Overexpression of hedgehog signaling is associated with epidermal tumor formation in vitamin D receptor-null mice.

The vitamin D receptor (VDR) ligand, 1,25 dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), reduces proliferation and enhances differentiation, and thus has been investigated for a role in preventing or treating cancer. Mice deficient for the VDR display a hyperproliferative response in the hair follicle and epidermis and decreased epidermal differentiation. Unlike their wild-type littermates, when treated with 7,12 dimethylbenzanthracene (DMBA) or UVB, they develop skin tumors, including some characteristic of overexpression of the hedgehog (Hh) pathway. Both the epidermis and utricles of the VDR-null animals overexpress elements of the Hh pathway (sonic hedgehog (Shh) 2.02-fold, patched1 1.58-fold, smoothened 3.54-fold, glioma-associated oncogene homolog (Gli)1 1.17-fold, and Gli2 1.66-fold). This overexpression occurs at an age (11 weeks) at which epidermal hyperproliferation is most visible and is spatially controlled in the epidermis. DMBA- or UVB-induced tumors in the VDR-null mice also overexpress elements of this pathway. Moreover, 1,25(OH)(2)D(3) downregulates the expression of some members of the Hh pathway in an epidermal explants culture system, suggesting a direct regulation by 1,25(OH)(2)D(3). Our results suggest that increased expression of Shh in the keratinocytes of the VDR-null animal activates the Hh pathway, predisposing the skin to the development of both malignant and benign epidermal neoplasms

Novel conantokins from Conus parius venom are specific antagonists of N-methyl-D-aspartate receptors

Journal ArticleWe report the discovery and characterization of three conantokin peptides from the venom of Conus parius. Each peptide (conantokin-Pr1, -Pr2, and -Pr3) contains 19 amino acids with three γ-carboxyglutamate (Gla) residues, a post-translationally modified amino acid characteristic of conantokins. The new peptides contain several amino acid residues that differ from previous conantokin consensus sequences

Uniquely selective inhibitor of the mammalian fetal neuromuscular nicotinic acetylcholine receptor

Journal ArticleWe have purified and characterized a novel conotoxin from the venom of Conus obscurus, which has the unique property of selectively and potently inhibiting the fetal form of the mammalian neuromuscular nicotinic acetylcholine receptor (nAChR) (α1β1γδ-subunits). Although this conotoxin, αA-conotoxin OIVB (αA-OIVB), is a high-affinity antagonist (IC50 of 56 nM) of the fetal muscle nAChR, it has >1800-fold lower affinity for the adult muscle nAChR (α1β1εδ-subunits) and virtually no inhibitory activity at a high concentration on various neuronal nAChRs (IC50 > 100 μM in all cases)

Comparing outpatient oral antibiotic use in Germany and the Netherlands from 2012 to 2016.

PURPOSE: Overuse of antibiotics is of concern, but may differ between European countries. This study compares outpatient use of oral antibiotics between Germany (DE) and the Netherlands (NL). METHODS: For DE, we used the DAPI database with information on dispensings at the expense of the Statutory Health Insurance Funds from > 80% of community pharmacies. For NL, data were obtained from the Dutch Foundation for Pharmaceutical Statistics. Use of oral antibiotics was estimated as defined daily doses per 1000 inhabitants per day (DID), except for age comparisons as packages per 1000 inhabitants annually. National time trends were assessed with linear regression, stratified for the major antibiotic classes, and individual substances. RESULTS: From 2012 to 2016, outpatient antibiotic use was lower in NL than in DE (9.64 vs 14.14 DID in 2016) and non-significantly decreased slightly over time in both countries. In DE, dispensings of oral antibiotics to children were higher compared with NL for the age groups 2 to 5 (2.0-fold in 2016) and 6 to 14 years (2.7-fold in 2016). Use of cephalosporins was very low in NL (0.02 DID in 2016), but the second most frequently dispensed class in DE (2.95 DID in 2016). CONCLUSION: From 2012 to 2016, outpatient use of oral antibiotics was lower in NL than in DE. Differences were primarily observed in the age groups 2 to 5 and 6 to 14 years, although the recommendations of evidence-based guidelines in both countries were in agreement

Data report: bulk mineralogical composition of Cascadia margin sediments, IODP Expedition 311

The bulk mineralogical compositions of sediment samples from Sites U1325–U1329, northern Cascadia margin, were determined by X-ray diffraction analyses. The results document a highly variable mineralogy dominated by detrital components, mainly quartz, feldspar, mica, and clay minerals. Carbonate minerals are present only in minor amounts (<5 wt%). The long-term variations in the relative abundance of each mineral correspond to the particular lithostratigraphic units

Prebiotic Nucleoside Synthesis: The Selectivity of Simplicity

Ever since the discovery of nucleic acids 150 years ago, major achievements have been made in understanding and decrypting the fascinating scientific questions of the genetic code. However, the most fundamental question about the origin and the evolution of the genetic code remains a mystery. How did nature manage to build up such intriguingly complex molecules able to encode structure and function from simple building blocks? What conditions were required? How could the precursors survive the unhostile environment of early Earth? Over the past decades, promising synthetic concepts were proposed providing clarity in the field of prebiotic nucleic acid research. In this Minireview, we show the current status and various approaches to answer these fascinating questions

Is all Internet gambling equally problematic? Considering the relationship between mode of access and gambling problems

Concerns exist that Internet gambling may increase rates of gambling harms, yet research to date has found inconsistent results. Internet gamblers are a heterogeneous group and considering this population as a whole may miss important differences between gamblers. The differential relationship of using mobile and other devices for gambling online has not been considered as compared to the use of computers. The true relationship of Internet gambling on related problems and differences between preferred modes for accessing online gambling may be obscured by confounding personal and behavioural factors. This paper thus uses the innovative approach of propensity score matching to estimate the consequence of gambling offline, or online through a computer, as compared to mobile or other supplementary devices by accounting for confounding effects of difference among groups of Australian gamblers (N = 4482). Gamblers who prefer to gamble online using computers had lower rates of gambling problems as compared to those using mobile and supplementary devices. Individual life cycle was useful to differentiate between groups, indicating age, marital, and employment status should be considered together to predict how people gamble online. This is the first empirical study to suggest that the mode of accessing Internet gambling may be related to subsequent harms.No funding was provided for this manuscript. Funding was provided for the original research to the lead author by the Menzies Foundation

Pharmacogenetic Aspects and Drug Interactions in Anticoagulation Therapy with Coumarins

The mysterious ability of blood to clot has fascinated people over millennia. In the beginning of the 20th century, the mechanisms became better understood. In 1922, the development of hemorrhagic disease in cattle caused by mouldy sweet clover was described by Schofield. The absence or delay of blood clotting was correlated to a greatly diminished quantity of prothrombin. This discovery remained unnoticed until twenty years later the ‘hemorrhagic agent’ was identified as dicoumarol, 3,3-methylene-bis. It was promptly made available for clinical studies and already one year later first experiences on the effectiveness in deep vein thrombosis as well as its hemorrhagic complications were published. From the coumarin derivates synthesized, the most potent one was warfarin, an acronym for the Wisconsin Alumni Research Foundation (WARF). As it was used successfully to fight rats, its name may also contribute to that ‘warfare’. It was patented in 1948 and is since then the most frequently used coumarin worldwide. In 1929, Dam observed haemorrhage and markedly prolonged coagulation times in chickens fed with diets from which fat was completely extracted. He concluded that the substance whose absence in the diet was responsible for the coagulation and bone growth pathologies should be a new fat-soluble vitamin which he named vitamin K (“Koagulation”). For the discovery of vitamin K and the purification, characterization and synthesis of the vitamin, Dam and Doisy were awarded the Nobel Prize in Medicine in 1943. It was known then empirically that vitamin K reversed the bleeding problem of mouldy sweet clover poisoning. However, it took three more decades until the vitamin K cycle was proposed in 1974. After another three decades, in 2004, the complex biochemical relationship between vitamin K, its epoxide, and coumarins was enlightened by identifying the VKORC1 gene. This gene encodes the protein which is the target of the coumarins. Genetically mutated variants of the gene have been shown to cause warfarin-resistance phenotypes as well as pathogenic deficiency of all vitamin K-dependent coagulation factors