Improved maximum likelihood estimators in a heteroskedastic errors-in-variables model

This paper develops a bias correction scheme for a multivariate heteroskedastic errors-in-variables model. The applicability of this model is justified in areas such as astrophysics, epidemiology and analytical chemistry, where the variables are subject to measurement errors and the variances vary with the observations. We conduct Monte Carlo simulations to investigate the performance of the corrected estimators. The numerical results show that the bias correction scheme yields nearly unbiased estimates. We also give an application to a real data set.Comment: 12 pages. Statistical Paper

Renormalization-group approach to superconductivity: from weak to strong electron-phonon coupling

We present the numerical solution of the renormalization group (RG) equations derived in Ref. [1], for the problem of superconductivity in the presence of both electron-electron and electron-phonon coupling at zero temperature. We study the instability of a Fermi liquid to a superconductor and the RG flow of the couplings in presence of retardation effects and the crossover from weak to strong coupling. We show that our numerical results provide an ansatz for the analytic solution of the problem in the asymptotic limits of weak and strong coupling.Comment: 8 pages, 3 figures, conference proceedings for the Electron Correlations and Materials Properties, in Kos, Greece, July 5-9, 200

Does training method matter? Evidence for the negative impact of aversive-based methods on companion dog welfare

Dog training methods range broadly from those using mostly positive punishment and negative reinforcement (aversive-based) to those using primarily positive reinforcement (rewardbased). Although aversive-based training has been strongly criticized for negatively affecting dog welfare, there is no comprehensive research focusing on companion dogs and mainstream techniques, and most studies rely on owner-reported assessment of training methods and dog behavior. The aim of the present study was to evaluate the effects of aversive- and reward-based training methods on companion dog welfare within and outside the training context. Ninety-two companion dogs were recruited from three reward-based schools (Group Reward, n = 42), and from four aversive-based schools, two using low proportions of aversive-based methods (Group Mixed, n = 22) and two using high proportions of aversive-based methods (Group Aversive, n = 28). For evaluating welfare during training, dogs were video recorded for three sessions and six saliva samples were collected, three at home (baseline levels) and three after training (post-training levels). Video recordings were used to examine the frequency of stress-related behaviors (e.g., lip lick, yawn) and the overall behavioral state of the dog (e.g., tense, relaxed), and saliva samples were analyzed for cortisol concentration. For evaluating welfare outside the training context, dogs participated in a cognitive bias task. Results showed that dogs from Group Aversive displayed more stress-related behaviors, were more frequently in tense and low behavioral states and panted more during training, and exhibited higher post-training increases in cortisol levels than dogs from Group Reward. Additionally, dogs from Group Aversive were more 'pessimistic' in the cognitive bias task than dogs from Group Reward. Dogs from Group Mixed displayed more stress-related behaviors, were more frequently in tense states and panted more during training than dogs from Group Reward. Finally, although Groups Mixed and Aversive did not differ in their performance in the cognitive bias task nor in cortisol levels, the former displayed more stress-related behaviors and was more frequently in tense and low behavioral states. These findings indicate that aversive-based training methods, especially if used in high proportions, compromise the welfare of companion dogs both within and outside the training context.The current research study was supported by FCT - Fundação Portuguesa para a Ciência e Tecnologia (Fellowship SFRH/BPD/ 111509/2015) and UFAW - Universities Federation for Animal Welfare (Grant 14-16/17), with grants awarded to ACVC. SP was supported by PIPOL - Regione Friuli Venezia Giulia. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. FCT - Fundação Portuguesa para a Ciência e Tecnologia: https://www.fct.pt/index. phtml.pt UFAW - Universities Federation for Animal Welfare: https://www.ufaw.org.uk/

An update on emerging drugs for asthma

Peer reviewedPreprin

Use of archival versus newly collected tumor samples for assessing PD-L1 expression and overall survival : an updated analysis of KEYNOTE-010 trial

Background: In KEYNOTE-010, pembrolizumab versus docetaxel improved overall survival (OS) in patients with programmed death-1 protein (PD)-L1-positive advanced non-small-cell lung cancer (NSCLC). A prespecified exploratory analysis compared outcomes in patients based on PD-L1 expression in archival versus newly collected tumor samples using recently updated survival data. Patients and methods: PD-L1 was assessed centrally by immunohistochemistry (22C3 antibody) in archival or newly collected tumor samples. Patients received pembrolizumab 2 or 10 mg/kg Q3W or docetaxel 75 mg/m2 Q3W for 24 months or until progression/intolerable toxicity/other reason. Response was assessed by RECIST v1.1 every 9 weeks, survival every 2 months. Primary end points were OS and progression-free survival (PFS) in tumor proportion score (TPS) 50% and 1%; pembrolizumab doses were pooled in this analysis. Results: At date cut-off of 24 March 2017, median follow-up was 31 months (range 23-41) representing 18 additional months of follow-up from the primary analysis. Pembrolizumab versus docetaxel continued to improve OS in patients with previously treated, PD-L1-expressing advanced NSCLC; hazard ratio (HR) was 0.66 [95% confidence interval (CI): 0.57, 0.77]. Of 1033 patients analyzed, 455(44%) were enrolled based on archival samples and 578 (56%) on newly collected tumor samples. Approximately 40% of archival samples and 45% of newly collected tumor samples were PD-L1 TPS 50%. For TPS 50%, the OS HRs were 0.64 (95% CI: 0.45, 0.91) and 0.40 (95% CI: 0.28, 0.56) for archival and newly collected samples, respectively. In patients with TPS 1%, OS HRs were 0.74 (95% CI: 0.59, 0.93) and 0.59 (95% CI: 0.48, 0.73) for archival and newly collected samples, respectively. In TPS 50%, PFS HRs were similar across archival [0.63 (95% CI: 0.45, 0.89)] and newly collected samples [0.53 (95% CI: 0.38, 0.72)]. In patients with TPS 1%, PFS HRs were similar across archival [0.82 (95% CI: 0.66, 1.02)] and newly collected samples [0.83 (95% CI: 0.68, 1.02)]. Conclusion: Pembrolizumab continued to improve OS over docetaxel in intention to treat population and in subsets of patients with newly collected and archival samples

Substrate-induced band gap opening in epitaxial graphene

Graphene has shown great application potentials as the host material for next generation electronic devices. However, despite its intriguing properties, one of the biggest hurdles for graphene to be useful as an electronic material is its lacking of an energy gap in the electronic spectra. This, for example, prevents the use of graphene in making transistors. Although several proposals have been made to open a gap in graphene's electronic spectra, they all require complex engineering of the graphene layer. Here we show that when graphene is epitaxially grown on the SiC substrate, a gap of ~ 0.26 is produced. This gap decreases as the sample thickness increases and eventually approaches zero when the number of layers exceeds four. We propose that the origin of this gap is the breaking of sublattice symmetry owing to the graphene-substrate interaction. We believe our results highlight a promising direction for band gap engineering of graphene.Comment: 10 pages, 4 figures; updated reference

Insulin trafficking in a glucose responsive engineered human liver cell line is regulated by the interaction of ATP-sensitive potassium channels and voltage- gated calcium channels

Type I diabetes is caused by the autoimmune destruction of pancreatic beta (â) cells [1]. Current treatment requires multiple daily injections of insulin to control blood glucose levels. Tight glucose control lowers, but does not eliminate, the onset of diabetic complications, which greatly reduce the quality and longevity of life for patients. Transplantation of pancreatic tissue as a treatment is restricted by the scarcity of donors and the requirement for lifelong immunosuppression to preserve the graft, which carries adverse side-effects. This is of particular concern as Type 1 diabetes predominantly affects children. Lack of glucose control could be overcome by genetically engineering "an artificial â-cell" that is capable of synthesising, storing and secreting insulin in response to metabolic signals. The donor cell type must be readily accessible and capable of being engineered to synthesise, process, store and secrete insulin under physiological conditions

Valproic acid restricts mast cell activation by Listeria monocytogenes.

Mast cells (MC) play a central role in the early containment of bacterial infections, such as that caused by Listeria monocytogenes (L.m). The mechanisms of MC activation induced by L.m infection are well known, so it is possible to evaluate whether they are susceptible to targeting and modulation by different drugs. Recent evidence indicates that valproic acid (VPA) inhibits the immune response which favors L.m pathogenesis in vivo. Herein, we examined the immunomodulatory effect of VPA on L.m-mediated MC activation. To this end, bone marrow-derived mast cells (BMMC) were pre-incubated with VPA and then stimulated with L.m. We found that VPA reduced MC degranulation and cytokine release induced by L.m. MC activation during L.m infection relies on Toll-Like Receptor 2 (TLR2) engagement, however VPA treatment did not affect MC TLR2 cell surface expression. Moreover, VPA was able to decrease MC activation by the classic TLR2 ligands, peptidoglycan and lipopeptide Pam3CSK4. VPA also reduced cytokine production in response to Listeriolysin O (LLO), which activates MC by a TLR2-independent mechanism. In addition, VPA decreased the activation of critical events on MC signaling cascades, such as the increase on intracellular Ca2+ and phosphorylation of p38, ERK1/2 and -p65 subunit of NF-κB. Altogether, our data demonstrate that VPA affects key cell signaling events that regulate MC activation following L.m infection. These results indicate that VPA can modulate the functional activity of different immune cells that participate in the control of L.m infection

Microscopic Polarization in Bilayer Graphene

Bilayer graphene has drawn significant attention due to the opening of a band gap in its low energy electronic spectrum, which offers a promising route to electronic applications. The gap can be either tunable through an external electric field or spontaneously formed through an interaction-induced symmetry breaking. Our scanning tunneling measurements reveal the microscopic nature of the bilayer gap to be very different from what is observed in previous macroscopic measurements or expected from current theoretical models. The potential difference between the layers, which is proportional to charge imbalance and determines the gap value, shows strong dependence on the disorder potential, varying spatially in both magnitude and sign on a microscopic level. Furthermore, the gap does not vanish at small charge densities. Additional interaction-induced effects are observed in a magnetic field with the opening of a subgap when the zero orbital Landau level is placed at the Fermi energy