The Glove-like Structure of the Conserved Membrane Protein TatC Provides Insight into Signal Sequence Recognition in Twin-Arginine Translocation

In bacteria, two signal-sequence-dependent secretion pathways translocate proteins across the cytoplasmic membrane. Although the mechanism of the ubiquitous general secretory pathway is becoming well understood, that of the twin-arginine translocation pathway, responsible for translocation of folded proteins across the bilayer, is more mysterious. TatC, the largest and most conserved of three integral membrane components, provides the initial binding site of the signal sequence prior to pore assembly. Here, we present two crystal structures of TatC from the thermophilic bacteria Aquifex aeolicus at 4.0 Å and 6.8 Å resolution. The membrane architecture of TatC includes a glove-shaped structure with a lipid-exposed pocket predicted by molecular dynamics to distort the membrane. Correlating the biochemical literature to these results suggests that the signal sequence binds in this pocket, leading to structural changes that facilitate higher order assemblies

Stabilization of Hydrodynamic Flows by Small Viscosity Variations

Motivated by the large effect of turbulent drag reduction by minute concentrations of polymers we study the effects of a weakly space-dependent viscosity on the stability of hydrodynamic flows. In a recent Letter [Phys. Rev. Lett. {\bf 87}, 174501, (2001)] we exposed the crucial role played by a localized region where the energy of fluctuations is produced by interactions with the mean flow (the "critical layer"). We showed that a layer of weakly space-dependent viscosity placed near the critical layer can have a very large stabilizing effect on hydrodynamic fluctuations, retarding significantly the onset of turbulence. In this paper we extend these observation in two directions: first we show that the strong stabilization of the primary instability is also obtained when the viscosity profile is realistic (inferred from simulations of turbulent flows with a small concentration of polymers). Second, we analyze the secondary instability (around the time-dependent primary instability) and find similar strong stabilization. Since the secondary instability develops around a time-dependent solution and is three-dimensional, this brings us closer to the turbulent case. We reiterate that the large effect is {\em not} due to a modified dissipation (as is assumed in some theories of drag reduction), but due to reduced energy intake from the mean flow to the fluctuations. We propose that similar physics act in turbulent drag reduction.Comment: 10 pages, 17 figs., REVTeX4, PRE, submitte

Megaesophagus in a Line of Transgenic Rats: A Model of Achalasia

Megaesophagus is defined as the abnormal enlargement or dilatation of the esophagus, characterized by a lack of normal contraction of the esophageal walls. This is called achalasia when associated with reduced or no relaxation of the lower esophageal sphincter (LES). To date, there are few naturally occurring models for this disease. A colony of transgenic (Pvrl3-Cre) rats presented with megaesophagus at 3 to 4 months of age; further breeding studies revealed a prevalence of 90% of transgene-positive animals having megaesophagus. Affected rats could be maintained on a total liquid diet long term and were shown to display the classic features of dilated esophagus, closed lower esophageal sphincter, and abnormal contractions on contrast radiography and fluoroscopy. Histologically, the findings of muscle degeneration, inflammation, and a reduced number of myenteric ganglia in the esophagus combined with ultrastructural lesions of muscle fiber disarray and mitochondrial changes in the striated muscle of these animals closely mimic that seen in the human condition. Muscle contractile studies looking at the response of the lower esophageal sphincter and fundus to electrical field stimulation, sodium nitroprusside, and L-nitro-L-arginine methyl ester also demonstrate the similarity between megaesophagus in the transgenic rats and patients with achalasia. No primary cause for megaesophagus was found, but the close parallel to the human form of the disease, as well as ease of care and manipulation of these rats, makes this a suitable model to better understand the etiology of achalasia as well as study new management and treatment options for this incurable condition.National Institutes of Health (U.S.) (Grant T32OD011141)National Institutes of Health (U.S.) (Grant P30ES002109

Helicobacter hepaticus Infection Promotes Hepatitis and Preneoplastic Foci in Farnesoid X Receptor (FXR) Deficient Mice

Farnesoid X receptor (FXR) is a nuclear receptor that regulates bile acid metabolism and transport. Mice lacking expression of FXR (FXR KO) have a high incidence of foci of cellular alterations (FCA) and liver tumors. Here, we report that Helicobacter hepaticus infection is necessary for the development of increased hepatitis scores and FCA in previously Helicobacter-free FXR KO mice. FXR KO and wild-type (WT) mice were sham-treated or orally inoculated with H. hepaticus. At 12 months post-infection, mice were euthanized and liver pathology, gene expression, and the cecal microbiome were analyzed. H. hepaticus induced significant increases hepatitis scores and FCA numbers in FXR KO mice (P<0.01 and P<0.05, respectively). H. hepaticus altered the beta diversity of cecal microbiome in both WT and FXR KO mice compared to uninfected mice (P<0.05). Significant upregulation of β-catenin, Rela, Slc10a1, Tlr2, Nos2, Vdr, and Cyp3a11 was observed in all FXR KO mice compared to controls (P<0.05). Importantly, H. hepaticus and FXR deficiency were necessary to significantly upregulate Cyp2b10 (P<0.01). FXR deficiency was also a potent modulator of the cecal microbiota, as observed by a strong decrease in alpha diversity. A significant decrease in Firmicutes, particularly members of the order Clostridiales, was observed in FXR KO mice (P<0.05 and FDR<5%, ANOVA). While FXR deficiency strongly affects expression of genes related to immunity and bile acid metabolism, as well as the composition of the microbiome; however, its deficiency was not able to produce significant histopathological changes in the absence of H. hepaticus infection.National Institutes of Health (U.S.) (NIH R01 OD011141)National Institutes of Health (U.S.) (NIH T32 OD010978)National Institutes of Health (U.S.) (NIH P30 ES002109)National Institutes of Health (U.S.) (P01 CA026731

Self-similar shear-thickening behavior in CTAB/NaSal surfactant solutions

The effect of salt concentration Cs on the critical shear rate required for the onset of shear thickening and apparent relaxation time of the shear-thickened phase, has been investigated systematically for dilute CTAB/NaSal solutions. Experimental data suggest a self-similar behavior of the critical shear rate and relaxation time as functions of Cs. Specifically, the former ~ Cs^(-6) whereas the latter ~ Cs^(6) such that an effective Weissenberg number for the onset of the shear thickened phase is only weakly dependent on Cs. A procedure has been developed to collapse the apparent shear viscosity versus shear rate data obtained for various values of Cs into a single master curve. The effect of Cs on the elastic modulus and mesh size of the shear-induced gel phase for different surfactant concentrations is discussed. Experiments performed using different flow cells (Couette and cone-and-plate) show that the critical shear rate, relaxation time and the maximum viscosity attained are geometry-independent. The elastic modulus of the gel phase inferred indirectly by employing simplified hydrodynamic instability analysis of a sheared gel-fluid interface is in qualitative agreement with that predicted for an entangled phase of living polymers. A qualitative mechanism that combines the effect of Cs on average micelle length and Debye parameter with shear-induced configurational changes of rod-like micelles is proposed to rationalize the self-similarity of SIS formation.Comment: 27 pages, 17 figure

Rokhlin Dimension and Inductive Limit Actions on AF-algebras

Given a separable, AF-algebra A and an inductive limit action on A of a finitely generated abelian group with finite Rokhlin dimension with commuting towers, we give a local description of the associated crossed product C*-algebra. In particular, when A is unital and $\alpha \in Aut(A)$ is approximately inner and has the Rokhlin property, we conclude that $A \rtimes_{\alpha} \mathbb{Z}$ is an A$\mathbb{T}$-algebra

Impaired cholecystokinin-induced gallbladder emptying incriminated in spontaneous “black” pigment gallstone formation in germfree Swiss Webster mice

“Black” pigment gallstones form in sterile gallbladder bile in the presence of excess bilirubin conjugates (“hyperbilirubinbilia”) from ineffective erythropoiesis, hemolysis, or induced enterohepatic cycling (EHC) of unconjugated bilirubin. Impaired gallbladder motility is a less well-studied risk factor. We evaluated the spontaneous occurrence of gallstones in adult germfree (GF) and conventionally housed specific pathogen-free (SPF) Swiss Webster (SW) mice. GF SW mice were more likely to have gallstones than SPF SW mice, with 75% and 23% prevalence, respectively. In GF SW mice, gallstones were observed predominately in heavier, older females. Gallbladders of GF SW mice were markedly enlarged, contained sterile black gallstones composed of calcium bilirubinate and <1% cholesterol, and had low-grade inflammation, edema, and epithelial hyperplasia. Hemograms were normal, but serum cholesterol was elevated in GF compared with SPF SW mice, and serum glucose levels were positively related to increasing age. Aged GF and SPF SW mice had deficits in gallbladder smooth muscle activity. In response to cholecystokinin (CCK), gallbladders of fasted GF SW mice showed impaired emptying (females: 29%; males: 1% emptying), whereas SPF SW females and males emptied 89% and 53% of volume, respectively. Bilirubin secretion rates of GF SW mice were not greater than SPF SW mice, repudiating an induced EHC. Gallstones likely developed in GF SW mice because of gallbladder hypomotility, enabled by features of GF physiology, including decreased intestinal CCK concentration and delayed intestinal transit, as well as an apparent genetic predisposition of the SW stock. GF SW mice may provide a valuable model to study gallbladder stasis as a cause of black pigment gallstones.National Institutes of Health (U.S.) (Training Grant T32-OD10978-26)National Institutes of Health (U.S.) (Training Grant P30-ES002109)Kinship Foundation. Searle Scholars Progra

Maximizing the Number of Spatial Nulls with Minimum Sensors

In this paper, we attempt to unify two array processing frameworks viz, Acoustic Vector Sensor (AVS) and two level nested array to enhance the Degrees of Freedom (DoF) significantly beyond the limit that is attained by a Uniform Linear Hydrophone Array (ULA) with specified number of sensors. The major focus is to design a line array architecture which provides high resolution unambiguous bearing estimation with increased number of spatial nulls to mitigate the multiple interferences in a deep ocean scenario. AVS can provide more information about the propagating acoustic field intensity vector by simultaneously measuring the acoustic pressure along with tri-axial particle velocity components. In this work, we have developed Nested AVS array (NAVS) ocean data model to demonstrate the performance enhancement. Conventional and MVDR spatial filters are used as the response function to evaluate the performance of the proposed architecture. Simulation results show significant improvement in performance viz, increase of DoF, and localization of more number of acoustic sources and high resolution bearing estimation with reduced side lobe level

Cancellation of Towing Ship Interference in Passive SONAR in a Shallow Ocean Environment

Towed array sonars are preferred for detecting stealthy underwater targets that emit faint acoustic signals in the ocean, especially in shallow waters. However, the towing ship being near to the array behaves as a loud target, introducing additional interfering signals to the array, severely affecting the detection and classification of potential targets. Canceling this underlying interference signal is a challenging task and is investigated in this paper for a shallow ocean operational scenario where the problem is more critical due to the multipath phenomenon. A method exploiting the eigenvector analysis of spatio-temporal covariance matrix based on space time adaptive processing is proposed for suppressing tow ship interference and thus improving target detection. The developed algorithm learns the interference patterns in the presence of target signals to mitigate the interference across azimuth and to remove the spectral leakage of own-ship. The algorithm is statistically analyzed through a set of relevant metrics and is tested on simulated data that are equivalent to the data received by a towed linear array of acoustic sensors in a shallow ocean. The results indicate a reduction of 20-25dB in the tow ship interference power while the detection of long-range low SNR targets remain largely unaffected with minimal power-loss. In addition, it is demonstrated that the spectral leakage of tow ship, on multiple beams across the azimuth, due to multipath, is also alleviated leading to superior classification capabilities. The robustness of the proposed algorithm is validated by the open ocean experiment in the coastal shallow region of the Arabian Sea at Off-Kochi area of India, which produced results in close agreement with the simulations. A comparison of the simulation and experimental results with the existing PCI and ECA methods is also carried out, suggesting the proposed method is quite effective in suppressing the tow ship interference and is immensely beneficial for the detection and classification of long-range targets