Molecular and Clinical Characteristics in 46 Families Affected with Peutz-Jeghers Syndrome

Germline mutations of the tumor suppressor gene LKB1/STK11 are responsible for the Peutz-Jeghers syndrome (PJS), an autosomal-dominant disorder characterized by mucocutaneous pigmentation, hamartomatous polyps, and an increased risk of associated malignancies. In this study, we assessed the presence of pathogenic mutations in the LKB1/STK11 gene in 46 unrelated PJS families, and also carried genotype-phenotype correlation in regard of the development of cancer in 170 PJS patients belonging to these families. All LKB1/STK11 variants detected with single-strand conformational polymorphism were confirmed by direct sequencing, and those without LKB1/STK11 mutation were further submitted to Southern blot analysis for detection of deletions/rearrangements. Statistical analysis for genotype-phenotype correlation was performed. In 59% (27/46) of unrelated PJS cases, pathogenic mutations in the LKB1/STK11 gene, including 9 novel mutations, were identified. The new mutations were 2 splice site deletion-insertions, 2 missenses, 1 nonsense, and 4 abnormal splice sites. Genotype-phenotype analysis did not yield any significant differences between patients carrying mutations in LKB1/STK11 versus those without mutations, even with respect to primary biliary adenocarcinoma. This study presents the molecular characterization and cancer occurrence of a large cohort of PJS patients, increases the mutational spectrum of LKB1/STK11 allelic variants worldwide, and provides a new insight useful for clinical diagnosis and genetic counseling of PJS familie

Antimony doped Tin Oxide/Polyethylenimine Electron Selective Contact for reliable and light soaking-free high Performance Inverted Organic Solar Cells

We have demonstrated a high-performance low temperature solution processed electron selective contact consisting of 10 at% antimony doped tin oxide (ATO) and the neutral polymer polyethylenimine (PEI). Inverted organic photovoltaics (OPVs) utilizing ATO/PEI as electron selective contact exhibited high power conversion efficiencies for both the reference P3HT: PCBM and the non-fullerene based P3HT- IDTBR active layer OPV material systems. Importantly it is shown that the proposed ATO/PEI carrier selective contact provides light soaking-free inverted OPVs. Furthermore, by increasing the thickness of ATO layer from 40 to 120 nm the power conversion efficiency of the corresponding inverted OPVs remain unaffected a parameter which indicates the potential of the proposed ATO/PEI carrier selective contact for high performance light-soaking-free and reliable roll-to-roll printing solutions processed inverted OPVs.Comment: 20 pages, 4 figures, 2 table

A Novel Neutrophil Elastase Inhibitor Prevents Elastase Activation and Surface Cleavage of the Epithelial Sodium Channel Expressed in Xenopus laevis Oocytes

The amiloride-sensitive epithelial sodium channel (ENaC) constitutes a limiting step in sodium reabsorption across distal airway epithelium and controlling mucociliary clearance. ENaC is activated by serine proteases secreted in the extracellular milieu. In cystic fibrosis lungs, high concentrations of secreted neutrophil elastase (NE) are observed. hNE could activate ENaC and contribute to further decreased mucociliary clearance. The aims of this study were (i) to test the ability of an engineered human neutrophil elastase inhibitor (EPI-hNE4) to specifically inhibit the elastase activation of ENaC-mediated amiloride-sensitive currents (I(Na)) and (ii) to examine the effect of elastase on cell surface expression of ENaC and its cleavage pattern (exogenous proteolysis). Oocytes were exposed to hNE (10-100 microg/ml) and/or trypsin (10 microg/ml) for 2-5 min in the presence or absence of EPI-hNE4 (0.7 microm). hNE activated I(Na) 3.6-fold (p < 0.001) relative to non-treated hENaC-injected oocytes. EPI-hNE4 fully inhibited hNE-activated I(Na) but had no effect on trypsin- or prostasin-activated I(Na). The co-activation of I(Na) by hNE and trypsin was not additive. Biotinylation experiments revealed that cell surface gamma ENaC (but not alpha or beta ENaC) exposed to hNE for 2 min was cleaved (as a 67-kDa fragment) and correlated with increased I(Na). The elastase-induced exogenous proteolysis pattern is distinct from the endogenous proteolysis pattern induced upon preferential assembly, suggesting a causal relationship between gamma ENaC cleavage and ENaC activation, taking place at the plasma membrane

Transduction of chemical signals in dictyostelium cells

Three different functions of cyclic AMP in D discoideum are known: (1) cAMP acts as a chemoattractant during cell aggregation, (2) it controls cell development, particularly the acquisition of aggregation competence, and (3) it is involved in terminal cell differentiation. In this report we will concentrate on the functions 1 and 2 of cAMP. Chemotaxis requires the recognition of concentration gradients in the environment by attractant binding to cell surface receptors, the processing of signals from the receptors to the contractile system of the cells, extension of pseudopods at one part, and contraction at other parts of the cells in accord with the external gradient. One pathway of signal processing from the receptors to the contractile system involves the regulation of a myosin kinase. The control of development up to aggregation competence is largely dependent on the temporal pattern of cAMP application: Only repetitive pulses enhance development. This effect has been studied using the expression of a membrane glycoprotein called contact site A as a differentiation marker

Preferential Assembly of Epithelial Sodium Channel (ENaC) Subunits in Xenopus Oocytes: ROLE OF FURIN-MEDIATED ENDOGENOUS PROTEOLYSIS

The epithelial sodium channel (ENaC) is preferentially assembled into heteromeric αβγ complexes. The α and γ (not β) subunits undergo proteolytic cleavage by endogenous furin-like activity correlating with increased ENaC function. We identified full-length subunits and their fragments at the cell surface, as well as in the intracellular pool, for all homo- and heteromeric combinations (α, β, γ, αβ, αγ, βγ, and αβγ). We assayed corresponding channel function as amiloride-sensitive sodium transport (INa). We varied furin-mediated proteolysis by mutating the P1 site in α and/or γ subunit furin consensus cleavage sites (αmut and γmut). Our findings were as follows. (i) The β subunit alone is not transported to the cell surface nor cleaved upon assembly with the α and/or γ subunits. (ii) The α subunit alone (or in combination with β and/or γ) is efficiently transported to the cell surface; a surface-expressed 65-kDa α ENaC fragment is undetected in αmutβγ, and INa is decreased by 60%. (iii) The γ subunit alone does not appear at the cell surface; γ co-expressed with α reaches the surface but is not detectably cleaved; and γ in αβγ complexes appears mainly as a 76-kDa species in the surface pool. Although basal INa of αβγmut was similar to αβγ, γmut was not detectably cleaved at the cell surface. Thus, furin-mediated cleavage is not essential for participation of α and γ in αβγ heteromers. Basal INa is reduced by preventing furin-mediated cleavage of the α, but not γ, subunits. Residual current in the absence of furin-mediated proteolysis may be due to non-furin endogenous proteases

The beginning of a new era

With this editorial, the Swiss Psychological Society (SPS) is relaunching its journal under the new name Swiss Psychology Open (SPO), published by UbiquityPress. Originally founded by Jean Piaget in 1942 as the Schweizerische Zeitschrift für Psychologie und ihre Anwendungen [engl. Swiss Journal of Psychology and its Applications], SPO will continue to serve its original mission – in an open and accessible way

The cancer glycocalyx mechanically primes integrin-mediated growth and survival

Malignancy is associated with altered expression of glycans and glycoproteins that contribute to the cellular glycocalyx. We constructed a glycoprotein expression signature, which revealed that metastatic tumours upregulate expression of bulky glycoproteins. A computational model predicted that these glycoproteins would influence transmembrane receptor spatial organization and function. We tested this prediction by investigating whether bulky glycoproteins in the glycocalyx promote a tumour phenotype in human cells by increasing integrin adhesion and signalling. Our data revealed that a bulky glycocalyx facilitates integrin clustering by funnelling active integrins into adhesions and altering integrin state by applying tension to matrix-bound integrins, independent of actomyosin contractility. Expression of large tumour-associated glycoproteins in non-transformed mammary cells promoted focal adhesion assembly and facilitated integrin-dependent growth factor signalling to support cell growth and survival. Clinical studies revealed that large glycoproteins are abundantly expressed on circulating tumour cells from patients with advanced disease. Thus, a bulky glycocalyx is a feature of tumour cells that could foster metastasis by mechanically enhancing cell-surface receptor function

Persistence of engineered nanoparticles in a municipal solid-waste incineration plant

More than 100 million tonnes of municipal solid waste are incinerated worldwide every year1. However, little is known about the fate of nanomaterials during incineration, even though the presence of engineered nanoparticles in waste is expected to grow2. Here, we show that cerium oxide nanoparticles introduced into a full-scale waste incineration plant bind loosely to solid residues from the combustion process and can be efficiently removed from flue gas using current filter technology. The nanoparticles were introduced either directly onto the waste before incineration or into the gas stream exiting the furnace of an incinerator that processes 200,000 tonnes of waste per year. Nanoparticles that attached to the surface of the solid residues did not become a fixed part of the residues and did not demonstrate any physical or chemical changes. Our observations show that although it is possible to incinerate waste without releasing nanoparticles into the atmosphere, the residues to which they bind eventually end up in landfills or recovered raw materials, confirming that there is a clear environmental need to develop degradable nanoparticles