Rotordynamic coefficients and leakage flow of parallel grooved seals and smooth seals

Based on Childs finite length solution for annular plain seals an extension of the bulk flow theory is derived to calculate the rotordynamic coefficients and the leakage flow of seals with parallel grooves in the stator. Hirs turbulent lubricant equations are modified to account for the different friction factors in circumferential and axial direction. Furthermore an average groove depth is introduced to consider the additional circumferential flow in the grooves. Theoretical and experimental results are compared for the smooth constant clearance seal and the corresponding seal with parallel grooves. Compared to the smooth seal the direct and cross-coupled stiffness coefficients as well as the direct damping coefficients are lower in the grooved seal configuration. Leakage is reduced by the grooving pattern

SnapShot: Tumor evolution

Understanding how tumors grow and evolve over time is crucial to help shed light on the underlying reasons why treatments fail and tumors metastasize. This SnapShot provides a brief introduction into the main concepts of tumor evolution

Large Oligomeric Complex Structures Can Be Computationally Assembled by Efficiently Combining Docked Interfaces

Macromolecular oligomeric assemblies are involved in many biochemical processes of living organisms. The benefits of such assemblies in crowded cellular environments include increased reaction rates, efficient feedback regulation, cooperativity and protective functions. However, an atom‐level structural determination of large assemblies is challenging due to the size of the complex and the difference in binding affinities of the involved proteins. In this study, we propose a novel combinatorial greedy algorithm for assembling large oligomeric complexes from information on the approximate position of interaction interfaces of pairs of monomers in the complex. Prior information on complex symmetry is not required but rather the symmetry is inferred during assembly. We implement an efficient geometric score, the transformation match score, that bypasses the model ranking problems of state‐of‐the‐art scoring functions by scoring the similarity between the inferred dimers of the same monomer simultaneously with different binding partners in a (sub)complex with a set of pregenerated docking poses. We compiled a diverse benchmark set of 308 homo and heteromeric complexes containing 6 to 60 monomers. To explore the applicability of the method, we considered 48 sets of parameters and selected those three sets of parameters, for which the algorithm can correctly reconstruct the maximum number, namely 252 complexes (81.8%) in, at least one of the respective three runs. The crossvalidation coverage, that is, the mean fraction of correctly reconstructed benchmark complexes during crossvalidation, was 78.1%, which demonstrates the ability of the presented method to correctly reconstruct topology of a large variety of biological complexes. Proteins 2015; 83:1887–1899. © 2015 The Authors. Proteins: Structure, Function, and Bioinformatics Published by Wiley Periodicals, Inc

Dynamics of apparent horizons in quantum gravitational collapse

We study the gravitational collapse of a massless scalar field within the effective scenario of loop quantum gravity. Classical singularity is avoided and replaced by a quantum bounce in this model. It is shown that, quantum gravity effects predict a threshold scale below which no horizon can form as the collapse evolves towards the bounce.Comment: Contribution to the Spanish Relativity Meeting in Portugal 2012 (ERE2012), Guimaraes, Portuga

Accumulation of soil carbon under elevated CO2 unaffected by warming and drought

Elevated atmospheric CO2 concentration (eCO2) and climate change may substantially alter soil carbon (C) dynamics and thus feedback to future climate. However, only very few field experiments world‐wide have combined eCO2 with both warming and changes in precipitation in order to study the potential combined effects of changes in these fundamental drivers of C cycling in ecosystems. We exposed a temperate heath/grassland to eCO2, warming, and drought, in all combinations for 8 years. At the end of the study, soil C stocks were on average 0.927 kg C m−2 higher across all treatment combinations with eCO2 compared to ambient CO2 treatments (equal to an increase of 0.120 ± 0.043 kg C m−2 y−1), and showed no sign of slowed accumulation over time. However, if observed pre‐treatment differences in soil C are taken into account, the annual rate of increase caused by eCO2 may be as high as 0.177 ± 0.070 kg C m−2 y−1. Further, the response to eCO2 was not affected by simultaneous exposure to warming and drought. The robust increase in soil C under eCO2 observed here, even when combined with other climate change factors, suggests that there is continued and strong potential for enhanced soil carbon sequestration in some ecosystems to mitigate increasing atmospheric CO2 concentrations under future climate conditions. The feedback between land C and climate remains one of the largest sources of uncertainty in future climate projections, yet experimental data under simulated future climate, and especially including combined changes, are still scarce. Globally coordinated and distributed experiments with long‐term measurements of changes in soil C in response to the three major climate change‐related global changes, eCO2, warming, and changes in precipitation patterns, are therefore urgently needed

GATA6 modulates the ductular reaction to bile duct ligation

Background GATA6, a transcription factor expressed in cholangiocytes, has been implicated in the response to liver injury. In biliary atresia, a disease characterized by extrahepatic bile duct obstruction, liver expression of GATA6 increases with pathological bile duct expansion and decreases after successful Kasai portoenterostomy. The aim of this study was to garner genetic evidence that GATA6 is involved in ductular formation/expansion. Methods The murine Gata6 gene was conditionally deleted using Alb-cre, a transgene expressed in hepatoblasts (the precursors of hepatocytes and cholangiocytes) and mature hepatocytes. Bile duct ligation (BDL) was used to model biliary obstruction. Results Alb-Cre;Gata6(flox/flox) mice were viable and fertile. Cre-mediated recombination of Gata6 in hepatocytes had little impact on cellular structure or function. GATA6 immunoreactivity was retained in a majority of biliary epithelial cells in adult Alb-Cre;Gata6(flox/flox) mice, implying that surviving cholangiocytes were derived from hepatoblasts that had escaped biallelic Cre-mediated recombination. Although GATA6 immunoreactivity was preserved in cholangiocytes, Alb-cre;Gata6(flox/flox) mice had a demonstrable biliary phenotype. A neutrophil-rich infiltrate surrounded newly formed bile ducts in neonatal Alb-Cre;Gata6(flox/flox) mice. Foci of fibrosis/necrosis, presumed to reflect patchy defects in bile duct formation, were observed in the livers of 37% of adult Alb-cre;Gata6(flox/flox) mice and 0% of controls (p <0.05). Most notably, Alb-cre;Gata6(flox/flox) mice had an altered response to BDL manifest as reduced survival, impaired bile ductule proliferation, increased parenchymal necrosis, reduced fibrosis, and enhanced macrophage accumulation in the portal space. Conclusions GATA6 orchestrates intrahepatic biliary remodeling and mitigates liver injury following extrahepatic bile duct obstruction. Graphic abstractPeer reviewe

Lipid nanodisc scaffold and size alter the structure of a pentameric ligand-gated ion channel

Lipid nanodiscs have become a standard tool for studying membrane proteins, including using single particle cryo-electron microscopy (cryo-EM). We find that reconstituting the pentameric ligand-gated ion channel (pLGIC), Erwinia ligand-gated ion channel (ELIC), in different nanodiscs produces distinct structures by cryo-EM. The effect of the nanodisc on ELIC structure extends to the extracellular domain and agonist binding site. Additionally, molecular dynamic simulations indicate that nanodiscs of different size impact ELIC structure and that the nanodisc scaffold directly interacts with ELIC. These findings suggest that the nanodisc plays a crucial role in determining the structure of pLGICs, and that reconstitution of ion channels in larger nanodiscs may better approximate a lipid membrane environment

A Forward Genetic Screen Reveals Novel Independent Regulators of Ulbp1, an Activating Ligand for Natural Killer Cells

Recognition and elimination of tumor cells by the immune system is crucial for limiting tumor growth. Natural killer (NK) cells become activated when the receptor NKG2D is engaged by ligands that are frequently upregulated in primary tumors and on cancer cell lines. However, the molecular mechanisms driving NKG2D ligand expression on tumor cells are not well defined. Using a forward genetic screen in a tumor-derived human cell line, we identified several novel factors supporting expression of the NKG2D ligand ULBP1. Our results show stepwise contributions of independent pathways working at multiple stages of ULBP1 biogenesis. Deeper investigation of selected hits from the screen showed that the transcription factor ATF4 drives ULBP1 gene expression in cancer cell lines, while the RNA-binding protein RBM4 supports ULBP1 expression by suppressing a novel alternatively spliced isoform of ULBP1 mRNA. These findings offer insight into the stress pathways that alert the immune system to danger

The BCL-2 family member BOK promotes KRAS-driven lung cancer progression in a p53-dependent manner.

A variety of cancer entities are driven by KRAS mutations, which remain difficult to target clinically. Survival pathways, such as resistance to cell death, may represent a promising treatment approach in KRAS mutated cancers. Based on the frequently observed genomic deletions of BCL-2-related ovarian killer (BOK) in cancer patients, we explored the function of BOK in a mutant KrasG12D-driven murine model of lung cancer. Using KrasG12D/+ Bok-/- mice, we observed an overall tumor-promoting function of BOK in vivo. Specifically, loss of BOK reduced proliferation both in cell lines in vitro as well as in KrasG12D-driven tumor lesions in vivo. During tumor development in vivo, loss of BOK resulted in a lower tumor burden, with fewer, smaller, and less advanced tumors. Using KrasG12D/+ Tp53Δ/Δ Bok-/- mice, we identified that this phenotype was entirely dependent on the presence of functional p53. Furthermore, analysis of a human dataset of untreated early-stage lung tumors did not identify any common deletion of the BOK locus, independently of the TP53 status or the histopathological classification. Taken together our data indicate that BOK supports tumor progression in Kras-driven lung cancer

Ketogenesis prevents diet-induced fatty liver injury and hyperglycemia

Nonalcoholic fatty liver disease (NAFLD) spectrum disorders affect approximately 1 billion individuals worldwide. However, the drivers of progressive steatohepatitis remain incompletely defined. Ketogenesis can dispose of much of the fat that enters the liver, and dysfunction in this pathway could promote the development of NAFLD. Here, we evaluated mice lacking mitochondrial 3-hydroxymethylglutaryl CoA synthase (HMGCS2) to determine the role of ketogenesis in preventing diet-induced steatohepatitis. Antisense oligonucleotide–induced loss of HMGCS2 in chow-fed adult mice caused mild hyperglycemia, increased hepatic gluconeogenesis from pyruvate, and augmented production of hundreds of hepatic metabolites, a suite of which indicated activation of the de novo lipogenesis pathway. High-fat diet feeding of mice with insufficient ketogenesis resulted in extensive hepatocyte injury and inflammation, decreased glycemia, deranged hepatic TCA cycle intermediate concentrations, and impaired hepatic gluconeogenesis due to sequestration of free coenzyme A (CoASH). Supplementation of the CoASH precursors pantothenic acid and cysteine normalized TCA intermediates and gluconeogenesis in the livers of ketogenesis-insufficient animals. Together, these findings indicate that ketogenesis is a critical regulator of hepatic acyl-CoA metabolism, glucose metabolism, and TCA cycle function in the absorptive state and suggest that ketogenesis may modulate fatty liver disease