Crystal structure of the heterotrimeric integrin-binding region of laminin-111

Laminins are cell - adhesive glycoproteins that are essential for basement membrane assembly and function. Integrins are important laminin receptors, but their binding site on the heterotrimeric laminin s is poorly defined structurally. We report the crystal structure at 2.13 Å resolution of a minimal integrin - binding fragment of mouse laminin - 111, consisting of ~50 resid ues of α 1 β 1 γ 1 coiled coil and the first three lam inin G - like (LG) domains of the α 1 chain . The LG domains adopt a triangular arrangem ent, with the C - terminus of the coiled coil situated between LG1 and LG2. The critical integrin - binding glutamic acid residue in the γ 1 chain tail is surface - exposed and predicted to bind to the metal ion - dependent adhesion site in the integrin β 1 subunit. Additional contacts to the integrin are likely to be made by the LG1 and LG2 surfaces adjacent to the γ 1 chain tail, which are notably conserved and free of obstructing glycans

Tauroursodeoxycholic acid exerts anticholestatic effects by a cooperative cPKC alpha-/PKA-dependent mechanism in rat liver.

Objective: Ursodeoxycholic acid (UDCA) exerts anticholestatic effects in part by protein kinase C (PKC)-dependent mechanisms. Its taurine conjugate, TUDCA, is a cPKCa agonist. We tested whether protein kinase A (PKA) might contribute to the anticholestatic action of TUDCA via cooperative cPKCa-/PKA-dependent mechanisms in taurolithocholic acid (TLCA)-induced cholestasis. Methods: In perfused rat liver, bile flow was determined gravimetrically, organic anion secretion spectrophotometrically, lactate dehydrogenase (LDH) release enzymatically, cAMP response-element binding protein (CREB) phosphorylation by immunoblotting, and cAMP by immunoassay. PKC/PKA inhibitors were tested radiochemically. In vitro phosphorylation of the conjugate export pump, Mrp2/Abcc2, was studied in rat hepatocytes and human Hep-G2 hepatoma cells. Results: In livers treated with TLCA (10 mmol/l)+TUDCA (25 mmol/l), combined inhibition of cPKC by the cPKCselective inhibitor Go¨6976 (100 nmol/l) or the nonselective PKC inhibitor staurosporine (10 nmol/l) and of PKA by H89 (100 nmol/l) reduced bile flow by 36% (p,0.05) and 48% (p,0.01), and secretion of the Mrp2/ Abcc2 substrate, 2,4-dinitrophenyl-S-glutathione, by 31% (p,0.05) and 41% (p,0.01), respectively; bile flow was unaffected in control livers or livers treated with TUDCA only or TLCA+taurocholic acid. Inhibition of cPKC or PKA alone did not affect the anticholestatic action of TUDCA. Hepatic cAMP levels and CREB phosphorylation as readout of PKA activity were unaffected by the bile acids tested, suggesting a permissive effect of PKA for the anticholestatic action of TUDCA. Rat and human hepatocellular Mrp2 were phosphorylated by phorbol ester pretreatment and recombinant cPKCa, nPKCe, and PKA, respectively, in a staurosporine-sensitive manner. Conclusion: UDCA conjugates exert their anticholestatic action in bile acid-induced cholestasis in part via cooperative post-translational cPKCa-/PKA-dependent mechanisms. Hepatocellular Mrp2 may be one target of bile acid-induced kinase activation

Mach-Zehnder interferometry with interacting trapped Bose-Einstein condensates

We theoretically analyze a Mach-Zehnder interferometer with trapped condensates, and find that it is surprisingly stable against the nonlinearity induced by inter-particle interactions. The phase sensitivity, which we study for number squeezed input states, can overcome the shot noise limit and be increased up to the Heisenberg limit provided that a Bayesian or Maximum-Likelihood phase estimation strategy is used. We finally demonstrate robustness of the Mach-Zehnder interferometer in presence of interactions against condensate oscillations and a realistic atom counting error.Comment: 4 pages, 5 figures, minor revision

Atom interferometry with trapped Bose-Einstein condensates: Impact of atom-atom interactions

Interferometry with ultracold atoms promises the possibility of ultraprecise and ultrasensitive measurements in many fields of physics, and is the basis of our most precise atomic clocks. Key to a high sensitivity is the possibility to achieve long measurement times and precise readout. Ultra cold atoms can be precisely manipulated at the quantum level, held for very long times in traps, and would therefore be an ideal setting for interferometry. In this paper we discuss how the non-linearities from atom-atom interactions on one hand allow to efficiently produce squeezed states for enhanced readout, but on the other hand result in phase diffusion which limits the phase accumulation time. We find that low dimensional geometries are favorable, with two-dimensional (2D) settings giving the smallest contribution of phase diffusion caused by atom-atom interactions. Even for time sequences generated by optimal control the achievable minimal detectable interaction energy $\Delta E^{\rm min}$ is on the order of 0.001 times the chemical potential of the BEC in the trap. From there we have to conclude that for more precise measurements with atom interferometers more sophisticated strategies, or turning off the interaction induced dephasing during the phase accumulation stage, will be necessary.Comment: 28 pages, 13 figures, extended and correcte

Biliary Bicarbonate Secretion Constitutes a Protective Mechanism against Bile Acid-Induced Injury in Man

Background: Cholangiocytes expose a striking resistance against bile acids: while other cell types, such as hepatocytes, are susceptible to bile acid-induced toxicity and apoptosis already at micromolar concentrations, cholangiocytes are continuously exposed to millimolar concentrations as present in bile. We present a hypothesis suggesting that biliary secretion of HCO(3)(-) in man serves to protect cholangiocytes against bile acid-induced damage by fostering the deprotonation of apolar bile acids to more polar bile salts. Here, we tested if bile acid-induced toxicity is pH-dependent and if anion exchanger 2 (AE2) protects against bile acid-induced damage. Methods: A human cholangiocyte cell line was exposed to chenodeoxycholate (CDC), or its glycine conjugate, from 0.5 mM to 2.0 mM at pH 7.4, 7.1, 6.7 or 6.4, or after knockdown of AE2. Cell viability and apoptosis were determined by WST and caspase-3/-7 assays, respectively. Results: Glycochenodeoxycholate (GCDC) uptake in cholangiocytes is pH-dependent. Furthermore, CDC and GCDC (pK(a) 4-5) induce cholangiocyte toxicity in a pH-dependent manner: 0.5 mM CDC and 1 mM GCDC at pH 7.4 had no effect on cell viability, but at pH 6.4 decreased viability by >80% and increased caspase activity almost 10- and 30-fold, respectively. Acidification alone had no effect. AE2 knockdown led to 3- and 2-fold enhanced apoptosis induced by 0.75 mM CDC or 2 mM GCDC at pH 7.4. Discussion: These data support our hypothesis of a biliary HCO(3)(-) umbrella serving to protect human cholangiocytes against bile acid-induced injury. AE2 is a key contributor to this protective mechanism. The development and progression of cholangiopathies, such as primary biliary cirrhosis, may be a consequence of genetic and acquired functional defects of genes involved in maintaining the biliary HCO(3)(-) umbrella. Copyright (C) 2011 S. Karger AG, Base

Phase Estimation from Atom Position Measurements

We study the measurement of the position of atoms as a means to estimate the relative phase between two Bose-Einstein condensates. First, we consider $N$ atoms released from a double-well trap, forming an interference pattern, and show that a simple least-squares fit to the density gives a shot-noise limited sensitivity. The shot-noise limit can instead be overcome by using correlation functions of order $\sqrt{N}$ or larger. The measurement of the $N\mathrm{th}$-order correlation function allows to estimate the relative phase at the Heisenberg limit. Phase estimation through the measurement of the center-of-mass of the interference pattern can also provide sub-shot-noise sensitivity. Finally, we study the effect of the overlap between the two clouds on the phase estimation, when Mach-Zehnder interferometry is performed in a double-well.Comment: 20 pages, 6 figure

Massive creation of entangled exciton states in semiconductor quantum dots

An intense laser pulse propagating in a medium of inhomogeneously broadened quantum dots massively creates entangled exciton states. After passage of the pulse all single-exciton states remain unpopulated (self-induced transparency) whereas biexciton coherence (exciton entanglement) is generated through two-photon transitions. We propose several experimental techniques for the observation of such unexpected behavior

Spin flip lifetimes in superconducting atom chips: BCS versus Eliashberg theory

We investigate theoretically the magnetic spin-flip transitions of neutral atoms trapped near a superconducting slab. Our calculations are based on a quantum-theoretical treatment of electromagnetic radiation near dielectric and metallic bodies. Specific results are given for rubidium atoms near a niobium superconductor. At the low frequencies typical of the atomic transitions, we find that BCS theory greatly overestimates coherence effects, which are much less pronounced when quasiparticle lifetime effects are included through Eliashberg theory. At 4.2 K, the typical atomic spin lifetime is found to be larger than a thousand seconds, even for atom-superconductor distances of one micrometer. This constitutes a large enhancement in comparison with normal metals.Comment: 10 pages, 4 figure

Molecular mechanism of decision-making in glycosaminoglycan biosynthesis

Two major glycosaminoglycan types, heparan sulfate (HS) and chondroitin sulfate (CS), control many aspects of development and physiology in a type-specific manner. HS and CS are attached to core proteins via a common linker tetrasaccharide, but differ in their polymer backbones. How core proteins are specifically modified with HS or CS has been an enduring mystery. By reconstituting glycosaminoglycan biosynthesis in vitro, we establish that the CS-initiating N-acetylgalactosaminyltransferase CSGALNACT2 modifies all glycopeptide substrates equally, whereas the HS-initiating N-acetylglucosaminyltransferase EXTL3 is selective. Structure-function analysis reveals that acidic residues in the glycopeptide substrate and a basic exosite in EXTL3 are critical for specifying HS biosynthesis. Linker phosphorylation by the xylose kinase FAM20B accelerates linker synthesis and initiation of both HS and CS, but has no effect on the subsequent polymerisation of the backbone. Our results demonstrate that modification with CS occurs by default and must be overridden by EXTL3 to produce HS

Shapiro effect in atomchip-based bosonic Josephson junctions

We analyze the emergence of Shapiro resonances in tunnel-coupled Bose-Einstein condensates, realizing a bosonic Josephson junction. Our analysis is based on an experimentally relevant implementation using magnetic double well potentials on an atomchip. In this configuration the potential bias (implementing the junction voltage) and the potential barrier (realizing the Josephson link) are intrinsically coupled. We show that the dynamically driven system exhibits significantly enhanced Shapiro resonances which will facilitate experimental observation. To describe the systems response to the dynamic drive we compare a single-mode Gross-Pitaevskii (GP) description, an improved two-mode (TM) model and the self-consistent multi-configurational time dependent Hartree for Bosons (MCTDHB) method. We show that in the case of significant atom-atom interactions or strong driving, the spatial dynamics of the involved modes have to be taken into account, and only the MCTDHB method allows reliable predictions.Comment: 16 pages, 4 figure