A new perspective on metformin therapy in type 1 diabetes

Metformin is quite frequently used off-label in type 1 diabetes to limit insulin dose requirement. Guidelines recommend that it can improve glucose control in those who are overweight and obese but evidence in support of this is limited. Recently-published findings from the REducing with MetfOrmin Vascular Adverse Lesions (REMOVAL) trial suggest that metformin therapy in type 1 diabetes can reduce atherosclerosis progression, weight and LDL-cholesterol levels. This provides a new perspective on metformin therapy in type 1 diabetes and suggests a potential role for reducing the long-term risk of cardiovascular disease

The Barker proposal: Combining robustness and efficiency in gradient-based MCMC

There is a tension between robustness and efficiency when designing Markov chain Monte Carlo (MCMC) sampling algorithms. Here we focus on robustness with respect to tuning parameters, showing that more sophisticated algorithms tend to be more sensitive to the choice of step-size parameter and less robust to heterogeneity of the distribution of interest. We characterise this phenomenon by studying the behaviour of spectral gaps as an increasingly poor step-size is chosen for the algorithm. Motivated by these considerations, we propose a novel and simple gradient-based MCMC algorithm, inspired by the classical Barker accept-reject rule, with improved robustness properties. Extensive theoretical results, dealing with robustness to tuning, geometric ergodicity and scaling with dimension, suggest that the novel scheme combines the robustness of simple schemes with the efficiency of gradient-based ones. We show numerically that this type of robustness is particularly beneficial in the context of adaptive MCMC, giving examples where our proposed scheme significantly outperforms state-of-the-art alternatives

Pulsar magnetic alignment and the pulsewidth-age relation

Using pulsewidth data for 872 isolated radio pulsars we test the hypothesis that pulsars evolve through a progressive narrowing of the emission cone combined with progressive alignment of the spin and magnetic axes. The new data provide strong evidence for the alignment over a time-scale of about 1 Myr with a log standard deviation of around 0.8 across the observed population. This time-scale is shorter than the time-scale of about 10 Myr found by previous authors, but the log standard deviation is larger. The results are inconsistent with models based on magnetic field decay alone or monotonic counter-alignment to orthogonal rotation. The best fits are obtained for a braking index parameter n_gamma approximately equal to 2.3, consistent the mean of the six measured values, but based on a much larger sample of young pulsars. The least-squares fitted models are used to predict the mean inclination angle between the spin and magnetic axes as a function of log characteristic age. Comparing these predictions to existing estimates it is found that the model in which pulsars are born with a random angle of inclination gives the best fit to the data. Plots of the mean beaming fraction as a function of characteristic age are presented using the best-fitting model parameters.Comment: 13 pages, 11 figures, Accepted for publication in MNRA

Using Student-Generated UV-Induced \u3cem\u3eEscherichia coli\u3c/em\u3e Mutants in a Directed Inquiry Undergraduate Genetics Laboratory

We report a thematic sequence of directed inquiry-based labs taking students from bacterial mutagenesis and phenotypic identification of their own self-created mutant, through identification of mutated genes by biochemical testing, to verification of mutant alleles by complementation, and finally to mutant allele characterization by DNA sequence analysis. The lab utilizes UV mutagenesis with wild-type Escherichia coli and a UV-sensitive isogenic derivative optimized for undergraduate use. The labs take advantage of the simplicity of E. coli in a realistic genetic investigation using safe UV irradiation methods for creation and characterization of novel mutants. Assessment data collected over three offerings of the course suggest that the labs, which combine original investigation in a scientifically realistic intellectual environment with learned techniques and concepts, were instrumental in improving students’ learning in a number of areas. These include the development of critical thinking skills and understanding of concepts and methods. Student responses also suggest the labs were helpful in improving students’understanding of the scientific process as a rational series of experimental investigations and awareness of the interdisciplinary nature of scientific inquiry

Cardiovascular benefits of GLP-1 agonists in type 2 diabetes: a comparative review

Type 2 diabetes (T2D) carries risks of both cardiovascular (CV) (myocardial infarction, stroke, and peripheral vascular disease) and microvascular (retinopathy/nephropathy/neuropathy) complications. Glucose-lowering is an effective strategy for preventing microvascular complications, but the extent to which it can reduce CV complications is less certain. Glucagon-like peptide-1 (GLP-1) agonists are potent glucose-lowering agents but also have potentially beneficial effects on other traditional (body weight, blood pressure (BP), and LDL cholesterol) and non-traditional risk factors (low grade inflammation and endothelial dysfunction). The results of four large CV outcome trials with GLP-1 agonists are now available. These have compared lixisenatide (ELIXA), liraglutide (LEADER), semaglutide (SUSTAIN-6), and long-acting exenatide (EXSCEL) with placebo and standard of care over 2–4 years; four others (including with dulaglutide and albiglutide) are ongoing. LEADER and SUSTAIN-6 have demonstrated reductions in rates of major adverse CV events with active GLP-1 treatment but ELIXA and EXSCEL have not. In this review, we discuss the mechanisms by which GLP-1 receptor agonists act on the CV system and the design and conduct of these trials. Contrary to the assertions that (a) all GLP-1 agonists reduce CV disease in T2D but to different extents or (b) the magnitude of CV protection is predominantly related to glucose-lowering, we argue that CV benefit is specific to agents that provide longer acting agonism at the GLP-1 receptor. The mechanisms involve reduction in body weight and BP, and lowering of LDL-cholesterol and glucose, but pleiotropic effects—including suppression of low grade inflammation, vasodilation, and natriuresis—are also likely relevant

An Introduction to Systems Biology for Mathematical Programmers

Many recent advances in biology, medicine and health care are due to computational efforts that rely on new mathematical results. These mathematical tools lie in discrete mathematics, statistics & probability, and optimization, and when combined with savvy computational tools and an understanding of cellular biology they are capable of remarkable results. One of the most significant areas of growth is in the field of systems biology, where we are using detailed biological information to construct models that describe larger entities. This chapter is designed to be an introduction to systems biology for individuals in Operations Research (OR) and mathematical programming who already know the supporting mathematics but are unaware of current research in this field

Palladium-catalyzed synthesis of aryl amides through silanoate-mediated hydrolysis of nitriles

A procedure for the formation of aryl amides through the palladium-catalyzed coupling of nitriles and aryl bromides, via the formation of intermediary silanoate derived imidate species is reported. Optimization was undertaken and examples of the process are described that furnish the products in up to 86% isolated yield

Posterior inferotemporal cortex cells use multiple input pathways for shape encoding

In the macaque monkey brain, posterior inferior temporal (PIT) cortex cells contribute to visual object recognition. They receive concurrent inputs from visual areas V4, V3, and V2. We asked how these different anatomical pathways shape PIT response properties by deactivating them while monitoring PIT activity in two male macaques. We found that cooling of V4 or V2|3 did not lead to consistent changes in population excitatory drive; however, population pattern analyses showed that V4-based pathways were more important than V2|3-based pathways.Wedid not find any image features that predicted decoding accuracy differences between both interventions. Using the HMAX hierarchical model of visual recognition, we found that different groups of simulated “PIT” units with different input histories (lacking “V2|3 or “V4 input) allowed for comparable levels of object-decoding performance and that removing a large fraction of “PIT” activity resulted in similar drops in performance as in the cooling experiments. We conclude that distinct input pathways to PIT relay similar types of shape information, with V1-dependent V4 cells providing more quantitatively useful information for overall encoding than cells in V2 projecting directly to PIT

Terrain classification using circular polarimetric features

Conventional representations of polarization response are referred to a horizontally and vertically polarized basis. Recent studies by Freeman and Durden, van Zyl, and others suggest that alternative polarimetric features which more easily resolve the contributions of simple scattering mechanisms such as odd-bounce, even-bounce, and diffuse scattering could offer several advantages in terrain classification. The circular polarization covariance matrix is a potential source of such features. In this paper, we derive its relationship to the Stokes matrix, describe some of its properties, and compare the utility of linear and circular polarimetric features in classifying an AIRSAR scene containing urban, park, and ocean terrain