S-wave/spin-triplet order in superconductors without inversion symmetry: Li2_2Pd3_3B and Li2_2Pt3_3B

We investigate the order parameter of noncentrosymmetric superconductors Li$_2$Pd$_3$B and Li$_2$Pt$_3$B via the behavior of the penetration depth $\lambda(T)$. The low-temperature penetration depth shows BCS-like behavior in Li$_2$Pd$_3$B, while in Li$_2$Pt$_3$B it follows a linear temperature dependence. We propose that broken inversion symmetry and the accompanying antisymmetric spin-orbit coupling, which admix spin-singlet and spin-triplet pairing, are responsible for this behavior. The triplet contribution is weak in Li$_2$Pd$_3$B, leading to a wholly open but anisotropic gap. The significantly larger spin-orbit coupling in Li$_2$Pt$_3$B allows the spin-triplet component to be larger in Li$_2$Pt$_3$B, producing line nodes in the energy gap as evidenced by the linear temperature dependence of $\lambda(T)$. The experimental data are in quantitative agreement with theory.Comment: Phys. Rev. Lett. (in press). More details are include

Effects of Geochemical and Environmental Parameters on Abiotic Organic Chemistry Driven by Iron Hydroxide Minerals

Geological conditions play a significant role in prebiotic/abiotic organic chemistry, especially when reactive minerals are present. Previous studies of the prebiotic synthesis of amino acids and other products in mineral‐containing systems have shown that a diverse array of compounds can be produced, depending on the experimental conditions. However, these previous experiments have not simulated the effects of varying geochemical conditions, in which factors such as pH, iron redox state, or chemical concentrations may vary over time and space in a natural environment. In geochemical systems that contain overlapping gradients, many permutations of individual conditions could exist and affect the outcome of an organic reaction network. We investigated reactions of pyruvate and glyoxylate, two compounds that are central to the emergence of metabolism, in simulated geological gradients of redox, pH, and ammonia concentration. Our results show that the positioning of pyruvate/glyoxylate reactions in this environmental parameter space determines the organic product distribution that results. Therefore, the distribution pattern of amino acids and alpha‐hydroxy acids produced prebiotically in a system reflects the specific reaction conditions, and would be distinct at various locations in an environment depending on local geochemistry. This is significant for origin of life chemistry in which the composition and function of oligomers could be affected by the environmentally driven distribution of monomers available. Also, for astrobiology and planetary science where organic distribution patterns are sometimes considered as a possible biosignature, it is important to consider environmentally driven abiotic organic reactions that might produce similar effects

Thermodynamic Stability of the Transcription Regulator PaaR2 from Escherichia coli O157:H7

PaaR2 is a putative transcription regulator encoded by a three-component parDE-like toxin-antitoxin module from Escherichia coli O157:H7. Although this module’s toxin, antitoxin, and toxin-antitoxin complex have been more thoroughly investigated, little remains known about its transcription regulator PaaR2. Using a wide range of biophysical techniques (circular dichroism spectroscopy, size-exclusion chromatography-multiangle laser light scattering, dynamic light scattering, small-angle x-ray scattering, and native mass spectrometry), we demonstrate that PaaR2 mainly consists of α-helices and displays a concentration-dependent octameric build-up in solution and that this octamer contains a global shape that is significantly nonspherical. Thermal unfolding of PaaR2 is reversible and displays several transitions, suggesting a complex unfolding mechanism. The unfolding data obtained from spectroscopic and calorimetric methods were combined into a unifying thermodynamic model, which suggests a five-state unfolding trajectory. Furthermore, the model allows the calculation of a stability phase diagram, which shows that, under physiological conditions, PaaR2 mainly exists as a dimer that can swiftly oligomerize into an octamer depending on local protein concentrations. These findings, based on a thorough biophysical and thermodynamic analysis of PaaR2, may provide important insights into biological function such as DNA binding and transcriptional regulation

Proton–hydride tautomerism in hydrogen evolution catalysis

Efficient generation of hydrogen from renewable resources requires development of catalysts that avoid deep wells and high barriers. Information about the energy landscape for H_2 production can be obtained by chemical characterization of catalytic intermediates, but few have been observed to date. We have isolated and characterized a key intermediate in 2e^– + 2H^+ → H_2 catalysis. This intermediate, obtained by treatment of Cp*Rh(bpy) (Cp*, η^5-pentamethylcyclopentadienyl; bpy, κ^2-2,2′-bipyridyl) with acid, is not a hydride species but rather, bears [η^4-Cp*H] as a ligand. Delivery of a second proton to this species leads to evolution of H_2 and reformation of η^5-Cp* bound to rhodium(III). With suitable choices of acids and bases, the Cp*Rh(bpy) complex catalyzes facile and reversible interconversion of H^+ and H_2

Myocardial production and release of MCP-1 and SDF-1 following myocardial infarction: differences between mice and man

<p>Abstract</p> <p>Background</p> <p>Stem cell homing to the heart is mediated by the release of chemo-attractant cytokines. Stromal derived factor -1 alpha (SDF-1a) and monocyte chemotactic factor 1(MCP-1) are detectable in peripheral blood after myocardial infarction (MI). It remains unknown if they are produced by, and released from, the heart in order to attract stem cells to repair the damaged myocardium.</p> <p>Methods</p> <p>Murine hearts were studied for expression of MCP-1 and SDF-1a at day 3 and day 28 following myocardial infarction to determine whether production is increased following MI. In addition, we studied the coronary artery and coronary sinus (venous) blood from patients with normal coronary arteries, stable coronary artery disease (CAD), unstable angina and MI to determine whether these cytokines are released from the heart into the systemic circulation following MI.</p> <p>Results</p> <p>Both MCP-1 and SDF-1a are constitutively produced and released by the heart. MCP-1 mRNA is upregulated following murine experimental MI, but SDF-1a is suppressed. There is less release of SDF-1a into the systemic circulation in patients with all stages of CAD including MI, mimicking the animal model. However MCP-1 release from the human heart following MI is also suppressed, which is the exact opposite of the animal model.</p> <p>Conclusions</p> <p>SDF-1a and MCP-1 release from the human heart are suppressed following MI. In the case of SDF-1a, the animal model appropriately reflects the human situation. However, for MCP-1 the animal model is the exact opposite of the human condition. Human observational studies like this one are paramount in guiding translation from experimental studies to clinical trials.</p

An initial event in insect innate immune response: structural and biological studies of interactions between β-1,3-glucan and the N-terminal domain of β-1,3-glucan recognition protein

In response to invading microorganisms, insect β-1,3-glucan recognition protein (βGRP), a soluble receptor in the hemolymph, binds to the surfaces of bacteria and fungi and activates serine protease cascades that promote destruction of pathogens by means of melanization or expression of antimicrobial peptides. Here we report on the NMR solution structure of the N-terminal domain of βGRP (N-βGRP) from Indian meal moth (Plodia interpunctella), which is sufficient to activate the prophenoloxidase (proPO) pathway resulting in melanin formation. NMR and isothermal calorimetric titrations of N-βGRP with laminarihexaose, a glucose hexamer containing β-1,3 links, suggest a weak binding of the ligand. However, addition of laminarin, a glucose polysaccharide (~ 6 kDa) containing β-1,3 and β-1,6 links that activates the proPO pathway, to N-βGRP results in the loss of NMR cross-peaks from the backbone 15N-1H groups of the protein, suggesting the formation of a large complex. Analytical ultra centrifugation (AUC) studies of formation of N-βGRP:laminarin complex show that ligand-binding induces sel-fassociation of the protein:carbohydrate complex into a macro structure, likely containing six protein and three laminarin molecules (~ 102 kDa). The macro complex is quite stable, as it does not undergo dissociation upon dilution to sub-micromolar concentrations. The structural model thus derived from the present studies for N-βGRP:laminarin complex in solution differs from the one in which a single N-βGRP molecule has been proposed to bind to a triple helical form of laminarin on the basis of an X-ray crystallographic structure of N-βGRP:laminarihexaose complex [Kanagawa, M., Satoh, T., Ikeda, A., Adachi, Y., Ohno, N., and Yamaguchi, Y. (2011) J. Biol. Chem. 286, 29158-29165]. AUC studies and phenoloxidase activation measurements carried out with the designed mutants of N-βGRP indicate that electrostatic interactions involving Asp45, Arg54, and Asp68 between the ligand-bound protein molecules contribute in part to the stability of N-βGRP:laminarin macro complex and that a decreased stability is accompanied by a reduced activation of the proPO pathway. Increased β-1,6 branching in laminarin also results in destabilization of the macro complex. These novel findings suggest that ligand-induced self-association of βGRP:β-1,3-glucan complex may form a platform on a microbial surface for recruitment of downstream proteases, as a means of amplification of the initial signal of pathogen recognition for the activation of the proPO pathway

Search for MSSM Higgs bosons decaying to μ+μ-in proton-proton collisions at √s=13TeV

A search is performed for neutral non-standard-model Higgs bosons decaying to two muons in the context of the minimal supersymmetric standard model (MSSM). Proton-proton collision data recorded by the CMS experiment at the CERN Large Hadron Collider at a center-of-mass energy of 13TeVwere used, corresponding to an integrated luminosity of 35.9fb-1. The search is sensitive to neutral Higgs bosons produced via the gluon fusion process or in association with a bbquark pair. No significant deviations from the standard model expectation are observed. Upper limits at 95% confidence level are set in the context of the mmod+hand phenomenological MSSM scenarios on the parameter tanβas a function of the mass of the pseudoscalar Aboson, in the range from 130 to 600GeV. The results are also used to set a model-independent limit on the product of the branching fraction for the decay into a muon pair and the cross section for the production of a scalar neutral boson, either via gluon fusion, or in association with bquarks, in the mass range from 130 to 1000GeV

Tim-3 Negatively Regulates IL-12 Expression by Monocytes in HCV Infection

T cell immunoglobulin and mucin domain-containing protein 3 (Tim-3) is a newly identified negative immunomodulator that is up-regulated on dysfunctional T cells during viral infections. The expression and function of Tim-3 on human innate immune responses during HCV infection, however, remains poorly characterized. In this study, we report that Tim-3 is constitutively expressed on human resting CD14+ monocyte/macrophages (M/MØ) and functions as a cap to block IL-12, a key pro-inflammatory cytokine linking innate and adaptive immune responses. Tim-3 expression is significantly reduced and IL-12 expression increased upon stimulation with Toll-like receptor 4 (TLR4) ligand - lipopolysaccharide (LPS) and TLR7/8 ligand - R848. Notably, Tim-3 is over-expressed on un-stimulated as well as TLR-stimulated M/MØ, which is inversely associated with the diminished IL-12 expression in chronically HCV-infected individuals when compared to healthy subjects. Up-regulation of Tim-3 and inhibition of IL-12 are also observed in M/MØ incubated with HCV-expressing hepatocytes, as well as in primary M/MØ or monocytic THP-1 cells incubated with HCV core protein, an effect that mimics the function of complement C1q and is reversible by blocking the HCV core/gC1qR interaction. Importantly, blockade of Tim-3 signaling significantly rescues HCV-mediated inhibition of IL-12, which is primarily expressed by Tim-3 negative M/MØ. Tim-3 blockade reduces HCV core-mediated expression of the negative immunoregulators PD-1 and SOCS-1 and increases STAT-1 phosphorylation. Conversely, blocking PD-1 or silencing SOCS-1 gene expression also decreases Tim-3 expression and enhances IL-12 secretion and STAT-1 phosphorylation. These findings suggest that Tim-3 plays a crucial role in negative regulation of innate immune responses, through crosstalk with PD-1 and SOCS-1 and limiting STAT-1 phosphorylation, and may be a novel target for immunotherapy to HCV infection

Aquatic therapy for boys with Duchenne muscular dystrophy (DMD): an external pilot randomised controlled trial

Background: Standard treatment of Duchenne muscular dystrophy (DMD) includes regular physiotherapy. There are no data to show whether adding aquatic therapy (AT) to land-based exercises helps maintain motor function. We assessed the feasibility of recruiting and collecting data from boys with DMD in a parallel-group pilot randomised trial (primary objective), also assessing how intervention and trial procedures work. Methods: Ambulant boys with DMD aged 7–16 years established on steroids, with North Star Ambulatory Assessment (NSAA) score ≥8, who were able to complete a 10-m walk test without aids or assistance, were randomly allocated (1:1) to 6 months of either optimised land-based exercises 4 to 6 days/week, defined by local community physiotherapists, or the same 4 days/week plus AT 2 days/week. Those unable to commit to a programme, with >20% variation between NSAA scores 4 weeks apart, or contraindications to AT were excluded. The main outcome measures included feasibility of recruiting 40 participants in 6 months from six UK centres, clinical outcomes including NSAA, independent assessment of treatment optimisation, participant/therapist views on acceptability of intervention and research protocols, value of information (VoI) analysis and cost-impact analysis. Results: Over 6 months, 348 boys were screened: most lived too far from centres or were enrolled in other trials; 12 (30% of the targets) were randomised to AT (n = 8) or control (n = 4). The mean change in NSAA at 6 months was −5.5 (SD 7.8) in the control arm and −2.8 (SD 4.1) in the AT arm. Harms included fatigue in two boys, pain in one. Physiotherapists and parents valued AT but believed it should be delivered in community settings. Randomisation was unattractive to families, who had already decided that AT was useful and who often preferred to enrol in drug studies. The AT prescription was considered to be optimised for three boys, with other boys given programmes that were too extensive and insufficiently focused. Recruitment was insufficient for VoI analysis. Conclusions: Neither a UK-based RCT of AT nor a twice weekly AT therapy delivered at tertiary centres is feasible. Our study will help in the optimisation of AT service provision and the design of future research. Trial registration: ISRCTN4100295