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.     

Failure analysis of a broken tooth

Several days after heart surgery, a patient discovered his upper right canine tooth had broken at the root. Such tooth damage, recognized post-operatively, is usually assumed to be caused by blunt mechanical force from an instrument used by the anesthesiologist during placement of a breathing tube at the start of surgery. In this case, the patient had saved the crown portion of the broken tooth, and it was possible to examine the root fracture characteristics. The curvature and direction of the crack path and natural tooth situation suggested that failure could be described through a cantilever beam model. This was confirmed when a whole extracted sample tooth was embedded and broken by a measured force in a manner consistent with the model. The resulting fracture surface matched that of the patient’s broken canine tooth. However, the high load and force direction necessary to fracture the root was inconsistent with forces applied during the anesthesia procedure. The failure analysis and further investigation indicated tooth clenching on the breathing tube during recovery was the likely cause of fracture. This paper presents an alternate explanation for intubation-related dental injury, demonstrates the practicality of fractographic analysis of biological materials, and introduces a methodology for simulating in vitro tooth settings for mechanical testing.     

Specification methods for material-handling control algorithms in flexible manufacturing systems

Good methods are needed to specify, test, and debug material-handling control logic. This article surveys a number of representative methods for defining and describing control algorithms for programmable material-handling equipment used in flexible manufacturing systems. The methods are evaluated with regard to their suitability for communication between people and as bases for interfaces to automatic program generators. It is concluded that no single method is entirely satisfactory. Three methods (position diagrams, function block diagrams, and operation networks) have potential to be combined into an effective hybrid approach that minimizes the need for the user to switch between various conceptual models.     

Comparison of two methods of surfactant administration and the effect on dosing-associated hypoxemia

OBJECTIVE: The purpose of our study was to test the hypothesis that surfactant dosing through a proximal sideport adapter on an endotracheal tube leads to more dosing-associated hypoxemia compared with a method of dosing that uses a double-lumen endotracheal tube. STUDY DESIGN: Using adequate sample size to compare significant changes in O2 saturation (power > 0.8, alpha < 0.05) we enrolled 36 infants with respiratory distress syndrome in this randomized trial. A 10% change in O2 saturation was considered clinically significant. Nineteen infants received 38 doses of surfactant through the sideport adapter. Seventeen infants received 31 doses of surfactant through the nonventilation lumen of a double-lumen endotracheal tube. Two main outcome measures were assessed: time-averaged O2 saturation values 30 minutes after dosing and the largest absolute fall in O2 saturation for each patient. RESULTS AND CONCLUSIONS: Time-averaged O2 saturation measures were higher in the proximal sideport group (p = 0.02), but the magnitude of difference was probably not clinically significant. No significant difference was detected between groups when we compared largest absolute drop in O2 saturation. Secondary analyses found no effect of birth weight or dose number (second vs third dose) on either outcome measure.     

Chicken acidic leucine-rich EGF-like domain containing brain protein (CALEB), a neural member of the EGF family of differentiation factors, is implicated in neurite formation

Chicken acidic leucine-rich EGF-like domain containing brain protein (CALEB) was identified by combining binding assays with immunological screens in the chicken nervous system as a novel member of the EGF family of differentiation factors. cDNA cloning indicates that CALEB is a multidomain protein that consists of an NH2-terminal glycosylation region, a leucine-proline-rich segment, an acidic box, a single EGF-like domain, a transmembrane, and a short cytoplasmic stretch. In the developing nervous system, CALEB is associated with glial and neuronal surfaces. CALEB is composed of a 140/130-kD doublet, an 80-kD band, and a chondroitinsulfate-containing 200-kD component. The latter two components are expressed in the embryonic nervous system and are downregulated in the adult nervous system. CALEB binds to the extracellular matrix glycoproteins tenascin-C and -R. In vitro antibody perturbation experiments reveal a participation of CALEB in neurite formation in a permissive environment.     

Distraction effects on muscle. Leg lengthening studied in rabbits

We investigated changes in the anterior tibial muscle during lengthening of the lower leg in rabbits. In 37 rabbits, an osteotomy of the right middle tibia was performed and was fixed by a unilateral external fixator. The rabbits were randomized into 6 groups. In groups 1, 2, and 3 the tibiae were distracted 0.5 mm/day. In groups 1 and 2, the rabbits were killed after 14 and 28 days of distraction, respectively, and in group 3 after 28 days of distraction, followed by 14 days of rest. Groups 1a, 2a, and 3a served as controls. They were treated similarly as groups 1, 2, and 3, but no distraction was performed. Proliferating cell nuclei were labeled with 5-bromo-2-deoxyuridine and were identified by immunohistochemical staining. The weight of the muscle was measured. During bone lengthening the muscle showed signs of growth, as indicated by increasing weight and number of proliferating cell nuclei. This was observed only during lengthening and it ceased when the lengthening was stopped.     

A process oriented semantics of the PRAM-language FORK

The parallel language FORK [1], based on a scalable shared memory model, is a PASCAL-like language with some additional parallel constructs. A PRAM (Parallel Random Access Machine) algorithm can be expressed on a high level of abstraction as a FORK program which is translated into efficient PRAM code guaranteeing theoretically predicted runtimes.

In this paper, we concentrate on those features of the language FORK related to parallelism, such as the group concept, a shared memory access and synchronous or asynchronous execution. We present a trace-based denotational interleaving semantics where processes describe synchronous computations. Processes are created or deleted dynamically and run asynchronously. Interleaving rules reflect the underlying CRCW (concurrent-read-concurrent-write) PRAM model.     

Uncertainty in Quantitative Electron Probe Microanalysis

Quantitative electron probe analysis is based on models based on the physics or x-ray generation, empirically adjusted to the analyses of specimens of known composition. Their accuracy can be estimated by applying them to a set of specimens of presumably well-known composition.