Impact-induced initiation of Snowball Earth: A model study

During the Neoproterozoic and Paleoproterozoic eras, geological evidence points to several “Snowball Earth” episodes when most of Earth’s surface was covered in ice. These global-scale glaciations represent the most marked climate changes in Earth’s history. We show that the impact winter following an asteroid impact comparable in size to the Chicxulub impact could have led to a runaway ice-albedo feedback and global glaciation. Using a state-of-the-art atmosphere-ocean climate model, we simulate the climate response following an impact for preindustrial, Last Glacial Maximum (LGM), Cretaceous-like, and Neoproterozoic climates. While warm ocean temperatures in the preindustrial and Cretaceous-like climates prevent Snowball initiation, the colder oceans of the LGM and cold Neoproterozoic climate scenarios rapidly form sea ice and demonstrate high sensitivity to the initial condition of the ocean. Given suggestions of a cold pre-Snowball climate, we argue the initiation of Snowball Earth by a large impact is a robust possible mechanism, as previously suggested by others, and conclude by discussing geologic tests

Structure and Function of Bacillus subtilis YphP, a Prokaryotic Disulfide Isomerase with a CXC Catalytic Motif†,‡

ABSTRACT: The DUF1094 family contains over 100 bacterial proteins, all containing a conserved CXCmotif, with unknown function. We solved the crystal structure of the Bacillus subtilis representative, the product of the yphP gene. The protein shows remarkable structural similarity to thioredoxins, with a canonical RβRβRββR topology, despite low amino acid sequence identity to thioredoxin. The CXC motif is found in the loop immediately downstream of the first β-strand, in a location equivalent to the CXXC motif of thioredoxins, with the first Cys occupying a position equivalent to the first Cys in canonical thioredoxin. The experimentally determined reduction potential of YphP is E0 =-130 mV, significantly higher than that of thioredoxin and consistent with disulfide isomerase activity. Functional assays confirmed that the protein displays a level of isomerase activity that might be biologically significant.We propose a mechanism by which the members of this family catalyze isomerization using the CXC catalytic site. The Bacillus subtilis yphP gene codes for a member of a superfamily of over 100 prokaryotic, highly conserved proteins (DUF1094), found predominantly in Firmicutes such as Staphy

The association between Toll-like receptor 2 single-nucleotide polymorphisms and hepatocellular carcinoma susceptibility

<p>Abstract</p> <p>Background</p> <p>Toll-like receptors (TLR) are key innate immunity receptors participating in an immune response. Growing evidence suggests that mutations of TLR2/TLR9 gene are associated with the progress of cancers. The present study aimed to investigate the temporal relationship of single nucleotide polymorphisms (SNP) of TLR2/TLR9 and the risk of hepatocellular carcinoma (HCC).</p> <p>Methods</p> <p>In this single center-based case-control study, SNaPshot method was used to genotype sequence variants of TLR2 and TLR9 in 211 patients with HCC and 232 subjects as controls.</p> <p>Results</p> <p>Two synonymous SNPs in the exon of TLR2 were closely associated with risk of HCC. Compared with those carrying wild-type homozygous genotypes (T/T), risk of HCC decreased significantly in individuals carrying the heterozygous genotypes (C/T) of the rs3804099 (adjusted odds ratio (OR), 0.493, 95% CI 0.331 - 0.736, <it>P </it>< 0.01) and rs3804100 (adjusted OR, 0.509, 95% CI 0.342 - 0.759, <it>P </it>< 0.01). There was no significant association found in two TLR9 SNPs concerning the risk of HCC. The haplotype TT for TLR2 was associated significantly with the decreased risk of HCC (OR 0.524, 95% CI 0.394 - 0.697, <it>P </it>= 0.000). Inversely, the risk of HCC increased significantly in patients with the haplotype CC (OR 2.743, 95% CI 1.915 - 3.930, <it>P </it>= 0.000).</p> <p>Conclusions</p> <p>These results suggested that TLR2 rs3804099 C/T and rs3804100 C/T polymorphisms were closely associated with HCC. In addition, the haplotypes composed of these two TLR2 synonymous SNPs have stronger effects on the susceptibility of HCC.</p

Risk factors for hospital morbidity and mortality after the Norwood procedure: A report from the Pediatric Heart Network Single Ventricle Reconstruction trial

ObjectivesWe sought to identify risk factors for mortality and morbidity during the Norwood hospitalization in newborn infants with hypoplastic left heart syndrome and other single right ventricle anomalies enrolled in the Single Ventricle Reconstruction trial.MethodsPotential predictors for outcome included patient- and procedure-related variables and center volume and surgeon volume. Outcome variables occurring during the Norwood procedure and before hospital discharge or stage II procedure included mortality, end-organ complications, length of ventilation, and hospital length of stay. Univariate and multivariable Cox regression analyses were performed with bootstrapping to estimate reliability for mortality.ResultsAnalysis included 549 subjects prospectively enrolled from 15 centers; 30-day and hospital mortality were 11.5% (63/549) and 16.0% (88/549), respectively. Independent risk factors for both 30-day and hospital mortality included lower birth weight, genetic abnormality, extracorporeal membrane oxygenation (ECMO) and open sternum on the day of the Norwood procedure. In addition, longer duration of deep hypothermic circulatory arrest was a risk factor for 30-day mortality. Shunt type at the end of the Norwood procedure was not a significant risk factor for 30-day or hospital mortality. Independent risk factors for postoperative renal failure (n = 46), sepsis (n = 93), increased length of ventilation, and hospital length of stay among survivors included genetic abnormality, lower center/surgeon volume, open sternum, and post-Norwood operations.ConclusionsInnate patient factors, ECMO, open sternum, and lower center/surgeon volume are important risk factors for postoperative mortality and/or morbidity during the Norwood hospitalization

Molecular basis of ALK1-mediated signalling by BMP9/BMP10 and their prodomain-bound forms

Abstract: Activin receptor-like kinase 1 (ALK1)-mediated endothelial cell signalling in response to bone morphogenetic protein 9 (BMP9) and BMP10 is of significant importance in cardiovascular disease and cancer. However, detailed molecular mechanisms of ALK1-mediated signalling remain unclear. Here, we report crystal structures of the BMP10:ALK1 complex at 2.3 Å and the prodomain-bound BMP9:ALK1 complex at 3.3 Å. Structural analyses reveal a tripartite recognition mechanism that defines BMP9 and BMP10 specificity for ALK1, and predict that crossveinless 2 is not an inhibitor of BMP9, which is confirmed by experimental evidence. Introduction of BMP10-specific residues into BMP9 yields BMP10-like ligands with diminished signalling activity in C2C12 cells, validating the tripartite mechanism. The loss of osteogenic signalling in C2C12 does not translate into non-osteogenic activity in vivo and BMP10 also induces bone-formation. Collectively, these data provide insight into ALK1-mediated BMP9 and BMP10 signalling, facilitating therapeutic targeting of this important pathway

Molecular basis of ALK1-mediated signalling by BMP9/BMP10 and their prodomain-bound forms

Abstract: Activin receptor-like kinase 1 (ALK1)-mediated endothelial cell signalling in response to bone morphogenetic protein 9 (BMP9) and BMP10 is of significant importance in cardiovascular disease and cancer. However, detailed molecular mechanisms of ALK1-mediated signalling remain unclear. Here, we report crystal structures of the BMP10:ALK1 complex at 2.3 Å and the prodomain-bound BMP9:ALK1 complex at 3.3 Å. Structural analyses reveal a tripartite recognition mechanism that defines BMP9 and BMP10 specificity for ALK1, and predict that crossveinless 2 is not an inhibitor of BMP9, which is confirmed by experimental evidence. Introduction of BMP10-specific residues into BMP9 yields BMP10-like ligands with diminished signalling activity in C2C12 cells, validating the tripartite mechanism. The loss of osteogenic signalling in C2C12 does not translate into non-osteogenic activity in vivo and BMP10 also induces bone-formation. Collectively, these data provide insight into ALK1-mediated BMP9 and BMP10 signalling, facilitating therapeutic targeting of this important pathway