Syntheses,biological evaluation and SAR of ingenol mebutate analogues for treatment of actinic keratosis and non-melanoma skin cancer

Ingenol mebutate is the active ingredient in Picato® a new drug for the treatment of actinic keratosis. A number of derivatives related to ingenol mebutate were prepared by chemical synthesis from ingenol with the purpose of investigating the SAR and potency in assays relating to pro-inflammatory effects (induction of PMN oxidative burst and keratinocyte cytokine release), the potential of cell death induction, as well as the chemical stability. By modifications of the ingenol scaffold several prerequisites for activity were identified. The chemical stability of the compounds could be linked to an acyl migration mechanism. We were able to find analogues of ingenol mebutate with comparable in vitro properties. Some key features for potent and more stable ingenol derivatives have been identified.     

Integrating multiple lines of evidence to better understand the evolutionary divergence of humpback dolphins along their entire distribution range: a new dolphin species in Australian waters?

The conservation of humpback dolphins, distributed in coastal waters of the Indo‐West Pacific and eastern Atlantic Oceans, has been hindered by a lack of understanding about the number of species in the genus (Sousa) and their population structure. To address this issue, we present a combined analysis of genetic and morphologic data collected from beach‐cast, remote‐biopsied and museum specimens from throughout the known Sousa range. We extracted genetic sequence data from 235 samples from extant populations and explored the mitochondrial control region and four nuclear introns through phylogenetic, population‐level and population aggregation frameworks. In addition, 180 cranial specimens from the same geographical regions allowed comparisons of 24 morphological characters through multivariate analyses. The genetic and morphological data showed significant and concordant patterns of geographical segregation, which are typical for the kind of demographic isolation displayed by species units, across the Sousa genus distribution range. Based on our combined genetic and morphological analyses, there is convincing evidence for at least four species within the genus (S. teuszii in the Atlantic off West Africa, S. plumbea in the central and western Indian Ocean, S. chinensis in the eastern Indian and West Pacific Oceans, and a new as‐yet‐unnamed species off northern Australia).     

Energetic Pathway Sampling in a Protein Interaction Domain

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Structure and content of pollutants in temporal surface sediments in small watersheds

ABSTRACT

Formation of gel-like surface sediments has been observed during spring and autumn in small watersheds in boreal areas with pH <5.7 and concentrations of humic substances above 3 mg L^?1. This structure efficiently accumulates dissolved, colloidal and particulate constituents. The gel consists of ferric (hydr)oxides and fulvic acid and has high viable counts of bacteria (notably Gallionella spp.) as well as fungal hyphae. The solid/solution distribution (log K_d; l kg^?1) for trace metals (Cd, Cu, Pb, V, Zn) ranges from 4 to 6.5 which indicate an efficient accumulation during periods with gel. The concentrations of adsorbable organic halogens in the gel were not different from forest soils in general.     

Does doping with aluminum alter the effects of ZnO nanoparticles on the metabolism of soil pseudomonads?

Doping of ZnO nanoparticles (NPs) is being used to increase their commercialization in the optical and semiconductor fields. This paper addresses whether doping with Al alters how ZnO NPs at nonlethal levels modifies the metabolism of soil-borne pseudomonads which are beneficial in performing bioremediation or promoting plant growth. The differences in X-ray diffraction (XRD) patterns, observed between commercial ZnO and Al-doped ZnO NPs indicated the aluminum was present as Al NPs. Both particles aggregated in the bacterial growth medium and formed colloids of different surface charges. They had similar effects on bacterial metabolism: rapid, dose-dependent loss in light output indicative of temporary toxicity in a biosensor constructed in Pseudomonas putida KT2440; increased production of a fluorescent pyoverdine-type siderophore, and decreased levels of indole acetic acid and phenazines in Pseudomonas chlororaphis O6. Solubilization of Zn and Al from the NPs contributed to these responses to different extents. These findings indicate that Al-doping of the ZnO NPs did not reduce the ability of the NPs to alter bacterial metabolism in ways that could influence performance of the pseudomonads in their soil environment.     

3D Microstructural Architecture of Muscle Attachments in Extant and Fossil Vertebrates Revealed by Synchrotron Microtomography

Background

Firm attachments binding muscles to skeleton are crucial mechanical components of the vertebrate body. These attachments (entheses) are complex three-dimensional structures, containing distinctive arrangements of cells and fibre systems embedded in the bone, which can be modified during ontogeny. Until recently it has only been possible to obtain 2D surface and thin section images of entheses, leaving their 3D histology largely unstudied except by extrapolation from 2D data. Entheses are frequently preserved in fossil bones, but sectioning is inappropriate for rare or unique fossil material.

Methodology/Principal Findings

Here we present the first non-destructive 3D investigation, by propagation phase contrast synchrotron microtomography (PPC-SRµCT), of enthesis histology in extant and fossil vertebrates. We are able to identify entheses in the humerus of the salamander Desmognathus from the organization of bone-cell lacunae and extrinsic fibres. Statistical analysis of the lacunae differentiates types of attachments, and the orientation of the fibres, reflect the approximate alignment of the muscle. Similar histological structures, including ontogenetically related pattern changes, are perfectly preserved in two 380 million year old fossil vertebrates, the placoderm Compagopiscis croucheri and the sarcopterygian fish Eusthenopteron foordi.

Conclusions/Significance

We are able to determine the position of entheses in fossil vertebrates, the approximate orientation of the attached muscles, and aspects of their ontogenetic histories, from PPC-SRµCT data. Sub-micron microtomography thus provides a powerful tool for studying the structure, development, evolution and palaeobiology of muscle attachments.     

Genetic Instability and Intratumoral Heterogeneity in Neuroblastoma with MYCN Amplification Plus 11q Deletion

Background/Aim

Genetic analysis in neuroblastoma has identified the profound influence of MYCN amplification and 11q deletion in patients’ prognosis. These two features of high-risk neuroblastoma usually occur as mutually exclusive genetic markers, although in rare cases both are present in the same tumor. The purpose of this study was to characterize the genetic profile of these uncommon neuroblastomas harboring both these high-risk features.

Methods

We selected 18 neuroblastomas with MNA plus 11q loss detected by FISH. Chromosomal aberrations were analyzed using Multiplex Ligation-dependent Probe Amplification and Single Nucleotide Polymorphism array techniques.

Results and Conclusion

This group of tumors has approximately the same high frequency of aberrations as found earlier for 11q deleted tumors. In some cases, DNA instability generates genetic heterogeneity, and must be taken into account in routine genetic diagnosis.