E. coli peptide deformylase (PDF) catalyzes the deformylation of nascent polypeptides generated during protein synthesis. While PDF was originally thought to be a zinc enzyme, subsequent studies revealed that the active site metal is iron. In an attempt to understand this unusual metal preference, high-resolution structures of Fe-, Co-, and Zn-PDF were determined in complex with its deformylation product, formate. In all three structures, the formate ion binds the metal and forms hydrogen-bonding interactions with the backbone nitrogen of Leu91, the amide side chain of Gln50, and the carboxylate side chain of Glu133. One key difference, however, is how the formate binds the metal. In Fe-PDF and Co-PDF, formate binds in a bidentate fashion, while in Zn-PDF, it binds in a monodentate fashion. Importantly, these structural results provide the first clues into the origins of PDF's metal-dependent activity differences. On the basis of these structures, we propose that the basis for the higher activity of Fe-PDF stems from the better ability of iron to bind and activate the tetrahedral transition state required for cleavage of the N-terminal formyl group.

In Drosophila, the neuropeptide pigment-dispersing factor (PDF) is a likely circadian molecule, secreted by central pacemaker neurons (LNvs). PDF is expressed in both small and large LNvs (sLNvs and lLNvs), and there are striking circadian oscillations of PDF staining intensity in the small cell termini, which require a functional molecular clock. This cycling may be relevant to the proposed role of PDF as a synchronizer of the clock system or as an output signal connecting pacemaker cells to locomotor activity centers. In this study, the authors use a generic neuropeptide fusion protein (atrial natriuretic factor-green fluorescent protein [ANF-GFP]) and show that it can be expressed in the same neurons as PDF itself. Yet, ANF-GFP as well as PDF itself does not manifest any cyclical accumulation in sLNv termini in adult transgenic flies. Surprisingly, the absence of detectable PDF cycling is not accompanied by any detectable behavioral pheno-type, since these transgenic flies have normal morning and evening anticipation in a light-dark cycle (LD) and are fully rhythmic in constant darkness (DD). The molecular clock is also not compromised. The results suggest that robust PDF cycling in sLNv termini plays no more than a minor role in the Drosophila circadian system and is apparently not even necessary for clock output function.

To define paediatric AML patients with a favourable outcome in order to design a risk-adapted therapy, we analysed 489 children under 17 years of age treated similarly in studies AML-BFM 83 and 87. 369 patients (75.4%) achieved remission. Estimated probabilities of survival, event-free survival (EFS) and disease-free survival (DFS) at 5 years were 50% (SE 2%), 43% (SE 2%) and 58% (SE 3%), respectively. Multivariate analysis revealed bone marrow blasts on day 15, morphologically defined risk groups and hyperleucocytosis to be of prognostic value. EFS at 5 years estimated for patients with < or = 5% and >5% blasts on day 15 were 56% (SE 3%) v 27% (SE 4%); for the favourable morphological subgroups (M1/M2 with Auer rods, M3 and M4eo) it was 60% (SE 4%) compared with other patients (33%, SE 3%), P (Kaplan-Meier) = 0.0001 each. Hyperleucocytosis proved to be an independent prognostic factor, indicating a high risk, especially for early failure. The specific karyotypes t(8;21), t(15;17) and inv16 were closely related to the favourable morphology and outcome was in the same range. We conclude that for the definition of a standard-risk group a combination of morphological and response criteria may be sufficient. The standard-risk group defined by favourable morphology and a blast cell reduction on day 15 (not required for M3) comprises 31% of all patients, P survival, pEFS and pDFS at 5 years were 73% (SE 4%), 68% (SE 5%) and 76% (SE 4%), respectively.

BACKGROUND

Although conventional peritoneal dialysis fluids (PDFs), such as Dianeal, are non-physiological in composition, new PDFs including Physioneal have a more neutral pH, are at least partially buffered with bicarbonate and, most importantly, contain low concentrations of glucose degradation products (GDPs).

METHODS

To evaluate the impact of new PDFs in childcare, we performed a comparative crossover study with Dianeal and Physioneal. We examined both intraperitoneal pressure (IPP), which partly reflects pain induction, and the total pore area available for exchange, which indicates the number of capillaries perfused in the peritoneal membrane at any given moment and therefore partly reflects peritoneal dialysis capacity. The IPP was determined after inflow of 1000 ml/m(2) body surface area (BSA) of dialysate (intraperitoneal volume; IPV). The steady-state unrestricted area over diffusion distance (A(0)/ triangle up x, in cm(2)/cm per 1.73 m(2) BSA) was calculated from the three-pore theory. Six children were enrolled in the study. On the first day, two consecutive peritoneal equilibration tests of 90 min each were performed using first Dianeal and then Physioneal. On the second study day, the procedure was repeated with the fluids given in the opposite order.

RESULTS

The mean IPP normalized to IPV (ml/m(2)) was significantly higher for Dianeal (9.5 +/- 0.9 cm/1000 ml/m(2)) than for Physioneal (7.9 +/- 1.2 cm/1000 ml/m(2), P < 0.01). The mean A(0)/ triangle up x was 17 +/- 4% larger with Dianeal (36 095 +/- 2009 cm(2)/cm per 1.73 m(2)) than with Physioneal (31 780 +/- 2185 cm(2)/cm per 1.73 m(2), P < 0.001; based on 24 data pairs).

CONCLUSIONS

These pilot study results suggest a higher biocompatibility for Physioneal than for Dianeal. Less inflow pain associated with Physioneal induced a lower IPP reflecting enhanced fill volume tolerance, and the lower A(0)/ triangle up x reflected less capillary recruitment. Taken together, these results suggest that the new more biocompatible PDFs will improve peritoneal dialysis therapy, although this conclusion will require verification in extended clinical trials.

We have investigated the paraelectric-to-ferroelectric phase transition of various sizes of nanocrystalline barium titanate (BaTiO3) by using temperature-dependent Raman spectroscopy and powder X-ray diffraction (XRD). Synchrotron X-ray scattering has been used to elucidate the room temperature structures of particles of different sizes by using both Rietveld refinement and pair distribution function (PDF) analysis. We observe the ferroelectric tetragonal phase even for the smallest particles at 26 nm. By using temperature-dependent Raman spectroscopy and XRD, we find that the phase transition is diffuse in temperature for the smaller particles, in contrast to the sharp transition that is found for the bulk sample. However, the actual transition temperature is almost unchanged. Rietveld and PDF analyses suggest increased distortions with decreasing particle size, albeit in conjunction with a tendency to a cubic average structure. These results suggest that although structural distortions are robust to changes in particle size, what is affected is the coherency of the distortions, which is decreased in the smaller particles.

BACKGROUND

MicroRNAs (miRNAs) are short regulatory RNAs derived from longer precursor RNAs. miRNA biogenesis has been studied in animals and plants, recently elucidating more complex aspects, such as non-conserved, species-specific, and heterogeneous miRNA precursor populations. Small RNA sequencing data can help in computationally identifying genomic loci of miRNA precursors. The challenge is to predict a valid miRNA precursor from inhomogeneous read coverage from a complex RNA library: while the mature miRNA typically produces many sequence reads, the remaining part of the precursor is covered very sparsely. As recent results suggest, alternative miRNA biogenesis pathways may lead to a more diverse miRNA precursor population than previously assumed. In plants, the latter manifests itself in e.g. complex secondary structures and expression from multiple loci within precursors. Current miRNA identification algorithms often depend on already existing gene annotation, and/or make use of specific miRNA precursor features such as precursor lengths, secondary structures etc. Consequently and in view of the emerging new understanding of a more complex miRNA biogenesis in plants, current tools may fail to characterise organism-specific and heterogeneous miRNA populations.

RESULTS

miRA is a new tool to identify miRNA precursors in plants, allowing for heterogeneous and complex precursor populations. miRA requires small RNA sequencing data and a corresponding reference genome, and evaluates precursor secondary structures and precursor processing accuracy; key parameters can be adapted based on the specific organism under investigation. We show that miRA outperforms the currently best plant miRNA prediction tools both in sensitivity and specificity, for data involving Arabidopsis thaliana and the Volvocine algae Chlamydomonas reinhardtii; the latter organism has been shown to exhibit a heterogeneous and complex precursor population with little cross-species miRNA sequence conservation, and therefore constitutes an ideal model organism. Furthermore we identify novel miRNAs in the Chlamydomonas-related organism Volvox carteri.

CONCLUSIONS

We propose miRA, a new plant miRNA identification tool that is well adapted to complex precursor populations. miRA is particularly suited for organisms with no existing miRNA annotation, or without a known related organism with well characterized miRNAs. Moreover, miRA has proven its ability to identify species-specific miRNAs. miRA is flexible in its parameter settings, and produces user-friendly output files in various formats (pdf, csv, genome-browser-suitable annotation files, etc.). It is freely available at https://github.com/mhuttner/miRA.

OBJECTIVE

To evaluate drug-polymer miscibility behavior in four different drug-polymer amorphous solid dispersion systems, namely felodipine-poly(vinyl pyrrolidone) (PVP), nifedipine-PVP, ketoconazole-PVP, and felodipine-poly(acrylic acid) (PAA).

METHODS

Amorphous solid dispersion samples were prepared at different drug-to-polymer ratios and analyzed using differential scanning calorimetry (DSC), mid-infrared (IR) spectroscopy, and powder X-ray diffractometry (PXRD). To help with interpretation of the IR spectra, principal components (PC) analysis was performed. Pair Distribution Functions (PDFs) of the components in the dispersion were determined from the PXRD data, and the pure curves of the components were also extracted from PXRD data using the Pure Curve Resolution Method (PCRM) and compared against experimentally obtained results.

RESULTS

Molecular-level mixing over the complete range of concentration was verified for nifedipine-PVP and felodipine-PVP. For felodipine-PAA, drug-polymer immiscibility was verified for samples containing 30 to 70% polymer, while IR results suggest at least some level of mixing for samples containing 10 and 90% polymer. For ketoconazole-PVP system, partial miscibility is suspected, whereby the presence of one-phase amorphous solid dispersion system could only be unambiguously verified at higher concentrations of polymer.

CONCLUSIONS

The three techniques mentioned complement each other in establishing drug-polymer miscibility in amorphous solid dispersion systems. In particular, IR spectroscopy and PXRD are sensitive to changes in local chemical environments and local structure, which makes them especially useful in elucidating the nature of miscibility in binary mixtures when DSC results are inconclusive or variable.

GABAergic signalling is important for normal sleep in humans and flies. Here we advance the current understanding of GABAergic modulation of daily sleep patterns by focusing on the role of slow metabotropic GABAB receptors in the fruit fly Drosophila melanogaster. We asked whether GABAB-R2 receptors are regulatory elements in sleep regulation in addition to the already identified fast ionotropic Rdl GABAA receptors. By immunocytochemical and reporter-based techniques we show that the pigment dispersing factor (PDF)-positive ventrolateral clock neurons (LNv) express GABAB-R2 receptors. Downregulation of GABAB-R2 receptors in the large PDF neurons (l-LNv) by RNAi reduced sleep maintenance in the second half of the night, whereas sleep latency at the beginning of the night that was previously shown to depend on ionotropic Rdl GABAA receptors remained unaltered. Our results confirm the role of the l-LNv neurons as an important part of the sleep circuit in D. melanogaster and also identify the GABAB-R2 receptors as the thus far missing component in GABA-signalling that is essential for sleep maintenance. Despite the significant effects on sleep, we did not observe any changes in circadian behaviour in flies with downregulated GABAB-R2 receptors, indicating that the regulation of sleep maintenance via l-LNv neurons is independent of their function in the circadian clock circuit.

The latest research outcomes indicate that metallothionein (MT) levels in peripheral blood and serum from cancer patients can provide many interesting information about type or clinical stage of the disease, or response to therapy. MT plays a key role in transport of essential heavy metals, detoxification of toxic metals and protection of cells against oxidation stress. Serum MT levels of cancer patients are three times higher than control patients (0.5 microM). The elevated MT levels in cancer cells are probably related to their increased proliferation and protection against apoptosis. Automated electrochemical detection of MT allows its serial analysis in a very small volume with excellent sensitivity, reliability and reproducibility and therefore it can be considered as a new tool for cancer diagnosis (Fig. 4, Ref. 55). Full Text (Free, PDF) www.bmj.sk.

Intravascular ultrasound (IVUS) is a catheter based medical imaging technique particularly useful for studying atherosclerotic disease. It produces cross-sectional images of blood vessels that provide quantitative assessment of the vascular wall, information about the nature of atherosclerotic lesions as well as plaque shape and size. Automatic processing of large IVUS data sets represents an important challenge due to ultrasound speckle, catheter artifacts or calcification shadows. A new three-dimensional (3-D) IVUS segmentation model, that is based on the fast-marching method and uses gray level probability density functions (PDFs) of the vessel wall structures, was developed. The gray level distribution of the whole IVUS pullback was modeled with a mixture of Rayleigh PDFs. With multiple interface fast-marching segmentation, the lumen, intima plus plaque structure, and media layers of the vessel wall were computed simultaneously. The PDF-based fast-marching was applied to 9 in vivo IVUS pullbacks of superficial femoral arteries and to a simulated IVUS pullback. Accurate results were obtained on simulated data with average point to point distances between detected vessel wall borders and ground truth <0.072 mm. On in vivo IVUS, a good overall performance was obtained with average distance between segmentation results and manually traced contours <0.16 mm. Moreover, the worst point to point variation between detected and manually traced contours stayed low with Hausdorff distances <0.40 mm, indicating a good performance in regions lacking information or containing artifacts. In conclusion, segmentation results demonstrated the potential of gray level PDF and fast-marching methods in 3-D IVUS image processing.

Ribosomal protein synthesis in eubacteria and eukaryotic organelles initiates with an N-formylmethionyl-tRNA(i), resulting in N-terminal formylation of all nascent polypeptides. Peptide deformylase (PDF) catalyzes the subsequent removal of the N-terminal formyl group from the majority of bacterial proteins. Until recently, PDF has been thought as an enzyme unique to the bacterial kingdom. Searches of the genomic DNA databases identified several genes that encode proteins of high sequence homology to bacterial PDF from eukaryotic organisms. The cDNA encoding Plasmodium falciparum PDF (PfPDF) has been cloned and overexpressed in Escherichia coli. The recombinant protein is catalytically active in deformylating N-formylated peptides, shares many of the properties of bacterial PDF, and is inhibited by specific PDF inhibitors. Western blot analysis indicated expression of mature PfPDF in trophozoite, schizont, and segmenter stages of intraerythrocytic development. These results provide strong evidence that a functional PDF is present in P. falciparum. In addition, PDF inhibitors inhibited the growth of P. falciparum in the intraerythrocytic culture.

Metabolic homeostasis requires coordination between circadian clocks in different tissues. Also, systemic signals appear to be required for some transcriptional rhythms in the mammalian liver and the Drosophila fat body. Here we show that free-running oscillations of the fat body clock require clock function in the PDF-positive cells of the fly brain. Interestingly, rhythmic expression of the cytochrome P450 transcripts, sex-specific enzyme 1 (sxe1) and Cyp6a21, which cycle in the fat body independently of the local clock, depends upon clocks in neurons expressing neuropeptide F (NPF). NPF signaling itself is required to drive cycling of sxe1 and Cyp6a21 in the fat body, and its mammalian ortholog, Npy, functions similarly to regulate cycling of cytochrome P450 genes in the mouse liver. These data highlight the importance of neuronal clocks for peripheral rhythms, particularly in a specific detoxification pathway, and identify a novel and conserved role for NPF/Npy in circadian rhythms.

Recent studies have firmly established pigment dispersing factor (PDF), a C-terminally amidated octodecapeptide, as a key neurotransmitter regulating rhythmic circadian locomotory behaviours in adult Drosophila melanogaster. The mechanisms by which PDF functions as a circadian peptide transmitter are not fully understood, however; in particular, nothing is known about the role of extracellular peptidases in terminating PDF signalling at synapses. In this study we show that PDF is susceptible to hydrolysis by neprilysin, an endopeptidase that is enriched in synaptic membranes of mammals and insects. Neprilysin cleaves PDF at the internal Ser7-Leu8 peptide bond to generate PDFPDFPDF receptor cDNA and a firefly luciferase reporter gene, confirming that such cleavage results in PDF inactivation. The Ser7-Leu8 peptide bond was also the principal cleavage site when PDF was incubated with membranes prepared from heads of adult Drosophila. This endopeptidase activity was inhibited by the neprilysin inhibitors phosphoramidon (IC(50,) 0.15 micromol l(-1)) and thiorphan (IC(50,) 1.2 micromol l(-1)). We propose that cleavage by a member of the Drosophila neprilysin family of endopeptidases is the most likely mechanism for inactivating synaptic PDF and that neprilysin might have an important role in regulating PDF signals within circadian neural circuits.

To characterize the mechanism by which diabetes affects the heart in diabetic (n = 15) and age-matched control subjects (n = 15), we quantified and compared diastolic function (DF) in terms of chamber stiffness and viscosity/relaxation by analyzing Doppler E- and E'-waves and simultaneous (high-fidelity) hemodynamic data. We compared tau, standard Doppler indexes and indexes of stiffness and viscosity/relaxation computed via the parameterized diastolic filling (PDF) formalism. Three PDF parameters uniquely characterize each E-wave in terms of load (x(o)), viscoelasticity or viscosity/relaxation (c) and stiffness (k). Significant differences for c (p = 0.00004), the peak atrioventricular pressure gradient (kx(o)) (p = 0.02) and the stored elastic energy available for early filling (1/2kx(o)2) (p = 0.04) were found. The only conventional index attaining significance was E-wave acceleration time (p = 0.007). Neither time constant of isovolumic relaxation (tau) nor E-wave deceleration time, E', k or x(o) differentiated between groups. We conclude that PDF based DF assessment differentiates between diabetic and nondiabetic controls better than conventional echo- or cath-based indexes. Our results in humans agree with published results from animal studies. We conclude that diabetes affects the heart via a quantifiable increase in chamber viscoelasticity (c) rather than an increase in chamber stiffness (k) and that phenotypic characterization of diabetic cardiomyopathy is facilitated by DF assessment via the PDF formalism.

OBJECTIVE

High concentrations of glucose and/or formation of glucose degradation products (GDPs) during heat sterilization of peritoneal dialysis fluids (PDFs) are believed to be key factors in the limited biocompatibility of PDFs. We have previously shown that several identified GDPs can specifically impair human peritoneal mesothelial cell (HPMC) function. In the present study we aimed at differentiating the respective roles of glucose and GDPs in the toxicity of PDF to mesothelial cells.

METHODS

HPMCs were acutely pre-exposed to or incubated chronically in the presence of pH-neutral PDF sterilized by either heat (H-PDF) or filtration (F-PDF). In addition, HPMCs were treated with commercially available H-PDF manufactured either conventionally, that is, in single-chamber containers, or using novel dual-chamber bags that help to substantially decrease GDP formation. Functional assessment of HPMCs included viability, release of interleukin (IL)-6, and proliferation.

RESULTS

Viability and release of IL-6 from HPMCs pretreated with H-PDF (pH 7.3) for 1 to 4 hours were significantly reduced compared to cells exposed to corresponding F-PDF. Incubation in medium mixed (1:1) with H-PDF considerably impaired growth of HPMCs, and over a period of 10 days gradually decreased both the viability of HPMCs and their ability to generate IL-6. These effects were either absent from or significantly less in HPMCs exposed to F-PDF. Similar differences were observed when commercial GDP-containing H-PDFs were compared with newly designed H-PDFs free of GDPs.

CONCLUSIONS

Impaired viability and function of HPMCs exposed to glucose-containing pH-neutral PDF is related predominantly to the presence of GDP and, to a significantly lesser extent, to the presence of glucose per se. Prevention of GDP formation during autoclaving markedly improves the biocompatibility of H-PDF with HPMCs.

The present study compares the effects of lactate and bicarbonate buffered PDF on human neutrophil (PMN) and human peritoneal mesothelial cell (HPMC) viability and function. Acute exposure of PMN to lactate buffered PDF at pH 5.5 (CAPD 2, 1.5% and CAPD 3, 4.25% glucose) resulted in significant reductions in cellular ATP levels, the phagocytosis of serum treated zymosan (STZ) and respiratory burst activation (CL). Exposure of PMN to bicarbonate buffered PDF (BIC 20, 1.5% glucose and BIC 30, 4.25% glucose both at pH 7.2) had no significant effect on cell viability or the CL response. Phagocytosis was, however, depressed significantly more following exposure to BIC 30 than BIC 20. PMN cellular ATP levels and phagocytosis were significantly better in cells exposed to BIC 30 than to CAPD 3 at pH 7.4 (P = 0.043 for both). Pre-exposure of HPMC to CAPD 2, CAPD 3 or BIC 30 for 30 minutes resulted in a significant reduction in cellular ATP content compared to control medium. Pre-exposure to BIC 20 did not result in a reduction in HPMC ATP levels. HPMC synthesis of IL-6 was unaffected by 15 or 30 minutes pre-exposure to BIC 20 or BIC 30, in contrast pre-exposure to CAPD 2 or CAPD 3 for 15 or 30 minutes resulted in a significant reduction in stimulated IL-6 synthesis (24.5 +/- 3.01 and 32.3 +/- 5.0 vs. 43.9 +/- 10 pg/microgram cell protein in M199, N = 6; P = 0.02). Neutralization of the pH of CAPD 2 and CAPD 3 resulted in normalization of HPMC IL-6 secretion. Analysis of IL-6 mRNA expression in control, BIC 20 and 30 pre-treated HPMC subsequently stimulated with IL-1 beta revealed no differences in the expression of the IL-6 specific 465 base pair transcripts. The improved cellular function in bicarbonate buffered PDF indicates potentially improved host defence status and preservation of the peritoneal membrane in CAPD patients.

This PDF receipt will only be used as the basis for generating PubMed Central (PMC) documents. PMC documents will be made available for review after conversion (approx. 2-3 weeks time). Any corrections that need to be made will be done at that time. No materials will be released to PMC without the approval of an author. Only the PMC documents will appear on PubMed Central -- this PDF Receipt will not appear on PubMed Central.Students who are not motivated and do not try to do well are unlikely to achieve at a level consistent with their abilities. This research assessed the relationships over time between school engagement and parenting practices and peer affiliation among 6(th)-9(th) graders using latent growth models (LGM). Participants included 2,453 students recruited from 7 public middle schools who were assessed 5 times between fall of 6(th) and 9(th) grades as part of a program evaluation study. During this period school engagement and adjustment declined somewhat, while substance use, conduct problems, and problem behaving friends increased, and authoritative parenting practices declined. The significant, positive over-time associations between school engagement and parent involvement, expectations, and monitoring were fully mediated by growth in problem behaving friends. School adjustment mediated the relationship between school engagement and parent expectations. These findings suggest that authoritative parenting practices may foster school engagement directly and also indirectly by discouraging affiliation with problem behaving friends and facilitating school adjustment.

Deformylases are metalloproteases in bacteria, plants, and humans that remove the N-formyl-methionine off peptides in vitro. The human homolog of peptide deformylase (HsPDF) resides in the mitochondria, along with its putative formylated substrates; however, the cellular function of HsPDF remains elusive. Here we report on the function of HsPDF in mitochondrial translation and oxidative phosphorylation complex biogenesis. Functional HsPDF appears to be necessary for the accumulation of mitochondrial DNA-encoded proteins and assembly of new respiratory complexes containing these proteins. Consequently, inhibition of HsPDF reduces respiratory function and cellular ATP levels, causing dependence on aerobic glycolysis for cell survival. A series of structurally different HsPDF inhibitors and control peptidase inhibitors confirmed that inhibition of HsPDF decreases mtDNA-encoded protein accumulation. Therefore, HsPDF appears to have a role in maintenance of mitochondrial respiratory function, and this function is analogous to that of chloroplast PDF.

According to the aim of the Treaty of Rome from 1957 which postulated the free movement of workers throughout the European Union, the European Board of Psychiatry in the UEMS (European Union of Medical Specialists) carried out a comprehensive survey of training in psychiatry, including all member countries in order to evaluate the present state of training in psychiatry in each. The survey should indicate whether the training requirements [UEMS Section Psychiatry. Charter on training of medical specialists in the EU: requirements for the speciality psychiatry. European Archives of Psychiatry and Clinical Neuroscience 1997;247(Suppl.):S45-7; UEMS Section Psychiatry. Charter on training of medical specialists in the EU: requirements for the speciality psychiatry. <www.uemspsychiatry.org/board/reports/Chapter6-11.10.03.<em>pdf</em>); 2003 [last revision]] have had an impact on the actual conditions of training in psychiatry in the member countries. We gathered 22 questionnaires from 31 national representatives involved and 424 questionnaires completed by the chief of training and the representative of trainees at the responding training centres from 22 countries. The results give an overview about the practice of training in psychiatry in many European countries. While there are great differences between the training centres in different countries, apparent progress towards developing high standards in training in psychiatry has been made.

BACKGROUND

Multi-drug resistant (MDR) bacteria have become a major concern in hospitals worldwide and urgently require the development of new antibacterial molecules. Peptide deformylase is an intracellular target now well-recognized for the design of new antibiotics. The bacterial susceptibility to such a cytoplasmic target primarily depends on the capacity of the compound to reach and accumulate in the cytosol.

RESULTS

To determine the respective involvement of penetration (influx) and pumping out (efflux) mechanisms to peptide deformylase inhibitors (PDF-I) activity, the potency of various series was determined using various genetic contexts (efflux overproducers or efflux-deleted strains) and membrane permeabilizers. Depending on the structure of the tested molecules, two behaviors could be observed: (i) for actinonin the first PDF-I characterized, the AcrAB efflux system was the main parameter involved in the bacterial susceptibility, and (ii), for the latest PDF-Is such as the derivatives of 2-(5-bromo-1H-indol-3-yl)-N-hydroxyacetamide, the penetration through the membrane was a important limiting step.

CONCLUSIONS

Our results clearly show that the bacterial membrane plays a key role in modulating the antibacterial activity of PDF-Is. The bacterial susceptibility for these new antibacterial molecules can be improved by two unrelated ways in MDR strains: by collapsing the Acr efflux activity or by increasing the uptake rate through the bacterial membrane. The efficiency of the second method is associated with the nature of the compound.

Compared with Diffusion Tensor Imaging (DTI), High Angular Resolution Imaging (HARDI) can better explore the complex microstructure of white matter. Orientation Distribution Function (ODF) is used to describe the probability of the fiber direction. Fisher information metric has been constructed for probability density family in Information Geometry theory and it has been successfully applied for tensor computing in DTI. In this paper, we present a state of the art Riemannian framework for ODF computing based on Information Geometry and sparse representation of orthonormal bases. In this Riemannian framework, the exponential map, logarithmic map and geodesic have closed forms. And the weighted Frechet mean exists uniquely on this manifold. We also propose a novel scalar measurement, named Geometric Anisotropy (GA), which is the Riemannian geodesic distance between the ODF and the isotropic ODF. The Renyi entropy H1/2 of the ODF can be computed from the GA. Moreover, we present an Affine-Euclidean framework and a Log-Euclidean framework so that we can work in an Euclidean space. As an application, Lagrange interpolation on ODF field is proposed based on weighted Frechet mean. We validate our methods on synthetic and real data experiments. Compared with existing Riemannian frameworks on ODF, our framework is model-free. The estimation of the parameters, i.e. Riemannian coordinates, is robust and linear. Moreover it should be noted that our theoretical results can be used for any probability density function (PDF) under an orthonormal basis representation.

Neuraminidase treatment of human peripheral blood lymphocytes uncovers cell surface receptors that bind purified A hemagglutinin from the snail Helix pomatia. No hemagglutinin was bound to untreated lymphocytes. Binding studies with (125)I-labeled hemagglutinin suggested that the number of receptors on neuraminidase-treated lymphocytes was approximately 1.10(6)/cell. The apparent association constant for hemagglutinin binding to lymphocytes, as calculated from Scatchard's plots, was 5-7.10(8) liters/mol. Immunofluorescent staining with FITC-conjugated hemagglutinin gave positive reactions with approximately 60% of the lymphocytes from normal donors. Positive staining was inversely related to the number of lymphocytes with Fc or complement receptors or with surface immunoglobulin, thus suggesting that See PDF for Structure the lymphocytes with receptors for Helix pomatia A hemagglutinin are T cells. Cell fractionation on columns charged with hemagglutinin indicate that these receptors may be used for separating subpopulations of human peripheral lymphocytes.

Lithium ion batteries (LIBs) containing silicon negative electrodes have been the subject of much recent investigation, because of the extremely large gravimetric and volumetric capacities of silicon. The crystalline-to-amorphous phase transition that occurs on electrochemical Li insertion into crystalline Si, during the first discharge, hinders attempts to link the structure in these systems with electrochemical performance. We apply a combination of local structure probes, ex situ (7)Li nuclear magnetic resonance (NMR) studies, and pair distribution function (PDF) analysis of X-ray data to investigate the changes in short-range order that occur during the initial charge and discharge cycles. The distinct electrochemical profiles observed subsequent to the first discharge have been shown to be associated with the formation of distinct amorphous lithiated silicide structures. For example, the first process seen on the second discharge is associated with the lithiation of the amorphous Si, forming small clusters. These clusters are broken in the second process to form isolated silicon anions. The (de)lithiation model helps explain the hysteresis and the steps in the electrochemical profile observed during the lithiation and delithiation of silicon.

BACKGROUND

Conventional peritoneal dialysis fluids (PDF) have been shown to compromise the function of both leukocytes and human peritoneal mesothelial cells (HPMC). Various in vitro studies have identified the low initial pH in combination with high lactate content, as well as the hyperosmolality and high glucose concentration present in currently used solutions as the primary determinants of their bioincompatibility. Bicarbonate buffered PDF (at neutral pH) display improved in vitro biocompatibility as compared to conventional, lactate buffered PDF. However, little information is currently available regarding the potential impact of PDF on the function of human peritoneal fibroblasts (HPFB), the major cell population present in peritoneal interstitium.

METHODS

The current study compares the effect of bicarbonate and lactate buffered PDF in a model system of resting peritoneal mesothelial cells and fibroblasts cultured from human omentum. Interleukin-1 beta-stimulated IL-6 release from HPMC and HPFB was used as the cell functional parameter.

RESULTS

While short (30 min) pre-exposure to lactate buffered PDF significantly reduced the IL-1 beta-stimulated IL-6 release from HPMC during a subsequent recovery period (24 hr), a significant decrease in HPMC IL-6 secretion with bicarbonate buffered PDF was only observed after prolonged >> or = 60 min) exposure. In contrast, no significant IL-6 inhibition was detected with HPFB pre-exposed to PDF for up to 90 minutes. A significant suppression of HPFB IL-6 secretion was only observed in coincubation experiments (24 hr) with dilutions of both types of PDF.

CONCLUSIONS

These results indicate that (i) bicarbonate buffered PDF are less inhibitory to peritoneal cell function as compared to conventional, lactate buffered PDF; and (ii) HPFB may be more resistant than HPMC to bioincompatible PDF.