A collaborative study to establish the 1st WHO International Standard for human cytomegalovirus for nucleic acid amplification technology.

Variability in the performance of nucleic acid amplification technology (NAT)-based assays presents a significant problem in the diagnosis and management of human cytomegalovirus (HCMV) infections. Here we describe a collaborative study to evaluate the suitability of candidate reference materials to harmonize HCMV viral load measurements in a wide range of NAT assays. Candidate materials comprised lyophilized Merlin virus, liquid Merlin virus, liquid AD169 virus, and purified HCMV Merlin DNA cloned into a bacterial artificial chromosome. Variability in the laboratory mean HCMV concentrations determined for virus samples across the different assays was 2 log10. Variability for the purified DNA sample was higher (>3 log10). The agreement between laboratories was markedly improved when the potencies of the liquid virus samples were expressed relative to the lyophilized virus candidate. In contrast, the agreement between laboratories for the purified DNA sample was not improved. Results indicated the suitability of the lyophilized Merlin virus preparation as the 1st WHO International Standard for HCMV for NAT. It was established in October 2010, with an assigned potency of 5 × 106 International Units (IU) (NIBSC code 09/162). It is intended to be used to calibrate secondary references, used in HCMV NAT assays, in IU

Accounting Problems Under the Excess Profits Tax

DNA vaccines based on subunits from pathogens have several advantages over other vaccine strategies. DNA vaccines can easily be modified, they show good safety profiles, are stable and inexpensive to produce, and the immune response can be focused to the antigen of interest. However, the immunogenicity of DNA vaccines which is generally quite low needs to be improved. Electroporation and co-delivery of genetically encoded immune adjuvants are two strategies aiming at increasing the efficacy of DNA vaccines. Here, we have examined whether targeting to antigen-presenting cells (APC) could increase the immune response to surface envelope glycoprotein (Env) gp120 from Human Immunodeficiency Virus type 1 (HIV- 1). To target APC, we utilized a homodimeric vaccine format denoted vaccibody, which enables covalent fusion of gp120 to molecules that can target APC. Two molecules were tested for their efficiency as targeting units: the antibody-derived single chain Fragment variable (scFv) specific for the major histocompatilibility complex (MHC) class II I-E molecules, and the CC chemokine ligand 3 (CCL3). The vaccines were delivered as DNA into muscle of mice with or without electroporation. Targeting of gp120 to MHC class II molecules induced antibodies that neutralized HIV-1 and that persisted for more than a year after one single immunization with electroporation. Targeting by CCL3 significantly increased the number of HIV-1 gp120-reactive CD8(+) T cells compared to non-targeted vaccines and gp120 delivered alone in the absence of electroporation. The data suggest that chemokines are promising molecular adjuvants because small amounts can attract immune cells and promote immune responses without advanced equipment such as electroporation.Funding Agencies|Research Council of Norway; Odd Fellow</p

Evidence of Differential Allelic Effects between Adolescents and Adults for Plasma High-Density Lipoprotein

A recent meta-analysis of genome-wide association (GWA) studies identified 95 loci that influence lipid traits in the adult population and found that collectively these explained about 25–30% of heritability for each trait. Little is known about how these loci affect lipid levels in early life, but there is evidence that genetic effects on HDL- and LDL-cholesterol (HDL-C, LDL-C) and triglycerides vary with age. We studied Australian adults (N = 10,151) and adolescents (N = 2,363) who participated in twin and family studies and for whom we have lipid phenotypes and genotype information for 91 of the 95 genetic variants. Heterogeneity tests between effect sizes in adult and adolescent cohorts showed an excess of heterogeneity for HDL-C (pHet<0.05 at 5 out of 37 loci), but no more than expected by chance for LDL-C (1 out of 14 loci), or trigycerides (0 out 24). There were 2 (out of 5) with opposite direction of effect in adolescents compared to adults for HDL-C, but none for LDL-C. The biggest difference in effect size was for LDL-C at rs6511720 near LDLR, adolescents (0.021±0.033 mmol/L) and adults (0.157±0.023 mmol/L), pHet = 0.013; followed by ZNF664 (pHet = 0.018) and PABPC4 (pHet = 0.034) for HDL-C. Our findings suggest that some of the previously identified variants associate differently with lipid traits in adolescents compared to adults, either because of developmental changes or because of greater interactions with environmental differences in adults

Hidden attractors in fundamental problems and engineering models

Recently a concept of self-excited and hidden attractors was suggested: an attractor is called a self-excited attractor if its basin of attraction overlaps with neighborhood of an equilibrium, otherwise it is called a hidden attractor. For example, hidden attractors are attractors in systems with no equilibria or with only one stable equilibrium (a special case of multistability and coexistence of attractors). While coexisting self-excited attractors can be found using the standard computational procedure, there is no standard way of predicting the existence or coexistence of hidden attractors in a system. In this plenary survey lecture the concept of self-excited and hidden attractors is discussed, and various corresponding examples of self-excited and hidden attractors are considered

RNAseq Analyses Identify Tumor Necrosis Factor-Mediated Inflammation as a Major Abnormality in ALS Spinal Cord

ALS is a rapidly progressive, devastating neurodegenerative illness of adults that produces disabling weakness and spasticity arising from death of lower and upper motor neurons. No meaningful therapies exist to slow ALS progression, and molecular insights into pathogenesis and progression are sorely needed. In that context, we used high-depth, next generation RNA sequencing (RNAseq, Illumina) to define gene network abnormalities in RNA samples depleted of rRNA and isolated from cervical spinal cord sections of 7 ALS and 8 CTL samples. We aligned \u3e50 million 2X150 bp paired-end sequences/sample to the hg19 human genome and applied three different algorithms (Cuffdiff2, DEseq2, EdgeR) for identification of differentially expressed genes (DEG’s). Ingenuity Pathways Analysis (IPA) and Weighted Gene Co-expression Network Analysis (WGCNA) identified inflammatory processes as significantly elevated in our ALS samples, with tumor necrosis factor (TNF) found to be a major pathway regulator (IPA) and TNFα-induced protein 2 (TNFAIP2) as a major network “hub” gene (WGCNA). Using the oPOSSUM algorithm, we analyzed transcription factors (TF) controlling expression of the nine DEG/hub genes in the ALS samples and identified TF’s involved in inflammation (NFkB, REL, NFkB1) and macrophage function (NR1H2::RXRA heterodimer). Transient expression in human iPSC-derived motor neurons of TNFAIP2 (also a DEG identified by all three algorithms) reduced cell viability and induced caspase 3/7 activation. Using high-density RNAseq, multiple algorithms for DEG identification, and an unsupervised gene co-expression network approach, we identified significant elevation of inflammatory processes in ALS spinal cord with TNF as a major regulatory molecule. Overexpression of the DEG TNFAIP2 in human motor neurons, the population most vulnerable to die in ALS, increased cell death and caspase 3/7 activation. We propose that therapies targeted to reduce inflammatory TNFα signaling may be helpful in ALS patients

The effect of gold kiwifruit consumed with an iron fortified breakfast cereal meal on iron status in women with low iron stores: A 16 week randomised controlled intervention study

<p>Abstract</p> <p>Background</p> <p>Dietary treatment is often recommended as the first line of treatment for women with mild iron deficiency. Although it is well established that ascorbic acid enhances iron absorption, it is less clear whether the consumption of ascorbic acid rich foods (such as kiwifruit) with meals fortified with iron improves iron status. The aim of this study is to investigate whether the consumption of ZESPRI^®GOLD kiwifruit (a fruit high in ascorbic acid and carotenoids) with an iron fortified breakfast cereal meal increases iron status in women with low iron stores.</p> <p>Methods/Design</p> <p>Eighty nine healthy women aged 18-44 years with low iron stores (serum ferritin (SF) ≤ 25 μg/L, haemoglobin (Hb) ≥ 115 g/L) living in Auckland, New Zealand were randomised to receive an iron fortified breakfast cereal (16 mg iron per serve) and either two ZESPRI^®GOLD kiwifruit or a banana (low ascorbic acid and carotenoid content) to eat at breakfast time every day for 16 weeks. Iron status (SF, Hb, C-reactive protein (CRP) and soluble transferrin receptor (sTfR)), ascorbic acid and carotenoid status were measured at baseline and after 16 weeks. Anthropometric measures, dietary intake, physical activity and blood loss were measured before and after the 16 week intervention.</p> <p>Discussion</p> <p>This randomised controlled intervention study will be the first study to investigate the effect of a dietary based intervention of an iron fortified breakfast cereal meal combined with an ascorbic acid and carotenoid rich fruit on improving iron status in women with low iron stores.</p> <p>Trial registration</p> <p>ACTRN12608000360314</p

Using GIS to create synthetic disease outbreaks

BACKGROUND: The ability to detect disease outbreaks in their early stages is a key component of efficient disease control and prevention. With the increased availability of electronic health-care data and spatio-temporal analysis techniques, there is great potential to develop algorithms to enable more effective disease surveillance. However, to ensure that the algorithms are effective they need to be evaluated. The objective of this research was to develop a transparent user-friendly method to simulate spatial-temporal disease outbreak data for outbreak detection algorithm evaluation. A state-transition model which simulates disease outbreaks in daily time steps using specified disease-specific parameters was developed to model the spread of infectious diseases transmitted by person-to-person contact. The software was developed using the MapBasic programming language for the MapInfo Professional geographic information system environment. RESULTS: The simulation model developed is a generalised and flexible model which utilises the underlying distribution of the population and incorporates patterns of disease spread that can be customised to represent a range of infectious diseases and geographic locations. This model provides a means to explore the ability of outbreak detection algorithms to detect a variety of events across a large number of stochastic replications where the influence of uncertainty can be controlled. The software also allows historical data which is free from known outbreaks to be combined with simulated outbreak data to produce files for algorithm performance assessment. CONCLUSION: This simulation model provides a flexible method to generate data which may be useful for the evaluation and comparison of outbreak detection algorithm performance

Exploring How We Teach: Lived Experiences, Lessons, and Research about Graduate Instructors by Graduate Instructors

This book combines the knowledge of 30 graduate student instructors sharing about how they teach and how they’ve learned how to teach

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition

A public health approach to understanding and preventing violent radicalization

<p>Abstract</p> <p>Background</p> <p>Very recent acts of terrorism in the UK were perpetrated by 'homegrown', well educated young people, rather than by foreign Islamist groups; consequently, a process of violent radicalization was proposed to explain how ordinary people were recruited and persuaded to sacrifice their lives.</p> <p>Discussion</p> <p>Counterterrorism approaches grounded in the criminal justice system have not prevented violent radicalization. Indeed there is some evidence that these approaches may have encouraged membership of radical groups by not recognizing Muslim communities as allies, citizens, victims of terrorism, and victims of discrimination, but only as suspect communities who were then further alienated. Informed by public health research and practice, a new approach is proposed to target populations vulnerable to recruitment, rather than rely only on research of well known terrorist groups and individual perpetrators of terrorist acts.</p> <p>Conclusions</p> <p>This paper proposes public health research and practice to guard against violent radicalization.</p