Flotillin-1-enriched lipid raft domains accumulate on maturing phagosomes

Flotillin-1 was recently shown to be enriched on detergent-resistant domains of the plasma membrane called lipid rafts. These rafts, enriched in sphingolipids and cholesterol, sequester certain proteins while excluding others. Lipid rafts have been implicated in numerous cellular processes including signal transduction, membrane trafficking and molecular sorting. In this study, we demonstrate both morphologically and biochemically that lipid rafts are present on phagosomes, These structures are enriched in flotillin-1 and devoid of the main phagosomes membrane protein lysosomal-associated membrane protein (LAMP1), The flotillin-1 present on phagosomes does not originate from the plasma membrane during phagocytosis but accumulates gradually on maturing phagosomes, Treatment with bafilomycin A1, a compound that inhibits the proton pump ATPase and prevents the fusion of phagosomes with late endocytic organelles, prevents the acquisition of flotillin-1 by phagosomes, indicating that this protein might be recruited on phagosomes from endosomal organelles. A proteomic characterization of the lipid rafts of phagosomes indicates that actin, the alpha- and beta -subunits of heterotrimeric G proteins, as well as subunits of the proton pump V-ATPase are among the constituents of these domains. Remarkably, the intracellular parasite Leishmania donovani can actively inhibit the acquisition of flotillin-1-enriched lipid rafts by phagosomes and the maturation of these organelles. These results indicate that specialized functions required for phagolysosome biogenesis may occur at focal points on the phagosome membrane, and therefore represent a potential target of intracellular pathogens.

A novel target-field method for finite-length magnetic resonance shim coils: I. Zonal shims

This paper presents a new approach for the design of genuinely finite-length shim and gradient coils, intended for use in magnetic resonance imaging equipment. A cylindrical target region is located asymmetrically, at an arbitrary position within a coil of finite length. A desired target field is specified on the surface of that region, and a method is given that enables winding patterns on the surface of the coil to be designed, to produce the desired field at the inner target region. The method uses a minimization technique combined with regularization, to find the current density on the surface of the coil. The method is illustrated for linear, quadratic and cubic magnetic target fields located asymmetrically within a finite-length coil.

ReoPro rules: results from the 'DoTirofiban and ReoPro give similar efficacy trial' (TARGET) - A Key Paper Evaluation (Topol, Ej et al)

In the treatment of atherosclerotic disease, stenting in the presence of a glycoprotein (GP) IIb/IIIa antagonist is becoming an increasingly common procedure. The ‘Do Tirofiban and ReoPro Give Similar Efficacy Trial’ (TARGET) was designed to determine whether the cheaper tirofiban was as effective and safe as abciximab in the prevention of ischaemic events with stenting. Unexpectedly, abciximab was shown to be superior to tirofiban. Tirofiban is a selective GP IIb/IIIa antagonist whereas abciximab has additional anti-inflammatory actions, which may contribute to its superiority.

Chest pain in the dental surgery: A brief review and practical points in diagnosis and management

If a dental patient develops chest pain it must always be managed promptly and properly, i.e., the practitioner immediately stops the procedure and, being aware of the patients's medical history, questions the patient regarding the nature of the pain to help determine the likely diagnosis. It will most likely be a manifestation of coronary artery disease (synonymous with ischaemic heart disease), i.e., angina pectoris or acute myocardial infarction, most usually the former. Angina will usually resolve with proper intervention whereas up to about one-half of myocardial infarction cases will develop cardiac arrest, mostly in the first few hours, and this will be fatal in up to two-thirds of cases. As health care professions, dental practitioners have an inherent duty of care to be able to initiate appropriate care if such a medical emergency occurs.

The number of rational points of a class of Artin-Schreier curves

We determine the number of F-q-rational points of a class of Artin-Schreier curves by using recent results concerning evaluations of some exponential sums. In particular, we determine infinitely many new examples of maximal and minimal plane curves in the context of the Hasse-Weil bound. (C) 2002 Elsevier Science (USA).

Crystal structure of yeast acetohydroxyacid synthase: A target for herbicidal inhibitors

Acetohydroxyacid synthase (AHAS; EC 4.1.3.18) catalyzes the first step in branched-chain amino acid biosynthesis. The enzyme requires thiamin diphosphate and FAD for activity, but the latter is unexpected, because the reaction involves no oxidation or reduction. Due to its presence in plants, AHAS is a target for sulfonylurea and imidazolinone herbicides. Here, the crystal structure to 2.6 A resolution of the catalytic subunit of yeast AHAS is reported. The active site is located at the dimer interface and is near the proposed herbicide-binding site. The conformation of FAD and its position in the active site are defined. The structure of AHAS provides a starting point for the rational design of new herbicides. (C) 2002 Elsevier Science Ltd.

Air target detection via bistatic radar based on LEOS communication signals

The paper discusses the bistatic radar parameters for the case when the transmitter is a satellite emitting communication signals. The model utilises signals from an Iridium-like low earth orbiting satellite system. The maximum detection range, when thermal noise-limited, is discussed at the theoretical level and these results are compared with experimentation. Satellite-radar signal levels and the power of ground reflections are evaluated.

Combined physiotherapy and education is efficacious for chronic low back pain

Manual therapy, exercise and education target distinct aspects of chronic low back pain and probably have distinct effects, This study aimed to determine the efficacy of a combined physiotherapy treatment that comprised all of these strategies. By concealed randomisation, 57 chronic low back pain patients were allocated to either the four-week physiotherapy program or management as directed by their general practitioners, The dependent variables of interest were pain and disability. Assessors were blind to treatment group. Outcome data from 49 subjects (86%) showed a significant treatment effect. The physiotherapy program reduced pain and disability by a mean of 1.5/10 points on a numerical rating scale (95% CI 0.7 to 2.3) and 3.9 points on the 18-point Roland Morris Disability Questionnaire (95% CI 2 to 5.8), respectively. The number needed to treat in order to gain a clinically meaningful change was 3 (95% CI 3 to 8) for pain, and 2 (95% CI 2 to 5) for disability. A treatment effect was maintained at one-year follow-up. The findings support the efficacy of combined physiotherapy treatment in producing symptomatic and functional change in moderately disabled chronic low back pain patients.

N4WBP5, a potential target for ubiquitination by the Nedd4 family of proteins, is a novel golgi-associated protein

Nedd4 belongs to a family of ubiquitin-protein ligases that is characterized by 2-4 WW domains, a carboxyl-terminal Hect ((h) under bar omologous to (E) under bar6-AP (C) under bar arboxyl (t) under bar erminus)-domain and in most cases an amino-terminal C2 domain. We had previously identified a series of proteins that associates with the WW domains of Nedd4. In this paper, we demonstrate that one of the Nedd4-binding proteins, N4WBP5, belongs to a small group of evolutionarily conserved proteins with three transmembrane domains. N4WBP5 binds Nedd4 WW domains via the two PPXY motifs present in the amino terminus of the protein. In addition to Nedd4, N4WBP5 can interact with the WW domains of a number of Nedd4 family members and is ubiquitinated. Endogenous N4WBP5 localizes to the Golgi complex. Ectopic expression of the protein disrupts the structure of the Golgi, suggesting that N4WBP5 forms part of a family of integral Golgi membrane proteins. Based on previous observations in yeast, we propose that N4WBP5 may act as an adaptor for Nedd4-like proteins and their putative targets to control ubiquitin-dependent protein sorting and trafficking.

Elucidating the molecular mechanisms that underlie the target control of motoneuron death

Approximately half of the motoneurons generated during normal embryonic development undergo programmed cell death. Most of this death occurs during the time when synaptic connections are being formed between motoneurons and their target, skeletal muscle. Subsequent muscle activity stemming from this connection helps determine the final number of surviving motoneurons. These observations have given rise to the idea that motoneuron survival is dependent upon access to muscle derived trophic factors, presumably through intact neuromuscular synapses. However, it is not yet understood how the muscle regulates the supply of such trophic factors, or if there are additional mechanisms operating to control the fate of the innervating motoneuron. Recent observations have highlighted target independent mechanisms that also operate to support the survival of motoneurons, such as early trophic-independent periods of motoneuron death, trophic factors derived from Schwann cells and selection of motoneurons during pathfinding. Here we review recent investigations into motoneuron cell death when the molecular signalling between motoneurons and muscle has been genetically disrupted. From these studies, we suggest that in addition to trophic factors from muscle and/or Schwann cells, specific adhesive interactions between motoneurons and muscle are needed to regulate motoneuron survival. Such interactions, along with intact synaptic basal lamina, may help to regulate the supply and presentation of trophic factors to motoneurons.

More on exact bicoverings of 12 points

The minimum number of incomplete blocks required to cover, exactly lambda times, all t-element subsets from a set V of cardinality v (v > t) is denoted by y(lambda, t; v). The value of g(2, 2; v) is known for v = 3, 4,..., 11. It was previously known that 14 less than or equal to g(2, 2; 12) less than or equal to 16. We prove that g(2, 2; 12) greater than or equal to 15.

The VCAM-1 gene that encodes the vascular cell adhesion molecule is a target of the Sry-related high mobility group box gene, Sox18

VCAM-1 (vascular cell adhesion molecule-1) and Sox18 are involved in vascular development. VCAM-1 is an important adhesion molecule that is expressed on endothelial cells and has a critical role in endothelial activation, inflammation, lymphatic pathophysiology, and atherogenesis. The Sry-related high mobility group box factor Sox18 has previously been implicated in endothelial pathologies. Mutations in human and mouse Sox18 leads to hypotrichosis and lymphedema. Furthermore, both Sox18 and VCAM-1 have very similar spatio-temporal patterns of expression, which is suggestive of crosstalk. We use biochemical techniques, cell culture systems, and the ragged opossum (RaOP) mouse model with a naturally occurring mutation in Sox18 to demonstrate that VCAM-1 is an important target of Sox18. Transfection, site-specific mutagenesis, and gel shift analyses demonstrated that Sox18 directly targeted and trans-activated VCAM-1 expression. Importantly, the naturally occurring Sox18 mutant attenuates the expression and activation of VCAM-1 in vitro. Furthermore, in vivo quantitation of VCAM-1 mRNA levels in wild type and RaOP mice demonstrates that RaOP animals show a dramatic and significant reduction in VCAM-1 mRNA expression in lung, skin, and skeletal muscle. Our observation that the VCAM-1 gene is an important target of SOX18 provides the first molecular insights into the vascular abnormalities in the mouse mutant ragged and the human hypotrichosis-lymphedematelangiectasia disorder.

The receptor tyrosine kinase regulator sprouty1 is a target of the tumor suppressor WT1 and important for kidney development

WT1 encodes a transcription factor involved in kidney development and tumorigenesis. Using representational difference analysis, we identified a new set of WT1 targets, including a homologue of the Drosophila receptor tyrosine kinase regulator, sprouty. Sprouty1 was up-regulated in cell lines expressing wild-type but not mutant WT1. WT1 bound to the endogenous sprouty1 promoter in vivo and directly regulated sprouty1 through an early growth response gene-1 binding site. Expression of Sprouty1 and WT1 overlapped in the developing metanephric mesenchyme, and Sprouty1, like WT1, plays a key role in the early steps of glomerulus formation. Disruption of Sprouty1 expression in embryonic kidney explants by antisense oligonucleotides reduced condensation of the metanephric mesenchyme, leading to a decreased number of glomeruli. In addition, sprouty1 was expressed in the ureteric tree and antisense-treated ureteric trees had cystic lumens. Therefore, sprouty1 represents a physiologically relevant target gene of WT1 during kidney development.