R116C mutation of cationic trypsinogen in a Turkish family with recurrent pancreatitis illustrates genetic microheterogeneity of hereditary pancreatitis

Hereditary pancreatitis is due to heterozygosity for gain-of-function mutations in the cationic trypsinogen gene which result in increased levels of active trypsin within pancreatic acinar cells and autodigestion of the pancreas. The number of disease-causing defects is generally considered to be low. To gain further insight into the molecular basis of this disorder, DNA sequence analysis of all five exons was performed in 109 unrelated patients with idiopathic chronic pancreatitis in order to determine the variability of the underlying mutations. Two German females and one German male were carriers of the most common N291 and R122H mutations (trypsinogen numbering system). In a Turkish proband, an arginine (CGT) to cysteine (TGT) substitution at amino acid position 116 was identified. Family screening demonstrated that the patient had inherited the mutation from his asymptomatic father and that he had transmitted it to both of his children, his daughter being symptomatic since the age of 3 years. In addition, a German male was found to be a heterozygote for a D100H (GAC-->CAC) amino acid replacement. Our data provide evidence for genetic heterogeneity of hereditary pancreatitis. The growing number of cationic trypsinogen mutations is expected to change current mutation screening practices for this disease

High resolution studies of low-energy electron attachment to SF5Cl: Product anions and absolute cross sections

Low energy electron attachment to SF$_5$Cl was studied at high energy resolution by mass spectrometric detection of the product anions. Two variants of the laser photoelectron attachment (LPA) technique (Kaiserslautern) were used for determining the threshold behaviour of the yield for SF$_5^-$ formation at about 1 meV resolution, and to investigate the relative cross sections for Cl$^-$, FCl$^-$, and SF$_5^-$ formation towards higher energies (up to 1 eV) at about 20 meV resolution. Thermal swarm measurements (Birmingham) were used to place the relative LPA cross sections on an absolute scale. A trochoidal electron monochromator (Innsbruck) was used for survey measurements of the relative cross sections for the different product anions over the energy range of 0-14 eV with a resolution of 0.30 eV. Combined with earlier beam data (taken at Berlin, J. Chem. Phys. 88 (1988) 149), the present experimental results provide a detailed set of partial cross sections for anion formation in low-energy electron collisions with SF$_5$Cl

Leveraging Entrepreneurial Ambition and Innovation : A Global Perspective on Entrepreneurship, Competitiveness and Development

The study described in this report combines two unique datasets, the World Economic Forum’s Global Competitiveness Index data, which ranks the economic competitiveness of 144 economies, and Global Entrepreneurship Monitor’s assessment of entrepreneurial activity across 70 economies. Using five years of data from both sets, the study analyses a sample of 44 economies by first examining three aspects of entrepreneurial activity, then grouping economies into five types of entrepreneurial clusters, and finally developing a deeper understanding of each type of cluster. Lastly, the study delves into what policymaking best benefits the unique characteristics of different economies

First-principles calculation of the thermal properties of silver

The thermal properties of silver are calculated within the quasi-harmonic approximation, by using phonon dispersions from density-functional perturbation theory, and the pseudopotential plane-wave method. The resulting free energy provides predictions for the temperature dependence of various quantities such as the equilibrium lattice parameter, the bulk modulus, and the heat capacity. Our results for the thermal properties are in good agreement with available experimental data in a wide range of temperatures. As a by-product, we calculate phonon frequency and Grueneisen parameter dispersion curves which are also in good agreement with experiment.Comment: 9 pages, 8 figures, submitted to Phys. Rev. B April 30, 1998). Other related publications can be found at http://www.rz-berlin.mpg.de/th/paper.htm

Plasma deoxysphingolipids: a novel class of biomarkers for the metabolic syndrome?

Aims/hypothesis: Sphingolipid synthesis is typically initiated by the conjugation of l-serine and palmitoyl-CoA, a reaction catalysed by serine palmitoyltransferase (SPT). SPT can also metabolise other acyl-CoAs (C12 to C18) and other amino acids such as l-alanine and glycine, giving rise to a spectrum of atypical sphingolipids. Here, we aimed to identify changes in plasma levels of these atypical sphingolipids to explore their potential as biomarkers in the metabolic syndrome and diabetes. Methods: We compared the plasma profiles of ten sphingoid bases in healthy individuals with those of patients with the metabolic syndrome but not diabetes, and diabetic patients (n = 25 per group). The results were verified in a streptozotocin (STZ) rat model. Univariate and multivariate statistical analyses were used. Results: Deoxysphingolipids (dSLs) were significantly elevated ( $$p = {5} \times {1}{0^{{ - {6}}}}$$ ) in patients with the metabolic syndrome (0.11 ± 0.04μmol/l) compared with controls (0.06 ± 0.02μmol/l) but did not differ between the metabolic syndrome and diabetes groups. Levels of C16-sphingosine-based sphingolipids were significantly lowered in diabetic patients but not in patients with the metabolic syndrome but without diabetes (p = 0.008). Significantly elevated dSL levels were also found in the plasma and liver of STZ rats. A principal component analysis revealed a similar or even closer association of dSLs with diabetes and the metabolic syndrome in comparison with the established biomarkers. Conclusions/interpretation: We showed that dSLs are significantly elevated in patients with type 2 diabetes mellitus and non-diabetic metabolic syndrome compared with healthy controls. They may, therefore, be useful novel biomarkers to improve risk prediction and therapy monitoring in these patient

An expert opinion paper on statin adherence and implementation of new lipid-lowering medications by the ESC Working Group on Cardiovascular Pharmacotherapy: Barriers to be overcome.

Benefits and safety on statins have been well-established over 20 years of research. Despite this, the vast majority of patients are not adequately treated and do not achieve the low-density lipoprotein cholesterol target levels. This is mainly due to poor adherence, which is associated with dangerous and sometimes fatal outcomes. To increase adherence and prevent worse outcomes, a combination therapy with lower dosage of statins and new lipid-lowering drugs may be used. However, the implementation of new lipid-lowering drugs in European countries is still at the beginning. For these reasons, the aim of this position paper is to give an up-to-date indication from the ESC Working Group on Cardiovascular Pharmacotherapy in order to discuss the barriers towards statins adherence and new lipid-lowering drugs implementation in Europe

Reversed anisotropies and thermal contraction of FCC (110) surfaces

The observed anisotropies of surface vibrations for unreconstructed FCC metal (110) surfaces are often reversed from the "common sense" expectation. The source of these reversals is investigated by performing ab initio density functional theory calculations to obtain the surface force constant tensors for Ag(110), Cu(110) and Al(110). The most striking result is a large enhancement in the coupling between the first and third layers of the relaxed surface, which strongly reduces the amplitude of out-of-plane vibrations of atoms in the first layer. This also provides a simple explanation for the thermal contraction of interlayer distances. Both the anisotropies and the thermal contraction arise primarily as a result of the bond topology, with all three (110) surfaces showing similar behavior.Comment: 13 pages, in revtex format, plus 1 postscript figur

Physicochemical characterization and quantification of nanoplastics: applicability, limitations and complementarity of batch and fractionation methods

A comprehensive physicochemical characterization of heterogeneous nanoplastic (NPL) samples remains an analytical challenge requiring a combination of orthogonal measurement techniques to improve the accuracy and robustness of the results. Here, batch methods, including dynamic light scattering (DLS), nanoparticle tracking analysis (NTA), tunable resistive pulse sensing (TRPS), transmission electron microscopy (TEM), and scanning electron microscopy (SEM), as well as separation/fractionation methods such as centrifugal liquid sedimentation (CLS) and field-flow fractionation (FFF)–multi-angle light scattering (MALS) combined with pyrolysis gas chromatography mass spectrometry (pyGC–MS) or Raman microspectroscopy (RM) were evaluated for NPL size, shape, and chemical composition measurements and for quantification. A set of representative/test particles of different chemical natures, including (i) polydisperse polyethylene (PE), (ii) (doped) polystyrene (PS) NPLs, (iii) titanium dioxide, and (iv) iron oxide nanoparticles (spherical and elongated), was used to assess the applicability and limitations of the selected methodologies. Particle sizes and number-based concentrations obtained by orthogonal batch methods (DLS, NTA, TRPS) were comparable for monodisperse spherical samples, while higher deviations were observed for polydisperse, agglomerated samples and for non-spherical particles, especially for light scattering methods. CLS and TRPS offer further insight with increased size resolution, while detailed morphological information can be derived by electron microscopy (EM)–based approaches. Combined techniques such as FFF coupled to MALS and RM can provide complementary information on physical and chemical properties by online measurements, while pyGC–MS analysis of FFF fractions can be used for the identification of polymer particles (vs. inorganic particles) and for their offline (semi)quantification. However, NPL analysis in complex samples will continue to present a serious challenge for the evaluated techniques without significant improvements in sample preparation.publishedVersio

The Inducible lac Operator-Repressor System Is Functional in Zebrafish Cells

BackgroundZebrafish are a foundational model organism for studying the spatio-temporal activity of genes and their regulatory sequences. A variety of approaches are currently available for editing genes and modifying gene expression in zebrafish, including RNAi, Cre/lox, and CRISPR-Cas9. However, the lac operator-repressor system, an E. coli lac operon component which has been adapted for use in many other species and is a valuable, flexible tool for inducible modulation of gene expression studies, has not been previously tested in zebrafish.ResultsHere we demonstrate that the lac operator-repressor system robustly decreases expression of firefly luciferase in cultured zebrafish fibroblast cells. Our work establishes the lac operator-repressor system as a promising tool for the manipulation of gene expression in whole zebrafish.ConclusionOur results lay the groundwork for the development of lac-based reporter assays in zebrafish, and adds to the tools available for investigating dynamic gene expression in embryogenesis. We believe this work will catalyze the development of new reporter assay systems to investigate uncharacterized regulatory elements and their cell-type specific activities