The practical synthesis of a novel and highly potent analogue of bryostatin

Macrocycle 1 is a new highly potent analogue of bryostatin 1, a promising anti-cancer agent currently in human clinical trials. In vitro, 1 displays picomolar affinity for PKC and exhibits over 100-fold greater potency than bryostatin 1 when tested against various human cancer cell lines. Macrocycle 1 can be generated in clinically required amounts by chemical synthesis in only 19 steps (LLS) and represents a new clinical lead for the treatment of cancer.     

Numerical approximation of AR‐XPS spectra for rough surfaces considering the effect of electron shadowing

A computational scheme is presented that takes into account the topography, i.e. the shadowing and hence the local emission angle of the electrons when evaluating AR‐XPS data of macroscopic rough surfaces. The topography of the sample surface is supposed to be recorded by atomic force microscopy and/or optical microscopy. The emitted photoelectrons are simulated based on an extension of the Beer–Lambert law that includes the shadowing, the current local emission angle, and the geometrical instrument setup. The obtained angle‐resolved XPS spectra are optimized in accordance with experimental ones via a self‐consistent minimization algorithm that also allows one to determine the layer thicknesses of the corrugated sample. In order to validate the proposed numerical scheme, the simulation program simulation of electron spectra for surface analysis is used. An additional analysis is then performed considering only experimental data. The numerical scheme gives good agreement in simulation–simulation as well as simulation–experiment comparisons and permits a comprehensible interpretation of the measured data. Copyright © 2014 John Wiley & Sons, Ltd.     

trans-[Pt(BCat')Me(PCy3)2]: an experimental case study of reductive elimination processes in Pt-Boryls through associative mechanisms

A stable trans‐(alkyl)(boryl) platinum complex trans‐[Pt(BCat′)Me(PCy₃)₂] (Cat′=Cat‐4‐tBu; Cy=cyclohexyl=C₆H₁₁) was synthesised by salt metathesis reaction of trans‐[Pt(BCat′)Br(PCy₃)₂] with LiMe and was fully characterised. Investigation of the reactivity of the title compound showed complete reductive elimination of Cat′BMe at 80 °C within four weeks. This process may be accelerated by the addition of a variety of alkynes, thereby leading to the formation of the corresponding η²‐alkyne platinum complexes, of which [Pt(η²‐MeCCMe)(PCy₃)₂] was characterised by X‐ray crystallography. Conversion of the trans‐configured title compound to a cis derivative remained unsuccessful due to an instantaneous reductive elimination process during the reaction with chelating phosphines. Treatment of trans‐[Pt(BCat′)Me(PCy₃)₂] with Cat₂B₂ led to the formation of CatBMe and Cat′BMe. In the course of further investigations into this reaction, indications for two indistinguishable reaction mechanisms were found: 1) associative formation of a six‐coordinate platinum centre prior to reductive elimination and 2) σ‐bond metathesis of B? B and C? Pt bonds. Mechanism 1 provides a straightforward explanation for the formation of both methylboranes. Scrambling of diboranes(4) Cat₂B₂ and Cat′₂B₂ in the presence of [Pt(PCy₃)₂], fully reductive elimination of CatBMe or Cat′BMe from trans‐[Pt(BCat′)Me(PCy₃)₂] in the presence of sub‐stoichiometric amounts of Cat₂B₂, and evidence for the reversibility of the oxidative addition of Cat₂B₂ to [Pt(PCy₃)₂] all support mechanism 2, which consists of sequential equilibria reactions. Furthermore, the solid‐state molecular structure of cis‐[Pt(BCat)₂(PCy₃)₂] and cis‐[Pt(BCat′)₂(PCy₃)₂] were investigated. The remarkably short B? B separations in both bis(boryl) complexes suggest that the two boryl ligands in each case are more loosely bound to the Pt^II centre than in related bis(boryl) species.     

Voltage-dependent anion channel transports calcium ions through biomimetic membranes

The mitochondrial outer membrane channel (VDAC), a central player in mitochondria and cell death, was reconstituted in polymer-supported phospholipid bilayers. Highly purified VDAC was first reconstituted in vesicles; channel properties and NADH-ferricyanide reductase activity were ascertained before deposition onto solid substrates. 1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine/1,2-distearoyl-sn-glycero-3-phosphoethanolamine-poly(ethylene glycol)-N-hydroxysuccinimide mixed vesicles containing VDAC were linked onto amine-grafted surfaces (glass and gold) and disrupted to form a VDAC-containing polymer-tethered planar bilayer. Surface plasmon spectroscopy, fluorescence microscopy, and atomic force microscopy measurements ascertained the membrane thickness, fluidity, and continuity. VDAC reconstituted in bilayers efficiently transported calcium ions and was modulable by two channel blockers, 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid and l-glutamate. The novel setup may allow the study of the assembly of a polyprotein complex centered on VDAC and its role in mitochondrial biology, calcium fluxes, and apoptosis.     

In-situ investigation of the adsorption of globular model proteins on stimuli-responsive binary polyelectrolyte brushes

Binary brushes constituted from two incompatible polymers can be used in the form of ultrathin polymeric layers as a versatile tool for surface engineering to tune physicochemical surface characteristics such as wettability, surface charge, chemical composition, and morphology and furthermore to create responsive surface properties. Mixed brushes of oppositely charged weak polyelectrolytes represent a special case of responding surfaces that are sensitive to changes in the pH value of the aqueous environment and therefore represent interesting tools for biosurface engineering. The polyelectrolyte brushes used for this study were composed of two oppositely charged polyelelctrolytes poly(2-vinylpyridine) (P2VP) and poly(acrylic acid) (PAA). The in-situ properties and surface characteristics such as as surface charge, surface tension, and extent of swelling of these brush layers are functions of the pH value of the surrounding aqueous solution. To test the behavior of the mixed polylelctrolyte brushes in contact with biosystems, protein adsorption experiments with globular model proteins were performed at different pH values and salt concentrations (confinement of counterions) of the buffer solutions. The influence of the pH value, buffer salt concentration, and isoelectric points (IEP) of the brush and protein on the adsorbed amount and the interfacial tension during protein adsorption as well as the protein adsorption mechanism postulated in reference to recently developed theories of protein adsorption on polyelectrolyte brushes is discussed. In the salted regime, protein adsorption was found to be similar to the often-described adsorption at hydrophobic surfaces. However, in the osmotic regime the balance of electrostatic repulsion and a strong entropic driving force, "counterion release", was found to be the main influence on protein adsorption.     

No Evidence of Induced Skin Cancer or Other Skin Abnormalities after Long-Term (66 week) Chronic Exposure to 222-nm Far-UVC Radiation

Far-UVC radiation, typically defined as 200–235 nm, has similar or greater anti-microbial efficacy compared with conventional 254-nm germicidal radiation. In addition, biophysical considerations of the interaction of far-UVC with tissue, as well as multiple short-term safety studies in animal models and humans, suggest that far-UVC exposure may be safe for skin and eye tissue. Nevertheless, the potential for skin cancer after chronic long-term exposure to far-UVC has not been studied. Here, we assessed far-UVC induced carcinogenic skin changes and other pathological dermal abnormalities in 96 SKH-1 hairless mice of both sexes that were exposed to average daily dorsal skin doses of 400, 130 or 55 mJ cm⁻² of 222 nm far-UVC radiation for 66 weeks, 5 days per week, 8 h per day, as well as similarly-treated unexposed controls. No evidence for increased skin cancer, abnormal skin growths or incidental skin pathology findings was observed in the far-UVC-exposed mice. In addition, there were no significant changes in morbidity or mortality. The findings from this study support the long-term safety of long-term chronic exposure to far-UVC radiation, and therefore its potential suitability as a practical anti-microbial approach to reduce airborne viral and bacterial loads in occupied indoor settings.     

Nonequilibrium statistical mechanics of dividing cell populations

We present and study a model for the nonequilibrium statistical mechanics of protein distributions in a proliferating cell population. Our model describes how the total protein variation is shaped by two processes: variation in protein production internal to the cells and variation in division and inheritance at the population level. It enables us to assess the contribution of each of these components separately. We find that, even if production is deterministic, cell division can generate a large variation in protein distribution. In this limit we solve exactly a special case and draw an analogy between protein distribution along cell generations and stress distribution in layers of granular material. At the other limit of extremely noisy protein production, we find that the population structure restrains variation and that the details of division do not affect the tail of the distribution.