Evidence for plunging river plume deposits in the Pahrump Hills member of the Murray formation, Gale crater, Mars

Recent robotic missions to Mars have offered new insights into the extent, diversity and habitability of the Martian sedimentary rock record. Since the Curiosity rover landed in Gale crater in August 2012, the Mars Science Laboratory Science Team has explored the origins and habitability of ancient fluvial, deltaic, lacustrine and aeolian deposits preserved within the crater. This study describes the sedimentology of a ca 13 m thick succession named the Pahrump Hills member of the Murray formation, the first thick fine‐grained deposit discovered in situ on Mars. This work evaluates the depositional processes responsible for its formation and reconstructs its palaeoenvironmental setting. The Pahrump Hills succession can be sub‐divided into four distinct sedimentary facies: (i) thinly laminated mudstone; (ii) low‐angle cross‐stratified mudstone; (iii) cross‐stratified sandstone; and (iv) thickly laminated mudstone–sandstone. The very fine grain size of the mudstone facies and abundant millimetre‐scale and sub‐millimetre‐scale laminations exhibiting quasi‐uniform thickness throughout the Pahrump Hills succession are most consistent with lacustrine deposition. Low‐angle geometric discordances in the mudstone facies are interpreted as ‘scour and drape’ structures and suggest the action of currents, such as those associated with hyperpycnal river‐generated plumes plunging into a lake. Observation of an overall upward coarsening in grain size and thickening of laminae throughout the Pahrump Hills succession is consistent with deposition from basinward progradation of a fluvial‐deltaic system derived from the northern crater rim into the Gale crater lake. Palaeohydraulic modelling constrains the salinity of the ancient lake in Gale crater: assuming river sediment concentrations typical of floods on Earth, plunging river plumes and sedimentary structures like those observed at Pahrump Hills would have required lake densities near freshwater to form. The depositional model for the Pahrump Hills member presented here implies the presence of an ancient sustained, habitable freshwater lake in Gale crater for at least ca 10^3 to 10^7 Earth years

Evidence for plunging river plume deposits in the Pahrump Hills member of the Murray formation, Gale crater, Mars

Recent robotic missions to Mars have offered new insights into the extent, diversity and habitability of the Martian sedimentary rock record. Since the Curiosity rover landed in Gale crater in August 2012, the Mars Science Laboratory Science Team has explored the origins and habitability of ancient fluvial, deltaic, lacustrine and aeolian deposits preserved within the crater. This study describes the sedimentology of a ca 13 m thick succession named the Pahrump Hills member of the Murray formation, the first thick fine‐grained deposit discovered in situ on Mars. This work evaluates the depositional processes responsible for its formation and reconstructs its palaeoenvironmental setting. The Pahrump Hills succession can be sub‐divided into four distinct sedimentary facies: (i) thinly laminated mudstone; (ii) low‐angle cross‐stratified mudstone; (iii) cross‐stratified sandstone; and (iv) thickly laminated mudstone–sandstone. The very fine grain size of the mudstone facies and abundant millimetre‐scale and sub‐millimetre‐scale laminations exhibiting quasi‐uniform thickness throughout the Pahrump Hills succession are most consistent with lacustrine deposition. Low‐angle geometric discordances in the mudstone facies are interpreted as ‘scour and drape’ structures and suggest the action of currents, such as those associated with hyperpycnal river‐generated plumes plunging into a lake. Observation of an overall upward coarsening in grain size and thickening of laminae throughout the Pahrump Hills succession is consistent with deposition from basinward progradation of a fluvial‐deltaic system derived from the northern crater rim into the Gale crater lake. Palaeohydraulic modelling constrains the salinity of the ancient lake in Gale crater: assuming river sediment concentrations typical of floods on Earth, plunging river plumes and sedimentary structures like those observed at Pahrump Hills would have required lake densities near freshwater to form. The depositional model for the Pahrump Hills member presented here implies the presence of an ancient sustained, habitable freshwater lake in Gale crater for at least ca 10^3 to 10^7 Earth years

Preventive antibiotic therapy in acute stroke patients: A systematic review and meta-analysis of individual patient data of randomized controlled trials

INTRODUCTION: Infection after stroke is associated with unfavorable outcome. Randomized controlled studies did not show benefit of preventive antibiotics in stroke but lacked power for subgroup analyses. Aim of this study is to assess whether preventive antibiotic therapy after stroke improves functional outcome for specific patient groups in an individual patient data meta-analysis. PATIENTS AND METHODS: We searched MEDLINE (1946–7 May 2021), Embase (1947–7 May 2021), CENTRAL (17th September 2021), trial registries, cross-checked references and contacted researchers for randomized controlled trials of preventive antibiotic therapy versus placebo or standard care in ischemic or hemorrhagic stroke patients. Meta-analysis was performed by a one-step and two-step approach. Primary outcome was functional outcome adjusted for age and stroke severity. Secondary outcomes were infections and mortality. RESULTS: 4197 patients from nine trials were included. Preventive antibiotic therapy was not associated with a shift in functional outcome (mRS) at 3 months (OR1.13, 95%CI 0.98–1.31) or unfavorable functional outcome (mRS 3–6) (OR0.85, 95%CI 0.60–1.19). Preventive antibiotics did not improve functional outcome in pre-defined subgroups (age, stroke severity, timing and type of antibiotic therapy, pneumonia prediction scores, dysphagia, type of stroke, and type of trial). Preventive antibiotics reduced infections (276/2066 (13.4%) in the preventive antibiotic group vs. 417/2059 (20.3%) in the control group, OR 0.60, 95% CI 0.51–0.71, p < 0.001), but not pneumonia (191/2066 (9.2%) in the preventive antibiotic group vs. 205/2061 (9.9%) in the control group (OR 0.92 (0.75–1.14), p = 0.450). DISCUSSION AND CONCLUSION: Preventive antibiotic therapy did not benefit any subgroup of patients with acute stroke and currently cannot be recommended

Distribution of primary and secondary features in the Pahrump Hills outcrop (Gale crater, Mars) as seen in a Mars Descent Imager (MARDI) "sidewalk" mosaic

The Mars Science Laboratory Curiosity rover conducted a reconnaissance traverse across the Pahrump Hills outcrop within Gale crater from Sols 780–797. During the traverse, the Mars Descent Imager (MARDI) acquired a continuous imaging record of primary and secondary sedimentary features throughout the outcrop. The characteristics of the features (laminae, resistant features, fractures, gray clasts) and their spatial distribution provide insight into the processes that contributed to the formation of Pahrump Hills. Thin, regular laminae (mm-scale) are ubiquitous in the bedrock, implying that depositional processes at that scale did not change appreciably during deposition of the mudstone succession at Pahrump Hills. Higher bedrock slopes correlate with undulatory bedrock surfaces, bedrock with elevated Mg contents, and fractures exhibiting wide, raised edges. These collective features are consistent with increased erosional resistance caused by greater quantities of erosionally-resistant, Mg-bearing cement within the bedrock permitted by coarser grain sizes. Resistant features exhibit a range of morphologies, elevated Mg contents, and do not deflect laminae within the bedrock. Their characteristics implicate the involvement of Mg-enriched fluids in a late diagenetic overprint affecting the bedrock. The variations of fracture fill and edge morphologies and chemistries further suggest repeated fracturing and fluid interaction events within the strata exposed at Pahrump Hills. Gray clasts strongly resemble fragments eroded from sandstone horizons interspersed throughout the Pahrump Hills outcrop

Native Aortic Valve Disease Progression and Bioprosthetic Valve Degeneration in Patients With Transcatheter Aortic Valve Implantation.

BACKGROUND: Major uncertainties remain regarding disease activity within the retained native aortic valve, and regarding bioprosthetic valve durability, after transcatheter aortic valve implantation (TAVI). We aimed to assess native aortic valve disease activity and bioprosthetic valve durability in patients with TAVI in comparison with subjects with bioprosthetic surgical aortic valve replacement (SAVR). METHODS: In a multicenter cross-sectional observational cohort study, patients with TAVI or bioprosthetic SAVR underwent baseline echocardiography, computed tomography angiography, and 18F-sodium fluoride (18F-NaF) positron emission tomography. Participants (n=47) were imaged once with 18F-NaF positron emission tomography/computed tomography either at 1 month (n=9, 19%), 2 years (n=22, 47%), or 5 years (16, 34%) after valve implantation. Patients subsequently underwent serial echocardiography to assess for changes in valve hemodynamic performance (change in peak aortic velocity) and evidence of structural valve dysfunction. Comparisons were made with matched patients with bioprosthetic SAVR (n=51) who had undergone the same imaging protocol. RESULTS: In patients with TAVI, native aortic valves demonstrated 18F-NaF uptake around the outside of the bioprostheses that showed a modest correlation with the time from TAVI (r=0.36, P=0.023). 18F-NaF uptake in the bioprosthetic leaflets was comparable between the SAVR and TAVI groups (target-to-background ratio, 1.3 [1.2-1.7] versus 1.3 [1.2-1.5], respectively; P=0.27). The frequencies of imaging evidence of bioprosthetic valve degeneration at baseline were similar on echocardiography (6% versus 8%, respectively; P=0.78), computed tomography (15% versus 14%, respectively; P=0.87), and positron emission tomography (15% versus 29%, respectively; P=0.09). Baseline 18F-NaF uptake was associated with a subsequent change in peak aortic velocity for both TAVI (r=0.7, P<0.001) and SAVR (r=0.7, P<0.001). On multivariable analysis, 18F-NaF uptake was the only predictor of peak velocity progression (P<0.001). CONCLUSIONS: In patients with TAVI, native aortic valves demonstrate evidence of ongoing active disease. Across imaging modalities, TAVI degeneration is of similar magnitude to bioprosthetic SAVR, suggesting comparable midterm durability. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02304276

Key Parameters of Tumor Epitope Immunogenicity Revealed Through a Consortium Approach Improve Neoantigen Prediction

Many approaches to identify therapeutically relevant neoantigens couple tumor sequencing with bioinformatic algorithms and inferred rules of tumor epitope immunogenicity. However, there are no reference data to compare these approaches, and the parameters governing tumor epitope immunogenicity remain unclear. Here, we assembled a global consortium wherein each participant predicted immunogenic epitopes from shared tumor sequencing data. 608 epitopes were subsequently assessed for T&nbsp;cell binding in patient-matched samples. By integrating peptide features associated with presentation and recognition, we developed a model of tumor epitope immunogenicity that filtered out 98% of non-immunogenic peptides&nbsp;with a precision above 0.70. Pipelines prioritizing model features had superior performance, and pipeline alterations leveraging them improved prediction performance. These findings were validated in an independent cohort of 310 epitopes prioritized from tumor sequencing data and assessed for T&nbsp;cell binding. This data resource enables identification of parameters underlying effective anti-tumor immunity and is available to the research community

A community-driven global reconstruction of human metabolism

Multiple models of human metabolism have been reconstructed, but each represents only a subset of our knowledge. Here we describe Recon 2, a community-driven, consensus 'metabolic reconstruction', which is the most comprehensive representation of human metabolism that is applicable to computational modeling. Compared with its predecessors, the reconstruction has improved topological and functional features, including ~2× more reactions and ~1.7× more unique metabolites. Using Recon 2 we predicted changes in metabolite biomarkers for 49 inborn errors of metabolism with 77% accuracy when compared to experimental data. Mapping metabolomic data and drug information onto Recon 2 demonstrates its potential for integrating and analyzing diverse data types. Using protein expression data, we automatically generated a compendium of 65 cell type–specific models, providing a basis for manual curation or investigation of cell-specific metabolic properties. Recon 2 will facilitate many future biomedical studies and is freely available at http://humanmetabolism.org/

Key Parameters of Tumor Epitope Immunogenicity Revealed Through a Consortium Approach Improve Neoantigen Prediction

Many approaches to identify therapeutically relevant neoantigens couple tumor sequencing with bioinformatic algorithms and inferred rules of tumor epitope immunogenicity. However, there are no reference data to compare these approaches, and the parameters governing tumor epitope immunogenicity remain unclear. Here, we assembled a global consortium wherein each participant predicted immunogenic epitopes from shared tumor sequencing data. 608 epitopes were subsequently assessed for T cell binding in patient-matched samples. By integrating peptide features associated with presentation and recognition, we developed a model of tumor epitope immunogenicity that filtered out 98% of non-immunogenic peptides with a precision above 0.70. Pipelines prioritizing model features had superior performance, and pipeline alterations leveraging them improved prediction performance. These findings were validated in an independent cohort of 310 epitopes prioritized from tumor sequencing data and assessed for T cell binding. This data resource enables identification of parameters underlying effective anti-tumor immunity and is available to the research community