Search

Rationale: Increased expression of CLIC4 (chloride intracellular channel 4) is a feature of endothelial dysfunction in pulmonary arterial hypertension, but its role in disease pathology is not fully understood. Objective: To identify CLIC4 effectors and evaluate strategies targeting CLIC4 signaling in pulmonary hypertension. Methods and Results: Proteomic analysis of CLIC4-interacting proteins in human pulmonary artery endothelial cells identified regulators of endosomal trafficking, including Arf6 (ADP ribosylation factor 6) GTPase activating proteins and clathrin, while CLIC4 overexpression affected protein regulators of vesicular trafficking, lysosomal function, and inflammation. CLIC4 reduced BMPRII (bone morphogenetic protein receptor II) expression and signaling as a result of Arf6-mediated reduction in gyrating clathrin and increased lysosomal targeting of the receptor. BMPRII expression was restored by Arf6 siRNA, Arf inhibitor Sec7 inhibitor H3 (SecinH3), and inhibitors of clathrin-mediated endocytosis but was unaffected by chloride channel inhibitor, indanyloxyacetic acid 94 or Arf1 siRNA. The effects of CLIC4 on NF-κB (nuclear factor-kappa B), HIF (hypoxia-inducible factor), and angiogenic response were prevented by Arf6 siRNA and SecinH3. Sugen/hypoxia mice and monocrotaline rats showed elevated expression of CLIC4, activation of Arf6 and NF-κB, and reduced expression of BMPRII in the lung. These changes were established early during disease development. Lung endothelium–targeted delivery of CLIC4 siRNA or treatment with SecinH3 attenuated the disease, reduced CLIC4/Arf activation, and restored BMPRII expression in the lung. Endothelial colony–forming cells from idiopathic pulmonary hypertensive patients showed upregulation of CLIC4 expression and Arf6 activity, suggesting potential importance of this pathway in the human condition. Conclusions: Arf6 is a novel effector of CLIC4 and a new therapeutic target in pulmonary hypertension.

The range of exoproteins and core exoproteome of 14 Staphylococcus aureus isolates representing major lineages associated with asymptomatic carriage and clinical disease in the UK was identified by MS proteomics using a combined database incorporating sequences derived from 39 S. aureus genomes. In all, 632 different proteins were identified and, of these, only 52 (8 %) were found in all 14 isolates whereas 144 (23 %) were found in just a single isolate. Comparison of the observed mass of each protein (based on migration by SDS-PAGE) with its predicted mass (based on amino acid sequence) suggested that 95 % of the proteins identified were not subject to any major post-translational modification. Migration of 5 % of the proteins was not as expected: 1 % of the proteins migrated at a mass greater than predicted, while 4 % appeared to have undergone proteolytic cleavage; these included SsaA2, Aur, SspP, Ebh as well as BlaR1, MecR1, FsH, OatA and LtaS. Intriguingly, a truncated SasG was produced by a single CC8 USA300-like strain. The analysis provided evidence of the marked heterogeneity in protein expression by S. aureus in broth, while yielding a core but narrow common exoproteome.

J. Neurochem. (2012) 122, 681690. Abstract The interactions of the neurotransmitter dopamine, and its precursor l-dopa, with membrane lipids were investigated through a set of molecular dynamic simulations with all atom resolution. The results obtained indicate that both dopamine and l-dopa have a pronounced association with the lipid head groups, predominantly mediated through H-bonds. As a result the molecules are anchored to the interfacial region of the membrane. The strength of this interaction is dependent on lipid composition the presence of phosphatidylserine leads to an increase in the strength of this interaction, resulting in an H-bond network with a lifetime much longer than the timescale of our simulations. Also, bilayers that include sphingomieline and cholesterol interact strongly with dopamine and l-dopa. We postulate that the high membrane association that we have observed for both dopamine and l-dopa could have the following effects: 1) when on the plasma membrane exterior, favour the availability of these compounds for cell membrane uptake processes and, 2) when on an internal membrane surface, accentuate the importance of membrane-bound metabolizing enzymes over their soluble counterparts.

Развитие местной печати зависит от профессиональной подготовки журналистов, материально-технической и организационной базы их работы, конкуренции на рынке, состояния экономики территории и маркетинга в деятельности редакции. Количество наименований местной прессы, издаваемой в Польше, кажется стабильным. Наступает процесс изменения читательской аудитории. Шансом развития местной прессы в последующие годы явится ее электронное оформление в Интернете. Местные СМИ являются основой развития гражданского общества на местном уровне. Development of local press depends on professional journalists preparing, their work conditions, job organizing, rivalry on the market, state region and marketing economics in media activity. The numbers of local titles publishing in Poland is stable. There are changes in ring readers. The chance of local press development is its electronic edition and workings in Internet. Local media are the base of society development on local level.

Although sterols constitute one of the most important molecular species in cells, the reasons for their structure-function relationships in lipid membranes are not well understood. The main objective of this work is to elucidate the recently suggested possibility that the ordering and condensing effects of sterols on phospholipid membranes are related to the smoothness of a sterol. We focus on cholesterol, which has two methyl groups attached to its β-face, and compare its properties to those of demethylated cholesterol (Dchol), from which the two methyl groups have been removed. Atomic-scale molecular dynamics simulations of lipid membranes comprised of saturated lipids and sterols, either cholesterol or Dchol, provide compelling evidence that despite its smoother structure, the ordering and condensing effects of Dchol are less effective than those of cholesterol. The ordering capability of both cholesterol and Dchol is highly asymmetric with respect to their ring structure, but whereas cholesterol favors the α-face, Dchol favors the β-face. The origin and implications of this difference are analyzed in detail. The picture that emerges from this study supports a view that the two methyl groups at the steroid ring system of cholesterol play an important role in cholesterol-lipid interactions by reducing sterol tilt in the bilayer and hence allowing for an optimal orientation for cholesterol.