455 research outputs found
Extensive alternative splicing within the amino-propeptide coding domain of Îą2(XI) procollagen mRNAs: Expression of transcripts encoding truncated pro-Îą chains
Heterogeneity in type XI procollagen structure is extensive because all three Îą(XI) collagen genes undergo complex alternative splicing within the amino-propeptide coding domain. Exon 7 of the human and exons 6-8 of the mouse Îą2(XI) collagen genes, encoding part of the amino-propeptide variable region, have recently been shown to be alternatively spliced. We show that exon 6-containing mRNAs for human Îą2(XI) procollagen are expressed at 28 weeks in fetal tendon and cartilage but not at 38-44 days or 11 weeks. In the mouse, exon 6 is expressed in chondrocytes from 13.5 days onward. We recently identified conserved sequences within intron 6 of the human and mouse Îą2(XI) collagen genes, containing additional consensus splice acceptor and donor sites that potentially increase the size of exon 7, dividing it into three parts, designated 7A, 7B, and 7C. We show by reverse transcription polymerase chain reaction and in situ hybridization that these potential splice sites are used to yield additional Îą2(XI) procollagen mRNA splice variants that are expressed in fetal tissues. In human, expression of exon 7B-containing transcripts may be developmental stage-specific. Interestingly, inclusion of exon 7A or exon 7B in human and mouse Îą2(XI) procollagen mRNAs, respectively, would result in the insertion of an in-frame termination codon, suggesting that some of the additional splice variants encode a truncated pro-Îą2(XI) chain
Accepting higher morbidity in exchange for sacrificing fewer animals in studies developing novel infection-control strategies.
Preventing bacterial infections from becoming the leading cause of death by the year 2050 requires the development of novel, infection-control strategies, building heavily on biomaterials science, including nanotechnology. Pre-clinical (animal) studies are indispensable for this development. Often, animal infection outcomes bear little relation to human clinical outcome. Here, we review conclusions from pathogen-inoculum dose-finding pilot studies for evaluation of novel infection-control strategies in murine models. Pathogen-inoculum doses are generally preferred that produce the largest differences in quantitative infection outcome parameters between a control and an experimental group, without death or termination of animals due to having reached an inhumane end-point during the study. However, animal death may represent a better end-point for evaluation than large differences in outcome parameters or number of days over which infection persists. The clinical relevance of lower pre-clinical outcomes, such as bioluminescence, colony forming units (CFUs) retrieved or more rapid clearance of infection is unknown, as most animals cure infection without intervention, depending on pathogen-species and pathogen-inoculum dose administered. In human clinical practice, patients suffering from infection present to hospital emergency wards, frequently in life-threatening conditions. Animal infection-models should therefore use prevention of death and recurrence of infection as primary efficacy targets to be addressed by novel strategies. To compensate for increased animal morbidity and mortality, animal experiments should solely be conducted for pre-clinical proof of principle and safety. With the advent of sophisticated in vitro models, we advocate limiting use of animal models when exploring pathogenesis or infection mechanisms
Gabapentin to reduce pain in women aged between 18 and 50 years with chronic pelvic pain: the GaPP2 RCT
Statistical anisotropy of magnetohydrodynamic turbulence
Direct numerical simulations of decaying and forced magnetohydrodynamic (MHD)
turbulence without and with mean magnetic field are analyzed by higher-order
two-point statistics. The turbulence exhibits statistical anisotropy with
respect to the direction of the local magnetic field even in the case of global
isotropy. A mean magnetic field reduces the parallel-field dynamics while in
the perpendicular direction a gradual transition towards two-dimensional MHD
turbulence is observed with inertial-range scaling of the
perpendicular energy spectrum. An intermittency model based on the Log-Poisson
approach, , is able to describe the observed
structure function scalings.Comment: 4 pages, 3 figures. To appear in Phys.Rev.
Multi-triangulations as complexes of star polygons
Maximal -crossing-free graphs on a planar point set in convex
position, that is, -triangulations, have received attention in recent
literature, with motivation coming from several interpretations of them.
We introduce a new way of looking at -triangulations, namely as complexes
of star polygons. With this tool we give new, direct, proofs of the fundamental
properties of -triangulations, as well as some new results. This
interpretation also opens-up new avenues of research, that we briefly explore
in the last section.Comment: 40 pages, 24 figures; added references, update Section
Evaluating Baculovirus as a Vector for Human Prostate Cancer Gene Therapy
Gene therapy represents an attractive strategy for the non-invasive treatment of prostate cancer, where current clinical interventions show limited efficacy. Here, we evaluate the use of the insect virus, baculovirus (BV), as a novel vector for human prostate cancer gene therapy. Since prostate tumours represent a heterogeneous environment, a therapeutic approach that achieves long-term regression must be capable of targeting multiple transformed cell populations. Furthermore, discrimination in the targeting of malignant compared to non-malignant cells would have value in minimising side effects. We employed a number of prostate cancer models to analyse the potential for BV to achieve these goals. In vitro, both traditional prostate cell lines as well as primary epithelial or stromal cells derived from patient prostate biopsies, in two- or three-dimensional cultures, were used. We also evaluated BV in vivo in murine prostate cancer xenograft models. BV was capable of preferentially transducing invasive malignant prostate cancer cell lines compared to early stage cancers and non-malignant samples, a restriction that was not a function of nuclear import. Of more clinical relevance, primary patient-derived prostate cancer cells were also efficiently transduced by BV, with robust rates observed in epithelial cells of basal phenotype, which expressed BV-encoded transgenes faster than epithelial cells of a more differentiated, luminal phenotype. Maximum transduction capacity was observed in stromal cells. BV was able to penetrate through three-dimensional structures, including in vitro spheroids and in vivo orthotopic xenografts. BV vectors containing a nitroreductase transgene in a gene-directed enzyme pro-drug therapy approach were capable of efficiently killing malignant prostate targets following administration of the pro-drug, CB1954. Thus, BV is capable of transducing a large proportion of prostate cell types within a heterogeneous 3-D prostate tumour, can facilitate cell death using a pro-drug approach, and shows promise as a vector for the treatment of prostate cancer
Mountain maple and balsam fir early response to partial and clear-cut harvesting under aspen stands of northern Quebec
This study is a component of the Sylviculture et am
Immune or genetic-mediated disruption of CASPR2 causes pain hypersensitivity due to enhanced primary afferent excitability
Human autoantibodies to contactin-associated protein-like 2 (CASPR2) are often associated with neuropathic pain, and CASPR2 mutations have been linked to autism spectrum disorders, in which sensory dysfunction is increasingly recognized. Human CASPR2 autoantibodies, when injected into mice, were peripherally restricted and resulted in mechanical pain-related hypersensitivity in the absence of neural injury. We therefore investigated the mechanism by which CASPR2 modulates nociceptive function. Mice lacking CASPR2 (Cntnap2(-/-)) demonstrated enhanced pain-related hypersensitivity to noxious mechanical stimuli, heat, and algogens. Both primary afferent excitability and subsequent nociceptive transmission within the dorsal horn were increased in Cntnap2(-/-) mice. Either immune or genetic-mediated ablation of CASPR2 enhanced the excitability of DRG neurons in a cell-autonomous fashion through regulation of Kv1 channel expression at the soma membrane. This is the first example of passive transfer of an autoimmune peripheral neuropathic pain disorder and demonstrates that CASPR2 has a key role in regulating cell-intrinsic dorsal root ganglion (DRG) neuron excitability
Measurements of Higgs boson production and couplings in diboson final states with the ATLAS detector at the LHC
Measurements are presented of production properties and couplings of the recently discovered Higgs boson using the decays into boson pairs, H âÎł Îł, H â Z Zâ â4l and H âW Wâ âlνlν. The results are based on the complete pp collision data sample recorded by the ATLAS experiment at the CERN Large Hadron Collider at centre-of-mass energies of âs = 7 TeV and âs = 8 TeV, corresponding to an integrated luminosity of about 25 fbâ1. Evidence for Higgs boson production through vector-boson fusion is reported. Results of combined ďŹts probing Higgs boson couplings to fermions and bosons, as well as anomalous contributions to loop-induced production and decay modes, are presented. All measurements are consistent with expectations for the Standard Model Higgs boson
Standalone vertex ďŹnding in the ATLAS muon spectrometer
A dedicated reconstruction algorithm to find decay vertices in the ATLAS muon spectrometer is presented. The algorithm searches the region just upstream of or inside the muon spectrometer volume for multi-particle vertices that originate from the decay of particles with long decay paths. The performance of the algorithm is evaluated using both a sample of simulated Higgs boson events, in which the Higgs boson decays to long-lived neutral particles that in turn decay to bbar b final states, and pp collision data at âs = 7 TeV collected with the ATLAS detector at the LHC during 2011
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