Policy makers, regulators and researchers’ perspectives on genomics research and the capacity of the National Health Research Act of 2013 to regulate genomics research in Zambia

Background: Health research in sub-Saharan Africa takes place against a lengthy history of exploitation and unfair collaboration. This has involved the export of samples and data from the continent for the benefit of institutions and researchers elsewhere. In this paper, we report the perspectives of people involved in conducting genomics research in Zambia and the capacity of the Health Research Act (HRA) of 2013 in regulating genomics research. Methods: We approached 14 purposively selected stakeholders involved in the development or implementation of the HRA in Zambia for in-depth interviews. These were members of research ethics committees, genomics researchers, Ministry of Health policy makers and institutional lawyers. Results: Participants reported that there are benefits in genomics research for Zambia such as diagnosing and treatment of diseases. Participants also expressed concerns, most of which were ethical in nature. Prominent concerns were on consent. Participants’ main concern was the possible misuse of samples in the future. These concerns resonated with the HRA, which prohibits the use of broad consent for the collection of samples and data for future unspecified research. The implications of this is that Zambians may not participate in any kind of health research for which the storage, sharing and re-use of data or samples is envisaged. The restrictive nature of HRA means that genomics research may be excluded from future health research collaborations, thus isolating the country from potentially beneficial health research. Some policy makers also worried the samples and data that comes from such research may be difficult to access by local scientists. Conclusion: In this article, we describe the views of Zambian policymakers on genomics research and the capacity of HRA in regulating genomics research. Our findings are relevant for the Zambian audience, and other African countries that are aiming to regulate health research, especially genomics research.</ns4:p

Radio Sources in Galaxy Clusters at 28.5 GHz

We present serendipitous detections of radio sources at 28.5 GHz (1 cm), which resulted from our program to image thermal Sunyaev-Zeldovich (SZ) effect in 56 galaxy clusters. We find 64 radio sources with fluxes down to 0.4 mJy, and within 250 arcseconds from the pointing centers. The spectral indices (S ~ \nu^-\alpha) of 54 sources with published low frequency flux densities range from -0.6 to 2 with a mean of 0.77, and a median of 0.84. Extending low frequency surveys of radio sources towards galaxy clusters CL 0016+16, Abell 665, and Abell 2218 to 28.5 GHz, and selecting sources with 1.4 GHz flux density greater than 7 mJy to form an unbiased sample, we find a mean spectral index of 0.71 and a median of 0.71. We find 4 to 7 times more sources predicted from a low frequency survey in areas without galaxy clusters. This excess cannot be accounted for by gravitational lensing of a background radio population by cluster potentials, indicating most of the detected sources are associated with galaxy clusters. For the cluster Abell 2218, the presence of unsubtracted radio sources with 28.5 GHz flux densities less than 0.5 mJy, can only contribute to temperature fluctuations at a level of 10 to 25 \muK. The corresponding error due to radio point source contamination in the Hubble constant derived through a combined analysis of 28.5 GHz SZ images and X-ray emission observations ranges from 1% to 6%.Comment: 18 pages, 8 figures, to appear in April 1998 issue of A

Genetic background modifies vulnerability to glaucoma related phenotypes in Lmx1b mutant mice

Variants in the LIM homeobox transcription factor 1-beta (LMX1B) gene predispose individuals to elevated intraocular pressure (IOP), a key risk factor for glaucoma. However, the effect of LMX1Bmutations varies widely between individuals. To better understand the mechanisms underlying LMX1B-related phenotypes and individual differences, we backcrossed the Lmx1bV265D (also known as Lmx1bIcst ) allele onto the C57BL/6J (B6), 129/Sj (129), C3A/BLiA-Pde6b+ /J (C3H) and DBA/2J-Gpnmb+ (D2-G) mouse strain backgrounds. Strain background had a significant effect on the onset and severity of ocular phenotypes in Lmx1bV265D/+ mutant mice. Mice of the B6 background were the most susceptible to developing abnormal IOP distribution, severe anterior segment developmental anomalies (including malformed eccentric pupils, iridocorneal strands and corneal abnormalities) and glaucomatous nerve damage. By contrast, Lmx1bV265D mice of the 129 background were the most resistant to developing anterior segment abnormalities, had less severe IOP elevation than B6 mutants at young ages and showed no detectable nerve damage. To identify genetic modifiers of susceptibility to Lmx1bV265D -induced glaucoma-associated phenotypes, we performed a mapping cross between mice of the B6 (susceptible) and 129 (resistant) backgrounds. We identified a modifier locus on Chromosome 18, with the 129 allele(s) substantially lessening severity of ocular phenotypes, as confirmed by congenic analysis. By demonstrating a clear effect of genetic background in modulating Lmx1b-induced phenotypes, providing a panel of strains with different phenotypic severities and identifying a modifier locus, this study lays a foundation for better understanding the roles of LMX1B in glaucoma with the goal of developing new treatments

Spontaneous emission and level shifts in absorbing disordered dielectrics and dense atomic gases: A Green's function approach

Spontaneous emission and Lamb shift of atoms in absorbing dielectrics are discussed. A Green's-function approach is used based on the multipolar interaction Hamiltonian of a collection of atomic dipoles with the quantised radiation field. The rate of decay and level shifts are determined by the retarded Green's-function of the interacting electric displacement field, which is calculated from a Dyson equation describing multiple scattering. The positions of the atomic dipoles forming the dielectrics are assumed to be uncorrelated and a continuum approximation is used. The associated unphysical interactions between different atoms at the same location is eliminated by removing the point-interaction term from the free-space Green's-function (local field correction). For the case of an atom in a purely dispersive medium the spontaneous emission rate is altered by the well-known Lorentz local-field factor. In the presence of absorption a result different from previously suggested expressions is found and nearest-neighbour interactions are shown to be important.Comment: 6 pages no figure

Association of Hepcidin-25 with survival after kidney transplantation

Background Hepcidin is considered the master regulator of iron homoeostasis. Novel hepcidin antagonists have recently been introduced as potential treatment for iron-restricted anaemia. Meanwhile, serum hepcidin has been shown to be positively associated with cardiovascular disease and inversely with acute kidney injury. These properties may lead to contrasting effects, especially in renal transplant recipients (RTR), which are prone to cardiovascular diseases and graft failure. To date, the role of serum hepcidin in RTR is unknown. We, therefore, prospectively determined the association of serum hepcidin with risk of graft failure, cardiovascular mortality and all-cause mortality in RTR. Materials and methods Serum hepcidin was assessed in an extensively phenotyped RTR cohort by dual-monoclonal sandwich ELISA specific immunoassay. Statistical analyses were performed using univariate linear regression followed by stepwise backward linear regression. Cox proportional hazard regression models were performed to determine prospective associations. Results We included 561 RTR (age 51 +/- 12 years). Mean haemoglobin (Hb) was 8.6 +/- 1.0 mM. Median [IQR] serum hepcidin was 7.2 [3.2-13.4] ng/mL. Mean estimated glomerular filtration rate was 47 +/- 16 mL/min/ 1.73 m(2). In univariate Cox regression analyses, serum hepcidin was not associated with risk of graft failure, cardiovascular mortality or all-cause mortality. Notably, after adjustment for high sensitivity C-reactive protein and ferritin, serum hepcidin became negatively associated with all-cause mortality (hazard ratio 0.89; 95% confidence interval 0.80-0.99, P = 0.3). Conclusions In this study, we did not find an association between serum hepcidin and outcomes, that is graft failure, cardiovascular mortality or all-cause mortality. Based on our results, it is questionable whether serum hepcidin may be used to predict a beneficial effect of hepcidin antagonists

Multipole interaction between atoms and their photonic environment

Macroscopic field quantization is presented for a nondispersive photonic dielectric environment, both in the absence and presence of guest atoms. Starting with a minimal-coupling Lagrangian, a careful look at functional derivatives shows how to obtain Maxwell's equations before and after choosing a suitable gauge. A Hamiltonian is derived with a multipolar interaction between the guest atoms and the electromagnetic field. Canonical variables and fields are determined and in particular the field canonically conjugate to the vector potential is identified by functional differentiation as minus the full displacement field. An important result is that inside the dielectric a dipole couples to a field that is neither the (transverse) electric nor the macroscopic displacement field. The dielectric function is different from the bulk dielectric function at the position of the dipole, so that local-field effects must be taken into account.Comment: 17 pages, to be published in Physical Review

Performance of the LHCb Vertex Detector Alignment Algorithm determined with Beam Test Data

LHCb is the dedicated heavy flavour experiment at the Large Hadron Collider at CERN. The partially assembled silicon vertex locator (VELO) of the LHCb experiment has been tested in a beam test. The data from this beam test have been used to determine the performance of the VELO alignment algorithm. The relative alignment of the two silicon sensors in a module and the relative alignment of the modules has been extracted. This alignment is shown to be accurate at a level of approximately 2 micron and 0.1 mrad for translations and rotations, respectively in the plane of the sensors. A single hit precision at normal track incidence of about 10 micron is obtained for the sensors. The alignment of the system is shown to be stable at better than the 10 micron level under air to vacuum pressure changes and mechanical movements of the assembled system.Comment: accepted for publication in NIM

Gene expression profiling of epithelium-associated FcRL4(+) B cells in primary Sjogren's syndrome reveals a pathogenic signature

In primary Sjögren's syndrome (pSS), FcRL4+ B cells are present in inflamed salivary gland tissue, within or in close proximity to ductal epithelium. FcRL4 is also expressed by nearly all pSS-related mucosa-associated lymphoid tissue (MALT) B cell lymphomas, linking FcRL4 expression to lymphomagenesis. Whether glandular FcRL4+ B cells are pathogenic, how these cells originate, and how they functionally differ from FcRL4- B cells in pSS is unclear. This study aimed to investigate the phenotype and function of FcRL4+ B cells in the periphery and parotid gland tissue of patients with pSS. First, circulating FcRL4+ B cells from 44 pSS and 54 non-SS-sicca patients were analyzed by flow cytometry. Additionally, RNA sequencing of FcRL4+ B cells sorted from parotid gland cell suspensions of 6 pSS patients was performed. B cells were sorted from cell suspensions as mini bulk (5 cells/well) based on the following definitions: CD19+CD27-FcRL4- ('naive'), CD19+CD27+FcRL4- ('memory'), and CD19+FcRL4+ B cells. We found that, although FcRL4+ B cells were not enriched in blood in pSS compared with non-SS sicca patients, these cells generally exhibited a pro-inflammatory phenotype. Genes coding for CD11c (ITGAX), T-bet (TBX21), TACI (TNFRSF13B), Src tyrosine kinases and NF-κB pathway-related genes were, among others, significantly upregulated in glandular FcRL4+ B cells versus FcRL4- B cells. Pathway analysis showed upregulation of B cell activation, cell cycle and metabolic pathways. Thus, FcRL4+ B cells in pSS exhibit many characteristics of chronically activated, pro-inflammatory B cells and their gene expression profile suggests increased risk of lymphomagenesis. We postulate that these cells contribute significantly to the epithelial damage seen in the glandular tissue and that FcRL4+ B cells are an important treatment target in pSS

Deep Underground Science and Engineering Laboratory - Preliminary Design Report

The DUSEL Project has produced the Preliminary Design of the Deep Underground Science and Engineering Laboratory (DUSEL) at the rehabilitated former Homestake mine in South Dakota. The Facility design calls for, on the surface, two new buildings - one a visitor and education center, the other an experiment assembly hall - and multiple repurposed existing buildings. To support underground research activities, the design includes two laboratory modules and additional spaces at a level 4,850 feet underground for physics, biology, engineering, and Earth science experiments. On the same level, the design includes a Department of Energy-shepherded Large Cavity supporting the Long Baseline Neutrino Experiment. At the 7,400-feet level, the design incorporates one laboratory module and additional spaces for physics and Earth science efforts. With input from some 25 science and engineering collaborations, the Project has designed critical experimental space and infrastructure needs, including space for a suite of multidisciplinary experiments in a laboratory whose projected life span is at least 30 years. From these experiments, a critical suite of experiments is outlined, whose construction will be funded along with the facility. The Facility design permits expansion and evolution, as may be driven by future science requirements, and enables participation by other agencies. The design leverages South Dakota's substantial investment in facility infrastructure, risk retirement, and operation of its Sanford Laboratory at Homestake. The Project is planning education and outreach programs, and has initiated efforts to establish regional partnerships with underserved populations - regional American Indian and rural populations

Genome-Wide Association Study and Gene Expression Analysis Identifies CD84 as a Predictor of Response to Etanercept Therapy in Rheumatoid Arthritis

Anti-tumor necrosis factor alpha (anti-TNF) biologic therapy is a widely used treatment for rheumatoid arthritis (RA). It is unknown why some RA patients fail to respond adequately to anti-TNF therapy, which limits the development of clinical biomarkers to predict response or new drugs to target refractory cases. To understand the biological basis of response to anti-TNF therapy, we conducted a genome-wide association study (GWAS) meta-analysis of more than 2 million common variants in 2,706 RA patients from 13 different collections. Patients were treated with one of three anti-TNF medications: etanercept (n = 733), infliximab (n = 894), or adalimumab (n = 1,071). We identified a SNP (rs6427528) at the 1q23 locus that was associated with change in disease activity score (ΔDAS) in the etanercept subset of patients (P = 8×10-8), but not in the infliximab or adalimumab subsets (P>0.05). The SNP is predicted to disrupt transcription factor binding site motifs in the 3′ UTR of an immune-related gene, CD84, and the allele associated with better response to etanercept was associated with higher CD84 gene expression in peripheral blood mononuclear cells (P = 1×10-11 in 228 non-RA patients and P = 0.004 in 132 RA patients). Consistent with the genetic findings, higher CD84 gene expression correlated with lower cross-sectional DAS (P = 0.02, n = 210) and showed a non-significant trend for better ΔDAS in a subset of RA patients with gene expression data (n = 31, etanercept-treated). A small, multi-ethnic replication showed a non-significant trend towards an association among etanercept-treated RA patients of Portuguese ancestry (n = 139, P = 0.4), but no association among patients of Japanese ancestry (n = 151, P = 0.8). Our study demonstrates that an allele associated with response to etanercept therapy is also associated with CD84 gene expression, and further that CD84 expression correlates with disease activity. These findings support a model in which CD84 genotypes and/or expression may serve as a useful biomarker for response to etanercept treatment in RA patients of European ancestry. © 2013 Cui et al