Proteome-based plasma biomarkers for Alzheimer's disease

Alzheimer's disease is a common and devastating disease for which there is no readily available biomarker to aid diagnosis or to monitor disease progression. Biomarkers have been sought in CSF but no previous study has used two-dimensional gel electrophoresis coupled with mass spectrometry to seek biomarkers in peripheral tissue. We performed a case-control study of plasma using this proteomics approach to identify proteins that differ in the disease state relative to aged controls. For discovery-phase proteomics analysis, 50 people with Alzheimer's dementia were recruited through secondary services and 50 normal elderly controls through primary care. For validation purposes a total of 511 subjects with Alzheimer's disease and other neurodegenerative diseases and normal elderly controls were examined. Image analysis of the protein distribution of the gels alone identifies disease cases with 56% sensitivity and 80% specificity. Mass spectrometric analysis of the changes observed in two-dimensional electrophoresis identified a number of proteins previously implicated in the disease pathology, including complement factor H (CFH) precursor and α-2-macroglobulin (α- 2M). Using semi-quantitative immunoblotting, the elevation of CFH and α- 2M was shown to be specific for Alzheimer's disease and to correlate with disease severity although alternative assays would be necessary to improve sensitivity and specificity. These findings suggest that blood may be a rich source for biomarkers of Alzheimer's disease and that CFH, together with other proteins such as α- 2M may be a specific markers of this illness. © 2006 The Author(s).link_to_subscribed_fulltex

The Formation of Cosmic Structures in a Light Gravitino Dominated Universe

We analyse the formation of cosmic structures in models where the dark matter is dominated by light gravitinos with mass of $100$ eV -- 1 keV, as predicted by gauge-mediated supersymmetry (SUSY) breaking models. After evaluating the number of degrees of freedom at the gravitinos decoupling ($g_*$), we compute the transfer function for matter fluctuations and show that gravitinos behave like warm dark matter (WDM) with free-streaming scale comparable to the galaxy mass scale. We consider different low-density variants of the WDM model, both with and without cosmological constant, and compare the predictions on the abundances of neutral hydrogen within high-redshift damped Ly--$\alpha$ systems and on the number density of local galaxy clusters with the corresponding observational constraints. We find that none of the models satisfies both constraints at the same time, unless a rather small $\Omega_0$ value (\mincir 0.4) and a rather large Hubble parameter (\magcir 0.9) is assumed. Furthermore, in a model with warm + hot dark matter, with hot component provided by massive neutrinos, the strong suppression of fluctuation on scales of \sim 1\hm precludes the formation of high-redshift objects, when the low--$z$ cluster abundance is required. We conclude that all different variants of a light gravitino DM dominated model show strong difficulties for what concerns cosmic structure formation. This gives a severe cosmological constraint on the gauge-mediated SUSY breaking scheme.Comment: 28 pages,Latex, submitted for publication to Phys.Rev.

Acquisition of pneumococci specific effector and regulatory Cd4+ T cells localising within human upper respiratory-tract mucosal lymphoid tissue

The upper respiratory tract mucosa is the location for commensal Streptococcus (S.) pneumoniae colonization and therefore represents a major site of contact between host and bacteria. The CD4(+) T cell response to pneumococcus is increasingly recognised as an important mediator of immunity that protects against invasive disease, with data suggesting a critical role for Th17 cells in mucosal clearance. By assessing CD4 T cell proliferative responses we demonstrate age-related sequestration of Th1 and Th17 CD4(+) T cells reactive to pneumococcal protein antigens within mucosal lymphoid tissue. CD25(hi) T cell depletion and utilisation of pneumococcal specific MHCII tetramers revealed the presence of antigen specific Tregs that utilised CTLA-4 and PDL-1 surface molecules to suppress these responses. The balance between mucosal effector and regulatory CD4(+) T cell immunity is likely to be critical to pneumococcal commensalism and the prevention of unwanted pathology associated with carriage. However, if dysregulated, such responses may render the host more susceptible to invasive pneumococcal infection and adversely affect the successful implementation of both polysaccharide-conjugate and novel protein-based pneumococcal vaccines

The impact of health status and human capital formation on regional performance: Empirical evidence

The purpose of this paper is to analyze the impact of health on growth, assuming that it is a fundamental component of the human capital of a region along with education. Various measures of population health status are used, together with a health index generated by Principal Component Analysis. Potential endogeneity between health and growth is controlled for using instrumental variable regressions and dynamic panel data. The results show a positive effect of a change in health status on regional output and a negative effect of proxy variables for health limitations on regional performance. This corroborates the importance of investing in health along with education with the aim of improving not only the well-being of individuals but the human capital and growth of a region

Transcription of toll-like receptors 2, 3, 4 and 9, FoxP3 and Th17 cytokines in a susceptible experimental model of canine Leishmania infantum infection

Canine leishmaniosis (CanL) due to Leishmania infantum is a chronic zoonotic systemic disease resulting from complex interactions between protozoa and the canine immune system. Toll-like receptors (TLRs) are essential components of the innate immune system and facilitate the early detection of many infections. However, the role of TLRs in CanL remains unknown and information describing TLR transcription during infection is extremely scarce. The aim of this research project was to investigate the impact of L. infantum infection on canine TLR transcription using a susceptible model. The objectives of this study were to evaluate transcription of TLRs 2, 3, 4 and 9 by means of quantitative reverse transcription polymerase chain reaction (qRT-PCR) in skin, spleen, lymph node and liver in the presence or absence of experimental L. infantum infection in Beagle dogs. These findings were compared with clinical and serological data, parasite densities in infected tissues and transcription of IL-17, IL-22 and FoxP3 in different tissues in non-infected dogs (n = 10), and at six months (n = 24) and 15 months (n = 7) post infection. Results revealed significant down regulation of transcription with disease progression in lymph node samples for TLR3, TLR4, TLR9, IL-17, IL-22 and FoxP3. In spleen samples, significant down regulation of transcription was seen in TLR4 and IL-22 when both infected groups were compared with controls. In liver samples, down regulation of transcription was evident with disease progression for IL-22. In the skin, upregulation was seen only for TLR9 and FoxP3 in the early stages of infection. Subtle changes or down regulation in TLR transcription, Th17 cytokines and FoxP3 are indicative of the silent establishment of infection that Leishmania is renowned for. These observations provide new insights about TLR transcription, Th17 cytokines and Foxp3 in the liver, spleen, lymph node and skin in CanL and highlight possible markers of disease susceptibility in this model

Integration concept of an Electron Cyclotron System in DEMO

The pre-conceptual layout for an electron cyclotron system (ECS) in DEMO is described. The present DEMO ECS considers only equatorial ports for both plasma heating and neoclassical tearing mode (NTM) control. This differs from ITER, where four launchers in upper oblique ports are dedicated to NTM control and one equatorial EC port for heating and current drive (H&CD) purposes as basic configuration. Rather than upper oblique ports, DEMO has upper vertical ports to allow the vertical removal of the large breeding blanket segments. While ITER is using front steering antennas for NTM control, in DEMO the antennas are recessed behind the breeding blanket and called mid-steering antennas, referred to the radially recessed position to the breeding blanket. In the DEMO pre-conceptual design phase two variants are studied to integrate the ECS in equatorial ports. The first option integrates waveguide bundles at four vertical levels inside EC port plugs with antennas with fixed and movable mid-steering mirrors that are powered by gyrotrons, operating at minimum two different multiples of the fundamental resonance frequency of the microwave output window. Alternatively, the second option integrates fixed antenna launchers connected to frequency step-tunable gyrotrons. The first variant is described in this paper, introducing the design and functional requirements, presenting the equatorial port allocation, the port plug design including its maintenance concept, the basic port cell layout, the transmission line system with diamond windows from the tokamak up to the RF building and the gyrotron sources. The ECS design studies are supported by neutronic and tokamak integration studies, quasi-optical and plasma physics studies, which will be summarized. Physics and technological gaps will be discussed and an outlook to future work will be given

Integration Concept of an Electron Cyclotron System in DEMO

The pre-conceptual layout for an electron cyclotron system (ECS) in DEMO is described. The present DEMO ECS considers only equatorial ports for both plasma heating and neoclassical tearing mode (NTM) control. This differs from ITER, where four launchers in upper oblique ports are dedicated to NTM control and one equatorial EC port for heating and current drive (H&CD) purposes as basic configuration. Rather than upper oblique ports, DEMO has upper vertical ports to allow the vertical removal of the large breeding blanket segments. While ITER is using front steering antennas for NTM control, in DEMO the antennas are recessed behind the breeding blanket and called mid-steering antennas, referred to the radially recessed position to the breeding blanket.In the DEMO pre-conceptual design phase two variants are studied to integrate the ECS in equatorial ports. The first option integrates waveguide bundles at four vertical levels inside EC port plugs with antennas with fixed and movable mid-steering mirrors that are powered by gyrotrons, operating at minimum two different multiples of the fundamental resonance frequency of the microwave output window. Alternatively, the second option integrates fixed antenna launchers connected to frequency step-tunable gyrotrons. The first variant is described in this paper, introducing the design and functional requirements, presenting the equatorial port allocation, the port plug design including its maintenance concept, the basic port cell layout, the transmission line system with diamond windows from the tokamak up to the RF building and the gyrotron sources.The ECS design studies are supported by neutronic and tokamak integration studies, quasi-optical and plasma physics studies, which will be summarized. Physics and technological gaps will be discussed and an outlook to future work will be given

Neutrophils in cancer: neutral no more

Neutrophils are indispensable antagonists of microbial infection and facilitators of wound healing. In the cancer setting, a newfound appreciation for neutrophils has come into view. The traditionally held belief that neutrophils are inert bystanders is being challenged by the recent literature. Emerging evidence indicates that tumours manipulate neutrophils, sometimes early in their differentiation process, to create diverse phenotypic and functional polarization states able to alter tumour behaviour. In this Review, we discuss the involvement of neutrophils in cancer initiation and progression, and their potential as clinical biomarkers and therapeutic targets

Evidence for the h_b(1P) meson in the decay Upsilon(3S) --> pi0 h_b(1P)

Using a sample of 122 million Upsilon(3S) events recorded with the BaBar detector at the PEP-II asymmetric-energy e+e- collider at SLAC, we search for the $h_b(1P)$ spin-singlet partner of the P-wave chi_{bJ}(1P) states in the sequential decay Upsilon(3S) --> pi0 h_b(1P), h_b(1P) --> gamma eta_b(1S). We observe an excess of events above background in the distribution of the recoil mass against the pi0 at mass 9902 +/- 4(stat.) +/- 2(syst.) MeV/c^2. The width of the observed signal is consistent with experimental resolution, and its significance is 3.1sigma, including systematic uncertainties. We obtain the value (4.3 +/- 1.1(stat.) +/- 0.9(syst.)) x 10^{-4} for the product branching fraction BF(Upsilon(3S)-->pi0 h_b) x BF(h_b-->gamma eta_b).Comment: 8 pages, 4 postscript figures, submitted to Phys. Rev. D (Rapid Communications

Search for squarks and gluinos in events with isolated leptons, jets and missing transverse momentum at s√=8 TeV with the ATLAS detector

The results of a search for supersymmetry in final states containing at least one isolated lepton (electron or muon), jets and large missing transverse momentum with the ATLAS detector at the Large Hadron Collider are reported. The search is based on proton-proton collision data at a centre-of-mass energy s√=8 TeV collected in 2012, corresponding to an integrated luminosity of 20 fb−1. No significant excess above the Standard Model expectation is observed. Limits are set on supersymmetric particle masses for various supersymmetric models. Depending on the model, the search excludes gluino masses up to 1.32 TeV and squark masses up to 840 GeV. Limits are also set on the parameters of a minimal universal extra dimension model, excluding a compactification radius of 1/R c = 950 GeV for a cut-off scale times radius (ΛR c) of approximately 30