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.     

Detection of four species of Borrelia burgdorferi sensu lato in Ixodes ricinus ticks collected from roe deer (Capreolus capreolus) in The Netherlands

Epiglottic disruption is an uncommon injury usually associated with significant supraglottic trauma. This injury may be overlooked because of the difficulty in examining the larynx or other associated severe injuries. We present two cases of clinically unsuspected epiglottic disruption that were first seen on MR images of the neck.     

Influence of lead on metabolism of vitamins B group in alimentary iron deficient rats

Gamma delta T-Cells represent a minor subpopulation of T-lymphocytes in man and their role in normal and diseased human skin is unknown. This article is a comprehensive review of T-lymphocytes bearing the gamma delta T-cell receptor in normal and pathological human skin. Firstly, we have documented the occurrence of gamma delta T-cells in normal skin and in a range of reactive and malignant skin conditions. We have then discussed the experimental findings regarding the repertoire used by gamma delta T-cells in normal human skin and in cutaneous disorders with an increased percentage of gamma delta T-cells.     

ERCP and CT findings of ectopic drainage of the common bile duct into the duodenal bulb

OBJECTIVE: The purpose of this study was to evaluate ERCP and CT findings of ectopic drainage of the common bile duct into the duodenal bulb. CONCLUSION: Although rare, the diagnosis of ectopic drainage of the common bile duct into the duodenal bulb is important to prevent inadvertent damage during biliary tract or gastric surgery and to clarify the cause of chronic peptic ulcers.     

The activity of acid phosphatase and its isoenzymes in patients with food poisonings

Changes in the activity of acid phosphatase (AP) and its isoenzymes (tartrate-insensitive AP and formalin-insensitive AP) were investigated in patients with food poisoning in the course of the disease. The activity of AP and its isoenzymes in the serum started to grow in early convalescence and reached maximum in late convalescence. Total activity of AP in food toxic infections consists primarily of the activity of its platelet fraction. AP activity may serve as an additional criterion to predict vascular platelet involvement of hemostasis.     

The partial testing design: a less costly way to test equivalence for sensitivity and specificity

We propose a new, less costly, design to test the equivalence of digital versus analogue mammography in terms of sensitivity and specificity. Because breast cancer is a rare event among asymptomatic women, the sample size for testing equivalence of sensitivity is larger than that for testing equivalence of specificity. Hence calculations of sample size are based on sensitivity. With the proposed design it is possible to achieve the same power as a completely paired design by increasing the number of less costly analogue mammograms and not giving the more expensive digital mammograms to some randomly selected subjects who are negative on the analogue mammogram. The key idea is that subjects who are negative on the analogue mammogram are unlikely to have cancer and hence contribute less information for estimating sensitivity than subjects who are positive on the analogue mammogram. To ascertain disease state among subjects not biopsied, we propose another analogue mammogram at a later time determined by a natural history model. The design differs from a double sampling design because it compares two imperfect tests instead of combining information from a perfect and imperfect test.     

A new epitope presenting system displays a HIV-1 V3 loop sequence and induces neutralizing antibodies

The principal neutralizing domain, IGPGRAF sequence, from the V3-loop of HIV-1 was inserted in two positions on the surface of the protein that makes up the capside shell of the insect Flock House Virus. The hybrid proteins were expressed in insect cells via recombinant baculoviruses. Three different hybrids were used as immunogens: two with a single copy of the insert in different positions of the carrier protein and a third with two copies of the insert at the same positions as before. All hybrid proteins induced strong and broad specific immune response in guinea pigs against different V3-loop sequences. However, only one of the hybrid proteins was able to induce a strong neutralizing response against MN and IIIB HIV-1 isolates. Our results demonstrate that a very short peptide sequence of HIV-1 can constitute a valuable immunogen able to induce a neutralizing response if presented to the immune system in the context of the FHV capsomer structure.