A Dual Inhibitor of DYRK1A and GSK3β for β-Cell Proliferation: Aminopyrazine Derivative GNF4877

Loss of β-cell mass and function can lead to insufficient insulin levels and ultimately to hyperglycemia and diabetes mellitus. The mainstream treatment approach involves regulation of insulin levels; however, approaches intended to increase β-cell mass are less developed. Promoting β-cell proliferation with low-molecular-weight inhibitors of dual-specificity tyrosine-regulated kinase 1A (DYRK1A) offers the potential to treat diabetes with oral therapies by restoring β-cell mass, insulin content and glycemic control. GNF4877, a potent dual inhibitor of DYRK1A and glycogen synthase kinase 3β (GSK3β) was previously reported to induce primary human β-cell proliferation in vitro and in vivo. Herein, we describe the lead optimization that lead to the identification of GNF4877 from an aminopyrazine hit identified in a phenotypic high-throughput screening campaign measuring β-cell proliferation.     

An experimental pilot study of tacalcitol activities during modulation of parakeratotic skin features

Establishing guidelines and experimental models preclinical and clinical evaluations of new agents for treatment, and/or prevention of human diseases has become a task of crucial importance. Psoriasis is such one disease holding great interest for dermatology owing to its high rate of incidence and complexity of treatment. However the absence of psoriatic lesions in animals and the inability to induce them, calls for experimental techniques both in vitro and in vivo. The purpose of this study was to evaluate experimentally the effects of tacalcitol on cell proliferation and differentiation process. Thereafter a human pilot study on psoriatic patients has been developed.     

A Profile of Psychologists' Views of Critical Risk Factors for Completed Suicide in Older Adults.

The ability to accurately and reliably predict whether an older adult will commit suicide has eluded clinicians and researchers. A random national sample of psychologists who work with older adults was surveyed regarding their perception of 36 risk factors for completed suicide and indirect self-destructive behavior in older adults. This study produced a profile of psychologists' assessment and treatment practices when working with suicidal older adults. Determining what psychologists consider to be the most salient risk factors for completed suicide is important in identifying a minimum standard that clinicians should follow when assessing older adults. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Neuropsychological and psychosocial effects of the FMR-1 full mutation: Case report of monozygotic twins discordant for the fragile X syndrome.

An extensive evaluation was conducted with 16-yr-old monozygotic twins concordant for the fragile X full mutation but discordant for mental retardation. The clearly affected twin had an IQ score of 47; 77% of her neuropsychological z scores were at least 2 SDs below average. Her sister had an IQ score of 105 and average neuropsychological performance. However, each girl demonstrated relative verbal strengths and visual-spatial weaknesses. Their parents rated each girl as having significant problems with attention, conduct, anxiety-withdrawal, and hyperactivity. The girls did not rate themselves as having significant anxiety. These findings are consistent with group data on females with fragile X and demonstrate the wide range of effects associated with the fragile X full mutation. This case report implicates the importance of a psychosocial phenotype of fragile X independent of cognitive ability level. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

How infants perceive a simple causal event.

Four experiments examined 10-mo-old infants' causal event perception. Exp 1 replicated previous studies except that the specific objects used as agent and recipient varied from trial to trial. Under these conditions infants did not process the causality. Instead they keyed on specific temporal and spatial differences among the events. Exp 2 showed that infants notice a change in the particular agent performing either a causal or noncausal action. Exp 3 showed that infants do not notice a change in the type of action done to a particular recipient. Exp 4 demonstrated that infants do not pay attention to the object used as a recipient. As a whole, the results indicate that 10-mo-old infants perceive the causality of simple events by associating a specific agent with the causal action. These results provide more support for an information-processing view than for the view that infants have a causal module. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Egg Thiamine Status of Lake Ontario Salmonines 1995–2004 with Emphasis on Lake Trout

Alewives (Alosa pseudoharengus), the major prey fish for Lake Ontario, contain thiaminase. They are associated with development of a thiamine deficiency in salmonines which greatly increases the potential for developing an early mortality syndrome (EMS). To assess the possible effects of thiamine deficiency on salmonine reproduction we measured egg thiamine concentrations for five species of Lake Ontario salmonines. From this we estimated the proportion of families susceptible to EMS based on whether they were below the ED20, the egg thiamine concentration associated with 20% mortality due to EMS. The ED20s were 1.52, 2.63, and 2.99 nmol/g egg for Chinook salmon (Oncorhynchus tshawytscha), lake trout (Salvelinus namaycush), and coho salmon (Oncorhynchus kisutch), respectively. Based on the proportion of fish having egg thiamine concentrations falling below the ED20, the risk of developing EMS in Lake Ontario was highest for lake trout, followed by coho (O. kisutch), and Chinook salmon, with the least risk for rainbow trout (O. mykiss). For lake trout from western Lake Ontario, mean egg thiamine concentration showed significant annual variability during 1994 to 2003, when the proportion of lake trout at risk of developing EMS based on ED20 ranged between 77 and 100%. Variation in the annual mean egg thiamine concentration for western Lake Ontario lake trout was positively related (p < 0.001, r² = 0.94) with indices of annual adult alewife biomass. While suggesting the possible involvement of density-dependent changes in alewives, the changes are small relative to egg thiamine concentrations when alewife are not part of the diet and are of insufficient magnitude to allow for natural reproduction by lake trout.     

Peristaltic pumping of solid particles

We simulate solid particle transport by peristalsis in a two-dimensional channel with sinusoidal waves. The fluid is regarded as viscous and incompressible, and the walls of the channel and the particle as neutrally buoyant elastic boundaries immersed in this fluid. Using the immersed boundary technique, we are able to computationally model fluid-particle interaction. To demonstrate the validity of our computational approach, we first present results of computations without solid particles and compare them with existing theory and computations. We then examine how the transport of the solid particle depends upon its diameter, the Reynolds number and its initial placement in the channel. We also present evidence that the mean transport speed of a particle increases geometrically as its diameter approaches the channel width.