Development and potential role of type-2 sodium-glucose transporter inhibitors for management of type 2 diabetes

There is a recognized need for new treatment options for type 2 diabetes mellitus (T2DM). Recovery of glucose from the glomerular filtrate represents an important mechanism in maintaining glucose homeostasis and represents a novel target for the management of T2DM. Recovery of glucose from the glomerular filtrate is executed principally by the type 2 sodium-glucose cotransporter (SGLT2). Inhibition of SGLT2 promotes glucose excretion and normalizes glycemia in animal models. First reports of specifically designed SGLT2 inhibitors began to appear in the second half of the 1990s. Several candidate SGLT2 inhibitors are currently under development, with four in the later stages of clinical testing. The safety profile of SGLT2 inhibitors is expected to be good, as their target is a highly specific membrane transporter expressed almost exclusively within the renal tubules. One safety concern is that of glycosuria, which could predispose patients to increased urinary tract infections. So far the reported safety profile of SGLT2 inhibitors in clinical studies appears to confirm that the class is well tolerated. Where SGLT2 inhibitors will fit in the current cascade of treatments for T2DM has yet to be established. The expected favorable safety profile and insulin-independent mechanism of action appear to support their use in combination with other antidiabetic drugs. Promotion of glucose excretion introduces the opportunity to clear calories (80–90 g [300–400 calories] of glucose per day) in patients that are generally overweight, and is expected to work synergistically with weight reduction programs. Experience will most likely lead to better understanding of which patients are likely to respond best to SGLT2 inhibitors, and under what circumstances

A rational analysis of memory search termination

Book synopsis: The International Conference on Cognitive Modeling (ICCM) is the premier conference for research on computational models and computation-based theories of human behavior. ICCM is a forum for presenting, discussing, and evaluating the complete spectrum of cognitive modeling approaches, including connectionism, symbolic modeling, dynamical systems, Bayesian modeling, and cognitive architectures. ICCM includes basic and applied research, across a wide variety of domains, ranging from low-level perception and attention to higher-level problem-solving and learning. Online-Version published by Universitätsverlag der TU Berlin (www.univerlag.tu-berlin.de

Rational search of associative memory

An important component of many, if not all, real-world retrieval tasks is the decision to terminate memory search. Despite its importance, systematic evaluations of the potential rules for terminating search are scarce. Recent work has focused on two variables: the total time spent in memory search before search is terminated and the exit latency (the time between the last retrieved item and the time of search termination). These variables have been shown to limit the number of plausible rules for terminating memory search. Here, we introduce an alternative stopping rule based on a rational moment-to-moment cost-benefit analysis. We show its ability to capture critical latency data and make testable predictions about the influence of changing the relative costs and benefits of memory search. Results from an experiment are presented that support the model’s predictions. We conclude that the decision to terminate memory search is based on moment-to-moment changes in subjective value

Value-creation space: The role of events in a service-dominant marketing paradigm

This paper provides a new conceptual contribution to our understanding of the value of events, examining their potential through the lens of service dominant logic. Through a conceptual analysis and discussion, augmented by a small-scale and exploratory empirical study using semi-structured interviews, it evaluates the growing resonance of events in modern-day marketing. The paper advances the conception of ‘value-creation space’ as an overarching term to coalesce the otherwise disparate range of organisational events that have marketing imperative and/or impact. The underpinning virtues of events are recognised and used to build a discussion that can provide a coherent basis for further conceptual development. The findings depict considerable synergy between the collaborative nature of events and the service dominant logic notions of co-creation (or co-destruction), and co-production. However, an intuitive and well-executed event marketing approach is critical to events' continued success as value-creation spaces

Genome-wide and fine-resolution association analysis of malaria in West Africa

We report a genome-wide association (GWA) study of severe malaria in The Gambia. The initial GWA scan included 2,500 children genotyped on the Affymetrix 500K GeneChip, and a replication study included 3,400 children. We used this to examine the performance of GWA methods in Africa. We found considerable population stratification, and also that signals of association at known malaria resistance loci were greatly attenuated owing to weak linkage disequilibrium (LD). To investigate possible solutions to the problem of low LD, we focused on the HbS locus, sequencing this region of the genome in 62 Gambian individuals and then using these data to conduct multipoint imputation in the GWA samples. This increased the signal of association, from P = 4 × 10(-7) to P = 4 × 10(-14), with the peak of the signal located precisely at the HbS causal variant. Our findings provide proof of principle that fine-resolution multipoint imputation, based on population-specific sequencing data, can substantially boost authentic GWA signals and enable fine mapping of causal variants in African populations