Extended-release niacin increases anti-apolipoprotein A-I antibodies that block the antioxidant effect of high-density lipoprotein-cholesterol: the EXPLORE clinical trial.

Extended-release niacin (ERN) is the most effective agent for increasing high-density lipoprotein-cholesterol (HDL-C). Having previously identified anti-HDL antibodies, we investigated whether ERN affected the antioxidant capacity of HDL and whether ERN was associated with the production of antibodies against HDL (aHDL) and apolipoprotein A-I (aApoA-I). METHODS: Twenty-one patients older than 18 years, with HDL-C ≤40 mg dl-1 (men) or ≤50 mg dl-1 (women) were randomly assigned to receive daily ERN (n = 10) or placebo (n = 11) for two sequential 12-week periods, with 4 weeks of wash-out before cross-over. Primary outcome was change of paraoxonase-1 (PON1) activity and secondary outcomes were changes in aHDL and aApoA-I antibodies. Clinical Trial Unique Identifier: EudraCT 2006-006889-42. RESULTS: The effect of ERN on PON1 activity was nonsignificant (coefficient estimate 20.83 U l-1 , 95% confidence interval [CI] -9.88 to 51.53; P = 0.184). ERN was associated with an increase in HDL-C levels (coefficient estimate 5.21 mg dl-1 , 95% CI 1.16 to 9.25; P = 0.012) and its subclasses HDL2 (coefficient estimate 2.46 mg dl-1 , 95% CI 0.57 to 4.34; P = 0.011) and HDL3 (coefficient estimate 2.73 mg dl-1 , 95% CI 0.47 to 4.98; P = 0.018). ERN was significantly associated with the production of aApoA-I antibodies (coefficient estimate 0.25 μg ml-1 , 95% CI 0.09-0.40; P = 0.001). aApoA-I titres at baseline were correlated with decreased PON activity. CONCLUSIONS: The rise in HDL-C achieved with ERN was not matched by improved antioxidant capacity, eventually hampered by the emergence of aApoA-I antibodies. These results may explain why Niacin and other lipid lowering agents fail to reduce cardiovascular risk.info:eu-repo/semantics/publishedVersio

Episodic Learning with Control Lyapunov Functions for Uncertain Robotic Systems

Many modern nonlinear control methods aim to endow systems with guaranteed properties, such as stability or safety, and have been successfully applied to the domain of robotics. However, model uncertainty remains a persistent challenge, weakening theoretical guarantees and causing implementation failures on physical systems. This paper develops a machine learning framework centered around Control Lyapunov Functions (CLFs) to adapt to parametric uncertainty and unmodeled dynamics in general robotic systems. Our proposed method proceeds by iteratively updating estimates of Lyapunov function derivatives and improving controllers, ultimately yielding a stabilizing quadratic program model-based controller. We validate our approach on a planar Segway simulation, demonstrating substantial performance improvements by iteratively refining on a base model-free controller

Isoprostane in systemic sclerosis: a systematic review and meta-analysis

Objectives: To further the knowledge of oxidative stress in systemic sclerosis (SSc), we performed a systematic review and meta-analysis on studies measuring isoprostane, a vasoactive agent deriving from arachidonic acid and implicated in the vasculopathy of SSc. Methods: Systematic search following the PRISMA guidelines in PubMed and EMBASE between January-1990/December-2017 using the terms: oxidative stress, isoprostane, systemic sclerosis and scleroderma. Results: After the screening process, 8 studies including 240 SSc patients and 192 controls were included in the systematic review and meta-analysis, 6 investigating urinary and 2 serum isoprostane: random effect meta-analysis revealed isoprostane overgeneration in SSc (p <.001) with wide heterogeneity (I 2 = 75%). Subgroup analysis on urinary isoprostane favoured excess excretion in SSc (p =.009) with slightly lower heterogeneity (I 2 = 67%); further subgroup analysis according to unit of measurement revealed no increased isoprostane excretion when expressed as pg/mg creatinine but increased when expressed as pmol/mmol creatinine (p =.05) with medium heterogeneity (I 2 = 32%). Subgroup analysis on serum isoprostane favoured overproduction in SSc (p <.0001) with no heterogeneity. Conclusion: There is some evidence for isoprostane overgeneration in SSc that confirms the occurrence of oxidative stress in this setting: further prospective studies with specified outcomes are needed to evaluate the prognostic value of this functional biomarker

Loop Quantum Cosmology IV: Discrete Time Evolution

Using general features of recent quantizations of the Hamiltonian constraint in loop quantum gravity and loop quantum cosmology, a dynamical interpretation of the constraint equation as evolution equation is presented. This involves a transformation from the connection to a dreibein representation and the selection of an internal time variable. Due to the discrete nature of geometrical quantities in loop quantum gravity also time turns out to be discrete leading to a difference rather than differential evolution equation. Furthermore, evolving observables are discussed in this framework which enables an investigation of physical spectra of geometrical quantities. In particular, the physical volume spectrum is proven to equal the discrete kinematical volume spectrum in loop quantum cosmology.Comment: 21 page

Interplay of chiral and helical states in a Quantum Spin Hall Insulator lateral junction

We study the electronic transport across an electrostatically-gated lateral junction in a HgTe quantum well, a canonical 2D topological insulator, with and without applied magnetic field. We control carrier density inside and outside a junction region independently and hence tune the number and nature of 1D edge modes propagating in each of those regions. Outside the 2D gap, magnetic field drives the system to the quantum Hall regime, and chiral states propagate at the edge. In this regime, we observe fractional plateaus which reflect the equilibration between 1D chiral modes across the junction. As carrier density approaches zero in the central region and at moderate fields, we observe oscillations in resistance that we attribute to Fabry-Perot interference in the helical states, enabled by the broken time reversal symmetry. At higher fields, those oscillations disappear, in agreement with the expected absence of helical states when band inversion is lifted.Comment: 5 pages, 4 figures, supp. ma

Spin transport theory in ferromagnet/semiconductor systems with non-collinear magnetization configurations

We present a comprehensive theory of spin transport in a non-degenerate semiconductor that is in contact with multiple ferromagnetic terminals. The spin dynamics in the semiconductor is studied during a perturbation of a general, non-collinear magnetization configuration and a method is shown to identify the various configurations from current signals. The conventional Landauer-B\"{u}ttiker description for spin transport across Schottky contacts is generalized by the use of a non-linearized I-V relation, and it is extended by taking into account non-coherent transport mechanisms. The theory is used to analyze a three terminal lateral structure where a significant difference in the spin accumulation profile is found when comparing the results of this model with the conventional model.Comment: 17 pages, 10 figure

Anti-proliferative but not anti-angiogenic tyrosine kinase inhibitors enrich for cancer stem cells in soft tissue sarcoma.

BackgroundIncreasing studies implicate cancer stem cells (CSCs) as the source of resistance and relapse following conventional cytotoxic therapies. Few studies have examined the response of CSCs to targeted therapies, such as tyrosine kinase inhibitors (TKIs). We hypothesized that TKIs would have differential effects on CSC populations depending on their mechanism of action (anti-proliferative vs. anti-angiogenic).MethodsWe exposed human sarcoma cell lines to sorafenib, regorafenib, and pazopanib and assessed cell viability and expression of CSC markers (ALDH, CD24, CD44, and CD133). We evaluated survival and CSC phenotype in mice harboring sarcoma metastases after TKI therapy. We exposed dissociated primary sarcoma tumors to sorafenib, regorafenib, and pazopanib, and we used tissue microarray (TMA) and primary sarcoma samples to evaluate the frequency and intensity of CSC markers after neoadjuvant therapy with sorafenib and pazopanib. Parametric and non-parametric statistical analyses were performed as appropriate.ResultsAfter functionally validating the CSC phenotype of ALDHbright sarcoma cells, we observed that sorafenib and regorafenib were cytotoxic to sarcoma cell lines (P < 0.05), with a corresponding 1.4 - 2.8 fold increase in ALDHbright cells from baseline (P < 0.05). In contrast, we observed negligible effects on viability and CSC sub-populations with pazopanib. At low doses, there was progressive CSC enrichment in vitro after longer term exposure to sorafenib although the anti-proliferative effects were attenuated. In vivo, sorafenib improved median survival by 11 days (P < 0.05), but enriched ALDHbright cells 2.5 - 2.8 fold (P < 0.05). Analysis of primary human sarcoma samples revealed direct cytotoxicity following exposure to sorafenib and regorafenib with a corresponding increase in ALDHbright cells (P < 0.05). Again, negligible effects from pazopanib were observed. TMA analysis of archived specimens from sarcoma patients treated with sorafenib demonstrated significant enrichment for ALDHbright cells in the post-treatment resection specimen (P < 0.05), whereas clinical specimens obtained longitudinally from a patient treated with pazopanib showed no enrichment for ALDHbright cells (P > 0.05).ConclusionsAnti-proliferative TKIs appear to enrich for sarcoma CSCs while anti-angiogenic TKIs do not. The rational selection of targeted therapies for sarcoma patients may benefit from an awareness of the differential impact of TKIs on CSC populations

Setting the stage: social-environmental and motivational predictors of optimal training engagement

In this paper, we will firstly explore the central tenets of SDT. Research that has examined the social-environmental and motivation-related correlates of optimal training, performance and health-related engagement through the theoretical lens of SDT will be reviewed. Drawing from SDT-driven work undertaken in educational, sport and dance settings, we will draw conclusions and suggest future directions from a research and applied perspective