Asymmetric reductions of ethyl 2-(benzamidomethyl)-3-oxobutanoate by yeasts

The stereoselective reduction of ethyl 2-(benzamidomethyl)-3-oxobutanoate 1 using yeasts was investigated among a restricted number (12) of yeasts. Kluyveromyces marxianus var. lactis CL69 diastereoselectively produced (2R,3S)-ethyl 2-(benzamidomethyl)-3-hydroxybutanoate 2, whereas Pichia glucozyma CBS 5766 gave (2S,3S)-2 as the major stereoisomer. The biotransformations were independently optimized for minimizing by-product formation and maximizing the diastereoselectivity. Under optimized conditions, K. marxianus var. lactis CL 69 gave the (2R,3S)-ethyl 2-(benzamidomethyl)-3-hydroxybutanoate 2 with ee > 99% and de = 98%, while P. glucozyma CBS 5766 allowed for the production of (2S,3S)-2 with ee > 99% and de = 86%.     

The cofinality of the least Berkeley cardinal and the extent of dependent choice

This paper is concerned with the possible values of the cofinality of the least Berkeley cardinal. Berkeley cardinals are very large cardinal axioms incompatible with the Axiom of Choice, and the interest in the cofinality of the least Berkeley arises from a result in [1], showing it is connected with the failure of . In fact, by a theorem of Bagaria, Koellner and Woodin, if γ is the cofinality of the least Berkeley cardinal then γ‐ fails. We shall prove that this result is optimal for or . In particular, it will follow that the cofinality of the least Berkeley is independent of .     

Structure and absolute configuration of new acidic metabolites from Stachys ehrenbergii

Two novel metabolites have been isolated from the aerial parts of Stachys ehrenberiigii. Their structures and stereochemistry were elucidated using a combination of ¹³C and ¹H homo and heteronuclear 2D NMR experiments and mass analysis. The development of an enantioselective synthesis of 3-(2′-acetoxy-4-phenylbut-3′-enoylamino)propionic acid allowed to confirm the structure and assign the (R) absolute configuration at C-2′ of the natural product.     

Polymer Lamellae as Reaction Intermediates in the Formation of Copper Nanospheres as Evidenced by In Situ X-ray Studies

The classical nucleation theory (CNT) is the most common theoretical framework used to explain particle formation. However, nucleation is a complex process with reaction pathways which are often not covered by the CNT. Herein, we study the formation mechanism of copper nanospheres using in situ X-ray absorption and scattering measurements. We reveal that their nucleation involves coordination polymer lamellae as pre-nucleation structures occupying a local minimum in the reaction energy landscape. Having learned this, we achieved a superior monodispersity for Cu nanospheres of different sizes. This report exemplifies the importance of developing a more realistic picture of the mechanism involved in the formation of inorganic nanoparticles to develop a rational approach to their synthesis.     

Reflectance Confocal Microscopy for In Vivo Skin Imaging†

Reflectance confocal microscopy (RCM) is a novel noninvasive technique for “in vivo” examination of the skin. In a confocal microscope, near‐ infrared light from a diode laser is focused on a microscopic skin target. As this light passes between cellular structures having different refraction indexes, it is naturally reflected, and this reflected light is then captured and recomposed into a two‐dimensional gray scale image by computer software. Focusing the microscope (adjusting the focal point on the z‐axis) allows images to be obtained of different levels within the skin. Commercially available microscope systems of this type can create images with enough detail for use in histological analysis. The first investigations using these microscopes served to identify the appearance of the various cell populations living in the different layers of normal skin. Today, the main interest has become focused on the use of these microscopes as a diagnostic tool: a means of investigating benign and malignant tumors of melanocytes and keratinocytes, and, more importantly, the findings of this field of study can be used to develop a diagnostic algorithm which would be not only highly sensitive but specific as well. The aim of the paper is to provide an updated literature review and an in‐depth critique of the state‐of‐the‐art of RCM for skin cancer imaging with a critical discussion of the possibilities and limitations for clinical use.     

Compressive deformation of ultralong amyloid fibrils

Involved in various neurodegenerative diseases, amyloid fibrils and plaques feature a hierarchical structure, ranging from the atomistic to the micrometer scale.At the atomistic level,a dense and organized hydrogen bond network is resembled in a beta-sheet rich secondary structure, which drives a remarkable stiffness in the range of 10-20GPa,larger than many other biological nanofibrils, a result confirmed by both experiment and theory.However, the understanding of how these exceptional mechanical properties transfer from the atomistic to the nanoscale remains unknown.Here we report a multiscale analysis that, from the atomistic-level structure of a single fibril,extends to the mesoscale level,reaching size scales of hundreds of nanometers.We use parameters directly derived from full atomistic simulations of Aβ（1-40） amyloid fibrils to parameterize a mesoscopic coarse-grained model,which is used to reproduce the elastic properties of amyloid fibrils.We then apply our mesoscopic model in an analysis of the buckling behavior of amyloid fibrils with different lengths and report a comparison with predictions from continuum beam theory. An important implication of our results is a severe reduction of the effective modulus due to buckling,an effect that could be important to interpret experimental results of ultralong amyloid fibrils.Our model represents a powerful tool to mechanically characterize molecular structures on the order of hundreds of nanometers to micrometers on the basis of the underlying atomistic behavior.The work provides insight into structural and mechanical properties of amyloid fibrils and may enable further analysis of larger-scale assemblies such as amyloidogenic bundles or plaques as found in disease states.     

Photodynamic antifungal chemotherapy

The growing resistance against antifungal drugs has renewed the search for alternative treatment modalities, and antimicrobial photodynamic therapy (PDT) seems to be a potential candidate. Preliminary findings have demonstrated that dermatophytes and yeasts can be effectively sensitized in vitro and in vivo by administering photosensitizers (PSs) belonging to four chemical groups: phenothiazine dyes, porphyrins and phthalocyanines, as well as aminolevulinic acid, which, while not a PS in itself, is effectively metabolized into protoporphyrin IX. Besides efficacy, PDT has shown other benefits. First, the sensitizers used are highly selective, i.e., fungi can be killed at combinations of drug and light doses much lower than that needed for a similar effect on keratinocytes. Second, all investigated PSs lack genotoxic and mutagenic activity. Finally, the hazard of selection of drug resistant fungal strains has been rarely reported. We review the studies published to date on antifungal applications of PDT, with special focus on yeast, and aim to raise awareness of this area of research, which has the potential to make a significant impact in future treatment of fungal infections.     

In vitro amyloid Aβ<Subscript>1-42</Subscript> peptide aggregation monitoring by asymmetrical flow field-flow fractionation with multi-angle light scattering detection

Self-assembly of the 42-amino-acid-long amyloid peptide Aβ_1-42 into insoluble fibrillar deposits in the brain is a crucial event in the pathogenesis of Alzheimer's disease. The fibril deposition occurs through an aggregation process during which transient and metastable oligomeric intermediates are intrinsically difficult to be accurately monitored and characterised. In this work, the time-dependent Aβ_1-42 aggregation pattern is studied by asymmetrical flow field-flow fractionation with on-line multi-angle light scattering detection. This technique allows separating and obtaining information on the molar mass (M _r) and size distribution of both the early-forming soluble aggregates and the late prefibrillar and fibrillar species, the latter having very high M _r. Preliminary results demonstrate that unique information on the dynamic aggregation process can be obtained, namely on the M _r and size of the forming aggregates as well as on their formation kinetics. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Modification in the side chain of solomonsterol A: discovery of cholestan disulfate as a potent pregnane-X-receptor agonist

Seven synthetic analogues of the PXR (pregnane-X-receptor) potent natural agonist solomonsterol A were prepared by total synthesis. Their activity toward PXR was assessed by transactivation and RT-PCR assays. The study discloses cholestan disulfate (8) as a new, simplified agonist of PXR. By in vitro studies on hepatic cells we have demonstrated that this compound is a potent PXR agonist and functional characterization in human macrophages and hepatic stellate cells provided evidence that cholestan disulfate (8) has the ability to modulate the immune response triggered by bacterial endotoxin as well as to counter-activate hepatic stellate cell activation induced by thrombin. Because inhibition of immune-driven circuits might have relevance in the treatment of inflammation and liver fibrosis, the present data support the development of cholestan disulfate (8) in preclinical models of inflammatory diseases.