Neutrophil elastase reduces secretion of secretory leukoproteinase inhibitor (SLPI) by lung epithelial cells: role of charge of the proteinase-inhibitor complex

<p>Abstract</p> <p>Background</p> <p>Secretory leukoproteinase inhibitor (SLPI) is an important inhibitor of neutrophil elastase (NE), a proteinase implicated in the pathogenesis of lung diseases such as COPD. SLPI also has antimicrobial and anti-inflammatory properties, but the concentration of SLPI in lung secretions in COPD varies inversely with infection and the concentration of NE. A fall in SLPI concentration is also seen in culture supernatants of respiratory cells exposed to NE, for unknown reasons. We investigated the hypothesis that SLPI complexed with NE associates with cell membranes <it>in vitro</it>.</p> <p>Methods</p> <p>Respiratory epithelial cells were cultured in the presence of SLPI, varying doses of proteinases over time, and in different experimental conditions. The likely predicted charge of the complex between SLPI and proteinases was assessed by theoretical molecular modelling.</p> <p>Results</p> <p>We observed a rapid, linear decrease in SLPI concentration in culture supernatants with increasing concentration of NE and cathepsin G, but not with other serine proteinases. The effect of NE was inhibited fully by a synthetic NE inhibitor only when added at the same time as NE. Direct contact between NE and SLPI was required for a fall in SLPI concentration. Passive binding to cell culture plate materials was able to remove a substantial amount of SLPI both with and without NE. Theoretical molecular modelling of the structure of SLPI in complex with various proteinases showed a greater positive charge for the complex with NE and cathepsin G than for other proteinases, such as trypsin and mast cell tryptase, that also bind SLPI but without reducing its concentration.</p> <p>Conclusion</p> <p>These data suggest that NE-mediated decrease in SLPI is a passive, charge-dependent phenomenon <it>in vitro</it>, which may correlate with changes observed <it>in vivo</it>.</p

Sequencing the genome of the Atlantic salmon (Salmo salar)

The International Collaboration to Sequence the Atlantic Salmon Genome (ICSASG) will produce a genome sequence that identifies and physically maps all genes in the Atlantic salmon genome and acts as a reference sequence for other salmonids

The autonomic nervous system as a therapeutic target in heart failure: a scientific position statement from the Translational Research Committee of the Heart Failure Association of the European Society of Cardiology

Despite improvements in medical therapy and device-based treatment, heart failure (HF) continues to impose enormous burdens on patients and health care systems worldwide. Alterations in autonomic nervous system (ANS) activity contribute to cardiac disease progression, and the recent development of invasive techniques and electrical stimulation devices has opened new avenues for specific targeting of the sympathetic and parasympathetic branches of the ANS. The Heart Failure Association of the European Society of Cardiology recently organized an expert workshop which brought together clinicians, trialists and basic scientists to discuss the ANS as a therapeutic target in HF. The questions addressed were: (i) What are the abnormalities of ANS in HF patients? (ii) What methods are available to measure autonomic dysfunction? (iii) What therapeutic interventions are available to target the ANS in patients with HF, and what are their specific strengths and weaknesses? (iv) What have we learned from previous ANS trials? (v) How should we proceed in the future

The Fast, Luminous Ultraviolet Transient AT2018cow: Extreme Supernova, or Disruption of a Star by an Intermediate-Mass Black Hole?

Wide-field optical surveys have begun to uncover large samples of fast (t_rise 10 days. The spectrum remains extremely hot throughout its evolution, and the photospheric radius contracts with time (receding below R<10^14 cm after 1 month). This behavior does not match that of any known supernova, although a relativistic jet within a fallback supernova could explain some of the observed features. Alternatively, the transient could originate from the disruption of a star by an intermediate-mass black hole, although this would require long-lasting emission of highly super-Eddington thermal radiation. In either case, AT 2018cow suggests that the population of fast luminous transients represents a new class of astrophysical event. Intensive follow-up of this event in its late phases, and of any future events found at comparable distance, will be essential to better constrain their origins

Exploring new directions for research in problem structuring methods: on the role of cognitive style

Prior research has argued that cognitive style can have a significant impact on group decision making. In addition, several scholars have proposed that cognitive style can play a key role in the design and use of group decision support systems. However, cognitive style has not received a great deal of attention in the problem structuring methods (PSMs) community. This is surprising, given that PSMs are specifically developed to support a group in their decision making. The purpose of this paper is thus to examine the significance of cognitive style within PSMs. The paper identifies and explores the role of four different cognitive style functions in problem structuring interventions. This analysis is carried out by focusing on the different tasks embedded within a group process supported by PSMs. Implications for the research and practice of PSMs are then discussed

Substance Use in Individuals with Mild to Borderline Intellectual Disability: an Exploration of Rates and Risks in the Netherlands

Little is known about rates and risk factors of substance use (SU) in individuals with mild to borderline intellectual disabilities (MBID, IQ 50–85). This hinders targeted prevention and treatment. In this study we assessed SU rates and risk factors in individuals with MBID in 419 adults (63% male, average IQ = 66) in 16 Dutch disability services. Lifetime and current SU, SU picture recognition, knowledge, attitudes and modeling were assessed with the Substance use and misuse in Intellectual Disability - Questionnaire (SumID-Q). Lifetime licit SU (alcohol and tobacco) was 97%, lifetime illicit SU (predominantly cannabis) was 50%. Current users of tobacco (62%), alcohol (64%), and cannabis (15%) initiated SU at a younger age than those who desisted SU (ps < .001). Participants with mild ID and those with borderline ID did not differ in SU rates (ps .429–.812), or age at SU initiation (ps .221–.853). Current licit SU and lifetime illicit SU were related to male gender, younger age, and (for smoking and stimulant use) to lack of daytime activities. However, these factors did not contribute to multivariate models when recognition, knowledge, attitudes and modeling were added. The models correctly identified current SU in 84% (smoking) and 74% (drinking), and lifetime SU in 76% (cannabis) and 84% (stimulants) of the participants. As almost all participants reported lifetime use of licit, and about half reported lifetime illicit substance use, systematic screening for substance use, and development of preventative and treatment interventions targeted to this group are needed