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.     

Analgesic,Anxiolytic and Anaesthetic Effects of Melatonin: New Potential Uses in Pediatrics

Exogenous melatonin is used in a number of situations, first and foremost in the treatment of sleep disorders and jet leg. However, the hypnotic, antinociceptive, and anticonvulsant properties of melatonin endow this neurohormone with the profile of a drug that modulates effects of anesthetic agents, supporting its potential use at different stages during anesthetic procedures, in both adults and children. In light of these properties, melatonin has been administered to children undergoing diagnostic procedures requiring sedation or general anesthesia, such as magnetic resonance imaging, auditory brainstem response tests and electroencephalogram. Controversial data support the use of melatonin as anxiolytic and antinociceptive agents in pediatric patients undergoing surgery. The aim of this review was to evaluate available evidence relating to efficacy and safety of melatonin as an analgesic and as a sedative agent in children. Melatonin and its analogs may have a role in antinociceptive therapies and as an alternative to midazolam in premedication of adults and children, although its effectiveness is still controversial and available data are clearly incomplete.     

Protecting the Melatonin Rhythm through Circadian Healthy Light Exposure

Currently, in developed countries, nights are excessively illuminated (light at night), whereas daytime is mainly spent indoors, and thus people are exposed to much lower light intensities than under natural conditions. In spite of the positive impact of artificial light, we pay a price for the easy access to light during the night: disorganization of our circadian system or chronodisruption (CD), including perturbations in melatonin rhythm. Epidemiological studies show that CD is associated with an increased incidence of diabetes, obesity, heart disease, cognitive and affective impairment, premature aging and some types of cancer. Knowledge of retinal photoreceptors and the discovery of melanopsin in some ganglion cells demonstrate that light intensity, timing and spectrum must be considered to keep the biological clock properly entrained. Importantly, not all wavelengths of light are equally chronodisrupting. Blue light, which is particularly beneficial during the daytime, seems to be more disruptive at night, and induces the strongest melatonin inhibition. Nocturnal blue light exposure is currently increasing, due to the proliferation of energy-efficient lighting (LEDs) and electronic devices. Thus, the development of lighting systems that preserve the melatonin rhythm could reduce the health risks induced by chronodisruption. This review addresses the state of the art regarding the crosstalk between light and the circadian system.     

Reprocessing of spent nuclear waste using ionic liquids

Nuclear power has once again attracted from all over the world due to many factors including the rise in oil process and environmental concerns on greenhouse gas emission resulting in global warming. However, spent fuel from nuclear power reactors is an enormous problem both from radiation hazard and economical point of view. Therefore, this review presents an overview of application of ionic liquids (ILs) in spent fuel reprocessing, particularly in the extraction of high-level radioactive aqueous waste from the processing of nuclear fuel.     

Towards the Automatic Measurement of Cashmere-fibre Diameter by Image Analysis

A digital-image-processing algorithm is described for automatically measuring the diameters of cashmere-goat fibres from microscope images. A correction factor is used to remove bias when fibres are out of focus. Diameters are estimated to within a standard error of 4%.     

Mechanically Induced Phase Transformation and Surface Segregation in Bismuth-Doped Tetragonal Zirconia

Compact pressure causes a martensitic transformation of partially stabilized tetragonal bismuth-doped ZrO₂ powders to the monoclinic phase. A similar effect is not observed when pelletization, followed by firing, of amorphous bismuth/ZrO₂ is performed. The stress-induced transition has been monitored via X-ray diffractometry, Raman spectroscopy, and Fourier transform infrared reflectivity. Surface bismuth segregation, which involves few ionic planes, has been probed by angle-resolved X-ray photoelectron spectroscopy. The bismuth segregation enthalpy has been evaluated.     

Hamiltonian optics of nonuniform photonic crystals

The passage of light through slowly varying nonuniform photonic crystal structures is treated using Hamiltonian optics. The approach allows the inverse design of complex and highly compact optical elements as well as providing insight and an appealing physical picture. It can also be used to treat the trapping and deflection of light at distributed defects in one- and two-dimensional (2-D) crystals, and to study the frequency-dependent time delay in chirped one-dimensional (1-D) fiber     

Mechanisms of drug transfer across the human placenta

In this review we summarized literature data on the mechanisms of human placental drug transport studied in the isolated perfused placental cotyledon, placental membrane vesicles or trophoblastic cell cultures. Overall human placental drug transport rarely exceeds the transfer of flow-dependent and membrane-limited marker compounds. Interestingly, relatively often placental drug transfer appeared to be much smaller, indicating impaired trans-placental transport, depending on the physico-chemical characteristics of the drug or placental factors such as tissue binding or metabolism. Although in perfusion studies overall human placental drug transport occurs by simple diffusion, at the membrane level several drug transport systems have been found, mainly for drugs structurally related to endogenous compounds.     

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.     

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.