Natural Theories of Ultra-Low Mass PNGB's: Axions and Quintessence

We consider the Wilson Line PNGB which arises in a U(1)^N gauge theory, abstracted from a latticized, periodically compactified extra dimension U(1). Planck scale breaking of the PNGB's global symmetry is suppressed, providing natural candidates for the axion and quintessence. We construct an explicit model in which the axion may be viewed as the 5th component of the U(1)_Y gauge field in a 1+4 latticized periodically compactified extra dimension. We also construct a quintessence PNGB model where the ultra-low mass arises from Planck-scale suppressed physics itself.Comment: 20 pages, fixed typo and reference

Exploring content and psychometric validity of newly developed assessment tools for itch and skin pain in atopic dermatitis.

BackgroundAtopic dermatitis (AD) is a common skin disorder characterized by chronic inflammation, altered skin barrier function, and inflammatory cell skin infiltration that decreases health-related quality of life (HRQoL). The study objective was to understand the patient perspective of AD burden and determine suitable patient-reported outcome (PRO) measures.MethodsThis mixed methods study involved the collection of qualitative and quantitative information from adults (≥ 18 years old) and adolescents (12 - 17 years old) with clinician-confirmed AD regarding their experiences of AD symptoms and its impact on HRQoL. The first part of the study included three stages: in-person concept elicitation (CE) interviews, a 2-week daily electronic diary (eDiary) study, and in-person cognitive debriefing (CD) interviews. An Itch numeric rating scale (NRS) (v1.0) and a Skin Pain NRS (v1.0) evaluation during CD interviews required participants to think about their 'worst' itch and 'worst' skin pain in the past 24 h. Other PRO measures allowed for psychometric testing. The second part of the study involved telephone-depth interviews (TDIs) and qualitative feedback from participants who had not participated in the CD interviews. Qualitative data were thematically analyzed. Psychometric evaluation of NRS measures was performed using eDiary data.ResultsIn the CE interviews, itch and/or itching and skin pain were the most prevalent symptoms consistently discussed by participants. Both NRS measures demonstrated strong psychometric reliability and were applicable across ages with suitable concurrent validity. During the CD interviews, some participants focused their answers on their 'average' itch/itching in the past 24 h, rather than their 'worst' itch. Some participants answered the Skin Pain NRS thinking about general pain or other types of pain, rather than skin pain specifically. Consequently, modifications to both measures addressed these issues and re-tested as paper-and-pen versions in subsequent TDIs. Itch NRS (v2.0) modifications helped participants focus on their worst itching. Most participants preferred Skin Pain NRS v2.0b, which included skin pain descriptors.ConclusionsItching and skin pain are the most important and relevant AD symptoms. The Itch NRS (v2.0) and Skin Pain NRS (v2.0b) appear to be appropriate endpoints for the assessment of itching and skin pain severity for clinical trials with adults and adolescents with AD

Spin Dynamics In Single-Molecule Magnets Combining Surface Acoustic Waves And High-Frequency Electron Paramagnetic Resonance

We report an experimental technique that integrates high-frequency surface acoustic waves (SAWs) with high-frequency electron paramagnetic resonance (HFEPR) spectroscopy in order to measure spin dynamics on fast time scales in single-molecule magnets. After the system is driven out of equilibrium by triggering magnetic avalanches, or simply by heating with short SAW pulses, the evolution of the spin populations within fixed energy levels is measured using HFEPR spectroscopy

Optimizing information flow in small genetic networks. I

In order to survive, reproduce and (in multicellular organisms) differentiate, cells must control the concentrations of the myriad different proteins that are encoded in the genome. The precision of this control is limited by the inevitable randomness of individual molecular events. Here we explore how cells can maximize their control power in the presence of these physical limits; formally, we solve the theoretical problem of maximizing the information transferred from inputs to outputs when the number of available molecules is held fixed. We start with the simplest version of the problem, in which a single transcription factor protein controls the readout of one or more genes by binding to DNA. We further simplify by assuming that this regulatory network operates in steady state, that the noise is small relative to the available dynamic range, and that the target genes do not interact. Even in this simple limit, we find a surprisingly rich set of optimal solutions. Importantly, for each locally optimal regulatory network, all parameters are determined once the physical constraints on the number of available molecules are specified. Although we are solving an over--simplified version of the problem facing real cells, we see parallels between the structure of these optimal solutions and the behavior of actual genetic regulatory networks. Subsequent papers will discuss more complete versions of the problem

What doesn't kill you makes you stranger: Dipeptidyl peptidase-4 (CD26) proteolysis differentially modulates the activity of many peptide hormones and cytokines generating novel cryptic bioactive ligands

Dipeptidyl peptidase 4 (DPP4) is an exopeptidase found either on cell surfaces where it is highly regulated in terms of its expression and surface availability (CD26) or in a free/circulating soluble constitutively available and intrinsically active form. It is responsible for proteolytic cleavage of many peptide substrates. In this review we discuss the idea that DPP4-cleaved peptides are not necessarily inactivated, but rather can possess either a modified receptor selectivity, modified bioactivity, new antagonistic activity, or even a novel activity relative to the intact parent ligand. We examine in detail five different major DPP4 substrates: glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), peptide tyrosine-tyrosine (PYY), and neuropeptide Y (NPY), and stromal derived factor 1 (SDF-1 aka CXCL12). We note that discussion of the cleaved forms of these five peptides are underrepresented in the research literature, and are both poorly investigated and poorly understood, representing a serious research literature gap. We believe they are understudied and misinterpreted as inactive due to several factors. This includes lack of accurate and specific quantification methods, sample collection techniques that are inherently inaccurate and inappropriate, and a general perception that DPP4 cleavage inactivates its ligand substrates. Increasing evidence points towards many DPP4-cleaved ligands having their own bioactivity. For example, GLP-1 can work through a different receptor than GLP-1R, DPP4-cleaved GIP can function as a GIP receptor antagonist at high doses, and DPP4-cleaved PYY, NPY, and CXCL12 can have different receptor selectivity, or can bind novel, previously unrecognized receptors to their intact ligands, resulting in altered signaling and functionality. We believe that more rigorous research in this area could lead to a better understanding of DPP4’s role and the biological importance of the generation of novel cryptic ligands. This will also significantly impact our understanding of the clinical effects and side effects of DPP4-inhibitors as a class of anti-diabetic drugs that potentially have an expanding clinical relevance. This will be specifically relevant in targeting DPP4 substrate ligands involved in a variety of other major clinical acute and chronic injury/disease areas including inflammation, immunology, cardiology, stroke, musculoskeletal disease and injury, as well as cancer biology and tissue maintenance in aging

Lower Energy Consequences of an Anomalous High-Energy Neutrino Cross-Section

A new strong-interaction has been postulated for neutrinos above ~10^{19} eV to explain the production of highest-energy cosmic ray events. We derive a dispersion relation relating the hypothesized high-energy cross-section to the lower-energy neutrino-nucleon elastic amplitude. Remarkably, we find that the real forward amplitude becomes anomalous seven orders of magnitude lower in energy than does the total cross-section. We discuss possible measurable consequences of this early onset of new neutrino physics, and conclude that a significantly enhanced elastic \nu-N scattering rate may occur for the neutrino beams available at Fermilab and CERN.Comment: 13 pages, LaTe

Thick domain wall universes

We investigate the spacetime of a thick gravitating domain wall for a general potential $V(\Phi)$. Using general analytical arguments we show that all nontrivial solutions fall into two categories: those interpretable as an isolated domain wall with a cosmological event horizon, and those which are pure false vacuum de Sitter solutions. Although this latter solution is always unstable to the field rolling coherently to its true vacuum, we show that there is an additional instability to wall formation if the scalar field does not couple too strongly to gravity. Using the $\lambda \Phi^4$ and sine-Gordon models as illustrative examples, we investigate the phase space of the gravitating domain wall in detail numerically, following the solutions from weak to strong gravity. We find excellent agreement with the analytic work. Then, we analyse the domain wall in the presence of a cosmological constant finding again the two kinds of solutions, wall and de Sitter, even in the presence of a negative cosmological constant.Comment: 20 pages revtex, epsfig, references added, some conclusions altere

Macrophages orchestrate the expansion of a proangiogenic perivascular niche during cancer progression

Tumor-associated macrophages (TAMs) are a highly plastic stromal cell type that support cancer progression. Using single-cell RNA sequencing of TAMs from a spontaneous murine model of mammary adenocarcinoma (MMTV-PyMT), we characterize a subset of these cells expressing lymphatic vessel endothelial hyaluronic acid receptor 1 (Lyve-1) that spatially reside proximal to blood vasculature. We demonstrate that Lyve-1+ TAMs support tumor growth and identify a pivotal role for these cells in maintaining a population of perivascular mesenchymal cells that express α-smooth muscle actin and phenotypically resemble pericytes. Using photolabeling techniques, we show that mesenchymal cells maintain their prevalence in the growing tumor through proliferation and uncover a role for Lyve-1+ TAMs in orchestrating a selective platelet-derived growth factor–CC–dependent expansion of the perivascular mesenchymal population, creating a proangiogenic niche. This study highlights the inter-reliance of the immune and nonimmune stromal network that supports cancer progression and provides therapeutic opportunities for tackling the disease

High-Energy Tests of Lorentz Invariance

We develop a perturbative framework with which to discuss departures from exact Lorentz invariance and explore their potentially observable ramifications. Tiny non-invariant terms introduced into the standard model Lagrangian are assumed to be renormalizable (dimension $\le 4$), invariant under $SU(3)\otimes SU(2)\otimes U(1)$ gauge transformations, and rotationally and translationally invariant in a preferred frame. There are a total of 46 independent TCP-even perturbations of this kind, all of which preserve anomaly cancellation. They define the energy-momentum eigenstates and their maximal attainable velocities in the high-energy limit. The effects of these perturbations increase rapidly with energy in the preferred frame, more rapidly than those of TCP-odd perturbations. Our analysis of Lorentz-violating kinematics reveals several striking new phenomena that are relevant both to cosmic-ray physics ({\it e.g.,} by undoing the GZK cutoff) and neutrino physics ({\it e.g.,} by generating novel types of neutrino oscillations). These may lead to new and sensitive high-energy tests of special relativity.Comment: 33 pages, uses harvmac. This 2nd revision corrects two typos, an error in the Appendix, and includes further acknowledgement

Neutrinos produced by ultrahigh-energy photons at high red shift

Some of the proposed explanations for the origin of ultrahigh-energy cosmic rays invoke new sources of energetic photons (e.g., topological defects, relic particles, etc.). At high red shift, when the cosmic microwave background has a higher temperature but the radio background is low, the ultrahigh-energy photons can generate neutrinos through pair-production of muons and pions. Neutrinos produced at high red shift by slowly evolving sources can be detected. Rapidly evolving sources of photons can be ruled out based on the existing upper limit on the neutrino flux.Comment: 4 pages, revtex; to appear in Phys. Rev. Let