Widespread amyloidogenicity potential of multiple myeloma patient-derived immunoglobulin light chains.

Background: In a range of human disorders such as multiple myeloma (MM), immunoglobulin light chains (IgLCs) can be produced at very high concentrations. This can lead to pathological aggregation and deposition of IgLCs in different tissues, which in turn leads to severe and potentially fatal organ damage. However, IgLCs can also be highly soluble and non-toxic.

Differentiation of subnucleus-sized oligomers and nucleation-competent assemblies of the Aβ peptide.

A significant feature of Alzheimer's disease is the formation of amyloid deposits in the brain consisting mainly of misfolded derivatives of proteolytic cleavage products of the amyloid precursor protein amyloid-β (Aβ) peptide. While high-resolution structures already exist for both the monomer and the amyloid fibril of the Aβ peptide, the mechanism of amyloid formation itself still defies precise characterization. In this study, low and high molecular weight oligomers (LMWOs and HMWOs) were identified by sedimentation velocity analysis, and for the first time, the temporal evolution of oligomer size distributions was correlated with the kinetics of amyloid formation as determined by thioflavin T-binding studies.

Met/Val129 polymorphism of the full-length human prion protein dictates distinct pathways of amyloid formation.

Methionine/valine polymorphism at position 129 of the human prion protein, huPrP, is tightly associated with the pathogenic phenotype, disease progress, and age of onset of neurodegenerative diseases such as Creutzfeldt-Jakob disease or Fatal Familial Insomnia. This raises the question of whether and how the amino acid type at position 129 influences the structural properties of huPrP, affecting its folding, stability, and amyloid formation behavior. Here, our detailed biophysical characterization of the 129M and 129V variants of recombinant full-length huPrP(23-230) by amyloid formation kinetics, CD spectroscopy, molecular dynamics simulations, and sedimentation velocity analysis reveals differences in their aggregation propensity and oligomer content, leading to deviating pathways for the conversion into amyloid at acidic pH.

Biophysical and pharmacokinetic characterization of a small-molecule inhibitor of RUNX1/ETO tetramerization with anti-leukemic effects.

Acute myeloid leukemia (AML) is a malignant disease of immature myeloid cells and the most prevalent acute leukemia among adults. The oncogenic homo-tetrameric fusion protein RUNX1/ETO results from the chromosomal translocation t(8;21) and is found in AML patients. The nervy homology region 2 (NHR2) domain of ETO mediates tetramerization; this oligomerization is essential for oncogenic activity.

Versatile Route toward Hydrophobically Polymer-Grafted Gold Nanoparticles from Aqueous Dispersions.

Stabilization of gold nanoparticles in organic solvents is a key challenge in making them available for a wider range of material applications. Polymers are often used as stabilizing ligands because they also allow for the introduction of new properties and functionalities. Many of the established synthesis protocols for gold nanoparticles are water-based.

Author Correction: Activating low-temperature diesel oxidation by single-atom Pt on TiO nanowire array.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Activating low-temperature diesel oxidation by single-atom Pt on TiO nanowire array.

Supported metal single atom catalysts (SACs) present an emerging class of low-temperature catalysts with high reactivity and selectivity, which, however, face challenges on both durability and practicality. Herein, we report a single-atom Pt catalyst that is strongly anchored on a robust nanowire forest of mesoporous rutile titania grown on the channeled walls of full-size cordierite honeycombs. This Pt SAC exhibits remarkable activity for oxidation of CO and hydrocarbons with 90% conversion at temperatures as low as ~160 C under simulated diesel exhaust conditions while using 5 times less Pt-group metals than a commercial oxidation catalyst.

A comparative health care inventory for primary hip arthroplasty between Germany versus the Netherlands. Is there a downside effect to fast-track surgery with regard to patient satisfaction and functional outcome?

Background: Treatment and rehabilitation protocol for hip arthroplasty differs between Germany and the Netherlands. The Dutch system promotes fast-track surgery whereas in Germany conventional care is provided with a longer hospital stay including rehabilitation. Clinical outcome, patient satisfaction and costs in both treatment protocols were compared in a prospective setup.

Tryptophan metabolism in rheumatoid arthritis is associated with rheumatoid factor and predicts joint pathology evaluated by the Rheumatoid Arthritis MRI Score (RAMRIS).

Objectives: Tryptophan and its metabolites have been suggested to play a role in inflammatory processes. However, studies in rheumatoid arthritis (RA) are scarce, which prompted us to investigate two cohorts of RA patients to better understand the importance of tryptophan metabolism in this disease.

Methods: Tryptophan and its metabolites were characterised by ELISA in a cross-sectional cohort 1 (81 RA, 55 OA) and a longitudinal cohort 2 (25 RA, 3 visits over 6 months) to investigate discriminatory power between diseases and predicitive value for radiologic outcome, respectively.

Stoichiometric Zn interferes with the self-association of Aβ42: Insights from size distribution analysis.

The abnormal aggregation of amyloid β (Aβ) peptides in the brain has been recognized as a central event in Alzheimer's disease (AD). Divalent metal ions such as Zn have been shown to be closely involved in modulating Aβ self-association. Although the link between Zn dyshomeostasis and brain Aβ deposition has been established, the effect of Zn on the aggregation of Aβ is still incompletely clarified.

Inhomogeneity of immune cell composition in the synovial sublining: linear mixed modelling indicates differences in distribution and spatial decline of CD68+ macrophages in osteoarthritis and rheumatoid arthritis.

Background: Inhomogeneity of immune cell distribution in the synovial sublining layer was analyzed in order to improve our mechanistic understanding of synovial inflammation and explore potential refinements for histological biomarkers in rheumatoid arthritis (RA) and osteoarthritis (OA).

Methods: Synovial tissue of 20 patients (11 RA, 9 OA) was immunohistochemically stained for macrophages (CD68), synovial fibroblasts (CD55), T cells (CD3), plasma cells (CD38), endothelial cells (vWF) and mast cells (MCT). The synovial sublining layer was divided into predefined adjacent zones and fractions of the stained area (SA) were determined by digital image analysis for each cell marker.

Dynamic contrast-enhanced magnetic resonance imaging of metacarpophalangeal joints reflects histological signs of synovitis in rheumatoid arthritis.

Introduction: Synovial inflammation and joint destruction in rheumatoid arthritis (RA) may progress despite clinical remission. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is increasingly used to detect synovial inflammation in RA. Although small joints such as metacarpophalangeal (MCP) joints are mainly affected by RA, MRI findings have never been directly compared to histological synovitis in MCP synovial tissue.

Inflammation and vascularisation markers of arthroscopically-guided finger joint synovial biospies reflect global disease activity in rheumatoid arthritis.

Objectives: To analyse whether synovial markers of the clinically dominant metacarpophalangeal (MCP) joint reflect global disease activity measures in rheumatoid arthritis (RA).

Methods: Arthroscopically-guided synovial biopsies from the dominant metacarpophalangeal (MCP) joint of 10 patients with RA (DAS28 >3.2) were stained for determination of the synovitis score, CD68, vascular endothelial growth factor (VEGF), hypoxia-inducible factor 1α (HIF-1α).

Fermentation Quality of Ensiled Water Hyacinth (Eichhornia crassipes) as Affected by Additives.

A lab-scale ensiling study was carried out to investigate the fermentation quality of water hyacinth (WH) supplemented with molasses, rice bran, as an absorbent, and an inoculant in the form of fermented vegetable juice and their combinations. After wilting the water hyacinths for 7 h to a dry matter (DM) content of 240 to 250 g/kg, the following treatments were applied: i) Control (C), WH only; ii) WH with sugarcane molasses at 40 g/kg WH (CM); iii) WH inoculated with fermented vegetable juice at 10 ml/kg WH (CI); iv) CM and CI (CMI) combined; v) WH with 150 g rice bran/kg WH (CA); vi) CA and CI combined (CAI); vii) CA and CM combined (CAM); and viii) CA, CM and CI combined (CAMI). After application of additives, the differently treated forages were mixed and ensiled in triplicates in 1,500-ml polyethylene jars.

Thioether benzenesulfonamide inhibitors of carbonic anhydrases II and IV: structure-based drug design, synthesis, and biological evaluation.

A novel series of potent thioether benzenesulfonamide inhibitors of carbonic anhydrases II and IV was discovered using structure-based drug design. Synthesis, structure-activity relationship, and optimization of physicochemical properties are described. Low nanomolar potency was achieved, and selected compounds with improved thermodynamic solubility showed promising in vitro inhibition of carbonic anhydrase activity in rabbit iris ciliary body homogenate.

N-(Pyridin-2-yl) arylsulfonamide inhibitors of 11beta-hydroxysteroid dehydrogenase type 1: Discovery of PF-915275.

N-(Pyridin-2-yl) arylsulfonamides are identified as inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1), an enzyme that catalyzes the reduction of the glucocorticoid cortisone to cortisol. Dysregulation of glucocorticoids has been implicated in the pathogenesis of diabetes and the metabolic syndrome. In this Letter, we present the development of an initial lead to an efficient ligand with improved physiochemical properties using a deletion strategy.

In utero nicotine exposure causes persistent, gender-dependant changes in locomotor activity and sensitivity to nicotine in C57Bl/6 mice.

Maternal cigarette smoking during pregnancy can result in a wide variety of adverse fetal outcomes, ranging from preterm delivery and low birth weight, to sudden infant death syndrome. In addition, in utero tobacco smoke exposure is associated with delayed or impaired neuropsychological development. Although the causative agent in tobacco smoke that leads to these aberrations is not known, some studies have concluded that nicotine may play an important role.

X-ray crystallographic and kinetic studies of human sorbitol dehydrogenase.

Sorbitol dehydrogenase (hSDH) and aldose reductase form the polyol pathway that interconverts glucose and fructose. Redox changes from overproduction of the coenzyme NADH by SDH may play a role in diabetes-induced dysfunction in sensitive tissues, making SDH a therapeutic target for diabetic complications. We have purified and determined the crystal structures of human SDH alone, SDH with NAD(+), and SDH with NADH and an inhibitor that is competitive with fructose.

Specificity determinants of human cathepsin s revealed by crystal structures of complexes.

Cathepsin S, a lysosomal cysteine protease of the papain superfamily, has been implicated in the preparation of MHC class II alphabeta-heterodimers for antigen presentation to CD4+ T lymphocytes and is considered a potential target for autoimmune-disease therapy. Selective inhibition of this enzyme may be therapeutically useful for attenuating the hyperimmune responses in a number of disorders. We determined the three-dimensional crystal structures of human cathepsin S in complex with potent covalent inhibitors, the aldehyde inhibitor 4-morpholinecarbonyl-Phe-(S-benzyl)Cys-Psi(CH=O), and the vinyl sulfone irreversible inhibitor 4-morpholinecarbonyl-Leu-Hph-Psi(CH=CH-SO(2)-phenyl) at resolutions of 1.

Maternal smoking and partial exchange transfusion for neonatal polycythemia.

The aim of this study was to determine if maternal smoking was associated with an increased need for partial exchange transfusion for symptomatic polycythemia in term neonates. The study population consisted of 8,961 term neonates, of whom 28.7% were categorized as babies born to mothers who smoked.

Structure-activity analysis of the purine binding site of human liver glycogen phosphorylase.

Human liver glycogen phosphorylase (HLGP) catalyzes the breakdown of glycogen to maintain serum glucose levels and is a therapeutic target for diabetes. HLGP is regulated by multiple interacting allosteric sites, each of which is a potential drug binding site. We used surface plasmon resonance (SPR) to screen for compounds that bind to the purine allosteric inhibitor site.

Mesostructured forms of gamma-Al(2)O(3).

gamma-Al2O3 is one of the most extensively utilized metal oxides in heterogeneous catalysis. Conventional forms of this oxide typically exhibit a surface area and pore volume less than 250 m2/g and 0.5 cm3/g, respectively.

Role of framework sodium versus local framework structure in determining the hydrothermal stability of MCM-41 mesostructures.

Two mesostructured MCM-41 silicas that differ dramatically in hydrothermal stability have been examined by (29)Si MAS NMR spectroscopy and pair distribution function (PDF) analysis of synchrotron X-ray scattering data. The less stable mesostructure assembled from sodium silicate and the substantially more stable derivative made from fumed silica possess equivalent local framework wall structures, as judged by NMR and PDF methods. Approximately 80% of the SiO(4) tetrahedra are fully cross-linked as Q(4) (Si(OSi)(4)) units in both calcined samples.