Physiology of renal glucose handling via SGLT1, SGLT2 and GLUT2.

The concentration of glucose in plasma is held within narrow limits (4-10 mmol/l), primarily to ensure fuel supply to the brain. Kidneys play a role in glucose homeostasis in the body by ensuring that glucose is not lost in the urine. Three membrane proteins are responsible for glucose reabsorption from the glomerular filtrate in the proximal tubule: sodium-glucose cotransporters SGLT1 and SGLT2, in the apical membrane, and GLUT2, a uniporter in the basolateral membrane. 'Knockout' of these transporters in mice and men results in the excretion of filtered glucose in the urine. In humans, intravenous injection of the plant glucoside phlorizin also results in excretion of the full filtered glucose load. This outcome and the finding that, in an animal model, phlorizin reversed the symptoms of diabetes, has stimulated the development and successful introduction of SGLT2 inhibitors, gliflozins, in the treatment of type 2 diabetes mellitus. Here we summarise the current state of our knowledge about the physiology of renal glucose handling and provide background to the development of SGLT2 inhibitors for type 2 diabetes treatment

Discrete-time dynamic modeling for software and services composition as an extension of the Markov chain approach

Discrete Time Markov Chains (DTMCs) and Continuous Time Markov Chains (CTMCs) are often used to model various types of phenomena, such as, for example, the behavior of software products. In that case, Markov chains are widely used to describe possible time-varying behavior of “self-adaptive” software systems, where the transition from one state to another represents alternative choices at the software code level, taken according to a certain probability distribution. From a control-theoretical standpoint, some of these probabilities can be interpreted as control signals and others can just be observed. However, the translation between a DTMC or CTMC model and a corresponding first principle model, that can be used to design a control system is not immediate. This paper investigates a possible solution for translating a CTMC model into a dynamic system, with focus on the control of computing systems components. Notice that DTMC models can be translated as well, providing additional information

Prefood and Preshock Stimulus Effects on Fixed-Interval and Fixed-Ratio Responding

Two experiments were designed to study with rats the effects of a preshock stimulus (Experiment I) and a prefood stimulus (Experiment II) on lever pressing maintained by a multiple fixed-ratio 100 fixed-interval 90 s schedule of food reinforcement. The purpose was to determine if the effects of these stimuli, identified as Pavlovian Css, were related to where within each component\u27s schedule they occurred; early in a ratio interval, or late in a ratio or interval. Experiment I indicated that when the CS was presented early in a ratio or interval, or late in an interval, nearly equivalent suppression occurred for contingent and noncontingent control subjects. When the CS was presented late in a ratio, suppression was greatest for the contingent subjects. One subject, who received the CS-US pair on-the-baseline, showed suppression during the CS, and depressed responding in the absence of the CS, at both points within each component schedule. These effects were accompanied by post-CS suppression and by a sharp increase in FR PRPs and work times. Experiment II showed a generally small effect of the CS on responding at both points within each component schedule; this was seen for contingent and noncontingent control subjects alike. In contrast, on-the-baseline training produced an increase in initial FR and FI responding during, and in the absence of, the CS that was accompanied by a decrease in FR and FI PRPs. In contrast, responding late in a ratio or interval was minimally affected. The present Experiment I provides the basis for rejecting earlier accounts of negative conditioned suppression of FR and FI maintained responding. In addition, Experiment I yielded new evidence regarding a) off- vs on-the-baseline conditioning procedures, and c) residual baseline effects. The present Experiment II provides evidence relevant to positive conditioned suppression of FR and FI maintained responding. In addition to yielding new information regarding this phenomenon, these data, together with a portion of those from Experiment I, question the traditional assumption that conditioned suppression (or acceleration) results from the contingent relation between a CS and a US

The Legacy of Jonathan A. Ship

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/71579/1/j.1754-4505.2008.00031.x.pd

Integration of oral health care into geriatric primary care: proposal for collaboration

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/91312/1/j.1754-4505.2012.00255.x.pd

The development of the Coalition for Oral Health for the Aging

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/86896/1/j.1754-4505.2011.00206.x.pd

A high-throughput screen identifies that CDK7 activates glucose consumption in lung cancer cells.

Elevated glucose consumption is fundamental to cancer, but selectively targeting this pathway is challenging. We develop a high-throughput assay for measuring glucose consumption and use it to screen non-small-cell lung cancer cell lines against bioactive small molecules. We identify Milciclib that blocks glucose consumption in H460 and H1975, but not in HCC827 or A549 cells, by decreasing SLC2A1 (GLUT1) mRNA and protein levels and by inhibiting glucose transport. Milciclib blocks glucose consumption by targeting cyclin-dependent kinase 7 (CDK7) similar to other CDK7 inhibitors including THZ1 and LDC4297. Enhanced PIK3CA signaling leads to CDK7 phosphorylation, which promotes RNA Polymerase II phosphorylation and transcription. Milciclib, THZ1, and LDC4297 lead to a reduction in RNA Polymerase II phosphorylation on the SLC2A1 promoter. These data indicate that our high-throughput assay can identify compounds that regulate glucose consumption and that CDK7 is a key regulator of glucose consumption in cells with an activated PI3K pathway

Attractions between charged colloids at water interfaces

The effective potential between charged colloids trapped at water interfaces is analyzed. It consists of a repulsive electrostatic and an attractive capillary part which asymptotically both show dipole--like behavior. For sufficiently large colloid charges, the capillary attraction dominates at large separations. The total effective potential exhibits a minimum at intermediate separations if the Debye screening length of water and the colloid radius are of comparable size.Comment: 8 pages, 1 figure, revised version (one paragraph added) accepted in JPC