Genome wide association mapping of grain arsenic, copper, molybdenum and zinc in rice (Oryza sativa L.) grown at four international field sites

Peer reviewedPublisher PD

Pemetrexed Induced Thymidylate Synthase Inhibition in Non-Small Cell Lung Cancer Patients: A Pilot Study with 3 '-Deoxy-3 '-[F-18]fluorothymidine Positron Emission Tomography

OBJECTIVES: Pemetrexed is a thymidylate synthase (TS) inhibitor and is effective in non-small cell lung cancer (NSCLC). 3'-deoxy-3'-[¹⁸F]fluorothymidine (¹⁸F-FLT), a proliferation marker, could potentially identify tumor specific TS-inhibition. The aim of this study was to investigate the effect of pemetrexed-induced TS-inhibition on ¹⁸F-FLT uptake 4 hours after pemetrexed administration in metastatic NSCLC patients. METHODS: Fourteen NSCLC patients underwent dynamic ¹⁸F-FLT positron emission tomography (PET) scans at baseline and 4 hours after the first dose of pemetrexed. Volumes of interest were defined with a 41%, 50% and 70% threshold of the maximum pixel. Kinetic analysis and simplified measures were performed. At one, two, four and six hours after pemetrexed, plasma deoxyuridine was measured as systemic indicator of TS-inhibition. Tumor response measured with response evaluation criteria in solid tumors (RECIST), time to progression (TTP) and overall survival (OS) were determined. RESULTS: Eleven patients had evaluable ¹⁸F-FLT PET scans at baseline and 4 hours after pemetrexed. Two patients had increased ¹⁸F-FLT uptake of 35% and 31% after pemetrexed, whereas two other patients had decreased uptake of 31%. In the remaining seven patients ¹⁸F-FLT uptake did not change beyond test-retest borders. In all patients deoxyuridine levels raised after administration of pemetrexed, implicating pemetrexed-induced TS-inhibition. ¹⁸F-FLT uptake in bone marrow was significantly increased 4 hours after pemetrexed administration. Six weeks after the start of treatment 5 patients had partial response, 4 stable disease and 2 progressive disease. Median TTP was 4.2 months (range 3.0-7.4 months); median OS was 13.0 months (range 5.1-30.8 months). Changes in ¹⁸F-FLT uptake were not predictive for tumor response, TTP or OS. CONCLUSIONS: Measuring TS-inhibition in a clinical setting 4 hours after pemetrexed revealed a non-systematic change in ¹⁸F-FLT uptake within the tumor. No significant association with tumor response, TTP or OS was observed

Intense violet–blue emission and paramagnetism of nanocrystalline Gd3+ doped ZnO ceramics

Nanocrystalline Zn1-xGdxO (x = 0, 0.02, 0.04, 0.06, and 0.08) ceramics were synthesized by ball milling and subsequent solid-state reaction. The transmission electron microscopy (TEM) micrograph of as synthesized samples revealed the formation of crystallites with an average diameter of 60 nm, and the selected area electron diffraction (SAED) pattern confirmed the formation of wurtzite structure. A red shift in the band gap was observed with increasing Gd3+ concentration. The photoluminescence of nanocrystalline Gd3+ doped ZnO exhibited a strong violet–blue emission. Concentration dependence of the emission intensity of Gd3+ in ZnO was studied, and the critical concentration was found to be 4 mol% of Gd3+. The Gd3+ doped ZnO exhibited paramagnetic behavior at room temperature, and the magnetic moment increased with Gd3+ concentration

Impact of gastro-oesophageal reflux on microRNA expression, location and function

We have shown that miRNA expression is altered in the oesophageal squamous mucosa from individuals with gastro-oesophageal reflux and ulcerative oesophagitis. These changes in miR-143, miR-145 and miR-205 expression appear to be most pronounced in the basal layer of the oesophageal epithelium. In the context of gastro-oesophageal reflux these expression changes might influence proliferation and apoptosis and thereby regulate epithelial restoration. It is reasonable to hypothesise that they could represent early molecular events preceding the development of Barrett’s oesophagus, although proving this will require further studies as described above. Future detailed analyses of the role of these miRNAs in progression from gastro-oesophageal reflux to Barrett’s oesophagus, and then to oesophageal adenocarcinoma will be valuable, and may help in efforts to control and treat these diseases.This study was funded by a Competing Project Grant from the National Health and Medical Research Council of Australia. Cameron Smith was supported by a PROBE-NET PhD scholarship funded by a Strategic research Partnerships Grant from the Cancer Council of New South Wales

Upregulation of P2Y2 receptors by retinoids in normal human epidermal keratinocytes

Retinoids, vitamin A derivatives, are important regulators of the growth and differentiation of skin cells. Although retinoids are therapeutically used for several skin ailments, little is known about their effects on P2 receptors, known to be involved in various functions in the skin. DNA array analysis showed that treatment of normal human epidermal keratinocytes (NHEKs) with all-trans-retinoic acid (ATRA), an agonist to RAR (retinoic acid receptor), enhanced the expression of mRNA for the P2Y2 receptor, a metabotropic P2 receptor that is known to be involved in the proliferation of the epidermis. The expression of other P2 receptors in NHEKs was not affected by ATRA. ATRA increased the mRNA for the P2Y2 receptor in a concentration-dependent fashion (1 nM to 1 μM). Am80, a synthesized agonist to RAR, showed a similar enhancement, whereas 9-cis-retinoic acid (9-cisRA), an agonist to RXR (retinoid X receptor), enhanced P2Y2 gene expression to a lesser extent. Ca2+ imaging analysis showed that ATRA also increased the function of P2Y2 receptors in NHEKs. Retinoids are known to enhance the turnover of the epidermis by increasing both proliferation and terminal differentiation. The DNA microarray analysis also revealed that ATRA upregulates various genes involved in the differentiation of NHEKs. Our present results suggest that retinoids, at least in part, exert their proliferative effects by upregulating P2Y2 receptors in NHEKs. This effect of retinoids may be closely related to their therapeutic effect against various ailments or aging events in skins such as over-keratinization, pigmentation and re-modeling

Local replication of simian immunodeficiency virus in the breast milk compartment of chronically-infected, lactating rhesus monkeys

Breast milk transmission remains a major mode of infant HIV acquisition, yet anatomic and immunologic forces shaping virus quasispecies in milk are not well characterized. In this study, phylogenic analysis of envelope sequences of milk SIV variants revealed groups of nearly identical viruses, indicating local virus production. However, comparison of the patterns and rates of CTL escape of blood and milk virus demonstrated only subtle differences between the compartments. These findings suggest that a substantial fraction of milk viruses are produced by locally-infected cells, but are shaped by cellular immune pressures similar to that in the blood

Conserved Expression Patterns Predict microRNA Targets

microRNAs (miRNAs) are major regulators of gene expression and thereby modulate many biological processes. Computational methods have been instrumental in understanding how miRNAs bind to mRNAs to induce their repression but have proven inaccurate. Here we describe a novel method that combines expression data from human and mouse to discover conserved patterns of expression between orthologous miRNAs and mRNA genes. This method allowed us to predict thousands of putative miRNA targets. Using the luciferase reporter assay, we confirmed 4 out of 6 of our predictions. In addition, this method predicted many miRNAs that act as expression enhancers. We show that many miRNA enhancer effects are mediated through the repression of negative transcriptional regulators and that this effect could be as common as the widely reported repression activity of miRNAs. Our findings suggest that the indirect enhancement of gene expression by miRNAs could be an important component of miRNA regulation that has been widely neglected to date

Evolutionary Analysis of Inter-Farm Transmission Dynamics in a Highly Pathogenic Avian Influenza Epidemic

Phylogenetic studies have largely contributed to better understand the emergence, spread and evolution of highly pathogenic avian influenza during epidemics, but sampling of genetic data has never been detailed enough to allow mapping of the spatiotemporal spread of avian influenza viruses during a single epidemic. Here, we present genetic data of H7N7 viruses produced from 72% of the poultry farms infected during the 2003 epidemic in the Netherlands. We use phylogenetic analyses to unravel the pathways of virus transmission between farms and between infected areas. In addition, we investigated the evolutionary processes shaping viral genetic diversity, and assess how they could have affected our phylogenetic analyses. Our results show that the H7N7 virus was characterized by a high level of genetic diversity driven mainly by a high neutral substitution rate, purifying selection and limited positive selection. We also identified potential reassortment in the three genes that we have tested, but they had only a limited effect on the resolution of the inter-farm transmission network. Clonal sequencing analyses performed on six farm samples showed that at least one farm sample presented very complex virus diversity and was probably at the origin of chronological anomalies in the transmission network. However, most virus sequences could be grouped within clearly defined and chronologically sound clusters of infection and some likely transmission events between farms located 0.8–13 Km apart were identified. In addition, three farms were found as most likely source of virus introduction in distantly located new areas. These long distance transmission events were likely facilitated by human-mediated transport, underlining the need for strict enforcement of biosafety measures during outbreaks. This study shows that in-depth genetic analysis of virus outbreaks at multiple scales can provide critical information on virus transmission dynamics and can be used to increase our capacity to efficiently control epidemics

B7-H1-Deficiency Enhances the Potential of Tolerogenic Dendritic Cells by Activating CD1d-Restricted Type II NKT Cells

Background: Dendritic cells (DC) can act tolerogenic at a semi-mature stage by induction of protective CD4+ T cell and NKT cell responses. Methodology/Principal Findings: Here we studied the role of the co-inhibitory molecule B7-H1 (PD-L1, CD274) on semimature DC that were generated from bone marrow (BM) cells of B7-H12/2 mice and applied to the model of Experimental Autoimmune Encephalomyelitis (EAE). Injections of B7-H1-deficient DC showed increased EAE protection as compared to wild type (WT)-DC. Injections of B7-H12/2 TNF-DC induced higher release of peptide-specific IL-10 and IL-13 after restimulation in vitro together with elevated serum cytokines IL-4 and IL-13 produced by NKT cells, and reduced IL-17 and IFN-c production in the CNS. Experiments in CD1d2/2 and Ja2812/2 mice as well as with type I and II NKT cell lines indicated that only type II NKT cells but not type I NKT cells (invariant NKT cells) could be stimulated by an endogenous CD1d-ligand on DC and were responsible for the increased serum cytokine production in the absence of B7-H1. Conclusions/Significance: Together, our data indicate that BM-DC express an endogenous CD1d ligand and B7-H1 to ihibit type II but not type I NKT cells. In the absence of B7-H1 on these DC their tolerogenic potential to stimulate tolerogenic CD4+ and NKT cell responses is enhanced

Advances in MRI-Based Detection of Cerebrovascular Changes after Experimental Traumatic Brain Injury

Traumatic brain injury is a heterogeneous and multifaceted neurological disorder that involves diverse pathophysiological pathways and mechanisms. Thorough characterization and monitoring of the brain’s status after neurotrauma is therefore highly complicated. Magnetic resonance imaging (MRI) provides a versatile tool for in vivo spatiotemporal assessment of various aspects of central nervous system injury, such as edema formation, perfusion disturbances and structural tissue damage. Moreover, recent advances in MRI methods that make use of contrast agents have opened up additional opportunities for measurement of events at the level of the cerebrovasculature, such as blood–brain barrier permeability, leukocyte infiltration, cell adhesion molecule upregulation and vascular remodeling. It is becoming increasingly clear that these cerebrovascular alterations play a significant role in the progression of post-traumatic brain injury as well as in the process of post-traumatic brain repair. Application of advanced multiparametric MRI strategies in experimental, preclinical studies may significantly aid in the elucidation of pathomechanisms, monitoring of treatment effects, and identification of predictive markers after traumatic brain injury