Influence of dietary nitrate supplementation on physiological and muscle metabolic adaptations to sprint interval training

This is the author accepted manuscript. The final version is available from the American Physiological Society via the DOI in this record.We hypothesized that 4 wk of dietary nitrate supplementation would enhance exercise performance and muscle metabolic adaptations to sprint interval training (SIT). Thirty-six recreationally active subjects, matched on key variables at baseline, completed a series of exercise tests before and following a 4-wk period in which they were allocated to one of the following groups: 1) SIT and NO3--depleted beetroot juice as a placebo (SIT+PL); 2) SIT and NO3--rich beetroot juice (∼13 mmol NO3-/day; SIT+BR); or 3) no training and NO3--rich beetroot juice (NT+BR). During moderate-intensity exercise, pulmonary oxygen uptake was reduced by 4% following 4 wk of SIT+BR and NT+BR (P 0.05). The relative proportion of type IIx muscle fibers in the vastus lateralis muscle was reduced in SIT+BR only (P < 0.05). These findings suggest that BR supplementation may enhance some aspects of the physiological adaptations to SIT. NEW & NOTEWORTHY We investigated the influence of nitraterich and nitrate-depleted beetroot juice on the muscle metabolic and physiological adaptations to 4 wk of sprint interval training. Compared with placebo, dietary nitrate supplementation reduced the O2 cost of submaximal exercise, resulted in greater improvement in incremental (but not severe-intensity) exercise performance, and augmented some muscle metabolic adaptations to training. Nitrate supplementation may facilitate some of the physiological responses to sprint interval training.PepsiC

A randomized study of solriamfetol for excessive sleepiness in narcolepsy

Objective: Solriamfetol (JZP-110) is a selective dopamine and norepinephrine reuptake inhibitor with wake-promoting effects. This phase 3 study (NCT02348593) evaluated the safety and efficacy of solriamfetol in narcolepsy. Methods: Patients with narcolepsy with mean sleep latency &lt;25 minutes on the Maintenance of Wakefulness Test (MWT), Epworth Sleepiness Scale (ESS) score ≥10, and usual nightly sleep ≥6 hours were randomized to solriamfetol 75, 150, or 300 mg, or placebo for 12 weeks. Coprimary endpoints were change from baseline to week 12 in MWT and ESS. Improvement on the Patient Global Impression of Change (PGI-C) was the key secondary endpoint. Results: Safety and modified intention-to-treat populations included 236 and 231 patients, respectively. Solriamfetol 300 and 150 mg were positive on both coprimary endpoints. Least squares mean (standard error [SE]) changes from baseline were 12.3 (SE = 1.4) and 9.8 (SE = 1.3) minutes for solriamfetol 300 and 150 mg on the MWT, respectively, versus 2.1 (SE = 1.3) minutes for placebo, and −6.4 (SE = 0.7) for 300 mg and −5.4 (SE = 0.7) for 150 mg on the ESS versus −1.6 (SE = 0.7) for placebo (all p &lt; 0.0001). At week 12, higher percentages of patients treated with solriamfetol 150 mg (78.2%) and 300 mg (84.7%) reported PGI-C improvement relative to placebo (39.7%; both p &lt; 0.0001). Adverse events ≥5% across all solriamfetol doses included headache (21.5%), nausea (10.7%), decreased appetite (10.7%), nasopharyngitis (9.0%), dry mouth (7.3%), and anxiety (5.1%). Interpretation: Solriamfetol has the potential to be an important therapeutic option for the treatment of impaired wakefulness and excessive sleepiness in patients with narcolepsy. ANN NEUROL 2019;85:359–370

On Weak Keys and Forgery Attacks Against Polynomial-Based MAC Schemes

Abstract. Universal hash functions are commonly used primitives for fast and secure message authentication in the form of Message Authentication Codes (MACs) or Authenticated Encryption with Associated Data (AEAD) schemes. These schemes are widely used and standardised, the most well known being McGrew and Viega’s Galois/Counter Mode (GCM). In this paper we identify some properties of hash functions based on polynomial evaluation that arise from the underlying algebraic structure. As a result we are able to describe a general forgery attack, of which Saarinen’s cycling attack from FSE 2012 is a special case. Our attack removes the requirement for long messages and applies regardless of the field in which the hash function is evaluated. Furthermore we provide a common description of all published attacks against GCM, by showing that the existing attacks are the result of these algebraic properties of the polynomial-based hash function. We also greatly expand the number of known weak GCM keys and show that almost every subset of the keyspace is a weak key class. Finally, we demonstrate that these algebraic properties and corresponding attacks are highly relevant to GCM/2 +, a variant of GCM designed to increase the efficiency in software

Electroweak Physics for Color Superconductivity

We construct the effective theories describing the electroweak interactions for the low energy excitations associated with the color superconductive phases of QCD at high matter density. The main result, for the 3 flavor case, is that the quasiparticle Goldstone boson $\pi^0$ decay into two physical massless photons is identical to the zero density case once we use the new Goldstone decay constant and the modified electric charge $\widetilde{e}=e \cos\theta$, with $\tan\theta =2e/\sqrt{3}g_s$ and $g_s$ the strong coupling constant. For 2 flavors we find that the coupling of the quarks to the neutral vector boson $Z^0$ is modified with respect to the zero density case. We finally point out possible applications of our result to the physics of compact objects.Comment: 23 pages, 1 Figure, RevTex. More discussion and references adde

Low Energy Theory for 2 flavors at High Density QCD

We construct the effective Lagrangian describing the low energy excitations for Quantum Chromodynamics with two flavors at high density. The non-linear realization framework is employed to properly construct the low energy effective theory. The light degrees of freedom, as required by 't Hooft anomaly conditions, contain massless fermions which we properly include in the effective Lagrangian. We also provide a discussion of the linearly realized Lagrangian.Comment: 17 pages, RevTeX format, references added. To appear in Phys. Rev.

Distinct Effects of Blood Flow and Temperature on Cutaneous Microvascular Adaptation

Aims: We performed two experiments to determine whether cutaneous microvascular adaptations in response to repeated core temperature elevation are mediated by increases in skin temperature, and/or, skin blood flow. Methods: Healthy subjects participated for 8-weeks in thrice-weekly bouts of 30mins lower limb heating (40°C). In Study 1, both forearms were “clamped” at basal skin temperature throughout each heating bout (n=9). Study 2 involved identical lower limb heating, with the forearms under ambient conditions (unclamped, n=10). In both studies, a cuff was inflated around one forearm during the heating bouts to assess the contribution of skin blood flow and temperature responses. We assessed forearm skin blood flow responses to both lower limb (systemic reflex) heating, and to local heating of the forearm skin, pre and post intervention. Results: Acutely, lower limb heating increased core temperature (Study 1: +0.63±0.15°C, Study 2: +0.69±0.19°C, P<0.001) and forearm skin blood flow (Study 1: 10±3 vs 125±44, Study 2: 16±9 vs 136±41 PU, P<0.001), with skin responses significantly attenuated in the cuffed forearm (P<0.01). Skin blood flow responses to local heating decreased in Study 1 (clamped forearms, week 0vs8: 1.46±0.52 vs 0.99±0.44 CVC, P<0.05), whereas increases occurred in Study 2 (unclamped; week 0vs8: 1.89±0.57 vs 2.27±0.52 CVC, P<0.05). Cuff placement abolished local adaptations in both studies. Conclusion: Our results indicate that repeated increases in skin blood flow and skin temperature result in increased skin flux responses to local heating, whereas repeated increases in skin blood flow in the absence of change in skin temperature induced the opposite response. Repeated increases in core temperature induce intrinsic microvascular changes, the nature of which are dependent upon both skin blood flow and skin temperature

H2 Temperatures in the Crab Nebula

We used K-band spectra to measure the H2 excitation temperatures in six molecular knots associated with the filaments in the Crab Nebula. The temperatures are quite high - in the range T ~ 2000-3000K, just below the H2 dissociation temperature. This is the temperature range over which the H2 1-0 S(1) line at 2.121\mum has its maximum emissivity per unit mass, so there may be many additional H2 cores with lower temperatures that are too faint to detect. We also measured the electron density in adjacent ionized gas, which on the assumption of gas pressure balance indicates densities in the molecular region n_mol ~ 20,000 H baryons cm-3, although this really is just a lower limit since the H2 gas may be confined by other means. The excited region may be just a thin skin on a much more extensive blob of molecular gas that does not have the correct temperature and density to be as easily detectable. At the opposite extreme, the observed knots could consist of a fine mist of molecular gas in which we are detecting essentially all of the H2. Future CO observations could distinguish between these two cases. The Crab filaments serve as the nearby laboratories for understanding the very much larger filamentary structures that have formed in the intracluster medium of cool-core galaxy clusters.Comment: 16 pages, 5 figure

Prospects for progress on health inequalities in England in the post-primary care trust era : professional views on challenges, risks and opportunities

Background - Addressing health inequalities remains a prominent policy objective of the current UK government, but current NHS reforms involve a significant shift in roles and responsibilities. Clinicians are now placed at the heart of healthcare commissioning through which significant inequalities in access, uptake and impact of healthcare services must be addressed. Questions arise as to whether these new arrangements will help or hinder progress on health inequalities. This paper explores the perspectives of experienced healthcare professionals working within the commissioning arena; many of whom are likely to remain key actors in this unfolding scenario. Methods - Semi-structured interviews were conducted with 42 professionals involved with health and social care commissioning at national and local levels. These included representatives from the Department of Health, Primary Care Trusts, Strategic Health Authorities, Local Authorities, and third sector organisations. Results - In general, respondents lamented the lack of progress on health inequalities during the PCT commissioning era, where strong policy had not resulted in measurable improvements. However, there was concern that GP-led commissioning will fare little better, particularly in a time of reduced spending. Specific concerns centred on: reduced commitment to a health inequalities agenda; inadequate skills and loss of expertise; and weakened partnership working and engagement. There were more mixed opinions as to whether GP commissioners would be better able than their predecessors to challenge large provider trusts and shift spend towards prevention and early intervention, and whether GPs’ clinical experience would support commissioning action on inequalities. Though largely pessimistic, respondents highlighted some opportunities, including the potential for greater accountability of healthcare commissioners to the public and more influential needs assessments via emergent Health & Wellbeing Boards. Conclusions - There is doubt about the ability of GP commissioners to take clearer action on health inequalities than PCTs have historically achieved. Key actors expect the contribution from commissioning to address health inequalities to become even more piecemeal in the new arrangements, as it will be dependent upon the interest and agency of particular individuals within the new commissioning groups to engage and influence a wider range of stakeholders.</p

Characterization of CDK(5) Inhibitor, 20-223 (aka CP668863) for Colorectal Cancer Therapy

Colorectal cancer (CRC) remains one of the leading causes of cancer related deaths in the United States. Currently, there are limited therapeutic options for patients suffering from CRC, none of which focus on the cell signaling mechanisms controlled by the popular kinase family, cyclin dependent kinases (CDKs). Here we evaluate a Pfizer developed compound, CP668863, that inhibits cyclin-dependent kinase 5 (CDK5) in neurodegenerative disorders. CDK5 has been implicated in a number of cancers, most recently as an oncogene in colorectal cancers. Our lab synthesized and characterized CP668863 – now called 20-223. In our established colorectal cancer xenograft model, 20-223 reduced tumor growth and tumor weight indicating its value as a potential anti-CRC agent. We subjected 20-223 to a series of cell-free and cell-based studies to understand the mechanism of its anti-tumor effects. In our hands, in vitro 20-223 is most potent against CDK2 and CDK5. The clinically used CDK inhibitor AT7519 and 20-223 share the aminopyrazole core and we used it to benchmark the 20-223 potency. In CDK5 and CDK2 kinase assays, 20-223 was ~3.5-fold and ~65.3-fold more potent than known clinically used CDK inhibitor, AT7519, respectively. Cell-based studies examining phosphorylation of downstream substrates revealed 20-223 inhibits the kinase activity of CDK5 and CDK2 in multiple CRC cell lines. Consistent with CDK5 inhibition, 20-223 inhibited migration of CRC cells in a wound-healing assay. Profiling a panel of CRC cell lines for growth inhibitory effects showed that 20-223 has nanomolar potency across multiple CRC cell lines and was on an average \u3e2-fold more potent than AT7519. Cell cycle analyses in CRC cells revealed that 20-223 phenocopied the effects associated with AT7519. Collectively, these findings suggest that 20-223 exerts anti-tumor effects against CRC by targeting CDK 2/5 and inducing cell cycle arrest. Our studies also indicate that 20-223 is a suitable lead compound for colorectal cancer therapy

The utilisation of health research in policy-making: Concepts, examples and methods of assessment

The importance of health research utilisation in policy-making, and of understanding the mechanisms involved, is increasingly recognised. Recent reports calling for more resources to improve health in developing countries, and global pressures for accountability, draw greater attention to research-informed policy-making. Key utilisation issues have been described for at least twenty years, but the growing focus on health research systems creates additional dimensions. The utilisation of health research in policy-making should contribute to policies that may eventually lead to desired outcomes, including health gains. In this article, exploration of these issues is combined with a review of various forms of policy-making. When this is linked to analysis of different types of health research, it assists in building a comprehensive account of the diverse meanings of research utilisation. Previous studies report methods and conceptual frameworks that have been applied, if with varying degrees of success, to record utilisation in policy-making. These studies reveal various examples of research impact within a general picture of underutilisation. Factors potentially enhancing utilisation can be identified by exploration of: priority setting; activities of the health research system at the interface between research and policy-making; and the role of the recipients, or 'receptors', of health research. An interfaces and receptors model provides a framework for analysis. Recommendations about possible methods for assessing health research utilisation follow identification of the purposes of such assessments. Our conclusion is that research utilisation can be better understood, and enhanced, by developing assessment methods informed by conceptual analysis and review of previous studies