A Model for Neutrino Masses and Dark Matter

We propose a model for neutrino masses that simultaneously results in a new dark matter candidate, the right-handed neutrino. We derive the dark matter abundance in this model, show how the hierarchy of neutrino masses is obtained, and verify that the model is compatible with existing experimental results. The model provides an economical method of unifying two seemingly separate puzzles in contemporary particle physics and cosmology.Comment: 4 pages, submitted to PR

Noise Thresholds for Higher Dimensional Systems using the Discrete Wigner Function

For a quantum computer acting on d-dimensional systems, we analyze the computational power of circuits wherein stabilizer operations are perfect and we allow access to imperfect non-stabilizer states or operations. If the noise rate affecting the non-stabilizer resource is sufficiently high, then these states and operations can become simulable in the sense of the Gottesman-Knill theorem, reducing the overall power of the circuit to no better than classical. In this paper we find the depolarizing noise rate at which this happens, and consequently the most robust non-stabilizer states and non-Clifford gates. In doing so, we make use of the discrete Wigner function and derive facets of the so-called qudit Clifford polytope i.e. the inequalities defining the convex hull of all qudit Clifford gates. Our results for robust states are provably optimal. For robust gates we find a critical noise rate that, as dimension increases, rapidly approaches the the theoretical optimum of 100%. Some connections with the question of qudit magic state distillation are discussed.Comment: 14 pages, 1 table; Minor changes vs. version

The Global Emerging Infection Surveillance and Response System (GEIS), a U.S. government tool for improved global biosurveillance: a review of 2009

The Armed Forces Health Surveillance Center, Global Emerging Infections Surveillance and Response System (AFHSC-GEIS) has the mission of performing surveillance for emerging infectious diseases that could affect the United States (U.S.) military. This mission is accomplished by orchestrating a global portfolio of surveillance projects, capacity-building efforts, outbreak investigations and training exercises. In 2009, this portfolio involved 39 funded partners, impacting 92 countries. This article discusses the current biosurveillance landscape, programmatic details of organization and implementation, and key contributions to force health protection and global public health in 2009

Pharmacological Inhibition of polysialyltransferase ST8SiaII Modulates Tumour Cell Migration

YesPolysialic acid (polySia), an α-2,8-glycosidically linked polymer of sialic acid, is a developmentally regulated posttranslational modification predominantly found on NCAM (neuronal cell adhesion molecule). Whilst high levels are expressed during development, peripheral adult organs do not express polySia-NCAM. However, tumours of neural crest-origin re-express polySia-NCAM: its occurrence correlates with aggressive and invasive disease and poor clinical prognosis in different cancer types, notably including small cell lung cancer (SCLC), pancreatic cancer and neuroblastoma. In neuronal development, polySia-NCAM biosynthesis is catalysed by two polysialyltransferases, ST8SiaII and ST8SiaIV, but it is ST8SiaII that is the prominent enzyme in tumours. The aim of this study was to determine the effect of ST8SiaII inhibition by a small molecule on tumour cell migration, utilising cytidine monophosphate (CMP) as a tool compound. Using immunoblotting we showed that CMP reduced ST8iaII-mediated polysialylation of NCAM. Utilizing a novel HPLC-based assay to quantify polysialylation of a fluorescent acceptor (DMB-DP3), we demonstrated that CMP is a competitive inhibitor of ST8SiaII (Ki = 10 μM). Importantly, we have shown that CMP causes a concentration-dependent reduction in tumour cell-surface polySia expression, with an absence of toxicity. When ST8SiaII-expressing tumour cells (SH-SY5Y and C6-STX) were evaluated in 2D cell migration assays, ST8SiaII inhibition led to significant reductions in migration, while CMP had no effect on cells not expressing ST8SiaII (DLD-1 and C6-WT). The study demonstrates for the first time that a polysialyltransferase inhibitor can modulate migration in ST8SiaII-expressing tumour cells. We conclude that ST8SiaII can be considered a druggable target with the potential for interfering with a critical mechanism in tumour cell dissemination in metastatic cancers.Yorkshire Cancer Research; EPSRC; Association for International Cancer Research; Jordanian Government PhD scholarshi

Synergisitic role of ADP and Ca2+ in diastolic myocardial stiffness

Heart failure (HF) with diastolic dysfunction has been attributed to increased myocardial stiffness that limits proper filling of the ventricle. Altered cross-bridge interaction may significantly contribute to high diastolic stiffness, but this has not been shown thus far. Cross-bridge interactions are dependent on cytosolic [Ca2+] and the regeneration of ATP from ADP. Depletion of myocardial energy reserve is a hallmark of HF leading to ADP accumulation and disturbed Ca2+-handling. Here, we investigated if ADP elevation in concert with increased diastolic [Ca2+] promotes diastolic cross-bridge formation and force generation and thereby increases diastolic stiffness. ADP dose-dependently increased force production in the absence of Ca2+ in membrane-permeabilized cardiomyocytes from human hearts. Moreover, physiological levels of ADP increased actomyosin force generation in the presence of Ca2+ both in human and rat membrane-permeabilized cardiomyocytes. Diastolic stress measured at physiological lattice spacing and 37°C in the presence of pathologicallevels of ADP and diastolic [Ca2+] revealed a 76±1% contribution of cross-bridge interaction to total diastolic stress in rat membrane-permeabilized cardiomyocytes. Inhibition of creatine kinase (CK), which increases cytosolic ADP, in enzyme-isolated intact rat cardiomyocytes impaired diastolic re-lengthening associated with diastolic Ca2+- overload. In isolated Langendorff-perfused rat hearts, CK-inhibition increased ventricular stiffness only in the presence of diastolic [Ca2+]. We propose that elevations of intracellular ADP in specific types of cardiac disease, including those where myocardial energy reserve is limited, contribute to diastolic dysfunction by recruiting cross-bridges even at low Ca2+ and thereby increase myocardial stiffness

Inhibition of the inositol kinase Itpkb augments calcium signaling in lymphocytes and reveals a novel strategy to treat autoimmune disease

Emerging approaches to treat immune disorders target positive regulatory kinases downstream of antigen receptors with small molecule inhibitors. Here we provide evidence for an alternative approach in which inhibition of the negative regulatory inositol kinase Itpkb in mature T lymphocytes results in enhanced intracellular calcium levels following antigen receptor activation leading to T cell death. Using Itpkb conditional knockout mice and LMW Itpkb inhibitors these studies reveal that Itpkb through its product IP4 inhibits the Orai1/Stim1 calcium channel on lymphocytes. Pharmacological inhibition or genetic deletion of Itpkb results in elevated intracellular Ca2+ and induction of FasL and Bim resulting in T cell apoptosis. Deletion of Itpkb or treatment with Itpkb inhibitors blocks T-cell dependent antibody responses in vivo and prevents T cell driven arthritis in rats. These data identify Itpkb as an essential mediator of T cell activation and suggest Itpkb inhibition as a novel approach to treat autoimmune disease

Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)

A growing global network’s role in outbreak response: AFHSC-GEIS 2008-2009

A cornerstone of effective disease surveillance programs comprises the early identification of infectious threats and the subsequent rapid response to prevent further spread. Effectively identifying, tracking and responding to these threats is often difficult and requires international cooperation due to the rapidity with which diseases cross national borders and spread throughout the global community as a result of travel and migration by humans and animals. From Oct.1, 2008 to Sept. 30, 2009, the United States Department of Defense’s (DoD) Armed Forces Health Surveillance Center Global Emerging Infections Surveillance and Response System (AFHSC-GEIS) identified 76 outbreaks in 53 countries. Emerging infectious disease outbreaks were identified by the global network and included a wide spectrum of support activities in collaboration with host country partners, several of which were in direct support of the World Health Organization’s (WHO) International Health Regulations (IHR) (2005). The network also supported military forces around the world affected by the novel influenza A/H1N1 pandemic of 2009. With IHR (2005) as the guiding framework for action, the AFHSC-GEIS network of international partners and overseas research laboratories continues to develop into a far-reaching system for identifying, analyzing and responding to emerging disease threats

Delivering the world’s most intense muon beam

A new muon beam line, the muon science innovative channel, was set up at the Research Center for Nuclear Physics, Osaka University, in Osaka, Japan, using the 392 MeV proton beam impinging on a target. The production of an intense muon beam relies on the efficient capture of pions, which subsequently decay to muons, using a novel superconducting solenoid magnet system. After the pion-capture solenoid, the first 36° of the curved muon transport line was commissioned and the muon flux was measured. In order to detect muons, a target of either copper or magnesium was placed to stop muons at the end of the muon beam line. Two stations of plastic scintillators located upstream and downstream from the muon target were used to reconstruct the decay spectrum of muons. In a complementary method to detect negatively charged muons, the x-ray spectrum yielded by muonic atoms in the target was measured in a germanium detector. Measurements, at a proton beam current of 6 pA, yielded (10.4±2.7)×10^{5}  muons per watt of proton beam power (μ^{+} and μ^{-}), far in excess of other facilities. At full beam power (400 W), this implies a rate of muons of (4.2±1.1)×10^{8}  muons s^{−1}, among the highest in the world. The number of μ^{-} measured was about a factor of 10 lower, again by far the most efficient muon beam produced. The setup is a prototype for future experiments requiring a high-intensity muon beam, such as a muon collider or neutrino factory, or the search for rare muon decays which would be a signature for phenomena beyond the Standard Model of particle physics. Such a muon beam can also be used in other branches of physics, nuclear and condensed matter, as well as other areas of scientific research