Diminished Virulence Of A Sar-lagr- Mutant Of Staphylococcus Aureus In The Rabbit Model Of Endocarditis

Microbial pathogenicity in Staphylococcus aureus is a complex process involving a number of virulence genes that are regulated by global regulatory systems including sar and agr. To evaluate the roles of these two loci in virulence, we constructed sar-lagr- mutants of strains RN6390 and RN450 and compared their phenotypic profiles to the corresponding single sar- and agr- mutants and parents. The secretion of all hemolysins was absent in the sar-lagr- mutants while residual β-hemolysin activity remained in single agr- mutants. The fibronectin binding capacity was significantly diminished in both single sar- mutants and double mutants when compared with parents while the reduction in fibrinogen binding capacity in the double mutants was modest. In the rabbit endocarditis model, there was a significant decrease in both infectivity rates and intravegetation bacterial densities with the double mutant as compared to the parent (RN6390) at 103-106 CFU inocula despite comparable levels of early bacteremia among various challenge groups. Notably, fewer bacteria in the double mutant group adhered to valvular vegetations at 30 min after challenge (106 CFU) than the parent group. These studies suggest that both the sar and agr loci are involved in initial valvular adherence, intravegetation persistence and multiplication of S. aureus in endocarditis.94518151822Waldvogel, F.A., Staphylococcus aureus (1985) Principles and Practice of Infectious Diseases, pp. 1097-1116. , G. L. Mandell, R. G. Douglas, Jr., and J. E. Bennett, editors. John Wiley & Sons, New YorkNeu, H.C., The crisis in antibiotic resistance (1992) Science (Wash. DC), 257, pp. 1064-1072Cohen, M.L., Epidemiology of drug resistance: Implications for a post-antibiotic era (1992) Science (Wash. DC), 257, pp. 1050-1055Easmon, C.S.F., Adlam, C., (1983) Staphylococci and Staphylococcal Infections, pp. 705-740. , Academic Press, New YorkCheung, A.L., Krishnan, M., Jaffe, E.A., Fischetti, V.A., Fibrinogen acts as a bridging molecule in the adherence of Staphylococcus aureus to cultured human endothelial cells (1991) J. Clin. Invest., 87, pp. 2236-2245Herrmann, M., Vaudaux, P.E., Pittet, D., Auckenthaler, R., Lew, P.D., Schumacher Perdreau, F., Peters, G., Waldvogel, F.A., Fibronectin, fibrinogen, and laminin act as mediators of adherence of clinical staphylococcal isolates to foreign material (1988) J. Infect. Dis., 158, pp. 693-701Kuypers, J.M., Proctor, R.A., Reduced adherence to traumatized rat heart valves by a low-fibronectin-binding mutant of Staphylococcus aureus (1989) Infect. Immun., 57, pp. 2306-2312DeRita, V.J., Mekalanos, J.J., Genetic regulation of bacterial virulence (1989) Annu. Rev. Genet., 23, pp. 455-482Kornblum, J., Kreiswirth, B., Projan, S.J., Ross, H., Novick, R.P., Agr: A polycistronic locus regulating exoprotein synthesis in Staphylococcus aureus (1990) Molecular Biology of the Staphylococci, pp. 373-402. , R. P. Novick, editor. VCH Publishers, New YorkNixon, B.T., Ronson, C.W., Ausubel, R.M., Two component regulatory systems responsive to environmental stimuli share strongly conserved domains with the nitrogen assimilation regulatory genes ntrB and btrC (1986) Proc. Natl. Acad. Sci. USA, 83, pp. 7850-7854Smeltzer, M.S., Hart, M.E., Iandolo, J.J., Phenotypic characterization of xpr, a global regulator of extracellular virulence factors in Staphylococcus aureus (1993) Infect. Immun., 61, pp. 919-925Cheung, A.L., Koomey, J.M., Butler, C.A., Projan, S.J., Fischetti, V.A., Regulation of exoprotein expression in Staphylococcus aureus by a locus (sar) distinct from agr (1992) Proc. Natl. Acad. Sci. USA, 89, pp. 6462-6466Cheung, A.L., Yeaman, M., Bayer, A.S., The role of the sar locus of Staphylococcus aureus in the induction of endocarditis in rabbits (1994) Infect. Immun., 62, pp. 1719-1725Vandenesch, F., Kornblum, J., Novick, R.P., A temporal signal, independent of agr, is required for hla but not spa transcription in Staphylococcus aureus (1991) J. Bacteriol., 173, pp. 6313-6320Cheung, A.L., Ying, P., Regulation of α and β hemolysins by the sar locus of Staphylococcus aureus (1994) J. Bacteriol., 176, pp. 580-585Rescei, P., Kreiswirth, B., O'Reilly, M., Schlievert, P., Gruss, A., Novick, R.P., Regulation of exoprotein gene expression in Staphylococcus aureus by agr (1986) Mol. & Gen. Genet., 202, pp. 58-61Fröman, G., Switalski, L., Speziale, P., Höök, M., Isolation and characterization of a fibronectin receptor from Staphylococcus aureus (1987) J. Biol. Chem., 262, pp. 6564-6571Lantz, M., Allen, R.D., Bounelis, P., Switalski, L.M., Höök, M., Bacteroides gingivalis and Bacteroides intermedius recognize different sites on human fibrinogen (1990) J. Bacteriol., 172, pp. 716-726Yeaman, M.R., Sullam, P.M., Dazin, P.F., Norman, D.C., Bayer, A.S., Characterization of Staphylococcus aureus-platelet binding by quantitative flow cytometric analysis (1992) J. Infect. Dis., 166, pp. 65-73Clawson, C.C., White, J.G., Herzberg, M.C., Platelet interaction with bacteria. VI. Contrasting the role of fibrinogen and fibronectin (1980) Am. J. Hematol., 9, pp. 43-53Yeaman, M.R., Norman, D.C., Bayer, A.S., Staphylococcus aureus susceptibility to thrombin-induced platelet microbicidal protein is independent of platelet adherence and aggregation in vitro (1992) Infect. Immun., 60, pp. 2368-2374Sullam, P.M., Payan, D.G., Dazin, P.F., Valone, F.H., Binding of viridans group streptococci to human platelets: A quantitative analysis (1990) Infect. Immun., 58, pp. 3802-3806Yeaman, M.R., Puentes, S.M., Norman, D.C., Bayer, A.S., Partial characterization and staphylocidal activity of thrombin-induced platelet microbicidal protein (1992) Infect. Immun., 60, pp. 1202-1209Kornblum, J., Projan, S.J., Moghazeh, S.L., Novick, R., A rapid method to quantitate non-labeled RNA species in bacterial cells (1988) Gene, 63, pp. 75-85Maniatis, T., Fritsch, E.F., Sambrook, J., (1989) Molecular Cloning, a Laboratory Manual, , Cold Spring Harbor Laboratory, Cold Spring Harbor, NYDurack, D.T., Beeson, P.B., Experimental bacterial endocarditis. I. Colonization of a sterile vegetation (1972) Br. J. Exp. Pathol., 53, pp. 44-49Scheld, W.M., Valone, J.A., Sande, M.A., Bacterial adherence in the pathogenesis of endocarditis. Interaction of bacterial dextran, platelets and fibrin (1978) J. Clin. Invest., 61, pp. 1394-1404Herzberg, M.C., Gong, K., McMarlane, G.D., Phenotypic characterization of Streptococcus sanguis virulence factors associated with bacterial endocarditis (1990) Infect. Immun., 58, pp. 515-522Cheung, A.L., Fischetti, V.A., The role of fibrinogen in staphylococcal adherence to catheters in vitro (1990) J. Infect. Dis., 161, pp. 1177-1186Herrmann, M., Vaudaux, P.E., Pittet, D., Auckenthaler, R., Lew, P.D., Schumacher Perdreau, F., Peters, G., Waldvogel, F.A., Fibronectin, fibrinogen, and laminin act as mediators of adherence of clinical staphylococcal isolates to foreign material (1988) J. Infect. Dis., 158, pp. 693-701Cheung, A.L., Projan, S.J., Cloning and sequencing of sarA: A gene required for the expression of agr (1994) J. Bacteriol., 176, pp. 4168-4172Scheld, W.M., Strunk, R.W., Balian, G., Calderone, R.A., Microbial adhesion to fibronectin in vitro correlates with production of endocarditis in rabbits (1985) Proc. Soc. Exp. Biol. Med., 180, pp. 474-482Durack, D.T., Beeson, P.B., Pathogenesis of infective endocarditis (1980) Infective Endocarditis, pp. 1-53. , S. H. Rahimtoola, editor. Grune and Stratton, Inc., New YorkJaffe, E., Cell biology of endothelial cells (1987) Hum. Pathol., 18, pp. 234-239Lopes, J.D., Reis, M.D., Bretani, R.R., Presence of laminin receptors in Staphylococcus aureus (1985) Science (Wash. DC), 229, pp. 275-277Patti, J.M., Bremell, T., Krajewska-Paetrasik, D., Adelnour, A., Tarkowski, A., Ryden, C., Höök, M., The Staphylococcus aureus collagen adhesin is a virulence determinant in experimental septic arthritis Infect. Immun., 62, pp. 152-161Herrmann, M., Suchard, S.J., Boxer, L.A., Waldvogel, F.A., Lew, P.D., Thrombospondin binds to Staphylococcus aureus and promotes staphylococcal adhesion to surfaces (1991) Infect. Immun., 59, pp. 279-288Bhakdi, S., Muhly, M., Mannhardt, U., Hugo, F., Klapettek, K., Muller-Eckhardt, C., Roka, L., Staphylococcal α-toxin promotes blood coagulation via attack on human platelets (1988) J. Exp. Med., 168, pp. 527-542Suttorp, N., Hessz, T., Seeger, W., Wilke, A., Koob, R., Lutz, F., Drenckhahn, D., Bacterial exotoxins and endothelial permeability for water and albumin in vitro (1988) Am. J. Physiol., 255, pp. C368Novick, R.P., Genetic systems in staphylococci (1991) Methods Enzymol., 204, pp. 587-636O'Reilly, M., De Azavedo, J.C.S., Kennedy, S., Foster, T.J., Inactivation of the alpha-hemolysin of Staphylococcus aureus 8325-4 by site directed mutagenesis and studies on the expression of its haemolysins (1986) Microb. Pathog., 1, pp. 125-138Projan, S.J., Kornblum, J., Kreiswirth, B., Moghazeh, S., Eisner, W., Novick, R.P., The β hemolysin gene of Staphylococcus aureus (1989) Nucleic Acids Res., 17, p. 3305Camilli, A., Portnoy, D.A., Youngman, P., Insertional mutagenesis of Listeria monocytogenes with a novel Tn917 derivative that allows direct cloning of DNA flanking transposon insertions (1990) J. Bacteriol., 172, pp. 3738-3744Nesin, M., Svec, P., Lupski, J.R., Godson, G.N., Kreiswirth, B., Kornblum, J., Projan, S.J., Cloning and nucleotide sequencing of a chromosomally encoded tetracycline resistance determinant, tetA(M), from a pathogenic, methicillin resistant strain of Staphylococcus aureus (1990) Antimicrob. Agents Chemother., 34, pp. 2273-227

Possible astrophysical signatures of heavy stable neutral relics in supergravity models

We consider heavy stable neutral particles in the context of supergravity and show that a gravitationally suppressed inflaton decay can produce such particles in cosmologically interesting abundances within a wide mass range $10^3 {\rm GeV} \leq m_X \leq 10^{11} {\rm GeV}$. In gravity-mediated supersymmetry breaking models, a heavy particle can decay into its superpartner and a photon-photino pair or a gravitino. Such decays only change the identity of a possible dark matter candidate. However, for $10^3 {\rm GeV} \leq m_X \leq 10^7 {\rm GeV}$, astrophysical bounds from gamma-ray background and photodissociation of light elements can be more stringent than the overclosure bound, thus ruling out the particle as a dark matter candidate.Comment: 12 page

Working time flexibility components and working time regimes in Europe: using company-level data across 21 countries

Working time ?exibility comprises a wide variety of arrangements, from part-time, overtime, to long-term leaves. Theoretical approaches to grouping these arrangements have been developed, but empirical underpinnings are rare. This article investigates the bundles that can be found for various ?exible working time arrangements, using the Establishment Survey on Working Time and Work–Life Balance, 2004/2005, covering 21 EU member states and 13 industries. The results from the factor analyses con?rmed that working time arrangements can be grouped into two bundles, one for the employee-centred arrangements and second for the employer-centred arrangements, and that these two bundles are separate dimensions.Wealso tested the stability of the factor analysisoutcome, showing that although we ?nd some deviations from the pan-Europe and pan-industry outcome, the naming of the components as ?exibility for employees and ?exibility for employers can be considered rather stable. Lastly, we ?nd three country clusters for the 21 European countries using the bundle approach. The ?rst group includes the Northern European countries along side Poland and Czech Republic, the second group the continental European countries with UK and Ireland, and lastly, the southern European countries with Hungary and Slovenia

A preferential attachment model with random initial degrees

In this paper, a random graph process ${G(t)}_{t\geq 1}$ is studied and its degree sequence is analyzed. Let $(W_t)_{t\geq 1}$ be an i.i.d. sequence. The graph process is defined so that, at each integer time $t$, a new vertex, with $W_t$ edges attached to it, is added to the graph. The new edges added at time t are then preferentially connected to older vertices, i.e., conditionally on $G(t-1)$, the probability that a given edge is connected to vertex i is proportional to $d_i(t-1)+\delta$, where $d_i(t-1)$ is the degree of vertex $i$ at time $t-1$, independently of the other edges. The main result is that the asymptotical degree sequence for this process is a power law with exponent $\tau=\min\{\tau_{W}, \tau_{P}\}$, where $\tau_{W}$ is the power-law exponent of the initial degrees $(W_t)_{t\geq 1}$ and $\tau_{P}$ the exponent predicted by pure preferential attachment. This result extends previous work by Cooper and Frieze, which is surveyed.Comment: In the published form of the paper, the proof of Proposition 2.1 is incomplete. This version contains the complete proo

Inferential reproduction analysis demonstrated that “paracetamol for acute low back pain” trial conclusions were reproducible

Objectives: The aim of this study was to reanalyze and reinterpret data obtained in Paracetamol in Acute Low Back Pain (PACE), the first large randomized controlled trial evaluating the efficacy of paracetamol in acute low back pain, to assess the inferential reproducibility of the original conclusions. Study Design and Setting: Mixed effects models were used to reanalyze pain intensity (primary outcome; 11-point Numeric Rating Scale) and physical functioning, health-related quality of life, sleep quality, and time until recovery (as secondary outcomes), according to the intention-to-treat principle. The original authors of the PACE study were not involved in the development of the methods for this reanalysis. Results: The reproduction analyses indicated no effect of treatment on pain intensity and confidence intervals excluded clinically worthwhile effects (adjusted main effect for regular paracetamol vs. placebo 0.00 [−0.02, 0.01; P = 0.85]; adjusted main effect for paracetamol as-needed vs. placebo 0.00 [−0.02, 0.01; P = 0.92]). Similar results were obtained for all secondary outcomes. Conclusion: This study indicates that the conclusions of the PACE trial are inferentially reproducible, even when using a different analytical approach. This reinforces the notion that the management of acute low back pain should focus on providing patients advice and reassurance without the addition of paracetamol

Terahertz emission by diffusion of carriers and metal-mask dipole inhibition of radiation

Terahertz (THz) radiation can be generated by ultrafast photo-excitation of carriers in a semiconductor partly masked by a gold surface. A simulation of the effect taking into account the diffusion of carriers and the electric field shows that the total net current is approximately zero and cannot account for the THz radiation. Finite element modelling and analytic calculations indicate that the THz emission arises because the metal inhibits the radiation from part of the dipole population, thus creating an asymmetry and therefore a net current. Experimental investigations confirm the simulations and show that metal-mask dipole inhibition can be used to create THz emitters.Comment: 9 pages, 5 figures; Fixed figure

Functional SYNTAX Score for Risk Assessment in Multivessel Coronary Artery Disease

ObjectivesThis study was aimed at investigating whether a fractional flow reserve (FFR)-guided SYNTAX score (SS), termed “functional SYNTAX score” (FSS), would predict clinical outcome better than the classic SS in patients with multivessel coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI).BackgroundThe SS is a purely anatomic score based on the coronary angiogram and predicts outcome after PCI in patients with multivessel CAD. FFR-guided PCI improves outcomes by adding functional information to the anatomic information obtained from the angiogram.MethodsThe SS was prospectively collected in 497 patients enrolled in the FAME (Fractional Flow Reserve versus Angiography for Multivessel Evaluation) study. FSS was determined by only counting ischemia-producing lesions (FFR ≤0.80). The ability of each score to predict major adverse cardiac events (MACE) at 1 year was compared.ResultsThe 497 patients were divided into tertiles of risk based on the SS. After determining the FSS for each patient, 32% moved to a lower-risk group as follows. MACE occurred in 9.0%, 11.3%, and 26.7% of patients in the low-, medium-, and high-FSS groups, respectively (p < 0.001). Only FSS and procedure time were independent predictors of 1-year MACE. FSS demonstrated a better predictive accuracy for MACE compared with SS (Harrell's C of FSS, 0.677 vs. SS, 0.630, p = 0.02; integrated discrimination improvement of 1.94%, p < 0.001).ConclusionsRecalculating SS by only incorporating ischemia-producing lesions as determined by FFR decreases the number of higher-risk patients and better discriminates risk for adverse events in patients with multivessel CAD undergoing PCI. (Fractional Flow Reserve versus Angiography for Multivessel Evaluation [FAME]; NCT00267774

Nucleon propagation through nuclear matter in chiral effective field theory

We treat the propagation of nucleon in nuclear matter by evaluating the ensemble average of the two-point function of nucleon currents in the framework of the chiral effective field theory. We first derive the effective parameters of nucleon to one loop. The resulting formula for the effective mass was known previously and gives an absurd value at normal nuclear density. We then modify it following Weinberg's method for the two-nucleon system in the effective theory. Our results for the effective mass and the width of nucleon are compared with those in the literature.Comment: 11 pages including 4 figures. To appear in Eur. J. Phys.

Gating a Single Cell:A Label-Free and Real-Time Measurement Method for Cellular Progression

There is an ever-growing need for more advanced methods to study the response of cancer cells to new therapies. To determine cancer cells’ response from a cell-mortality perspective to various cancer therapies, we report a label-free and real time method to monitor the in situ response of individual HeLa cells using a single cell gated transistor (SCGT). As a cell undergoes apoptotic cell death, it experiences changes in morphology and ion concentrations. This change is well in line with the threshold voltage of the SCGT, which has been verified by correlating the data with the cell morphologies by scanning electron microscopy and the ion-concentration analysis by inductively-coupled plasma mass spectrometry (ICPMS). This SCGT could replace patch clamps to study single cell activity via direct measurement in real time. Importantly, this SCGT can be used to study the electrical response of a single cell to stimuli that leaves the membrane intact

Fingertip‐skin‐inspired highly sensitive and multifunctional sensor with hierarchically structured conductive graphite/polydimethylsiloxane foams

Fingertip skin exhibits high sensitivity in a broad pressure range, and can detect diverse stimuli, including textures, temperature, humidity, etc. Despite adopting diverse microstructures and functional materials, achieving skin sensor devices possessing high pressure sensitivity over a wide linear range and with multifunctional sensing capabilities is still challenging. Herein, inspired by the microstructures of fingertip skin, a highly sensitive skin sensor is demonstrated with a linear response over a broad pressure range and multifunctional sensing capabilities. The porous sensing layer is designed with hierarchical microstructures on the surface. By optimizing the porosity and the graphite concentration, a fabricated skin sensor device exhibits a superior sensitivity of 245 kPa−1 over a broad linear pressure range from 5 Pa to 120 kPa. For practical application demonstrations, the sensor devices are utilized to monitor subtle wrist pulse and diverse human motions including finger bending, wrist bending, and feet movement. Furthermore, this novel sensor device demonstrates potential applications in recognizing textures and detecting environmental temperatures, thereby marking an important progress for constructing advanced electronic skin