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.     

A simple handling technique for mammalian oocytes and embryos during preparation for transmission electron microscopy

Due to their small size, mammalian oocytes and embryos pose unique problems during preparation for transmission electron microscopy. This paper outlines a method which combines protein embedding with centrifugation to locate the specimens on the face of a Beem capsule mould. This method facilitates both the processing of oocytes with minimal loss and rapid location of the specimens within the block for simultaneous sectioning, staining and examination.     

Instructional texts rewritten by five expert teams: Revisions and retention improvements.

700 undergraduates were tested in 3 experiments on original or rewritten versions of 52 instructional texts about Army job tasks, general science, philosophy, and history. Five experts had rewritten various sets of the texts and stated hypotheses about the efficacious features of their revisions. We tested their hypotheses and several others. Recall and recognition tests were given immediately and after a 24-hr delay. Results showed that revisions made by 3 of the 5 experts improved retention of text information. The kind and number of revisions and improvements varied across the text sets. Most expert hypotheses were not supported, and they made many revisions they were declaratively unaware of. Some of our hypotheses about the revision features were supported, but different features were effective for different sets of texts. It was concluded that some experts have effective knowledge about improving instructional text, but it exists primarily in procedural form. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Metastatic parathyroid carcinoma in the MEN2A syndrome

We report a patient with a metastatic parathyroid carcinoma and medullary carcinoma of the thyroid. This patient represents a variation of the multiple endocrine neoplasia syndrome (MEN) type 2A. There was no evidence of a phaeochromocytoma. The case illustrates the difficulties that may be encountered in localising the source of PTH secretion; the patient underwent four unsuccessful exploratory operations of the neck and mediastinum before further investigations revealed a single metastatic deposit of parathyroid carcinoma involving the first thoracic vertebra. PCR amplification and sequencing of the RET oncogene from the metastatic parathyroid carcinoma and genomic DNA revealed a heterozygous mutation (Cys634Tyr) in exon 11, as has previously been described to occur in MEN 2A. In addition, loss of tumour heterozygosity was demonstrated at loci from chromosomes 1, 2, 3p, 13q and 16p. This represents the first report of a parathyroid carcinoma in a MEN2A patient, in which the multiple allelic deletions are consistent with the generalised losses observed in aggressive tumours.     

Effects of anxiety arousal and mental stress on the vestibulo-ocular reflex

Although the subjective reports of patients suggest that anxiety may aggravate vertigo and imbalance, there has been little research into how anxiety might directly affect balance system functioning. We conducted two studies to examine the effect of anxiety and arousal on the vestibulo-ocular reflex (VOR). In the first study, pre-lest fear ratings were obtained from 20 normal subjects and 36 anxious subjects immediately prior to rotation and caloric testing. Fear ratings were significantly correlated with the maximum slow-phase velocity (SPV) of nystagmus induced by caloric testing. In the second study, we assessed the VOR response to rotation of 36 normal subjects under 3 task conditions: a) minimal alerting (counting backwards during rotation), b) physical arousal (induced by exertion prior to rotation); c) mental arousal (induced by performance of stressful mental tasks during rotation). Both the physical and mental tasks induced a significant increase in heart rate compared with the alerting condition. The maximum SPV of the nystagmus induced by rotation was significantly greater during performance of the mental task than in the other two conditions. These combined results indicate that anxiety may influence the gain of the VOR.     

Datum-Hierarchy Tree Method for Tolerance Analysis of Plating and Heat Treatment Operations

This paper presents a new method for the tolerance analysis of plating and heat treatment operations. It is suitable for both manual and computerised tolerance analysis. The new method uses a datum-hierarchy tree to identify tolerance stacks and a stock removal set matrix to calculate the positions of surfaces created during the manufacturing sequence. A tolerance chart is used to associate stock removal sets with the geometry of the workpiece, to show the manufacturing sequence, and to record the operation data and the tolerance analysis results. Plating and heat treatment operations are represented as edges in the tree, so that for each operation (edge) the input and output nodes represent consecutive surfaces in a stock removal set. Rules are given for calculating the tolerance stackups and the positions of the surfaces in the stock removal sets. The method is illustrated with an example.     

Modulation of postural tremors at the wrist by supramaximal electrical median nerve shocks in essential tremor, Parkinson's disease and normal subjects mimicking tremor

The response of postural wrist tremors to supramaximal median nerve stimulation was examined in patients with hereditary essential tremor (n = 10) and Parkinson's disease (n = 9), and in normal subjects mimicking wrist tremor (n = 8). The average frequency of on-going tremor was the same in all three groups. Supramaximal peripheral nerve shocks inhibited and then synchronised the rhythmic electromyographic (EMG) activity of all types of tremor. The duration of inhibition ranged from 90 to 210ms, varying inversely with the frequency of on-going tremor. There was no significant difference in mean duration of inhibition or in the timing of the first peak after stimulation on the average rectified EMG records between the three groups. The degree to which supramaximal peripheral nerve shocks could modulate the timing of rhythmic EMG bursts in the forearm flexor muscles was also quantified by deriving a resetting index. No significant difference in mean resetting index of the three groups was found. These results suggest that such studies cannot be used to differentiate between the common causes of postural wrist tremors.     

Prediction of psychoticlike symptoms in hypothetically psychosis-prone college students.

Correlates of psychotic and psychoticlike symptoms were examined in 60 college students who scored deviantly high on the Perceptual Aberration Scale. High scorers on this scale who also scored high on both the Impulsive Nonconformity Scale and the Depression subscale of the General Behavior Inventory (GBI) showed the most deviant psychotic and psychoticlike symptoms. Moreover, performance on a task of referential communication, the Password Task, was significantly related to such symptoms. The Perceptual Aberration Scale, the Impulsive Nonconformity Scale, and the GBI Depression subscale are recommended for concurrent use in mass screening to select individuals likely to exhibit psychotic or psychoticlike symptoms. (PsycINFO Database Record (c) 2010 APA, all rights reserved)