Addendum: "The Dynamics of M15: Observations of the Velocity Dispersion Profile and Fokker-Planck Models" (ApJ, 481, 267 [1997])

It has recently come to our attention that there are axis scale errors in three of the figures of Dull et al. (1997, hereafter D97). D97 presented Fokker-Planck models for the collapsed-core globular cluster M15 that include a dense, centrally concentrated population of neutron stars and massive white dwarfs, but do not include a central black hole. In this Addendum, we present corrected versions of Figures 9, 10, and 12, and an expanded version of Figure 6. This latter figure, which shows the full run of the velocity dispersion profile, indicates that the D97 model predictions are in good agreement with the moderately rising HST-STIS velocity dispersion profile for M15 reported by Gerssen et al. (2002, astro-ph/0209315). Thus, a central black hole is not required to fit the new STIS velocity measurements, provided that there is a sufficient population of neutron stars and massive white dwarfs. This conclusion is consistent with the findings of Gerssen et al. (2002, astro-ph/0210158), based on a reapplication of their Jeans equation analysis using the corrected mass-to-light profile (Figure 12) for the D97 models.Comment: 4 pages, 4 figures, submitted to Ap

Targeting lentiviral vectors to antigen-specific immunoglobulins

Gene transfer into B cells by lentivectors can provide an alternative approach to managing B lymphocyte malignancies and autoreactive B cell-mediated autoimmune diseases. These pathogenic B cell Populations can be distinguished by their surface expression of monospecific immunoglobulin. Development of a novel vector system to deliver genes to these specific B cells could improve the safety and efficacy of gene therapy. We have developed an efficient rnethod to target lentivectors to monospecific immunoglobulin-expressing cells in vitro and hi vivo. We were able to incorporate a model antigen CD20 and a fusogenic protein derived from the Sindbis virus as two distinct molecules into the lentiviral Surface. This engineered vector could specifically bind to cells expressing Surface immunoglobulin recognizing CD20 (αCD20), resulting in efficient transduction of target cells in a cognate antigen-dependent manner in vitro, and in vivo in a xenografted tumor model. Tumor suppression was observed in vivo, using the engineered lentivector to deliver a suicide gene to a xenografted tumor expressing αCD20. These results show the feasibility of engineering lentivectors to target immunoglobulin-specific cells to deliver a therapeutic effect. Such targeting lentivectors also Could potentially be used to genetically mark antigen-specific B cells in vivo to study their B cell biology

American Naval History, 1607-1865

For its first eighty-five years, the United States was only a minor naval power. Its fledgling fleet had been virtually annihilated during the War of Independence and was mostly trapped in port by the end of the War of 1812. How this meager presence became the major naval power it remains to this day is the subject of American Naval History, 1607–1865: Overcoming the Colonial Legacy. A wide-ranging yet concise survey of the U.S. Navy from the colonial era through the Civil War, the book draws on American, British, and French history to reveal how navies reflect diplomatic, political, economic, and social developments and to show how the foundation of America’s future naval greatness was laid during the Civil War. Award-winning author Jonathan R. Dull documents the remarkable transformation of the U.S. Navy between 1861 and 1865, thanks largely to brilliant naval officers like David Farragut, David D. Porter, and Andrew Foote; visionary politicians like Abraham Lincoln and Gideon Welles; and progressive industrialists like James Eads and John Ericsson. But only by understanding the failings of the antebellum navy can the accomplishments of Lincoln’s navy be fully appreciated. Exploring such topics as delays in American naval development, differences between the U.S. and European fleets, and the effect that the country’s colonial past had on its naval policies, Dull offers a new perspective on both American naval history and the history of the developing republic

Monte Carlo Simulations of Star Clusters - IV. Calibration of the Monte Carlo Code and Comparison with Observations for the Open Cluster M67

We outline the steps needed in order to incorporate the evolution of single and binary stars into a particular Monte Carlo code for the dynamical evolution of a star cluster. We calibrate the results against N-body simulations, and present models for the evolution of the old open cluster M67 (which has been studied thoroughly in the literature with N-body techniques). The calibration is done by choosing appropriate free code parameters. We describe in particular the evolution of the binary, white dwarf and blue straggler populations, though not all channels for blue straggler formation are represented yet in our simulations. Calibrated Monte Carlo runs show good agreement with results of N-body simulations not only for global cluster parameters, but also for e.g. binary fraction, luminosity function and surface brightness. Comparison of Monte Carlo simulations with observational data for M67 shows that is possible to get reasonably good agreement between them. Unfortunately, because of the large statistical fluctuations of the numerical data and uncertainties in the observational data the inferred conclusions about the cluster initial conditions are not firm.Comment: 15 pages, 24 figure

Impact of a quadrivalent meningococcal ACWY glycoconjugate or a serogroup B meningococcal vaccine on meningococcal carriage: an observer-blind, phase 3 randomised clinical trial

Background: Meningococcal conjugate vaccines protect individuals directly, but also confer herd protection by interrupting carriage transmission. This Phase III observer-blind, randomised, controlled study evaluated the effects of meningococcal quadrivalent (ACWY) glycoconjugate (MenACWY-CRM) or serogroup B (4CMenB) vaccination on meningococcal carriage rates in young adults. Methods: University students (aged 18–24 years) from ten sites in England were randomised to receive two vaccinations one month apart: two doses of Japanese Encephalitis vaccine (controls), two doses of 4CMenB (4CMenB), or one dose of MenACWY-CRM then placebo (MenACWY-CRM). Meningococci were isolated from oropharyngeal swabs collected before vaccination and at five scheduled intervals over one year. Primary analysis was cross-sectional carriage one month after the vaccine course; secondary analyses included comparison of carriage at any time point after primary analysis until study termination. Findings: 2954 subjects were randomised (control, n=987; 4CMenB, n=988; MenACWY-CRM, n=979); approximately one-third of each group was positive for meningococcal carriage at study entry. By one month, there was no significant difference in carriage between controls and 4CMenB (Odds Ratios (OR) [95% CI]; 1·2 [0·8−1·7]) or MenACWY-CRM (OR [95% CI], 0·9 [0·6–1·3]) groups. From three months after dose two, 4CMenB vaccination resulted in significantly lower carriage of any meningococcal strain (calculated efficacy 18·2% [95% CI: 3·4–30·8]) and capsular groups BCWY (calculated efficacy 26·6% [95% CI: 10·5–39·9]) compared to control vaccination. Significantly lower carriage rates were also observed in the MenACWY-CRM group compared with controls: calculated efficacies 39·0% [95%CI: 17·3-55·0] and 36.2% [95%CI: 15·6-51·7] for serogroups Y and CWY, respectively. Interpretation: MenACWY-CRM and 4CMenB vaccines reduced meningococcal carriage rates over 12 months post-vaccination and, therefore, may affect transmission where widely implemented

Measuring gravitational waves from binary black hole coalescences: I. Signal to noise for inspiral, merger, and ringdown

We estimate the expected signal-to-noise ratios (SNRs) from the three phases (inspiral,merger,ringdown) of coalescing binary black holes (BBHs) for initial and advanced ground-based interferometers (LIGO/VIRGO) and for space-based interferometers (LISA). LIGO/VIRGO can do moderate SNR (a few tens), moderate accuracy studies of BBH coalescences in the mass range of a few to about 2000 solar masses; LISA can do high SNR (of order 10^4) high accuracy studies in the mass range of about 10^5 to 10^8 solar masses. BBHs might well be the first sources detected by LIGO/VIRGO: they are visible to much larger distances (up to 500 Mpc by initial interferometers) than coalescing neutron star binaries (heretofore regarded as the "bread and butter" workhorse source for LIGO/VIRGO, visible to about 30 Mpc by initial interferometers). Low-mass BBHs (up to 50 solar masses for initial LIGO interferometers; 100 for advanced; 10^6 for LISA) are best searched for via their well-understood inspiral waves; higher mass BBHs must be searched for via their poorly understood merger waves and/or their well-understood ringdown waves. A matched filtering search for massive BBHs based on ringdown waves should be capable of finding BBHs in the mass range of about 100 to 700 solar masses out to 200 Mpc (initial LIGO interferometers), and 200 to 3000 solar masses out to about z=1 (advanced interferometers). The required number of templates is of order 6000 or less. Searches based on merger waves could increase the number of detected massive BBHs by a factor of order 10 or more over those found from inspiral and ringdown waves, without detailed knowledge of the waveform shapes, using a "noise monitoring" search algorithm. A full set of merger templates from numerical relativity could further increase the number of detected BBHs by an additional factor of up to 4.Comment: 40 pages, Revtex, psfig.tex, seven figures, submitted to Phys Rev

Lentivirus-meditated frataxin gene delivery reverses genome instability in Friedreich ataxia patient and mouse model fibroblasts

Friedreich ataxia (FRDA) is a progressive neurodegenerative disease caused by deficiency of frataxin protein, with the primary sites of pathology being the large sensory neurons of the dorsal root ganglia and the cerebellum. FRDA is also often accompanied by severe cardiomyopathy and diabetes mellitus. Frataxin is important in mitochondrial iron–sulfur cluster (ISC) biogenesis and low-frataxin expression is due to a GAA repeat expansion in intron 1 of the FXN gene. FRDA cells are genomically unstable, with increased levels of reactive oxygen species and sensitivity to oxidative stress. Here we report the identification of elevated levels of DNA double strand breaks (DSBs) in FRDA patient and YG8sR FRDA mouse model fibroblasts compared to normal fibroblasts. Using lentivirus FXN gene delivery to FRDA patient and YG8sR cells, we obtained long-term overexpression of FXN mRNA and frataxin protein levels with reduced DSB levels towards normal. Furthermore, γ-irradiation of FRDA patient and YG8sR cells revealed impaired DSB repair that was recovered on FXN gene transfer. This suggests that frataxin may be involved in DSB repair, either directly by an unknown mechanism, or indirectly via ISC biogenesis for DNA repair enzymes, which may be essential for the prevention of neurodegeneration.Ataxia UK, FARA Australasia and FARA US

Inhibition of cervical cancer cell growth in vitro and in vivo with dual shRNAs

RNA interference (RNAi)-based gene silencing is widely used in laboratories for gene function studies and also holds a great promise for developing treatments for diseases. However, in vivo delivery of RNAi therapy remains a key issue. Lentiviral vectors have been employed for stable gene transfer and gene therapy and therefore are expected to deliver a stable and durable RNAi therapy. But this does not seem to be true in some disease models. Here, we showed that lentivirus delivered short-hairpin RNA (shRNA) against human papillomavirus (HPV) E6/E7 oncogenes were effective for only 2 weeks in a cervical cancer model. However, using this vector to carry two copies of the same shRNA or two shRNAs targeting at two different but closely related genes (HPV E6 and vascular endothelial growth factor) was more effective at silencing the gene targets and inhibiting cell or even tumor growth than their single shRNA counterparts. The cancer cells treated with dual shRNA were also more sensitive to chemotherapeutic drugs than single shRNA-treated cells. These results suggest that a multi-shRNA strategy may be a more attractive approach for developing an RNAi therapy for this cancer. Cancer Gene Therapy (2011) 18, 219-227; doi: 10.1038/cgt.2010.72; published online 19 November 201

Clinically relevant concentrations of lidocaine and ropivacaine inhibit TNFα-induced invasion of lung adenocarcinoma cells in vitro by blocking the activation of Akt and focal adhesion kinase

BACKGROUND Matrix-metalloproteinases (MMP) and cancer cell invasion are crucial for solid tumour metastasis. Important signalling events triggered by inflammatory cytokines, such as tumour necrosis factor α (TNFα), include Src-kinase-dependent activation of Akt and focal adhesion kinase (FAK) and phosphorylation of caveolin-1. Based on previous studies where we demonstrated amide-type local anaesthetics block TNFα-induced Src activation in malignant cells, we hypothesized that local anaesthetics might also inhibit the activation and/or phosphorylation of Akt, FAK and caveolin-1, thus attenuating MMP release and invasion of malignant cells. METHODS NCI-H838 lung adenocarcinoma cells were incubated with ropivacaine or lidocaine (1 nM-100 µM) in absence/presence of TNFα (20 ng ml(-1)) for 20 min or 4 h, respectively. Activation/phosphorylation of Akt, FAK and caveolin-1 were evaluated by Western blot, and MMP-9 secretion was determined by enzyme-linked immunosorbent assay. Tumour cell migration (electrical wound-healing assay) and invasion were also assessed. RESULTS Ropivacaine (1 nM-100 μM) and lidocaine (1-100 µM) significantly reduced TNFα-induced activation/phosphorylation of Akt, FAK and caveolin-1 in NCI-H838 cells. MMP-9 secretion triggered by TNFα was significantly attenuated by both lidocaine and ropivacaine (half-maximal inhibitory concentration [IC50]=3.29×10(-6) M for lidocaine; IC50=1.52×10(-10) M for ropivacaine). The TNFα-induced increase in invasion was completely blocked by both lidocaine (10 µM) and ropivacaine (1 µM). CONCLUSIONS At clinically relevant concentrations both ropivacaine and lidocaine blocked tumour cell invasion and MMP-9 secretion by attenuating Src-dependent inflammatory signalling events. Although determined entirely in vitro, these findings provide significant insight into the potential mechanism by which local anaesthetics might diminish metastasi