α-CGRP disrupts amylin fibrillization and regulates insulin secretion: implications on diabetes and migraine

Despite being relatively benign and not an indicative signature of toxicity, fibril formation and fibrillar structures continue to be key factors in assessing the structure–function relationship in protein aggregation diseases. The inability to capture molecular cross-talk among key players at the tissue level before fibril formation greatly accounts for the missing link toward the development of an efficacious therapeutic intervention for Type II diabetes mellitus (T2DM). We show that human α-calcitonin gene-related peptide (α-CGRP) remodeled amylin fibrillization. Furthermore, while CGRP and/or amylin monomers reduce the secretion of both mouse Ins1 and Ins2 proteins, CGRP oligomers have a reverse effect on Ins1. Genetically reduced Ins2, the orthologous version of human insulin, has been shown to enhance insulin sensitivity and extend the life-span in old female mice. Beyond the mechanistic insights, our data suggest that CGRP regulates insulin secretion and lowers the risk of T2DM. Our result rationalizes how migraine might be protective against T2DM. We envision the new paradigm of CGRP : amylin interactions as a pivotal aspect for T2DM diagnostics and therapeutics. Maintaining a low level of amylin while increasing the level of CGRP could become a viable approach toward T2DM prevention and treatment.

CGRP concentration is elevated in migraine conditions. The protective effect of migraine against type 2 diabetes is attributed to the ability of CGRP to remodel human amylin aggregation and to suppress the secretion of mouse insulin 2 (the orthologue of human insulin).     

Heteroatom derivatives of indene: V. Vibrational spectra of benzimidazole

Infrared and Raman measurements for benzimidazole are presented and discussed, including its argon-matrix infrared spectrum. To assist in the assignment, benzimidazole's harmonic force fields for the 321G* and 631G* levels were scaled by scaled factors derived by fitting the respective computed force fields of other indene derivatives to previously reported experimental vibrational frequencies. Comparison to the best set of experimental wavenumbers, usually taken from the matrix, shows mean 321G* and 631G* deviations of 7.0 and 5.8 cm⁻¹ for the planar modes, and 14.0 and 6.8 cm⁻¹ for the nonplanar modes, respectively, with much of the error residing in imino-hydrogen group modes. Standard entropies are derived with the matrix wavenumbers and the methods of statistical mechanics. An attempt to determine standard entropies by calorimetric methods was unsuccessful. The triple-point temperature T_tp and enthalpy of fusion Δ¹_crH_m only are reported.     

PHOTOREAaIVITY OF CHLORAMPHENICOL in vitro AND in vivo

Abstract The negative side effects of chlorarnphenicol (CAP) mostly involve blood dyscrasias (e.g. irreversible nondose-dependent aplastic anemia), allergic skin reactions and eye damage. To learn the cause of these side effects, most research focuses on metabolically formed nitroso- and hydroxylamino derivatives in the predisposed patient. In previous investigations it was demonstrated that photochemical decomposition of CAP in vitro by UV-A leads to formation of p-nitrobenzaldehyde (pNB), p-nitrobenzoic acid (pNBA) and p-nitrosobenzoic acid (pNOBA); the latter comprises up to 45 mol% of the starting amount of CAP. Incubation of these photoproducts in rat blood showed that pNB and pNOBA rapidly react and that PNBA is stable under these conditions. Reaction products from pNB (half-life 1.7 min) proved to be pNBA and p-nitrobenzyl alcohol (pNBOH) while pNOBA (half-life 3.7 min) was converted into p-aminobenzoic acid (pABA). Exposure of CAP in rat blood to UV-A yielded the same end products: pNBA, PABA and pNBOH. To estimate the amount of oxidative stress generated in vivo by these compounds, the ability to form methemoglobin (MetHb) in erythrocytes was tested; only pNOBA and p-hydroxylaminobenzoic acid (pHABA), a possible intermediate in the decomposition of pNOBA, proved to be reactive. Ultraviolet-A exposure of rats, after intraperitoneal injection of CAP, led to 3.6 times the basic level of MetHb. In addition, covalent binding of ³H-labeled CAP photoproducts to the skin of the back and to the ears was found, which was 9.1 and 3.2 times higher, respectively, than the dark values. Toxicity toward bone marrow cells of all photoproducts was established in vitro. p-Nitrobenzaldehyde, pNOBA andpHABA were 20, 6 and 6 times more toxic than CAP, respectively. These results show that photodecomposition of CAP in vivo does occur. Its reactive photoproducts are able to cause damage that may lead to (systemic) side effects. The latter is supported by the fact that the nature of the reactive products, nitroso- and hydroxylamino derivatives, is the same as the expected metabolites.     

Analytical chemistry and the cone penetrometer: In situ chemical characterization of the subsurface

The development of novel microanalytical techniques forin situ chemical characterization of the terrestrial subsurface environment has grown significantly over the last decade, particularly those instruments that are interfaced to the cone penetrometer. Cone penetrometer testing (CPT) has emerged as an effective means to introduce samplers and probes forin situ analysis of contaminants in soil and groundwater matrices. A variety ofin situ chemical samplers for CPT have been developed that can be driven into the subsurface to collect soil gas, groundwater, or soil samples at depth, thus providing a means of determining the vertical and horizontal extent of contamination. Cone penetrometer testing is also being explored as a means to deliverin situ subsurface sensor probes, including probes based on laser-induced fluorescence, Raman, and infrared spectroscopies for organics; on laser-induced breakdown and X-ray fluorescence spectroscopies for heavy metals; and on passive gamma-ray spectroscopy for radionuclides. The range of analytical technologies used in CPT for the determination of organic and inorganic species in the subsurface is described.     

Enantiomerically pure alpha-amino acid synthesis via hydroboration-suzuki cross-coupling

The Garner aldehyde-derived methylene alkene 5 and the corresponding benzyloxycarbonyl compound 25 undergo hydroboration with 9-BBN-H followed by palladium-catalyzed Suzuki coupling reactions with aryl and vinyl halides. After one-pot hydrolysis-oxidation, a range of known and novel nonproteinogenic amino acids were isolated as their N-protected derivatives. These novel organoborane homoalanine anion equivalents are generated and transformed under mild conditions and with wide functional group tolerance: electron-rich and -poor aromatic iodides and bromides (and a vinyl bromide) all undergo efficient Suzuki coupling. The extension of this methodology to prepare meso-DAP, R,R-DAP, and R,R-DAS is also described.     

Time-dependent internal Quantum Efficiency and diffusion Modulation Transfer Function of N/P photodiodes

The minority carrier continuity equation has been solved with the Green’s function approach in a N/P photodiode under the low-level injection assumption. The analytical solution obtained with this approach depends on the three spatial coordinates and on time. The diffusion and the collection of the excess minority carriers have been studied during the transitional period corresponding to very short integration times. The internal Quantum Efficiency and the diffusion Modulation Transfer Function have been calculated according to time. The simulations showed that they evolve with time until their steady-state values. When the integration time is very short, this evolution has to be taken into account for the estimation of the sensitivity of a photodiode and the contrast on an image of a sensor based on several adjacent N/P-type photodiodes.     

New reaction of formation of the fused tricyclic bispyrroloquinone ring system

A one-pot procedure to difunctionalized fused tricyclic bispyrroloquinone derivatives involving the condensation of N-tosylindoledione and α-ketoamines is described.     

Locally s-distance transitive graphs and pairwise transitive designs

The study of locally s-distance transitive graphs initiated by the authors in previous work, identified that graphs with a star quotient are of particular interest. This paper shows that the study of locally s-distance transitive graphs with a star quotient is equivalent to the study of a particular family of designs with strong symmetry properties that we call nicely affine and pairwise transitive. We show that a group acting regularly on the points of such a design must be abelian and give general construction for this case.     

An Alternative Way to Generalize the Pentagon

We introduce the concept of a pentagonal geometry as a generalization of the pentagon and the Desargues configuration, in the same vein that the generalized polygons share the fundamental properties of ordinary polygons. In short, a pentagonal geometry is a regular partial linear space in which for all points x, the points not collinear with the point x, form a line. We compute bounds on their parameters, give some constructions, obtain some nonexistence results for seemingly feasible parameters and suggest a cryptographic application related to identifying codes of partial linear spaces.