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.     

Denial in the aftermath of traumatic head injury: Its manifestations, measurement, and treatment.

Reviews available research on the meaning and measurement of denial and strategies for treating maladaptive denial, with special reference to its occurrence in traumatic head injuries. Questionnaire or interview measures, rather than behavioral indices, are used to assess denial. Denial may be manifested with respect to past, present, or future status; and it may have both positive and negative consequences for coping, motivation, and rehabilitation. Where denial limits a patient's functioning or recovery, several treatment strategies are possible. Intervention should involve a balance between supportive and confrontational elements, with a focus on behaviors rather than verbalizations. Computer feedback, videotaping, focused group therapy, and supervised activities are possible interventions for confronting maladaptive forms of denial. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Fuzzy logic with biomolecules

 The uncertain and inexact nature of the chemical reactions used to implement DNA computations can be turned into an advantage for implementing robust soft computing systems. The key feature of DNA hybridization that makes it appropriate for fuzzy computing is the uncertainty and incompleteness in the formation of a double-stranded duplex from single-stranded oligonucleotides. To implement fuzzy computing, a set of encoding DNA molecules is given that reproduces a specific membership function in the energetics of the DNA duplex. In addition, a fuzzy inference system implemented with DNA hybridization on solid supports is discussed. The ultimate success of this idea as a general technique, however, is dependent on the actual geometry of the Gibbs free-energy landscapes in the space of all duplex formations. Elucidating this problem is undoubtedly of great importance for biomolecular implementation of soft-computing because it may, in particular, shed light on the true import of fuzzy models in biological processes fundamental to life.     

Statistical thermodynamic analysis and designof DNA-based computers

A principal research area in biomolecular computing is the development of analytical methods for evaluating computational fidelity and efficiency. In this work, the equilibrium theory of the DNA helix-coil transition is reviewed and expanded, as applied to the analysis and design of oligonucleotide-based computers. After a review of the equilibrium apparatus for modeling the helix-coil transition for single dsDNA species, application to complex hybridizing systems is discussed, via decomposition into component equilibria, which are presumed to proceed independently. The alternative approach, which involves estimation of a mean error probability per hybridized structure, or computational incoherence, is then presented, along with a discussion of a special-case exact solution (directed dimer formation), and an approximate general solution, applicable to conditions of uniform fractional-saturation. In order to clarify the opposing nature of the predictions of these two models, simulations are presented for the uniform saturation solution for , as applied to a small Tag–Antitag (TAT) system, along with the behavior expected via isolated melting curves. By a comparison with the predictions of a recent, TAT-specific solution for , the views provided by these generalized approximate models are shown to define the opposing limits of a more general error-response.     

Early transvaginal ultrasound following an accurately dated pregnancy: the importance of finding a yolk sac or fetal heart motion

Our goals were to determine the prognostic value of a yolk sac or fetal heart motion seen during an early accurately dated transvaginal ultrasound (TVU). We reviewed 225 consecutive pregnancies for fetal heart motion data. Furthermore, 63 pregnancies following in-vitro fertilization were reviewed for yolk sac information. The TVU was performed between 5 and 6 weeks following presumed conception (heart motion data) and between 22 and 32 days following in-vitro fertilization (yolk sac data). Pregnancies were followed until an ongoing pregnancy or spontaneous abortion was documented. The presence of a yolk sac between 22 and 32 days from fertilization was associated with the development of fetal heart motion in 94% of cases. The absence of the yolk sac by 32 days after fertilization was always associated with a poor outcome. In women < 36 years of age, the presence of fetal heart motion was associated with a spontaneous abortion in only 4.5% of the cases. However, the incidence of spontaneous abortion following fetal heart motion increased to 10% in women 36-39 years and 29% in women > or = 40 years of age. The presence of heart motion should not be considered a reassuring sign in the older woman. These data have implications regarding early embryology and the counselling of infertility patients.     

A theoretical framework for examining the role of third-party certifiers

Third-party certifiers play a significant role in the global food system. The information economics literature provides a rich theoretical structure for understanding the emergence of third-party certification bodies. In this theoretical structure, third-party certifiers provide market signals concerning food quality claims. Successful third-party certifiers ensure buyers of food quality and reduce the potential for market failure that might otherwise occur when information about food quality is uncertain and information is asymmetrically distributed.     

Ethical issues in pediatric rehabilitation: Exploring an uneven terrain.

Discusses issues that arise during the stages of the pediatric rehabilitation process as they relate to such ethical principles as patient autonomy, provider beneficence/nonmaleficence, and fairness/justice.These include initial decision making in rehabilitation, information sharing and negotiation, treatment consent/refusal, transitioning from rehabilitation to community, and long-term planning. Case examples are used to illustrate potential resolution of specific dilemmas. Future directions for pediatric rehabilitation psychologists are outlined. Among these are rationing of care, integration of systems, research on pediatric rehabilitation outcomes, training, and responsible use of technology. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Electronic speckle pattern interferometry on a microscopic scale

An electronic speckle pattern interferometer that incorporates a commercial, long-working-distance microscope is described which provides new opportunities to perform nondestructive inspection for applications in fields such as microelectronics. The long-working-distance microscrope was attached directly to the CCD camera to form a compact, portable system with a field of view that was variable over several mm in width. Alignment was greatly simplified because the skewed Michelson interferometer configuration used a speckled reference beam imaged from a diffusely reflecting reference surface that was positioned adjacent to the test object. To demonstrate the performance of the micro-ESPI instrument, fringe patterns were recorded for the quasi-static cantilever deflection of a 1 mm-wide interconnect clip from an electronics socket.