Mouse mutants have a key role in discerning mammalian gene function and modelling human disease; however, at present mutants exist for only 1-2% of all mouse genes. In order to address this phenotype ...gap, we have embarked on a genome-wide, phenotype-driven, large-scale N-ethyl-N--nitrosourea (ENU) mutagenesis screen for dominant mutations of clinical and pharmacological interest in the mouse. Here we describe the identification of two similar neurological phenotypes and determination of the underlying mutations using a novel rapid mapping strategy incorporating speed back-crosses and high throughput genotyping. Two mutant mice were identified with marked resting tremor and further characterized using the SHIRPA behavioural and functional assessment protocol. Back-cross animals were generated using in vitro fertilization and genome scans performed utilizing DNA pools derived from multiple mutant mice. Both mutants were mapped to a region on chromosome 11 containing the peripheral myelin protein 22 gene (Pmp22). Sequence analysis revealed novel point mutations in Pmp22 in both lines. The first mutation, H12R, alters the same amino acid as in the severe human peripheral neuropathy Dejerine Sottas syndrome and Y153TER in the other mutant truncates the Pmp22 protein by seven amino acids. Histological analysis of both lines revealed hypo-myelination of peripheral nerves. This is the first report of the generation of a clinically relevant neurological mutant and its rapid genetic characterization from a large-scale mutagenesis screen for dominant phenotypes in the mouse, and validates the use of large-scale screens to generate desired clinical phenotypes in mice.
We report the discovery of very-high-energy (VHE) g-ray emission of the binary system PSR B 1259-63/SS 2883 of a radio pulsar orbiting a massive, luminous Be star in a highly eccentric orbit. The ...observations around the 2004 periastron passage of the pulsar were performed with the four 13 m Cherenkov telescopes of the HESS experiment, recently installed in Namibia and in full operation since December 2003. Between February and June 2004, a g-ray signal from the binary system was detected with a total significance above 13s. The flux was found to vary significantly on timescales of days which makes PSR B 1259-63 the first variable galactic source of VHE g-rays observed so far. Strong emission signals were observed in pre- and post-periastron phases with a flux minimum around periastron, followed by a gradual flux decrease in the months after. The measured time-averaged energy spectrum above a mean threshold energy of 380 GeV can be fitted by a simple power law F0(E/1 TeV)G with a photon index G = 2.7 c 0.2stat c 0.2sys and flux normalisation F0 = (1.3 c 0.1stat c 0.3sys) x 10-12 TeV-1 cm-2 s-1. This detection of VHE g-rays provides unambiguous evidence for particle acceleration to multi-TeV energies in the binary system. In combination with coeval observations of the X-ray synchrotron emission by the RXTE and INTEGRAL instruments, and assuming the VHE g-ray emission to be produced by the inverse Compton mechanism, the magnetic field strength can be directly estimated to be of the order of 1 G.
Greater recognition of the seriousness of global environmental change has led to an increase in research that assesses the vulnerability of households, communities and regions to changing ...environmental or economic conditions. So far, however, there has been relatively little attention given to how assessments can be conducted in ways that help build capacity for local communities to understand and find their own solutions to their problems. This paper reports on an approach that was designed and used to work with a local grass roots organization in the Solomon Islands to promote inclusivity and participation in decision-making and to build the capacity of the organization to reduce the vulnerability of communities to drivers of change. The process involved working collaboratively with the organization and training its members to conduct vulnerability assessments with communities using participatory and deliberative methods. To make best use of the learning opportunities provided by the research process, specific periods for formal reflection were incorporated for the three key stakeholders involved: the primary researchers; research assistants; and community members. Overall, the approach: (1) promoted learning about the current situation in Kahua and encouraged deeper analysis of problems; (2) built capacity for communities to manage the challenges they were facing; and (3) fostered local ownership and responsibility for problems and set precedents for future participation in decision-making. While the local organization and the communities it serves still face significant challenges, the research approach set the scene for greater local participation and effort to maintain and enhance livelihoods and wellbeing. The outcomes highlight the need for greater emphasis on embedding participatory approaches in vulnerability assessments for communities to benefit fully from the process.
Aims.We study the efficiency and reliability of cluster mass estimators that are based on the projected phase-space distribution of galaxies in a cluster region. Methods.We analyse a data-set of 62 ...clusters extracted from a concordance ΛCDM cosmological hydrodynamical simulation. We consider both dark matter (DM) particles and simulated galaxies as tracers of the clusters gravitational potential. Two cluster mass estimators are considered: the virial mass estimator, corrected for the surface-pressure term, and a mass estimator (that we call $M_{\sigma}$) based entirely on the velocity dispersion estimate of the cluster. In order to simulate observations, galaxies (or DM particles) are first selected in cylinders of given radius (from 0.5 to 1.5h-1 Mpc) and $\simeq$$200h^{-1}$ Mpc length. Cluster members are then identified by applying a suitable interloper removal algorithm. Results.The virial mass estimator overestimates the true mass by $\simeq$10% on average, for sample sizes of $\ga$60 cluster members. For similar sample sizes, $M_{\sigma}$ underestimates the true mass by $\simeq$15%, on average. For smaller sample sizes, the bias of the virial mass estimator substantially increases, while the $M_{\sigma}$ estimator becomes essentially unbiased. The dispersion of both mass estimates increases by a factor ~2 as the number of cluster members decreases from ~400 to ~20. It is possible to reduce the bias in the virial mass estimates either by removing clusters with significant evidence for subclustering or by selecting early-type galaxies, which substantially reduces the interloper contamination. Early-type galaxies cannot however be used to improve the $M_{\sigma}$ estimates since their intrinsic velocity distribution is slightly biased relative to that of the DM particles. Radially-dependent incompleteness can drastically affect the virial mass estimates, but leaves the $M_{\sigma}$ estimates almost unaffected. Other observational effects, like centering and velocity errors and different observational apertures, have little effect on the mass estimates.
A new cationic complex, 99mTc(tetrofosmin)2O2+, where tetrofosmin is the ether functionalized diphosphine ligand 1,2-bisbis(2-ethoxyethyl)phosphinoethane, has been synthesized and evaluated for ...potential use in myocardial perfusion imaging. The structure of the complex has been determined by x-ray crystallography of the 99Tc analog. In comparison with previously reported 99mTc complexes of alkyl-phosphines, the tetrofosmin species shows substantially increased clearance from nontarget tissue, especially blood and liver. A freeze-dried kit formulation has been developed. The kit provides a product of high radiochemical purity up to 8 hr after reconstitution at room temperature.
Collecting duct carcinoma (CDC) of the kidney is a rare neoplasm arising from the medullary collecting ducts. The clinicopathological features of three cases are here presented to add to the 42 cases ...reported so far in the English language literature. Hematuria is the most common presenting symptom, although 10% of patients present with metastatic disease, often in neck lymph nodes. The tumor mass is typically centred on the medulla of the kidney and extends into the cortex. Radiological diagnosis may be difficult because the radiological features of CDC are poorly described. The histological appearances have been described as tubulo-papiflary, tubular, solid and sarcomatoid. Intracytoplasmic mucin may be present. The typical immunohistochemicat profile is positive staining with antibodies for low and high molecular weight keratin and epithelial membrane antigen (EMA) and positive staining with the lectin Utex europaeus agglutinin. Literature reports of cytogenetic characterisation show loss of chromosomes resulting in monosomies. Prognosis is poor as more than half of the reported cases have developed metastases or died within two years of presentation.
Very high energy (>100 GeV) gamma-ray emission has been detected for the first time from the composite supernova remnant G 0.9+0.1 using the HESS instrument. The source is detected with a ...significance of ≈$13\sigma$, and a photon flux above 200 GeV of ($5.7\pm0.7_{\rm stat}\pm1.2_{\rm sys})\times10^{-12}$ cm-2 s-1, making it one of the weakest sources ever detected at TeV energies. The photon spectrum is compatible with a power law (${\rm d}N/{\rm d}E \propto E^{-\Gamma}$) with photon index $\Gamma = 2.40\pm0.11_{\rm stat}\pm0.20_{\rm sys}$. The gamma-ray emission appears to originate in the plerionic core of the remnant, rather than the shell, and can be plausibly explained as inverse Compton scattering of relativistic electrons.
Aims.Search for Very High Energy γ-ray emission in the Kookaburra complex through observations with the HESS array. Methods.Stereoscopic imaging of Cherenkov light emission of the γ-ray showers in ...the atmosphere is used for the reconstruction and selection of the events to search for γ-ray signals. Their spectrum is derived by a forward-folding maximum likelihood fit. Results.Two extended γ-ray sources with an angular (68%) radius of $3.3{-}3.4$´ are discovered at high (>13σ) statistical significance: HESS J1420-607 and HESS J1418-609. They exhibit a flux above 1 TeV of ($2.97 \pm 0.18_{\rm stat} \pm 0.60_{\rm sys}) \times 10^{-12}$ and ($2.17 \pm 0.17_{\rm stat} \pm 0.43_{\rm sys}) \times 10^{-12}$ cm-2 s-1, respectively, and similar hard photon indices ~2.2. Multi-wavelength comparisons show spatial coincidence with the wings of the Kookaburra. Two pulsar wind nebulæ candidates, K3/PSR J1420-6048 and the Rabbit, lie on the edge of the HESS sources. Conclusions. The two new sources confirm the non-thermal nature of at least parts of the two radio wings which overlap with the γ-ray emission and establish their connection with the two X-ray pulsar wind nebulæ candidates. Given the large point spread function of EGRET, the unidentified source(s) 3EG J1420-6038/GeV J1417-6100 could possibly be related to either or both HESS sources. The most likely explanation for the Very High Energy γ-rays discovered by HESS is inverse Compton emission of accelerated electrons on the Cosmic Microwave Background near the two candidate pulsar wind nebulæ, K3/PSR J1420-6048 and the Rabbit. Two scenarios which could lead to the observed large (~10 pc) offset-nebula type morphologies are briefly discussed.
The extreme synchrotron BL Lac object H 2356-309, located at a redshift of z = 0.165, was observed from June to December 2004 with a total exposure of approx40 h live-time with the HESS (High Energy ...Stereoscopic System) array of atmospheric-Cherenkov telescopes (ACTs). Analysis of this data set yields, for the first time, a strong excess of 453 gamma-rays (10 standard deviations above background) from H 2356-309, corresponding to an observed integral flux above 200 GeV of I (>200 GeV) = (4.1 pm 0.5) times 10 super(-12) cm super(-2) s super(-1) (statistical error only). The differential energy spectrum of the source between 200 GeV and 1.3 TeV is well-described by a power law with a normalisation (at 1 TeV) of N sub(0) = (4.1 pm 0.5) times 10 super(-13) cm super(-2) s super(-1) TeV super(-1) and a photon index of Gamma = gamma-rays so far. Results from simultaneous observations from ROTSE-III (optical), RXTE (X-rays) and NRT (radio) are also included and used together with the HESS data to constrain a single-zone homogeneous synchrotron self- Compton (SSC) model. This model provides an adequate fit to the HESS data when using a reasonable set of model parameters.
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