralogical data sets, underscoring the complex geological history of the region. We report the crystalline, clay mineral, and amorphous phase distributions of four Gale crater rocks from an 80-m stratigraphic interval. The mineralogy of the four samples is strongly influenced by aqueous alteration processes, including variations in water chemistries, redox, pH, and temperature. Localized hydrothermal events are evidenced by gray hematite and maturation of amorphous SiO2 to opal-CT. Low-temperature diagenetic events are associated with fluctuating lake levels, evaporative events, and groundwater infiltration. Among all mudstones analyzed in Gale crater, the diversity in diagenetic processes is primarily captured by the mineralogy and X-ray amorphous chemistry of the drilled rocks. Variations indicate a transition from magnetite to hematite and an increase in matrix-associated sulfates suggesting intensifying influence from oxic, diagenetic fluids upsection. Furthermore, diagenetic fluid pathways are shown to be strongly affected by unconformities and sedimentary transitions, as evidenced by the intensity of alteration inferred from the mineralogy of sediments sampled adjacent to stratigraphic contacts.

Evidence for a Diagenetic Origin of Vera Rubin Ridge, Gale Crater, Mars: Summary and Synthesis of Curiosity's Exploration Campaign.

This paper provides an overview of the Curiosity rover's exploration at Vera Rubin ridge (VRR) and summarizes the science results. VRR is a distinct geomorphic feature on lower Aeolis Mons (informally known as Mount Sharp) that was identified in orbital data based on its distinct texture, topographic expression, and association with a hematite spectral signature. Curiosity conducted extensive remote sensing observations, acquired data on dozens of contact science targets, and drilled three outcrop samples from the ridge, as well as one outcrop sample immediately below the ridge. Our observations indicate that strata composing VRR were deposited in a predominantly lacustrine setting and are part of the Murray formation. The rocks within the ridge are chemically in family with underlying Murray formation strata. Red hematite is dispersed throughout much of the VRR bedrock, and this is the source of the orbital spectral detection. Gray hematite is also present in isolated, gray-colored patches concentrated toward the upper elevations of VRR, and these gray patches also contain small, dark Fe-rich nodules. We propose that VRR formed when diagenetic event(s) preferentially hardened rocks, which were subsequently eroded into a ridge by wind. Diagenesis also led to enhanced crystallization and/or cementation that deepened the ferric-related spectral absorptions on the ridge, which helped make them readily distinguishable from orbit. Results add to existing evidence of protracted aqueous environments at Gale crater and give new insight into how diagenesis shaped Mars' rock record.

Comparative Earth history and Late Permian mass extinction.

The repeated association during the late Neoproterozoic Era of large carbon-isotopic excursions, continental glaciation, and stratigraphically anomalous carbonate precipitation provides a framework for interpreting the reprise of these conditions on the Late Permian Earth. A paleoceanographic model that was developed to explain these stratigraphically linked phenomena suggests that the overturn of anoxic deep oceans during the Late Permian introduced high concentrations of carbon dioxide into surficial environments. The predicted physiological and climatic consequences for marine and terrestrial organisms are in good accord with the observed timing and selectivity of Late Permian mass extinction.

Calibrating rates of early Cambrian evolution.

An explosive episode of biological diversification occurred near the beginning of the Cambrian period. Evolutionary rates in the Cambrian have been difficult to quantify accurately because of a lack of high-precision ages. Currently, uranium-lead zircon geochronology is the most powerful method for dating rocks of Cambrian age. Uranium-lead zircon data from lower Cambrian rocks located in northeast Siberia indicate that the Cambrian period began at approximately 544 million years ago and that its oldest (Manykaian) stage lasted no less than 10 million years. Other data indicate that the Tommotian and Atdabanian stages together lasted only 5 to 10 million years. The resulting compression of Early Cambrian time accentuates the rapidity of both the faunal diversification and subsequent Cambrian turnover.

A Field Guide to Finding Fossils on Mars.

The Martian surface is cold, dry, exposed to biologically harmful radiation and apparently barren today. Nevertheless, there is clear geological evidence for warmer, wetter intervals in the past that could have supported life at or near the surface. This evidence has motivated National Aeronautics and Space Administration and European Space Agency to prioritize the search for any remains or traces of organisms from early Mars in forthcoming missions. Informed by (1) stratigraphic, mineralogical and geochemical data collected by previous and current missions, (2) Earth's fossil record, and (3) experimental studies of organic decay and preservation, we here consider whether, how, and where fossils and isotopic biosignatures could have been preserved in the depositional environments and mineralizing media thought to have been present in habitable settings on early Mars. We conclude that Noachian-Hesperian Fe-bearing clay-rich fluvio-lacustrine siliciclastic deposits, especially where enriched in silica, currently represent the most promising and best understood astropaleontological targets. Siliceous sinters would also be an excellent target, but their presence on Mars awaits confirmation. More work is needed to improve our understanding of fossil preservation in the context of other environments specific to Mars, particularly within evaporative salts and pore/fracture-filling subsurface minerals.

MMP-9-hemopexin domain hampers adhesion and migration of colorectal cancer cells.

Matrix metalloproteinases (MMPs), in particular MMP-2 and MMP-9, are involved in colon cancer progression and metastasis due to their ability to degrade extracellular matrix (ECM) components. In previous studies we described the MMP-9 hemopexin like domain (MMP-9-PEX) as an MMP-9 antagonist. In the present study it was examined whether recombinant MMP-9-PEX has an inhibitory effect on migration and adhesion of colorectal carcinoma cells. Furthermore, we searched for MMP-9 substrate binding sites within the MMP-9-PEX by surface plasmon resonance. Migration of SW620 and LS174 cells was investigated in a modified Boyden chamber assay. In the presence of 0.2 microg/ml MMP-9-PEX migration of SW620 was decreased by 34%, while addition of 0.4 microg/ml diminished migration by 56%. Migration of LS174 cells was not affected by MMP-9-PEX. Adhesion studies were performed on 96-well plates coated with gelatin, collagen type I, and laminin, respectively. In the presence of MMP-9-PEX, adhesion of SW620 cells to these coating substrates was significantly inhibited. Surface plasmon resonance studies revealed binding of collagen type I and IV, elastin, and fibrinogen to proMMP-9 as well as to MMP-9-PEX. However, equilibrium constants (Kd) indicated a higher affinity of proMMP-9 to the matrix proteins. This could indicate that there is more than one binding site for matrix components within the entire proMMP-9 molecule. Since migration and adhesion of metastatic colorectal carcinoma cells were reduced by MMP-9-PEX, this recombinant MMP-9 antagonist might be of therapeutical interest.

I. A bioactive designer cytokine for human hematopoietic progenitor cell expansion.

Efficient expansion of hematopoietic progenitor cells requires, at least, the simultaneous stimulation of the receptors c-kit and gp130. While c-kit is activated by SCF; gp130, in cells which do not express sufficient amounts of IL-6R, can be activated by the complex of soluble IL-6R (sIL-6R) and IL-6. The therapeutic use of IL-6/sIL-6R, however, has been hampered by the high concentrations of the sIL-6R protein required. We have designed a fusion protein of sIL-6R and IL-6, linked by a flexible peptide chain, that was expressed to high levels. On gp130 expressing cells the fusion protein turned out to be fully active at 100 to 1,000-fold lower concentration than the combination of unlinked IL-6 and IL-6R. The fusion protein was used to effectively expand human hematopoietic progenitor cells ex vivo in a dose dependent fashion.

Paleoecology and paleoceanography of the Athel silicilyte, Ediacaran-Cambrian boundary, Sultanate of Oman.

The Athel silicilyte is an enigmatic, hundreds of meters thick, finely laminated quartz deposit, in which silica precipitated in deep water (>~100-200 m) at the Ediacaran-Cambrian boundary in the South Oman Salt Basin. In contrast, Meso-Neoproterozoic sinks for marine silica were dominantly restricted to peritidal settings. The silicilyte is known to contain sterane biomarkers for demosponges, which today are benthic, obligately aerobic organisms. However, the basin has previously been described as permanently sulfidic and time-equivalent shallow-water carbonate platform and evaporitic facies lack silica. The Athel silicilyte thus represents a unique and poorly understood depositional system with implications for late Ediacaran marine chemistry and paleoecology. To address these issues, we made petrographic observations, analyzed biomarkers in the solvent-extractable bitumen, and measured whole-rock iron speciation and oxygen and silicon isotopes. These data indicate that the silicilyte is a distinct rock type both in its sedimentology and geochemistry and in the original biology present as compared to other facies from the same time period in Oman. The depositional environment of the silicilyte, as compared to the bounding shales, appears to have been more reducing at depth in sediments and possibly bottom waters with a significantly different biological community contributing to the preserved biomarkers. We propose a conceptual model for this system in which deeper, nutrient-rich waters mixed with surface seawater via episodic mixing, which stimulated primary production. The silica nucleated on this organic matter and then sank to the seafloor, forming the silicilyte in a sediment-starved system. We propose that the silicilyte may represent a type of environment that existed elsewhere during the Neoproterozoic. These environments may have represented an important locus for silica removal from the oceans.

Redox stratification of an ancient lake in Gale crater, Mars.

In 2012, NASA's Curiosity rover landed on Mars to assess its potential as a habitat for past life and investigate the paleoclimate record preserved by sedimentary rocks inside the ~150-kilometer-diameter Gale impact crater. Geological reconstructions from Curiosity rover data have revealed an ancient, habitable lake environment fed by rivers draining into the crater. We synthesize geochemical and mineralogical data from lake-bed mudstones collected during the first 1300 martian solar days of rover operations in Gale. We present evidence for lake redox stratification, established by depth-dependent variations in atmospheric oxidant and dissolved-solute concentrations. Paleoclimate proxy data indicate that a transition from colder to warmer climate conditions is preserved in the stratigraphy. Finally, a late phase of geochemical modification by saline fluids is recognized.