Testing General Relativity with LISA including Spin Precession and Higher Harmonics in the Waveform

We compute the accuracy at which a LISA-like space-based gravitational wave detector will be able to observe deviations from General Relativity in the low frequency approximation. To do so, we introduce six correction parameters that account for modified gravity in the second post-Newtonian gravitational wave phase for inspiralling supermassive black hole binaries with spin precession on quasi-circular orbits. Our implementation can be regarded as a subset of the ppE formalism developed by Yunes and Pretorius, being able to investigate also next-to-leading order effects. In order to find error distributions for the alternative theory parameters, we use the Fisher information formalism and carry out Monte Carlo simulations for 17 different binary black hole mass configurations in the range 10^5 Msun < M < 10^8 Msun with 10^3 randomly distributed points in the parameter space each, comparing the full (FWF) and restricted (RWF) version of the gravitational waveform. We find that the binaries can roughly be separated into two groups: one with low (< ~10^7 Msun) and one with high total masses (> ~10^7 Msun). The RWF errors on the alternative theory parameters are two orders of magnitude higher than the FWF errors for high-mass binaries while almost comparable for low-mass binaries. Due to dilution of the available information, the accuracy of the binary parameters is reduced by factors of a few, except for the luminosity distance which is affected more seriously in the high-mass regime. As an application and to compare our research with previous work, we compute an optimal lower bound on the graviton Compton wavelength which is increased by a factor of ~1.6 when using the FWF.Comment: 33 pages, 37 figure

A Scoping Review on the Therapeutic Potential of Resin From the Species Larix decidua Mill. [Pinaceae] to Treat Ulcerating Wounds.

Malignant ulcerating wounds or neoplastic lesions are a considerable burden for patients suffering from advanced cancer. These wounds have no effective treatment and are very difficult to manage. The present review summarizes evidence in support of a hypothesis put forward in anthroposophic medicine, which suggests a beneficial role of resin from the species Larix decidua Mill. [Pinaceae] for treating such wounds. A systematic search strategy was performed using the databases PubMed, EMBASE and SciFinder. The included publications described the chemical composition of this species, as well as in vitro, in vivo, and ex vivo experiments using plant extracts and isolated compounds. The results show that among the phytochemical classes, terpenoids were the major components of this species, especially in the resin. The summarized biological experiments revealed antimicrobial, antioxidant and anti-inflammatory effects, with promising potential for the extracts and isolated compounds. However, the molecular mechanisms and toxicological effects are as of yet not conclusively evaluated. From the data of our study, we can conclude that L. decidua might indeed have a promising potential for the treatment of malignant wounds, but definitive information that can prove its effectiveness is still lacking. We therefore suggest that future efforts should be dedicated to the evaluation of L. decidua resin's therapeutic use considering its antiseptic action and proposed wound healing properties

Spin induced multipole moments for the gravitational wave amplitude from binary inspirals to 2.5 Post-Newtonian order

Using the NRGR effective field theory formalism we calculate the remaining source multipole moments necessary to obtain the spin contributions to the gravitational wave amplitude to 2.5 Post-Newtonian (PN) order. We also reproduce the tail contribution to the waveform linear in spin at 2.5PN arising from the nonlinear interaction between the current quadrupole and the mass monopole.Comment: 17 pages, 4 figures. v2 Minor changes, to appear in JCA

Gravitational waves from intermediate-mass black holes in young clusters

Massive young clusters (YCs) are expected to host intermediate-mass black holes (IMBHs) born via runaway collapse. These IMBHs are likely in binaries and can undergo mergers with other compact objects, such as stellar mass black holes (BHs) and neutron stars (NSs). We derive the frequency of such mergers starting from information available in the Local Universe. Mergers of IMBH-NS and IMBH-BH binaries are sources of gravitational waves (GWs), which might allow us to reveal the presence of IMBHs. We thus examine their detectability by current and future GW observatories, both ground- and space-based. In particular, as representative of different classes of instruments we consider Initial and Advanced LIGO, the Einstein gravitational-wave Telescope (ET) and the Laser Interferometer Space Antenna (LISA). We find that IMBH mergers are unlikely to be detected with instruments operating at the current sensitivity (Initial LIGO). LISA detections are disfavored by the mass range of IMBH-NS and IMBH-BH binaries: less than one event per year is expected to be observed by such instrument. Advanced LIGO is expected to observe a few merger events involving IMBH binaries in a 1-year long observation. Advanced LIGO is particularly suited for mergers of relatively light IMBHs (~100 Msun) with stellar mass BHs. The number of mergers detectable with ET is much larger: tens (hundreds) of IMBH-NS (IMBH-BH) mergers might be observed per year, according to the runaway collapse scenario for the formation of IMBHs. We note that our results are affected by large uncertainties, produced by poor observational constraints on many of the physical processes involved in this study, such as the evolution of the YC density with redshift.[abridged]Comment: 29 pages, 4 figures, accepted for publication in Ap

Duloxetine Inhibits Effects of MDMA (“Ecstasy") In Vitro and in Humans in a Randomized Placebo-Controlled Laboratory Study

This study assessed the effects of the serotonin (5-HT) and norepinephrine (NE) transporter inhibitor duloxetine on the effects of 3,4–methylenedioxy­methamphetamine (MDMA, ecstasy) in vitro and in 16 healthy subjects. The clinical study used a double-blind, randomized, placebo-controlled, four-session, crossover design. In vitro, duloxetine blocked the release of both 5-HT and NE by MDMA or by its metabolite 3,4-methylenedioxyamphetamine from transmitter-loaded human cells expressing the 5-HT or NE transporter. In humans, duloxetine inhibited the effects of MDMA including elevations in circulating NE, increases in blood pressure and heart rate, and the subjective drug effects. Duloxetine inhibited the pharmacodynamic response to MDMA despite an increase in duloxetine-associated elevations in plasma MDMA levels. The findings confirm the important role of MDMA-induced 5-HT and NE release in the psychotropic effects of MDMA. Duloxetine may be useful in the treatment of psychostimulant dependence

Report from the EPAA workshop: In vitro ADME in safety testing used by EPAA industry sectors

AbstractThere are now numerous in vitro and in silico ADME alternatives to in vivo assays but how do different industries incorporate them into their decision tree approaches for risk assessment, bearing in mind that the chemicals tested are intended for widely varying purposes? The extent of the use of animal tests is mainly driven by regulations or by the lack of a suitable in vitro model. Therefore, what considerations are needed for alternative models and how can they be improved so that they can be used as part of the risk assessment process? To address these issues, the European Partnership for Alternative Approaches to Animal Testing (EPAA) working group on prioritisation, promotion and implementation of the 3Rs research held a workshop in November, 2008 in Duesseldorf, Germany. Participants included different industry sectors such as pharmaceuticals, cosmetics, industrial- and agro-chemicals. This report describes the outcome of the discussions and recommendations (a) to reduce the number of animals used for determining the ADME properties of chemicals and (b) for considerations and actions regarding in vitro and in silico assays. These included: standardisation and promotion of in vitro assays so that they may become accepted by regulators; increased availability of industry in vivo kinetic data for a central database to increase the power of in silico predictions; expansion of the applicability domains of in vitro and in silico tools (which are not necessarily more applicable or even exclusive to one particular sector) and continued collaborations between regulators, academia and industry. A recommended immediate course of action was to establish an expert panel of users, developers and regulators to define the testing scope of models for different chemical classes. It was agreed by all participants that improvement and harmonization of alternative approaches is needed for all sectors and this will most effectively be achieved by stakeholders from different sectors sharing data

Nonviral Approaches for Neuronal Delivery of Nucleic Acids

The delivery of therapeutic nucleic acids to neurons has the potential to treat neurological disease and spinal cord injury. While select viral vectors have shown promise as gene carriers to neurons, their potential as therapeutic agents is limited by their toxicity and immunogenicity, their broad tropism, and the cost of large-scale formulation. Nonviral vectors are an attractive alternative in that they offer improved safety profiles compared to viruses, are less expensive to produce, and can be targeted to specific neuronal subpopulations. However, most nonviral vectors suffer from significantly lower transfection efficiencies than neurotropic viruses, severely limiting their utility in neuron-targeted delivery applications. To realize the potential of nonviral delivery technology in neurons, vectors must be designed to overcome a series of extra- and intracellular barriers. In this article, we describe the challenges preventing successful nonviral delivery of nucleic acids to neurons and review strategies aimed at overcoming these challenges

CNS Delivery Via Adsorptive Transcytosis

Adsorptive-mediated transcytosis (AMT) provides a means for brain delivery of medicines across the blood-brain barrier (BBB). The BBB is readily equipped for the AMT process: it provides both the potential for binding and uptake of cationic molecules to the luminal surface of endothelial cells, and then for exocytosis at the abluminal surface. The transcytotic pathways present at the BBB and its morphological and enzymatic properties provide the means for movement of the molecules through the endothelial cytoplasm. AMT-based drug delivery to the brain was performed using cationic proteins and cell-penetrating peptides (CPPs). Protein cationization using either synthetic or natural polyamines is discussed and some examples of diamine/polyamine modified proteins that cross BBB are described. Two main families of CPPs belonging to the Tat-derived peptides and Syn-B vectors have been extensively used in CPP vector-mediated strategies allowing delivery of a large variety of small molecules as well as proteins across cell membranes in vitro and the BBB in vivo. CPP strategy suffers from several limitations such as toxicity and immunogenicity—like the cationization strategy—as well as the instability of peptide vectors in biological media. The review concludes by stressing the need to improve the understanding of AMT mechanisms at BBB and the effectiveness of cationized proteins and CPP-vectorized proteins as neurotherapeutics