Borcalein: a Carborane-Based Analogue of Baicalein with 12-Lipoxygenase-Independent Toxicity

12-Lipoxygenase is crucial for tumour angiogenesis. 5,6,7-Trihydroxy-2-phenyl-4H-1-benzopyran-4-one (baicalein) is a suitable inhibitor for this enzyme but is rapidly metabolised in vivo. Thus, an improvement of the metabolic stability is necessary to enhance the therapeutic efficiency. An emerging approach to enhance metabolic stability of carbon-based pharmaceuticals is the use of metabolically stable, non-toxic boron clusters, such as dicarba-closo-dodecaborane(12)s (carboranes) as phenyl mimetics. Therefore, the unsubstituted phenyl ring of baicalein was replaced by meta-carborane, resulting in borcalein, the carborane analogue of baicalein. This substitution resulted in a decreased inhibitory activity toward 12-lipoxygenase, but led to increased toxicity in melanoma (A375, B16, B16F10) and colon cancer cell lines (SW480, HCT116, CT26CL25) with decreased tumour selectivity in comparison to baicalein. Surprisingly, borcalein displays a different mechanism of cytotoxicity with increased intracellular production of reactive oxygen species (ROS), reactive nitrogen species (RNS) and nitric oxide (NO).     

One Question,Multiple Answers: Biochemical and Biophysical Screening Methods Retrieve Deviating Fragment Hit Lists

Fragment‐based lead discovery is gaining momentum in drug development. Typically, a hierarchical cascade of several screening techniques is consulted to identify fragment hits which are then analyzed by crystallography. Because crystal structures with bound fragments are essential for the subsequent hit‐to‐lead‐to‐drug optimization, the screening process should distinguish reliably between binders and non‐binders. We therefore investigated whether different screening methods would reveal similar collections of putative binders. First we used a biochemical assay to identify fragments that bind to endothiapepsin, a surrogate for disease‐relevant aspartic proteases. In a comprehensive screening approach, we then evaluated our 361‐entry library by using a reporter‐displacement assay, saturation‐transfer difference NMR, native mass spectrometry, thermophoresis, and a thermal shift assay. While the combined results of these screening methods retrieve 10 of the 11 crystal structures originally predicted by the biochemical assay, the mutual overlap of individual hit lists is surprisingly low, highlighting that each technique operates on different biophysical principles and conditions.     

Phylogenetic positions of Clostridium chauvoei and Clostridium septicum based on 16S rRNA gene sequences

The sequences of the 16S rRNA genes (rrs genes) of Clostridium chauvoei, the causative agent of blackleg in cattle, and the phenotypically related organism Clostridium septicum were determined. After amplification of 1,507-bp PCR fragments from the corresponding rrs genes, the sequences were determined in a single round of sequencing by using conserved region primers. A sequence similarity analysis of the sequences revealed the close phylogenetic relationship of C. chauvoei and C. septicum in Clostridium cluster I (M. D. Collins, P. A. Lawson, A. Willems, J. J. Cordoba, J. Fernandez-Garayzabal, P. Garcia, J. Cai, H. Hippe, and J. A. E. Farrow, Int. J. Syst. Bacteriol. 44:812-826, 1994), which includes Clostridium carnis, Clostridium perfringens, Clostridium botulinum, and Clostridium tetani. We found that 99.3% of the nucleotides in the genes of C. chauvoei and C. septicum are identical.     

Comment on: “Component relevancy in multistate reliabilitymodels”

The author comments on the paper by A.M. Abouammoh and M.A. Al-Kadi (see ibid., vol.40, p.370-4, 1991) which discusses various notions of component relevancy for multistate systems and suggests a unified form of relevancy. The paper contains many misprints, some wrong examples, and several results that need clarification. The most important are mentioned     

Simulating soil carbon sequestration from long term fertilizer and manure additions under continuous wheat using the DailyDayCent model

The widely used ecosystem model DailyDayCent (DDC) was used to predict soil organic carbon (SOC) sequestration and yield under different fertilization treatments on a wheat (Triticum aestivum) monoculture on Broadbalk field, Rothamsted, UK. Over a period of about 170 years, the management practices on the test site, which is separated into plots with different treatments of fertilizer and manure application, are well documented. Four treatments consisting of control (no fertilizer), mineral nitrogen (N) fertilizer (MN), farm yard manure (FYM) and a combination of both (FYMN) have been selected for the study. DDC simulated the greatest increases in SOC (three times higher compared to simulation of the control plot) in the FYM plot. Overall a good agreement between modelled and measured yield was obtained (except in control plots). As observed in the experimental plots, the highest yield predicted by the model is with FYMN plot (more than three times higher relative to the control plot). A sensitivity test for the MN and FYM plots demonstrated that predicted SOC was relatively insensitive (1%) to bulk density, pH and field capacity. Higher sensitivity (4–7%) of predicted SOC changes were observed by changes in external C input. An increase of temperature by 1 °C or precipitation by 10% decreased predicted SOC by 2–4% and vice versa, and simulated a 1–4% variability in yield. DDC is a useful tool for simulating SOC in the long term plots, with a good fit to data, and is useful for examining alternate hypotheses of yield and SOC responses.     

LC–MS analysis of the cis isomers of chlorogenic acids

The behaviour of cis isomers of selected mono- and di-acyl chlorogenic acids produced by UV-irradiation has been investigated by LC–MSⁿ. cis Isomers fragment identically to the more common trans isomers. cis-5-Acyl chlorogenic acids are more hydrophobic and elute later than their mono- or di-trans counterparts whereas the reverse is true for cis-3-acyl and cis-4-acyl chlorogenic acids. The cis isomers of 1,3-dicaffeoylquinic acid, the only 1-acyl chlorogenic acid investigated, are also more hydrophobic than the di-trans isomer. Coffee leaves had a proportionately greater content of cis isomers relative to trans isomers compared with coffee beans suggesting that UV-irradiation in vivo may also cause geometric isomerisation.     

GPU‐Based Spherical Light Field Rendering with Per‐Fragment Depth Correction

Image‐based rendering techniques are a powerful alternative to traditional polygon‐based computer graphics. This paper presents a novel light field rendering technique which performs per‐pixel depth correction of rays for high‐quality reconstruction. Our technique stores combined RGB and depth values in a parabolic 2D texture for every light field sample acquired at discrete positions on a uniform spherical setup. Image synthesis is implemented on the GPU as a fragment program which extracts the correct image information from adjacent cameras for each fragment by applying per‐pixel depth correction of rays. We show that the presented image‐based rendering technique provides a significant improvement compared to previous approaches. We explain two different rendering implementations which make use of a uniform parametrisation to minimise disparity problems and ensure full six degrees of freedom for virtual view synthesis. While one rendering algorithm implements an iterative refinement approach for rendering light fields with per pixel depth correction, the other approach employs a raycaster, which provides superior rendering quality at moderate frame rates. GPU based per‐fragment depth correction of rays, used in both implementations, helps reducing ghosting artifacts to a non‐noticeable amount and provides a rendering technique that performs without exhaustive pre‐processing for 3D object reconstruction and without real‐time ray‐object intersection calculations at rendering time.