626 research outputs found
Coagulation factor IX gene transfer to non-human primates using engineered AAV3 capsid and hepatic optimized expression cassette
Hepatic gene transfer with adeno-associated viral (AAV) vectors shows much promise for the treatment of the X-linked bleeding disorder hemophilia B in multiple clinical trials. In an effort to further innovate this approach and to introduce alternative vector designs with potentially superior features into clinical development, we recently built a vector platform based on AAV serotype 3 because of its superior tropism for human hepatocytes. A vector genome with serotype-matched inverted terminal repeats expressing hyperactive human coagulation factor IX (FIX)-Padua was designed for clinical use that is optimized for translation using hepatocyte-specific codon-usage bias and is depleted of immune stimulatory CpG motifs. Here, this vector genome was packaged into AAV3 (T492V + S663V) capsid for hepatic gene transfer in non-human primates. FIX activity within or near the normal range was obtained at a low vector dose of 5 x 10(11) vector genomes/kg. Pre-existing neutralizing antibodies, however, completely or partially blocked hepatic gene transfer at that dose. No CD8(+) T cell response against capsid was observed. Antibodies against the human FIX transgene product formed at a 10-fold higher vector dose, albeit hepatic gene transfer was remarkably consistent, and sustained FIX activity in the normal range was nonetheless achieved in two of three animals for the 3-month duration of the study. These results support the use of this vector at low vector doses for gene therapy of hemophilia B in humans
Bacillus cereus Biovar Anthracis Causing Anthrax in Sub-Saharan AfricaâChromosomal Monophyly and Broad Geographic Distribution
Through full genome analyses of four atypical Bacillus cereus isolates, designated B. cereus biovar anthracis, we describe a distinct clade within the B. cereus group that presents with anthrax-like disease, carrying virulence plasmids similar to those of classic Bacillus anthracis. We have isolated members of this clade from different mammals (wild chimpanzees, gorillas, an elephant and goats) in West and Central Africa (CĂŽte dâIvoire, Cameroon, Central African Republic and Democratic Republic of Congo). The isolates shared several phenotypic features of both B. anthracis and B. cereus, but differed amongst each other in motility and their resistance or sensitivity to penicillin. They all possessed the same mutation in the regulator gene plcR, different from the one found in B. anthracis, and in addition, carry genes which enable them to produce a second capsule composed of hyaluronic acid. Our findings show the existence of a discrete clade of the B. cereus group capable of causing anthrax-like disease, found in areas of high biodiversity, which are possibly also the origin of the worldwide distributed B. anthracis. Establishing the impact of these pathogenic bacteria on threatened wildlife species will require systematic investigation. Furthermore, the consumption of wildlife found dead by the local population and presence in a domestic animal reveal potential sources of exposure to humans
Persistent anthrax as a major driver of wildlife mortality in a tropical rainforest
Anthrax is a globally important animal disease and zoonosis. Despite this, our current knowledge of anthrax ecology is largely limited to arid ecosystems, where outbreaks are most commonly reported. Here we show that the dynamics of an anthrax-causing agent, Bacillus cereus biovar anthracis, in a tropical rainforest have severe consequences for local wildlife communities. Using data and samples collected over three decades, we show that rainforest anthrax is a persistent and widespread cause of death for a broad range of mammalian hosts. We predict that this pathogen will accelerate the decline and possibly result in the extirpation of local chimpanzee (Pan troglodytes verus) populations. We present the epidemiology of a cryptic pathogen and show that its presence has important implications for conservation
A longitudinal, multi-level comparative study of quality and safety in European hospitals: the QUASER study protocol
although there is a wealth of information available about quality improvement tools and techniques in healthcare there is little understanding about overcoming the challenges of day-to-day implementation in complex organisations like hospitals. The 'Quality and Safety in Europe by Research' (QUASER) study will investigate how hospitals implement, spread and sustain quality improvement, including the difficulties they face and how they overcome them. The overall aim of the study is to explore relationships between the organisational and cultural characteristics of hospitals and how these impact on the quality of health care; the findings will be designed to help policy makers, payers and hospital managers understand the factors and processes that enable hospitals in Europe to achieve-and sustain-high quality services for their patients
Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.
Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis
First-principles calculation of the effect of strain on the diffusion of Ge adatoms on Si and Ge (001) surfaces
First-principles calculations are used to calculate the strain dependencies
of the binding and diffusion-activation energies for Ge adatoms on both Si(001)
and Ge(001) surfaces. Our calculations reveal that the binding and activation
energies on a strained Ge(001) surface increase and decrease, respectively, by
0.21 eV and 0.12 eV per percent compressive strain. For a growth temperature of
600 degrees C, these strain-dependencies give rise to a 16-fold increase in
adatom density and a 5-fold decrease in adatom diffusivity in the region of
compressive strain surrounding a Ge island with a characteristic size of 10 nm.Comment: 4 pages, 4 figure
The First Habitable Zone Earth-Sized Planet From TESS II: Spitzer Confirms TOI-700 d
We present Spitzer 4.5 ÎŒm observations of the transit of TOI-700 d, a habitable-zone Earth-sized planet in a multiplanet system transiting a nearby M-dwarf star (TIC 150428135, 2MASS J06282325â6534456). TOI-700 d has a radius of 1.144^(+0.062)_(-0.061) Râ and orbits within its host star's conservative habitable zone with a period of 37.42 days (T_(eq) ~ 269 K). TOI-700 also hosts two small inner planets (R_b = 1.037^(+0.0065)_(-0.064) Râ and R_c = 2.65^(+0.16)_(-0.15) Râ) with periods of 9.98 and 16.05 days, respectively. Our Spitzer observations confirm the Transiting Exoplanet Survey Satellite (TESS) detection of TOI-700 d and remove any remaining doubt that it is a genuine planet. We analyze the Spitzer light curve combined with the 11 sectors of TESS observations and a transit of TOI-700 c from the LCOGT network to determine the full system parameters. Although studying the atmosphere of TOI-700 d is not likely feasible with upcoming facilities, it may be possible to measure the mass of TOI-700 d using state-of-the-art radial velocity (RV) instruments (expected RV semiamplitude of ~70 cm sâ»Âč)
EU counter-terrorism offences
To several governments, modern international terrorism cannot be handled adequately within the ordinary criminal justice system. To fight terrorism (including the criminalization of certain âabstract dangerâ, preparatory activities such as terrorist training, membership in a terrorist organization) more effectively, criminal law had to be adapted
TESS discovery of a super-Earth and two sub-Neptunes orbiting the bright, nearby, Sun-like star HD 22946
We report the Transiting Exoplanet Survey Satellite (TESS) discovery of a
three-planet system around the bright Sun-like star HD~22946(V=8.3 mag),also
known as TIC~100990000, located 63 parsecs away.The system was observed by TESS
in Sectors 3, 4, 30 and 31 and two planet candidates, labelled TESS Objects of
Interest (TOIs) 411.01 (planet ) and 411.02 (planet ), were identified on
orbits of 9.57 and 4.04 days, respectively. In this work, we validate the two
planets and recover an additional single transit-like signal in the light
curve, which suggests the presence of a third transiting planet with a longer
period of about 46 days.We assess the veracity of the TESS transit signals and
use follow-up imaging and time series photometry to rule out false positive
scenarios, including unresolved binary systems, nearby eclipsing binaries or
background/foreground stars contaminating the light curves. Parallax
measurements from Gaia EDR3, together with broad-band photometry and
spectroscopic follow-up by TFOP allowed us to constrain the stellar parameters
of TOI-411, including its radius of. Adopting this value,
we determined the radii for the three exoplanet candidates and found that
planet is a super-Earth, with a radius of , while
planet and are sub-Neptunian planets, with radii
of and respectively. By using
dynamical simulations, we assessed the stability of the system and evaluated
the possibility of the presence of other undetected, non-transiting planets by
investigating its dynamical packing. We find that the system is dynamically
stable and potentially unpacked, with enough space to host at least one more
planet between and .(Abridged)Comment: 21 pages, 12 figures. Accepted for publication on A&
Persistent anthrax as a major driver of wildlife mortality in a tropical rainforest
Anthrax is a globally important animal disease and zoonosis. Despite this, our current knowledge of anthrax ecology is largely limited to arid ecosystems, where outbreaks are most commonly reported. Here we show that the dynamics of an anthrax-causing agent, Bacillus cereus biovar anthracis, in a tropical rainforest have severe consequences for local wildlife communities. Using data and samples collected over three decades, we show that rainforest anthrax is a persistent and widespread cause of death for a broad range of mammalian hosts. We predict that this pathogen will accelerate the decline and possibly result in the extirpation of local chimpanzee (Pan troglodytes verus) populations. We present the epidemiology of a cryptic pathogen and show that its presence has important implications for conservation
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