Capture and decay of electroweak WIMPonium

The spectrum of Weakly-Interacting-Massive-Particle (WIMP) dark matter generically possesses bound states when the WIMP mass becomes sufficiently large relative to the mass of the electroweak gauge bosons. The presence of these bound states enhances the annihilation rate via resonances in the Sommerfeld enhancement, but they can also be produced directly with the emission of a low-energy photon. In this work we compute the rate for SU(2) triplet dark matter (the wino) to bind into WIMPonium - which is possible via single-photon emission for wino masses above 5 TeV for relative velocity v < O(10-2) - and study the subsequent decays of these bound states. We present results with applications beyond the wino case, e.g. for dark matter inhabiting a nonabelian dark sector; these include analytic capture and transition rates for general dark sectors in the limit of vanishing force carrier mass, efficient numerical routines for calculating positive and negative-energy eigenstates of a Hamiltonian containing interactions with both massive and massless force carriers, and a study of the scaling of bound state formation in the short-range Hulth&apos;{e}n potential. In the specific case of the wino, we find that the rate for bound state formation is suppressed relative to direct annihilation, and so provides only a small correction to the overall annihilation rate. The soft photons radiated by the capture process and by bound state transitions could permit measurement of the dark matter's quantum numbers; for wino-like dark matter, such photons are rare, but might be observable by a future ground-based gamma-ray telescope combining large effective area and a low energy threshold

A randomised phase I study of etrolizumab (rhuMAb β7) in moderate to severe ulcerative colitis.

ObjectiveEtrolizumab (rhuMAb β7, anti-β7, PRO145223) is a humanised monoclonal antibody targeting the β7 subunit of the heterodimeric integrins α4β7 and αEβ7, which are implicated in leucocyte migration and retention in ulcerative colitis (UC). This randomised phase I study evaluated the safety and pharmacology of etrolizumab in patients with moderate to severe UC.DesignIn the single ascending dose (SAD) stage, etrolizumab (0.3, 1.0, 3.0, 10 mg/kg intravenous, 3.0 mg/kg subcutaneous (SC) or placebo) was administered 4:1 (n=25) in each cohort. In the multiple dose (MD) stage, new patients received monthly etrolizumab (0.5 mg/kg SC (n=4), 1.5 mg/kg SC (n=5), 3.0 mg/kg SC (n=4), 4.0 mg/kg intravenous (n=5)) or placebo (n=5). The pharmacokinetics was studied and Mayo Clinic Score evaluated at baseline, day 29 (SAD), and days 43 and 71 (MD).ResultsIn the SAD stage, there were no dose limiting toxicities, infusion or injection site reactions. Two impaired wound healing serious adverse events occurred in two patients receiving etrolizumab. In the MD stage, there were no dose limiting toxicities, and no infusion or injection site reactions. Headache was the most common adverse event, occurring more often in etrolizumab patients. Antietrolizumab antibodies were detected in two subjects. The duration of β7 receptor full occupancy was dose related. A clinical response was observed in 12/18 patients, and clinical remission in 3/18 patients treated with etrolizumab in the MD stage, compared with 4/5 and 1/5 placebo patients, respectively.ConclusionEtrolizumab is well tolerated in moderate to severe UC. Further investigation is warranted

Polarization of Bi2Te3 Thin Film in a Floating-Gate Capacitor Structure

Metal-Oxide-Semiconductor (MOS) capacitors with Bi2Te3 thin film sandwiched and embedded inside the oxide layer have been fabricated and studied. The capacitors exhibit ferroelectric-like hysteresis which is a result of the robust, reversible polarization of the Bi2Te3 thin film while the gate voltage sweeps. The temperature-dependent capacitance measurement indicates that the activation energy is about 0.33 eV for separating the electron and hole pairs in the bulk of Bi2Te3, and driving them to either the top or bottom surface of the thin film. Because of the fast polarization speed, potentially excellent endurance, and the complementary metal - oxide - semiconductor compatibility, the Bi2Te3 embedded MOS structures are very interesting for memory application. © 2014 AIP Publishing LLC

The Impact of Experience with a Family Member with Alzheimer's Disease on Views about the Disease across Five Countries

The objective of this paper is to understand how the public's beliefs in five countries may change as more families have direct experience with Alzheimer's disease. The data are derived from a questionnaire survey conducted by telephone (landline and cell) with 2678 randomly selected adults in France, Germany, Poland, Spain, and the United States. The paper analyzes the beliefs and anticipated behavior of those in each country who report having had a family member with Alzheimer's disease versus those who do not. In one or more countries, differences were found between the two groups in their concern about getting Alzheimer's disease, knowledge that the disease is fatal, awareness of certain symptoms, and support for increased public spending. The results suggest that as more people have experience with a family member who has Alzheimer's disease, the public will generally become more concerned about Alzheimer's disease and more likely to recognize that Alzheimer's disease is a fatal disease. The findings suggest that other beliefs may only be affected if there are future major educational campaigns about the disease. The publics in individual countries, with differing cultures and health systems, are likely to respond in different ways as more families have experience with Alzheimer's disease

Objective Assessment of Arterial Steal Phenomenon in Direct Carotid Cavernous Fistula Using 2D Parametric Parenchymal Blood Flow Analysis

The aim of the study is to evaluate the hemodynamic changes and the parenchymal perfusion associated with carotid cavernous fistulas before and after embolization using two-dimensional (2D) parenchymal blood flow analysis. A 15-year-old boy presented with 2-month history of progressive right eye proptosis, chemosis, and diplopia after a motor vehicle accident. Intracranial liquid embolization using Onyx-18 through the inferior petrosal approach was done with balloon protection at the opening of the fistula in the internal carotid artery, resulting in complete occlusion of the fistula. Parenchymal blood flow analysis was done before and immediately after embolization. 2D parametric parenchymal blood flow analysis is newly introduced software that can provide data cannot be conveyed by conventional digital subtraction angiography alone. The software allows for objective assessment of the arterial steal and the parenchymal perfusion both pre, and post-embolization. Pre-embolization assessment may influence the therapeutic decision, while post-embolization assessment can evaluate the treatment efficacy

Hybridization from Guest-Host Interactions Reduces the Thermal Conductivity of Metal-Organic Frameworks

We experimentally and theoretically investigate the thermal conductivity and mechanical properties of polycrystalline HKUST-1 metal–organic frameworks (MOFs) infiltrated with three guest molecules: tetracyanoquinodimethane (TCNQ), 2,3,5,6-tetrafluoro-7,7,8,8-tetracyanoquinodimethane (F4-TCNQ), and (cyclohexane-1,4-diylidene)dimalononitrile (H4-TCNQ). This allows for modification of the interaction strength between the guest and host, presenting an opportunity to study the fundamental atomic scale mechanisms of how guest molecules impact the thermal conductivity of large unit cell porous crystals. The thermal conductivities of the guest@MOF systems decrease significantly, by on average a factor of 4, for all infiltrated samples as compared to the uninfiltrated, pristine HKUST-1. This reduction in thermal conductivity goes in tandem with an increase in density of 38% and corresponding increase in heat capacity of ∼48%, defying conventional effective medium scaling of thermal properties of porous materials. We explore the origin of this reduction by experimentally investigating the guest molecules’ effects on the mechanical properties of the MOF and performing atomistic simulations to elucidate the roles of the mass and bonding environments on thermal conductivity. The reduction in thermal conductivity can be ascribed to an increase in vibrational scattering introduced by extrinsic guest-MOF collisions as well as guest molecule-induced modifications to the intrinsic vibrational structure of the MOF in the form of hybridization of low frequency modes that is concomitant with an enhanced population of localized modes. The concentration of localized modes and resulting reduction in thermal conductivity do not seem to be significantly affected by the mass or bonding strength of the guest species

Vedolizumab for Treating Moderately to Severely Active Crohn’s Disease After Prior Therapy: An Evidence Review Group Perspective of a NICE Single Technology Appraisal

As part of its single technology appraisal process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer of vedolizumab (Takeda UK) to submit evidence of the clinical effectiveness and cost effectiveness of vedolizumab for the treatment of patients with moderate-to-severe, active Crohn’s disease. The School of Health and Related Research (ScHARR) at the University of Sheffield was commissioned as the Evidence Review Group (ERG) and produced a critical review of the evidence of the clinical effectiveness and cost effectiveness of the technology, based upon the company’s submission to NICE. The GEMINI II and III trials formed the main supporting evidence for the intervention. Both studies were phase III, randomised, double-blind, placebo-controlled, multicentre trials designed to evaluate the efficacy and safety of vedolizumab. They included patients who were naïve to tumour necrosis factor alpha antagonist (anti-TNF-α) therapy and patients who had an inadequate response to, loss of response to or intolerance of immunomodulators or anti-TNF-α agents. GEMINI II was designed to evaluate the efficacy and safety of vedolizumab as an induction treatment (dosing at weeks 0 and 2, with assessment at week 6) and maintenance treatment (during weeks 6–52). In contrast, GEMINI III was designed to evaluate the efficacy and safety of vedolizumab as an induction treatment only, with doses at weeks 0, 2 and 6, and assessment at weeks 6 and 10. In the absence of any direct head-to-head, randomised, controlled trials comparing vedolizumab with other relevant biologic therapies (adalimumab and infliximab) for the treatment of moderate-to-severe Crohn’s disease, the company conducted a network meta-analysis, which compared vedolizumab, adalimumab, infliximab and placebo for the outcomes of clinical response, enhanced clinical response, clinical remission and discontinuation due to adverse events. The company model estimated the incremental cost-effectiveness ratio (ICER) for vedolizumab compared with the standard of care (consisting of 5-aminosalicylic acids, corticosteroids and immunosuppressants) to be £21,620 per quality-adjusted life-year (QALY) gained within the anti-TNF-α-failure population (which included a confidential patient access scheme for vedolizumab). The ICERs were above £30,000 per QALY gained for the mixed intention-to-treat population (including both anti-TNF-α-naïve and anti-TNF-α-failure populations) and in patients who were anti-TNF-α naïve only. The ERG identified a number of limitations that were believed to limit the robustness of the results presented by the company. These limitations could not be addressed by the ERG without major restructuring of the economic model. Therefore, the ERG concluded that the results from the company’s model needed to be interpreted with caution and that it was unclear whether the ICERs would increase or decrease following amendment of the identified structural issues

Association Between Response to Etrolizumab and Expression of Integrin αE and Granzyme A in Colon Biopsies of Patients With Ulcerative Colitis

Background & AimsEtrolizumab is a humanized monoclonal antibody against the β7 integrin subunit that has shown efficacy vs placebo in patients with moderate to severely active ulcerative colitis (UC). Patients with colon tissues that expressed high levels of the integrin αE gene (ITGAE) appeared to have the best response. We compared differences in colonic expression of ITGAE and other genes between patients who achieved clinical remission with etrolizumab vs those who did.MethodsWe performed a retrospective analysis of data collected from 110 patients with UC who participated in a phase 2 placebo-controlled trial of etrolizumab, as well as from 21 patients with UC or without inflammatory bowel disease (controls) enrolled in an observational study at a separate site. Colon biopsies were collected from patients in both studies and analyzed by immunohistochemistry and gene expression profiling. Mononuclear cells were isolated and analyzed by flow cytometry. We identified biomarkers associated with response to etrolizumab. In the placebo-controlled trial, clinical remission was defined as total Mayo Clinic Score ≤2, with no individual subscore >1, and mucosal healing was defined as endoscopic score ≤1.ResultsColon tissues collected at baseline from patients who had a clinical response to etrolizumab expressed higher levels of T-cell−associated genes than patients who did not respond (P < .05). Colonic CD4+ integrin αE+ cells from patients with UC expressed higher levels of granzyme A messenger RNA (GZMA mRNA) than CD4+ αE− cells (P < .0001); granzyme A and integrin αE protein were detected in the same cells. Of patients receiving 100 mg etrolizumab, a higher proportion of those with high levels of GZMA mRNA (41%) or ITGAE mRNA (38%) than those with low levels of GZMA (6%) or ITGAE mRNA (13%) achieved clinical remission (P < .05) and mucosal healing (41% GZMAhigh vs 19% GZMAlow and 44% ITGAEhigh vs 19% ITGAElow). Compared with ITGAElow and GZMAlow patients, patients with ITGAEhigh and GZMAhigh had higher baseline numbers of epithelial crypt-associated integrin αE+ cells (P < .01 for both), but a smaller number of crypt-associated integrin αE+ cells after etrolizumab treatment (P < .05 for both). After 10 weeks of etrolizumab treatment, expression of genes associated with T-cell activation and genes encoding inflammatory cytokines decreased by 40%−80% from baseline (P < .05) in patients with colon tissues expressing high levels of GZMA at baseline.ConclusionsLevels of GZMA and ITGAE mRNAs in colon tissues can identify patients with UC who are most likely to benefit from etrolizumab; expression levels decrease with etrolizumab administration in biomarkerhigh patients. Larger, prospective studies of markers are needed to assess their clinical value

Direct Bacterial Killing In Vitro by Recombinant Nod2 Is Compromised by Crohn's Disease-Associated Mutations

Background: A homeostatic relationship with the intestinal microflora is increasingly appreciated as essential for human health and wellbeing. Mutations in the leucine-rich repeat (LRR) domain of Nod2, a bacterial recognition protein, are associated with development of the inflammatory bowel disorder, Crohn’s disease. We investigated the molecular mechanisms underlying disruption of intestinal symbiosis in patients carrying Nod2 mutations. Methodology/Principal Findings: In this study, using purified recombinant LRR domains, we demonstrate that Nod2 is a direct antimicrobial agent and this activity is generally deficient in proteins carrying Crohn’s-associated mutations. Wildtype, but not Crohn’s-associated, Nod2 LRR domains directly interacted with bacteria in vitro, altered their metabolism and disrupted the integrity of the plasma membrane. Antibiotic activity was also expressed by the LRR domains of Nod1 and other pattern recognition receptors suggesting that the LRR domain is a conserved anti-microbial motif supporting innate cellular immunity. Conclusions/Significance: The lack of anti-bacterial activity demonstrated with Crohn’s-associated Nod2 mutations in vitro, supports the hypothesis that a deficiency in direct bacterial killing contributes to the association of Nod2 polymorphism

Signal integration by lipid-mediated spatial cross talk between Ras nanoclusters

Lipid-anchored Ras GTPases form transient, spatially segregated nanoclusters on the plasma membrane that are essential for high-fidelity signal transmission. The lipid composition of Ras nanoclusters however has not previously been investigated. High-resolution spatial mapping shows that different Ras nanoclusters have distinct lipid compositions indicating that Ras proteins engage in isoform-selective lipid sorting, and accounting for different signal outputs from each Ras isoform. Phosphatidylserine is a common constituent of all Ras nanoclusters but is only an obligate structural component of K-Ras nanoclusters. Segregation of K-Ras and H-Ras into spatially and compositionally distinct lipid assemblies is exquisitely sensitive to plasma membrane phosphatidylserine levels. Phosphatidylserine spatial organization is also modified by Ras nanocluster formation. In consequence Ras nanoclusters engage in remote lipid-mediated communication, whereby activated H-Ras disrupts the assembly and operation of spatially segregated K-Ras nanoclusters. Computational modeling and experiment reveal that complex effects of caveolin and cortical actin on Ras nanoclustering are similarly mediated through regulation of phosphatidylserine spatiotemporal dynamics. We conclude that phosphatidylserine maintains the lateral segregation of diverse lipid-based assemblies on the plasma membrane and that lateral connectivity between spatially remote lipid assemblies offers important, previously unexplored opportunities for signal integration and signal processing