A Statistical DOI Estimation Algorithm for a SiPM-Based Clinical SPECT Insert

A prototype clinical brain SPECT insert has been designed for use in simultaneous SPECT/MRI. The system utilises novel slit-slat collimators which, like pinhole collimators, suffers from parallax errors due to the large incident angle of photons. A statistical algorithm has been developed to determine the depth-of-interaction (DOI) with a view to improving image performance. The importance of DOI correction was demonstrated using Monte Carlo simulation. This simulation also indicated that 4 DOI layers (3×1.5 mm+3.5 mm) may be sufficient. The improvement in event localisation was demonstrated on a single detector before implementing the algorithm on the full clinical prototype where some limitations in event localisation in layers close to the readout plane were observed. Nevertheless DOI enabled the rejection of poorly localised events with improved resolution in reconstructed line sources

Vitamin D receptor binding, chromatin states and association with multiple sclerosis.

Both genetic and environmental factors contribute to the aetiology of multiple sclerosis (MS). More than 50 genomic regions have been associated with MS susceptibility and vitamin D status also influences the risk of this complex disease. However, how these factors interact in disease causation is unclear. We aimed to investigate the relationship between vitamin D receptor (VDR) binding in lymphoblastoid cell lines (LCLs), chromatin states in LCLs and MS-associated genomic regions. Using the Genomic Hyperbrowser, we found that VDR-binding regions overlapped with active regulatory regions [active promoter (AP) and strong enhancer (SE)] in LCLs more than expected by chance [45.3-fold enrichment for SE (P < 2.0e-05) and 63.41-fold enrichment for AP (P < 2.0e-05)]. Approximately 77% of VDR regions were covered by either AP or SE elements. The overlap between VDR binding and regulatory elements was significantly greater in LCLs than in non-immune cells (P < 2.0e-05). VDR binding also occurred within MS regions more than expected by chance (3.7-fold enrichment, P < 2.0e-05). Furthermore, regions of joint overlap SE-VDR and AP-VDR were even more enriched within MS regions and near to several disease-associated genes. These findings provide relevant insights into how vitamin D influences the immune system and the risk of MS through VDR interactions with the chromatin state inside MS regions. Furthermore, the data provide additional evidence for an important role played by B cells in MS. Further analyses in other immune cell types and functional studies are warranted to fully elucidate the role of vitamin D in the immune system

Acquisition Correction and Reconstruction for a Clinical SPECT/MRI Insert

The development of the first clinical simultaneous Single Photon Emission Computed Tomography (SPECT) and Magnetic Resonance Imaging (MRI) system was carried out within the INSERT project. The INSERT scanner was constructed under the initial project, but its performance was not fully evaluated; here we have reconstructed the first images on the SPECT system. Calibration and acquisition protocols were developed and used to establish the clinical feasibility of the system. The image reconstruction procedures were implemented on the first phantom images in order to assess the system's imaging capabilities. This study solved issues involving incomplete data sets and pixel failure in the prototype detector system. The final images determined a measure of trans-axial image resolution, giving average values of 9.14 mm and 6.75 mm in the radial and tangential directions respectively. The work carried out on the complete system produced several clinical phantom images which utilized the capabilities of both SPECT and MRI

SYSGENET: a meeting report from a new European network for systems genetics

The first scientific meeting of the newly established European SYSGENET network took place at the Helmholtz Centre for Infection Research (HZI) in Braunschweig, April 7-9, 2010. About 50 researchers working in the field of systems genetics using mouse genetic reference populations (GRP) participated in the meeting and exchanged their results, phenotyping approaches, and data analysis tools for studying systems genetics. In addition, the future of GRP resources and phenotyping in Europe was discussed

Genetic, environmental and stochastic factors in monozygotic twin discordance with a focus on epigenetic differences

PMCID: PMC3566971This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

The Moving Junction Protein RON8 Facilitates Firm Attachment and Host Cell Invasion in Toxoplasma gondii

The apicomplexan moving junction (MJ) is a highly conserved structure formed during host cell entry that anchors the invading parasite to the host cell and serves as a molecular sieve of host membrane proteins that protects the parasitophorous vacuole from host lysosomal destruction. While recent work in Toxoplasma and Plasmodium has reinforced the composition of the MJ as an important association of rhoptry neck proteins (RONs) with micronemal AMA1, little is known of the precise role of RONs in the junction or how they are targeted to the neck subcompartment. We report the first functional analysis of a MJ/RON protein by disrupting RON8 in T. gondii. Parasites lacking RON8 are severely impaired in both attachment and invasion, indicating that RON8 enables the parasite to establish a firm clasp on the host cell and commit to invasion. The remaining junction components frequently drag in trails behind invading knockout parasites and illustrate a malformed complex without RON8. Complementation of Δron8 parasites restores invasion and reveals a processing event at the RON8 C-terminus. Replacement of an N-terminal region of RON8 with a mCherry reporter separates regions within RON8 that are necessary for rhoptry targeting and complex formation from those required for function during invasion. Finally, the invasion defects in Δron8 parasites seen in vitro translate to radically impaired virulence in infected mice, promoting a model in which RON8 has a crucial and unprecedented task in committing Toxoplasma to host cell entry

Genetic Determination and Linkage Mapping of Plasmodium falciparum Malaria Related Traits in Senegal

Plasmodium falciparum malaria episodes may vary considerably in their severity and clinical manifestations. There is good evidence that host genetic factors contribute to this variability. To date, most genetic studies aiming at the identification of these genes have used a case/control study design for severe malaria, exploring specific candidate genes. Here, we performed a family-based genetic study of falciparum malaria related phenotypes in two independent longitudinal survey cohorts, as a first step towards the identification of genes and mechanisms involved in the outcome of infection. We studied two Senegalese villages, Dielmo and Ndiop that differ in ethnicity, malaria transmission and endemicity. We performed genome-scan linkage analysis of several malaria-related phenotypes both during clinical attacks and asymptomatic infection. We show evidence for a strong genetic contribution to both the number of clinical falciparum malaria attacks and the asymptomatic parasite density. The asymptomatic parasite density showed linkage to chromosome 5q31 (LOD = 2.26, empirical p = 0.0014, Dielmo), confirming previous findings in other studies. Suggestive linkage values were also obtained at three additional chromosome regions: the number of clinical malaria attacks on chromosome 5p15 (LOD = 2.57, empirical p = 0.001, Dielmo) and 13q13 (LOD = 2.37, empirical p = 0.0014 Dielmo), and the maximum parasite density during asymptomatic infection on chromosome 12q21 (LOD = 3.1, empirical p<10−4, Ndiop). While regions of linkage show little overlap with genes known to be involved in severe malaria, the four regions appear to overlap with regions linked to asthma or atopy related traits, suggesting that common immune related pathways may be involved

Lymphocyte recruitment and homing to the liver in primary biliary cirrhosis and primary sclerosing cholangitis

The mechanisms operating in lymphocyte recruitment and homing to liver are reviewed. A literature review was performed on primary biliary cirrhosis (PBC), progressive sclerosing cholangitis (PSC), and homing mechanisms; a total of 130 papers were selected for discussion. Available data suggest that in addition to a specific role for CCL25 in PSC, the CC chemokines CCL21 and CCL28 and the CXC chemokines CXCL9 and CXCL10 are involved in the recruitment of T lymphocytes into the portal tract in PBC and PSC. Once entering the liver, lymphocytes localize to bile duct and retain by the combinatorial or sequential action of CXCL12, CXCL16, CX3CL1, and CCL28 and possibly CXCL9 and CXCL10. The relative importance of these chemokines in the recruitment or the retention of lymphocytes around the bile ducts remains unclear. The available data remain limited but underscore the importance of recruitment and homing