A novel small molecule target in human airway smooth muscle for potential treatment of obstructive lung diseases: a staged high-throughput biophysical screening

<p>Abstract</p> <p>Background</p> <p>A newly identified mechanism of smooth muscle relaxation is the interaction between the small heat shock protein 20 (HSP20) and 14-3-3 proteins. Focusing upon this class of interactions, we describe here a novel drug target screening approach for treating airflow obstruction in asthma.</p> <p>Methods</p> <p>Using a high-throughput fluorescence polarization (FP) assay, we screened a library of compounds that could act as small molecule modulators of HSP20 signals. We then applied two quantitative, cell-based biophysical methods to assess the functional efficacy of these molecules and rank-ordered their abilities to relax isolated human airway smooth muscle (ASM). Scaling up to the level of an intact tissue, we confirmed in a concentration-responsive manner the potency of the cell-based hit compounds.</p> <p>Results</p> <p>Among 58,019 compound tested, 268 compounds caused 20% or more reduction of the polarized emission in the FP assay. A small subset of these primary screen hits, belonging to two scaffolds, caused relaxation of isolated ASM cell <it>in vitro </it>and attenuated active force development of intact tissue <it>ex vivo</it>.</p> <p>Conclusions</p> <p>This staged biophysical screening paradigm provides proof-of-principle for high-throughput and cost-effective discovery of new small molecule therapeutic agents for obstructive lung diseases.</p

Coupling Unification, GUT-Scale Baryogenesis and Neutron-Antineutron Oscillation in SO(10)

We show that unification of the three gauge couplings can be realized consistently in a class of non-supersymmetric SO(10) models with a one-step breaking to the Standard Model if a color-sextet scalar field survives down to the TeV scale. Such scalars, which should be accessible to the LHC for direct detection, arise naturally in SO(10) as remnants of the seesaw mechanism for neutrino masses. The diquark couplings of these scalars lead to \Delta B = 2 baryon number violating processes such as neutron-antineutron oscillation. We estimate the free neutron-antineutron transition time to be \tau_{n-\bar{n}} \approx (10^9-10^{12}) sec., which is in the interesting range for next generation n-\bar{n} oscillation experiments. These models also realize naturally the recently proposed (B-L)-violating GUT scale baryogenesis which survives to low temperatures unaffected by the electroweak sphaleron interactions.Comment: 15 pages, 4 eps figures, references added, to appear in Phys. Lett.

Defining an olfactory receptor function in airway smooth muscle cells

Pathways that control, or can be exploited to alter, the increase in airway smooth muscle (ASM) mass and cellular remodeling that occur in asthma are not well defined. Here we report the expression of odorant receptors (ORs) belonging to the superfamily of G-protein coupled receptors (GPCRs), as well as the canonical olfaction machinery (G olf and AC3) in the smooth muscle of human bronchi. In primary cultures of isolated human ASM, we identified mRNA expression for multiple ORs. Strikingly, OR51E2 was the most highly enriched OR transcript mapped to the human olfactome in lung-resident cells. In a heterologous expression system, OR51E2 trafficked readily to the cell surface and showed ligand selectivity and sensitivity to the short chain fatty acids (SCFAs) acetate and propionate. These endogenous metabolic byproducts of the gut microbiota slowed the rate of cytoskeletal remodeling, as well as the proliferation of human ASM cells. These cellular responses in vitro were found in ASM from non-asthmatics and asthmatics, and were absent in OR51E2-deleted primary human ASM. These results demonstrate a novel chemo-mechanical signaling network in the ASM and serve as a proof-of-concept that a specific receptor of the gut-lung axis can be targeted to treat airflow obstruction in asthma.open0

General CP Violation in Minimal Left-Right Symmetric Model and Constraints on the Right-Handed Scale

In minimal left-right symmetric theories, the requirement of parity invariance allows only one complex phase in the Higgs potential and one in the Yukawa couplings, leading to a two-phase theory with both spontaneous and explicit CP violations. We present a systematic way to solve the right-handed quark mixing matrix analytically in this model and find that the leading order solution has the same hierarchical structure as the left-handed CKM matrix with one more CP-violating phase coming from the complex Higgs vev. Armed with this explicit right-handed mixing matrix, we explore its implications for flavor changing and conserving processes in detail, low-energy CP-violating observables in particular. We report an improved lower bound on the $W_R$ mass of 2.5 TeV from $\Delta M_K$ and $\Delta M_{B}$, and a somewhat higher bound (4 TeV) from kaon decay parameters $\epsilon$, $\epsilon'$, and neutron electric dipole moment. The new bound on the flavor-changing neutral Higgs mass is 25 TeV.Comment: 35 pages, 14 figure

Asymmetric Inelastic Inert Doublet Dark Matter from Triplet Scalar Leptogenesis

The nature of dark matter (DM) particles and the mechanism that provides their measured relic abundance are currently unknown. In this paper we investigate inert scalar and vector like fermion doublet DM candidates with a charge asymmetry in the dark sector, which is generated by the same mechanism that provides the baryon asymmetry, namely baryogenesis-via-leptogenesis induced by decays of scalar triplets. At the same time the model gives rise to neutrino masses in the ballpark of oscillation experiments via type II seesaw. We discuss possible sources of depletion of asymmetry in the DM and visible sectors and solve the relevant Boltzmann equations for quasi-equilibrium decay of triplet scalars. A Monte-Carlo-Markov-Chain analysis is performed for the whole parameter space. The survival of the asymmetry in the dark sector leads to inelastic scattering off nuclei. We then apply bayesian statistic to infer the model parameters favoured by the current experimental data, in particular the DAMA annual modulation and Xenon100 exclusion limit. The latter strongly disfavours asymmetric scalar doublet DM of mass \mathcal{O}(\TeV) as required by DM-$\bar{\rm DM}$ oscillations, while an asymmetric vector like fermion doublet DM with mass around 100 GeV is a good candidate for DAMA annual modulation yet satisfying the constraints from Xenon100 data.Comment: 35 pages and 15 figures, references adde

Accidental stability of dark matter

We propose that dark matter is stable as a consequence of an accidental Z2 that results from a flavour-symmetry group which is the double-cover group of the symmetry group of one of the regular geometric solids. Although model-dependent, the phenomenology resembles that of a generic Higgs portal dark matter scheme.Comment: 12 pages, final version, published in JHE

Theoretical Review of B-physics

Weak decays and mixing of B-hadrons play a special role in our understanding of the physics of the Standard Model and beyond. The measured amplitudes, however, result from a complicated interplay of weak and strong interaction effects. Understanding strong interaction dynamics, which becomes simpler for heavy quarks, is thus a fundamental part of the game. In this review, several theoretical aspects of B dynamics which are relevant for current and future experimental measurements are discussed.Comment: LaTeX, 27 pages, 5 figures. Summary talk given at BEAUTY 96, June 17-21 1996, Rome (Italy), to appear in the Proceeding

Effective Lagrangian approach to neutrinoless double beta decay and neutrino masses

Neutrinoless double beta ($0\nu\beta\beta$) decay can in general produce electrons of either chirality, in contrast with the minimal Standard Model (SM) extension with only the addition of the Weinberg operator, which predicts two left-handed electrons in the final state. We classify the lepton number violating (LNV) effective operators with two leptons of either chirality but no quarks, ordered according to the magnitude of their contribution to \znbb decay. We point out that, for each of the three chirality assignments, $e_Le_L, e_Le_R$ and $e_Re_R$, there is only one LNV operator of the corresponding type to lowest order, and these have dimensions 5, 7 and 9, respectively. Neutrino masses are always induced by these extra operators but can be delayed to one or two loops, depending on the number of RH leptons entering in the operator. Then, the comparison of the $0\nu\beta\beta$ decay rate and neutrino masses should indicate the effective scenario at work, which confronted with the LHC searches should also eventually decide on the specific model elected by nature. We also list the SM additions generating these operators upon integration of the heavy modes, and discuss simple realistic examples of renormalizable theories for each case.Comment: Accepted for publication. Few misprints corrected and new references adde

5-a-day fruit and vegetable food product labels: reduced fruit and vegetable consumption following an exaggerated compared to a modest label.

BACKGROUND: Food product labels based on the WHO 5-a-day fruit and vegetable (FV) message are becoming increasingly common, but these labels may impact negatively on complementary or subsequent FV consumption. This study aimed to investigate the impact of a '3 of your 5-a-day' versus a '1 of your 5-a-day' smoothie product label on subsequent FV consumption. METHODS: Using an acute experimental design, 194 participants (90 males, 104 females) were randomised to consume a smoothie labelled as either '3 of your 5-a-day' (N = 97) or '1 of your 5-a-day' (N = 97) in full, following a usual breakfast. Subsequent FV consumption was measured for the rest of the day using 24-h recall. Usual FV consumption was also assessed via 24-h recall for the day before the study. RESULTS: Regression analyses revealed a significantly lower subsequent FV consumption following smoothies displaying the '3 of your 5-a-day' label compared to the '1 of your 5-a-day' label (Beta = - 0.15, p = 0.04). Secondary analyses revealed these effects to be driven mainly by changes to consumption in usual high FV consumers, in females and in vegetable as opposed to fruit consumption. CONCLUSIONS: These findings demonstrate a role for label information in food intake, and the potential negative impacts of an exaggerated food product label on healthy food consumption and healthy dietary profiles

Dark sectors 2016 Workshop: community report

This report, based on the Dark Sectors workshop at SLAC in April 2016, summarizes the scientific importance of searches for dark sector dark matter and forces at masses beneath the weak-scale, the status of this broad international field, the important milestones motivating future exploration, and promising experimental opportunities to reach these milestones over the next 5-10 years