Elevated Toll-Like Receptor 4 Expression and Signaling in Muscle From Insulin-Resistant Subjects

OBJECTIVE— Tall-like receptor (TLR)4 has been implicated in the pathogenesis of free fatty acid (FFA)-induced insulin resistance by activating inflammatory pathways, including inhibitor of κB (IκB)/nuclear factor κB (NFκB). However, it is not known whether insulin-resistant subjects have abnormal TLR4 signaling. We examined whether insulin-resistant subjects have abnormal TLR4 expression and TLR4-driven (IκB/NFκB) signaling in skeletal muscle

Effect of Acute Exercise on AMPK Signaling in Skeletal Muscle of Subjects With Type 2 Diabetes

Activation of AMP-activated protein kinase (AMPK) by exercise induces several cellular processes in muscle. Exercise activation of AMPK is unaffected in lean (BMI ~25 kg/m2) subjects with type 2 diabetes. However, most type 2 diabetic subjects are obese (BMI \u3e30 kg/m2), and exercise stimulation of AMPK is blunted in obese rodents. We examined whether obese type 2 diabetic subjects have impaired exercise stimulation of AMPK, at different signaling levels, spanning from the upstream kinase, LKB1, to the putative AMPK targets, AS160 and peroxisome proliferator–activated receptor coactivator (PGC)-1α, involved in glucose transport regulation and mitochondrial biogenesis, respectively. Twelve type 2 diabetic, eight obese, and eight lean subjects exercised on a cycle ergometer for 40 min. Muscle biopsies were done before, during, and after exercise. Subjects underwent this protocol on two occasions, at low (50% VO2max) and moderate (70% VO2max) intensities, with a 4–6 week interval. Exercise had no effect on LKB1 activity. Exercise had a time- and intensity-dependent effect to increase AMPK activity and AS160 phosphorylation. Obese and type 2 diabetic subjects had attenuated exercise-stimulated AMPK activity and AS160 phosphorylation. Type 2 diabetic subjects had reduced basal PGC-1 gene expression but normal exercise-induced increases in PGC-1 expression. Our findings suggest that obese type 2 diabetic subjects may need to exercise at higher intensity to stimulate the AMPK-AS160 axis to the same level as lean subjects

Multiple programs: essential to the scientific vitality of the DOE Defense Program Laboratories

The future of the Department of Energy� s Defense Program (DP) laboratories-Los Alamos, Livermore, and Sandia-has been extensively debated and examined over the past several years. To assist in this process, I have asked that a set of documents be prepared, which, when taken together, present a comprehensive picture of the three laboratories. This document describes the multiprogram nature of the DP laboratories and the value of their involvement in non-DP work as it relates to the nuclear weapons program. The other two documents, Integration and Collaboration.. Solving Science and Technology Problems for the Nation (DOE/DP-96009797) and Roles and Responsibilities of the Department of Energy Nuclear Weapons Laboratories in the Stockpile Stewardship and Management Program (DOE/DP-97000280), describe respectively the integrated nature of the DP laboratories and the roles of the laboratories as they meet their individual and collective responsibilities of ensuring the safety and reliabilities of the U.S. nuclear weapons stockpile. The scientific and technical challenges inherent in the DP laboratories� national security responsibilities today are as complex as those during the Manhattan Project and the Cold War years. Science-based stockpile stewardship and management require in-depth understanding of the full spectrum of nuclear weapons science and technology- physics, chemistry, materials, manufacturing, computational modeling, engineering, and electronics, to name a few-as well as a combination of capabilities and facilities unavailable anywhere else in the country. In addition to stockpile stewardship and management, many other nationally important issues involve science and technology-for example, nuclear nonproliferation, energy security, and environmental protection and remediation. Over the years, the DP laboratories have applied expertise and technologies developed in their nuclear weapons work to these other issues, focusing on those areas where they can make unique and valuable contributions. The nation has invested substantially in the three DP laboratories, creating an unmatched resource of scientific and engineering expertise, facilities, and capabilities. In this era of tight budgets, it is important that the laboratories extract maximum leverage from this investment and fulfill their nuclear weapons responsibilities as cost-effectively as possible. The multiprogram nature of the DP laboratories has been key to their success in achieving the outstanding level of scientific and technical excellence that has become their hallmark and in carrying out their national security mission. The multiprogram work of the laboratories also provides an extremely effective way of leveraging the nation� s investment in science and technology. It makes sense for the DP laboratories to apply their expertise to non-nuclear-weapons programs of national importance. It also makes sense for the DP laboratories to collaborate with other government laboratories, universities, and industry to apply the unique expertise, facilities, and capabilities of these institutions to national security challenges. This report briefly reviews the challenges faced by the DP laboratories in fulfilling their stockpile stewardship and management responsibilities. It then discusses the benefits of the synergy and the accelerated pace of scientific achievement that arise from the laboratories� multiple programs. A representative selection of accomplishments is presented that illustrates the importance of the contributions made to the laboratories� national security mission by their non-nuclear-weapons projects and their connections with the wider scientific community

Search for non-relativistic Magnetic Monopoles with IceCube

The IceCube Neutrino Observatory is a large Cherenkov detector instrumenting $1\,\mathrm{km}^3$ of Antarctic ice. The detector can be used to search for signatures of particle physics beyond the Standard Model. Here, we describe the search for non-relativistic, magnetic monopoles as remnants of the GUT (Grand Unified Theory) era shortly after the Big Bang. These monopoles may catalyze the decay of nucleons via the Rubakov-Callan effect with a cross section suggested to be in the range of $10^{-27}\,\mathrm{cm^2}$ to $10^{-21}\,\mathrm{cm^2}$. In IceCube, the Cherenkov light from nucleon decays along the monopole trajectory would produce a characteristic hit pattern. This paper presents the results of an analysis of first data taken from May 2011 until May 2012 with a dedicated slow-particle trigger for DeepCore, a subdetector of IceCube. A second analysis provides better sensitivity for the brightest non-relativistic monopoles using data taken from May 2009 until May 2010. In both analyses no monopole signal was observed. For catalysis cross sections of $10^{-22}\,(10^{-24})\,\mathrm{cm^2}$ the flux of non-relativistic GUT monopoles is constrained up to a level of $\Phi_{90} \le 10^{-18}\,(10^{-17})\,\mathrm{cm^{-2}s^{-1}sr^{-1}}$ at a 90% confidence level, which is three orders of magnitude below the Parker bound. The limits assume a dominant decay of the proton into a positron and a neutral pion. These results improve the current best experimental limits by one to two orders of magnitude, for a wide range of assumed speeds and catalysis cross sections.Comment: 20 pages, 20 figure

Flavor Ratio of Astrophysical Neutrinos above 35 TeV in IceCube

A diffuse flux of astrophysical neutrinos above $100\,\mathrm{TeV}$ has been observed at the IceCube Neutrino Observatory. Here we extend this analysis to probe the astrophysical flux down to $35\,\mathrm{TeV}$ and analyze its flavor composition by classifying events as showers or tracks. Taking advantage of lower atmospheric backgrounds for shower-like events, we obtain a shower-biased sample containing 129 showers and 8 tracks collected in three years from 2010 to 2013. We demonstrate consistency with the $(f_e:f_{\mu}:f_\tau)_\oplus\approx(1:1:1)_\oplus$ flavor ratio at Earth commonly expected from the averaged oscillations of neutrinos produced by pion decay in distant astrophysical sources. Limits are placed on non-standard flavor compositions that cannot be produced by averaged neutrino oscillations but could arise in exotic physics scenarios. A maximally track-like composition of $(0:1:0)_\oplus$ is excluded at $3.3\sigma$, and a purely shower-like composition of $(1:0:0)_\oplus$ is excluded at $2.3\sigma$.Comment: 8 pages, 3 figures. Submitted to PR

Determining neutrino oscillation parameters from atmospheric muon neutrino disappearance with three years of IceCube DeepCore data

We present a measurement of neutrino oscillations via atmospheric muon neutrino disappearance with three years of data of the completed IceCube neutrino detector. DeepCore, a region of denser instrumentation, enables the detection and reconstruction of atmospheric muon neutrinos between 10 GeV and 100 GeV, where a strong disappearance signal is expected. The detector volume surrounding DeepCore is used as a veto region to suppress the atmospheric muon background. Neutrino events are selected where the detected Cherenkov photons of the secondary particles minimally scatter, and the neutrino energy and arrival direction are reconstructed. Both variables are used to obtain the neutrino oscillation parameters from the data, with the best fit given by $\Delta m^2_{32}=2.72^{+0.19}_{-0.20}\times 10^{-3}\,\mathrm{eV}^2$ and $\sin^2\theta_{23} = 0.53^{+0.09}_{-0.12}$ (normal mass hierarchy assumed). The results are compatible and comparable in precision to those of dedicated oscillation experiments.Comment: 10 pages, 7 figure

Determining neutrino oscillation parameters from atmospheric muon neutrino disappearance with three years of IceCube DeepCore data

We present a measurement of neutrino oscillations via atmospheric muon neutrino disappearance with three years of data of the completed IceCube neutrino detector. DeepCore, a region of denser instrumentation, enables the detection and reconstruction of atmospheric muon neutrinos between 10 GeV and 100 GeV, where a strong disappearance signal is expected. The detector volume surrounding DeepCore is used as a veto region to suppress the atmospheric muon background. Neutrino events are selected where the detected Cherenkov photons of the secondary particles minimally scatter, and the neutrino energy and arrival direction are reconstructed. Both variables are used to obtain the neutrino oscillation parameters from the data, with the best fit given by $\Delta m^2_{32}=2.72^{+0.19}_{-0.20}\times 10^{-3}\,\mathrm{eV}^2$ and $\sin^2\theta_{23} = 0.53^{+0.09}_{-0.12}$ (normal mass hierarchy assumed). The results are compatible and comparable in precision to those of dedicated oscillation experiments.Comment: 10 pages, 7 figure

Lateral Distribution of Muons in IceCube Cosmic Ray Events

In cosmic ray air showers, the muon lateral separation from the center of the shower is a measure of the transverse momentum that the muon parent acquired in the cosmic ray interaction. IceCube has observed cosmic ray interactions that produce muons laterally separated by up to 400 m from the shower core, a factor of 6 larger distance than previous measurements. These muons originate in high pT (> 2 GeV/c) interactions from the incident cosmic ray, or high-energy secondary interactions. The separation distribution shows a transition to a power law at large values, indicating the presence of a hard pT component that can be described by perturbative quantum chromodynamics. However, the rates and the zenith angle distributions of these events are not well reproduced with the cosmic ray models tested here, even those that include charm interactions. This discrepancy may be explained by a larger fraction of kaons and charmed particles than is currently incorporated in the simulations