Enhanced fluorescence from X-Ray line coincidence pumping

Many resonant photo-pumped X-ray laser schemes that use a strong pump line such as Ly-α or He-α to populate the upper laser state of a separate lasing material have been proposed over the last four decades but none have been demonstrated. As a first step to creating a photo-pumped X-ray laser we have decided to reinvestigate some of these schemes at the Orion laser facility with the goal to show enhanced fluorescence. In particular we look at using the Ly-α or He-α K lines to pump the 1s–3p and 4p transitions in H-like Cl and see fluorescence on the 4f–3d line at 65 Å and the 3d–2p line at 23 Å. Preliminary experiments are presented that show a modest enhancement. As an alternative we also look at enhancing the 2p–2s line in Ne-like Ge at 65 Å using the Ly-α Mg line to photo-pump the 2s–3p line of Ne-like Ge. Calculations are presented that suggest modest enhancements of 2.5

A novel class of microRNA-recognition elements that function only within open reading frames.

MicroRNAs (miRNAs) are well known to target 3' untranslated regions (3' UTRs) in mRNAs, thereby silencing gene expression at the post-transcriptional level. Multiple reports have also indicated the ability of miRNAs to target protein-coding sequences (CDS); however, miRNAs have been generally believed to function through similar mechanisms regardless of the locations of their sites of action. Here, we report a class of miRNA-recognition elements (MREs) that function exclusively in CDS regions. Through functional and mechanistic characterization of these 'unusual' MREs, we demonstrate that CDS-targeted miRNAs require extensive base-pairing at the 3' side rather than the 5' seed; cause gene silencing in an Argonaute-dependent but GW182-independent manner; and repress translation by inducing transient ribosome stalling instead of mRNA destabilization. These findings reveal distinct mechanisms and functional consequences of miRNAs that target CDS versus the 3' UTR and suggest that CDS-targeted miRNAs may use a translational quality-control-related mechanism to regulate translation in mammalian cells

To respond or not to respond - a personal perspective of intestinal tolerance

For many years, the intestine was one of the poor relations of the immunology world, being a realm inhabited mostly by specialists and those interested in unusual phenomena. However, this has changed dramatically in recent years with the realization of how important the microbiota is in shaping immune function throughout the body, and almost every major immunology institution now includes the intestine as an area of interest. One of the most important aspects of the intestinal immune system is how it discriminates carefully between harmless and harmful antigens, in particular, its ability to generate active tolerance to materials such as commensal bacteria and food proteins. This phenomenon has been recognized for more than 100 years, and it is essential for preventing inflammatory disease in the intestine, but its basis remains enigmatic. Here, I discuss the progress that has been made in understanding oral tolerance during my 40 years in the field and highlight the topics that will be the focus of future research

Blood pressure and renal cancer risk: the HUNT Study in Norway

In a prospective study of 36 728 women and 35 688 men during 18 years of follow-up, compared to systolic pressure <130 mm Hg, levels of 130–149, 150–169 and ⩾170 mm Hg in women were associated with relative risks of renal cell cancer of 1.7, 2.0 and 2.0, respectively (P for linear trend, 0.11). In men, there was no association with blood pressure

Differential clonal evolution in oesophageal cancers in response to neo-adjuvant chemotherapy

How chemotherapy affects carcinoma genomes is largely unknown. Here we report whole-exome and deep sequencing of 30 paired oesophageal adenocarcinomas sampled before and after neo-adjuvant chemotherapy. Most, but not all, good responders pass through genetic bottlenecks, a feature associated with higher mutation burden pre-treatment. Some poor responders pass through bottlenecks, but re-grow by the time of surgical resection, suggesting a missed therapeutic opportunity. Cancers often show major changes in driver mutation presence or frequency after treatment, owing to outgrowth persistence or loss of sub-clones, copy number changes, polyclonality and/or spatial genetic heterogeneity. Post-therapy mutation spectrum shifts are also common, particularly C&gt;A and TT&gt;CT changes in good responders or bottleneckers. Post-treatment samples may also acquire mutations in known cancer driver genes (for example, SF3B1, TAF1 and CCND2) that are absent from the paired pre-treatment sample. Neo-adjuvant chemotherapy can rapidly and profoundly affect the oesophageal adenocarcinoma genome. Monitoring molecular changes during treatment may be clinically useful

Use of Non-Amplified RNA Samples for Microarray Analysis of Gene Expression

Demand for high quality gene expression data has driven the development of revolutionary microarray technologies. The quality of the data is affected by the performance of the microarray platform as well as how the nucleic acid targets are prepared. The most common method for target nucleic acid preparation includes in vitro transcription amplification of the sample RNA. Although this method requires a small amount of starting material and is reported to have high reproducibility, there are also technical disadvantages such as amplification bias and the long, laborious protocol. Using RNA derived from human brain, breast and colon, we demonstrate that a non-amplification method, which was previously shown to be inferior, could be transformed to a highly quantitative method with a dynamic range of five orders of magnitude. Furthermore, the correlation coefficient calculated by comparing microarray assays using non-amplified samples with qRT-PCR assays was approximately 0.9, a value much higher than when samples were prepared using amplification methods. Our results were also compared with data from various microarray platforms studied in the MicroArray Quality Control (MAQC) project. In combination with micro-columnar 3D-Gene™ microarray, this non-amplification method is applicable to a variety of genetic analyses, including biomarker screening and diagnostic tests for cancer

Loss of estrogen receptor β decreases mitochondrial energetic potential and increases thrombogenicity of platelets in aged female mice

Platelets derived from aged (reproductively senescent) female mice with genetic deletion of estrogen receptor beta (βER) are more thrombogenic than those from age-matched wild-type (WT) mice. Intracellular processes contributing to this increased thrombogenicity are not known. Experiments were designed to identify subcellular localization of estrogen receptors and evaluate both glycolytic and mitochondrial energetic processes which might affect platelet activation. Platelets and blood from aged (22–24 months) WT and estrogen receptor β knockout (βERKO) female mice were used in this study. Body, spleen weight, and serum concentrations of follicle-stimulating hormone and 17β-estradiol were comparable between WT and βERKO mice. Number of spontaneous deaths was greater in the βERKO colony (50% compared to 30% in WT) over the course of 24 months. In resting (nonactivated) platelets, estrogen receptors did not appear to colocalize with mitochondria by immunostaining. Lactate production and mitochondrial membrane potential of intact platelets were similar in both groups of mice. However, activities of NADH dehydrogenase, cytochrome bc1 complex, and cytochrome c oxidase of the electron transport chain were reduced in mitochondria isolated from platelets from βERKO compared to WT mice. There were a significantly higher number of phosphatidylserine-expressing platelet-derived microvesicles in the plasma and a greater thrombin-generating capacity in βERKO compared to WT mice. These results suggest that deficiencies in βER affect energy metabolism of platelets resulting in greater production of circulating thrombogenic microvesicles and could potentially explain increased predisposition to thromboembolism in some elderly females

Lay perceptions of evidence-based information – a qualitative evaluation of a website for back pain sufferers

BACKGROUND: In an evidence-informed patient choice the patient has access to research-based information about the effectiveness of health care options and is encouraged to use this information in treatment decisions. This concept has seen growing popularity in recent years. However, we still know relatively little about users' attitudes to the use of research-based information, possibly because people have been unexposed to this type of information. After developing the BackInfo website where the results of Cochrane systematic reviews on the effects of low back pain were adapted and presented to lay users we evaluated how users responded to this information. METHODS: Focus group meetings were held with 18 chronic back pain sufferers, after they had been sent a link to the website before the meetings. RESULTS: The focus groups suggest that the most important challenges to the use of BackInfo's research-based information are not primarily tied to the comprehension or presentation of the information, but are mainly associated with participants' attitudes towards the credibility of research and researchers, and the applicability of research results to themselves as individuals. Possible explanations for participants' lack of trust in research and their apparent difficulties in applying this research to their own situations include aspects that may be typical for the general public including the media's presentation of research, and a lack of familiarity with and feelings of distance to research evidence. Other aspects may be typical for patient groups with chronic and unclear medical conditions, such as a lack of trust in the health care establishment in general. CONCLUSION: In order to enhance the credibility and applicability of research evidence, providers of research-based information could explore a number of possibilities including the use of including personal stories to illustrate the research outcomes