DMT1 Protects Macrophages from Salmonella Infection by Controlling Cellular Iron Turnover and Lipocalin 2 Expression

Macrophages are at the center of innate pathogen control and iron recycling. Divalent metal transporter 1 (DMT1) is essential for the uptake of non-transferrin-bound iron (NTBI) into macrophages and for the transfer of transferrin-bound iron from the endosome to the cytoplasm. As the control of cellular iron trafficking is central for the control of infection with siderophilic pathogens such as Salmonella Typhimurium, a Gram-negative bacterium residing within the phagosome of macrophages, we examined the potential role of DMT1 for infection control. Bone marrow derived macrophages lacking DMT1 (DMT1fl/fl^LysMCre(+)) present with reduced NTBI uptake and reduced levels of the iron storage protein ferritin, the iron exporter ferroportin and, surprisingly, of the iron uptake protein transferrin receptor. Further, DMT1-deficient macrophages have an impaired control of Salmonella Typhimurium infection, paralleled by reduced levels of the peptide lipocalin-2 (LCN2). LCN2 exerts anti-bacterial activity upon binding of microbial siderophores but also facilitates systemic and cellular hypoferremia. Remarkably, nifedipine, a pharmacological DMT1 activator, stimulates LCN2 expression in RAW264.7 macrophages, confirming its DMT1-dependent regulation. In addition, the absence of DMT1 increases the availability of iron for Salmonella upon infection and leads to increased bacterial proliferation and persistence within macrophages. Accordingly, mice harboring a macrophage-selective DMT1 disruption demonstrate reduced survival following Salmonella infection. This study highlights the importance of DMT1 in nutritional immunity and the significance of iron delivery for the control of infection with siderophilic bacteria.     

Early Postoperative Immunothrombosis of Bioprosthetic Mitral Valve and Left Atrium: A Case Report

A 72-year-old female patient with mixed rheumatic mitral valve disease and persistent atrial fibrillation underwent mitral valve replacement and suffered from a combined thrombosis of the bioprosthetic valve and the left atrium as soon as 2 days post operation. The patient immediately underwent repeated valve replacement and left atrial thrombectomy. Yet, four days later the patient died due to the recurrent prosthetic valve and left atrial thrombosis which both resulted in an extremely low cardiac output. In this patient’s case, the thrombosis was notable for the resistance to anticoagulant therapy as well as for aggressive neutrophil infiltration and release of neutrophil extracellular traps (NETs) within the clot, as demonstrated by immunostaining. The reasons behind these phenomena remained unclear, as no signs of sepsis or contamination of the BHV were documented, although the patient was diagnosed with inherited thrombophilia that could impede the fibrinolysis. The described case highlights the hazard of immunothrombosis upon valve replacement and elucidates its mechanisms in this surgical setting.     

Decentralized adaptive recurrent neural control structure

This paper presents a novel decentralized variable structure neural control approach for large-scale uncertain systems, which is developed using recurrent high-order neural networks (RHONN). It is assumed that each subsystem belongs to a class of block-controllable nonlinear systems whose vector fields includes interconnection terms, which are bounded by nonlinear functions. A decentralized RHONN structure and the respective learning law are proposed in order to approximate online the dynamical behavior of each nonlinear subsystem. The control law, which is able to regulate and to track the desired reference signals, is designed using the well-known variable structure theory. The stability of the whole system is analyzed via the Lyapunov methodology. The applicability of the proposed decentralized identification and control algorithm is illustrated via simulations as applied to an interconnected double inverted pendulum.     

Comments on 'Formal specification of user interfaces: a comparison and evaluation of four axiomatic approaches' by U.H. Chi

A recent paper (see ibid., vol.11, no.8, p.671-88, Aug. 1985) compared several axiomatic methods of formal specification, one of which was Z. As a result of a comparison made with Z and a similar, but executable, specification language called Me too, it was pointed out that one of the Z specifications given was not correct. In this response, the erroneous function is described and some conclusions are drawn about the process of formal specification.<>     

Analyzing Nonindependent Outcomes in Couple Therapy Using the Actor-Partner Interdependence Model.

The nonindependent components of couple data require data-analytic strategies tailored to the interpersonal processes occurring between relationship partners. This article examines the benefits of a specifically dyadic analytic method, the actor-partner interdependence model (APIM), for evaluating interpartner influence across time. Both conceptual and methodological features of the APIM are exemplified by applying this model to observations of negative and positive affect and global distress in spouses participating in a randomized trial of couple therapy. In addition to elucidating specific advantages of the APIM relative to alternative data-analytic strategies, the current results shed new light on previous findings from a comparative treatment outcome study evaluating behavioral and insight-oriented approaches to couple therapy. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Sphingolipid Catabolism and Glycerophospholipid Levels Are Altered in Erythrocytes and Plasma from Multiple Sclerosis Patients

Multiple sclerosis (MS) is an autoimmune, inflammatory, degenerative disease of the central nervous system. Changes in lipid metabolism have been suggested to play important roles in MS pathophysiology and progression. In this work we analyzed the lipid composition and sphingolipid-catabolizing enzymes in erythrocytes and plasma from MS patients and healthy controls. We observed reduction of sphingomyelin (SM) and elevation of its products—ceramide (CER) and shingosine (SPH). These changes were supported by the detected up-regulation of the activity of acid sphingomyelinase (ASM) in MS plasma and alkaline ceramidase (ALCER) in erythrocytes from MS patients. In addition, Western blot analysis showed elevated expression of ASM, but not of ALCER. We also compared the ratios between saturated (SAT), unsaturated (UNSAT) and polyunsaturated fatty acids and suggest, based on the significant differences observed for this ratio, that the UNSAT/SAT values could serve as a marker distinguishing erythrocytes and plasma of MS from controls. In conclusion, the application of lipid analysis in the medical practice would contribute to definition of more precise diagnosis, analysis of disease progression, and evaluation of therapeutic strategies. Based on the molecular changes of blood lipids in neurodegenerative pathologies, including MS, clinical lipidomic analytical approaches could become a promising contemporary tool for personalized medicine.     

Fabrication of transparent polymer-matrix nanocomposites with enhanced mechanical properties from chemically modified ZrO<Subscript>2</Subscript> nanoparticles

Optically transparent nanocomposites with enhanced mechanical properties were fabricated using stable dispersions of sub 10 nm ZrO₂ nanoparticles. The ZrO₂ dispersions were mixed with a commercially available bisphenol-A-based epoxy resin (RIMR 135i) and cured with a mixture of two amine-based curing agents (RIMH 134 and RIMH 137) after complete solvent removal. The colloidal dispersions of ZrO₂ nanoparticles, synthesized through a non-aqueous approach, were obtained through a chemical modification of the ZrO₂ nanoparticle surface, employing different organic ligands through simple mixing at room temperature. Successful binding of the ligands to the surface was studied utilizing ATR–FT-IR and thermogravimetric analysis. The homogeneous distribution of the nanoparticles within the matrix was proven by SAXS and the observed high optical transmittance for ZrO₂ contents of up to 8 wt%. Nanocomposites with a ZrO₂ content of only 2 wt% showed a significant enhancement of the mechanical properties, e.g., an increase of the tensile strength and Young’s modulus by up to 11.9 and 12.5%, respectively. Also the effect of different surface bound ligands on the mechanical properties is discussed.     

Electronic fingerprints of DNA bases on graphene

We calculate the electronic local density of states (LDOS) of DNA nucleotide bases (A,C,G,T), deposited on graphene. We observe significant base-dependent features in the LDOS in an energy range within a few electronvolts of the Fermi level. These features can serve as electronic fingerprints for the identification of individual bases in scanning tunneling spectroscopy (STS) experiments that perform image and site dependent spectroscopy on biomolecules. Thus the fingerprints of DNA-graphene hybrid structures may provide an alternative route to DNA sequencing using STS.