An extracellular steric seeding mechanism for Eph-ephrin signaling platform assembly

Erythropoetin-producing hepatoma (Eph) receptors are cell-surface protein tyrosine kinases mediating cell-cell communication. Upon activation, they form signaling clusters. We report crystal structures of the full ectodomain of human EphA2 (eEphA2) both alone and in complex with the receptor-binding domain of the ligand ephrinA5 (ephrinA5 RBD). Unliganded eEphA2 forms linear arrays of staggered parallel receptors involving two patches of residues conserved across A-class Ephs. eEphA2-ephrinA5 RBD forms a more elaborate assembly, whose interfaces include the same conserved regions on eEphA2, but rearranged to accommodate ephrinA5 RBD. Cell-surface expression of mutant EphA2s showed that these interfaces are critical for localization at cell-cell contacts and activation-dependent degradation. Our results suggest a 'nucleation' mechanism whereby a limited number of ligand-receptor interactions 'seed' an arrangement of receptors which can propagate into extended signaling arrays

Cost-effectiveness of HBV and HCV screening strategies:a systematic review of existing modelling techniques

Introduction: Studies evaluating the cost-effectiveness of screening for Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) are generally heterogeneous in terms of risk groups, settings, screening intervention, outcomes and the economic modelling framework. It is therefore difficult to compare cost-effectiveness results between studies. This systematic review aims to summarise and critically assess existing economic models for HBV and HCV in order to identify the main methodological differences in modelling approaches. Methods: A structured search strategy was developed and a systematic review carried out. A critical assessment of the decision-analytic models was carried out according to the guidelines and framework developed for assessment of decision-analytic models in Health Technology Assessment of health care interventions. Results: The overall approach to analysing the cost-effectiveness of screening strategies was found to be broadly consistent for HBV and HCV. However, modelling parameters and related structure differed between models, producing different results. More recent publications performed better against a performance matrix, evaluating model components and methodology. Conclusion: When assessing screening strategies for HBV and HCV infection, the focus should be on more recent studies, which applied the latest treatment regimes, test methods and had better and more complete data on which to base their models. In addition to parameter selection and associated assumptions, careful consideration of dynamic versus static modelling is recommended. Future research may want to focus on these methodological issues. In addition, the ability to evaluate screening strategies for multiple infectious diseases, (HCV and HIV at the same time) might prove important for decision makers

Reinforcement learning or active inference?

This paper questions the need for reinforcement learning or control theory when optimising behaviour. We show that it is fairly simple to teach an agent complicated and adaptive behaviours using a free-energy formulation of perception. In this formulation, agents adjust their internal states and sampling of the environment to minimize their free-energy. Such agents learn causal structure in the environment and sample it in an adaptive and self-supervised fashion. This results in behavioural policies that reproduce those optimised by reinforcement learning and dynamic programming. Critically, we do not need to invoke the notion of reward, value or utility. We illustrate these points by solving a benchmark problem in dynamic programming; namely the mountain-car problem, using active perception or inference under the free-energy principle. The ensuing proof-of-concept may be important because the free-energy formulation furnishes a unified account of both action and perception and may speak to a reappraisal of the role of dopamine in the brain

Study of 2b-decay of Mo-100 and Se-82 using the NEMO3 detector

After analysis of 5797 h of data from the detector NEMO3, new limits on neutrinoless double beta decay of Mo-100 (T_{1/2} > 3.1 10^{23} y, 90% CL) and Se-82 (T_{1/2} > 1.4 10^{23} y, 90% CL) have been obtained. The corresponding limits on the effective majorana neutrino mass are: m < (0.8-1.2) eV and m < (1.5-3.1) eV, respectively. Also the limits on double-beta decay with Majoron emission are: T_{1/2} > 1.4 10^{22} y (90% CL) for Mo-100 and T_{1/2}> 1.2 10^{22} y (90%CL) for Se-82. Corresponding bounds on the Majoron-neutrino coupling constant are g < (0.5-0.9) 10^{-4} and < (0.7-1.6) 10^{-4}. Two-neutrino 2b-decay half-lives have been measured with a high accuracy, T_{1/2} Mo-100 = [7.68 +- 0.02(stat) +- 0.54(syst) ] 10^{18} y and T_{1/2} Se-82 = [10.3 +- 0.3(stat) +- 0.7(syst) ] 10^{19} y.Comment: 5 pages, 4 figure

Technical design and performance of the NEMO3 detector

The development of the NEMO3 detector, which is now running in the Frejus Underground Laboratory (L.S.M. Laboratoire Souterrain de Modane), was begun more than ten years ago. The NEMO3 detector uses a tracking-calorimeter technique in order to investigate double beta decay processes for several isotopes. The technical description of the detector is followed by the presentation of its performance.Comment: Preprint submitted to Nucl. Instrum. Methods A Corresponding author: Corinne Augier ([email protected]

Measurement of double beta decay of 100Mo to excited states in the NEMO 3 experiment

The double beta decay of 100Mo to the 0^+_1 and 2^+_1 excited states of 100Ru is studied using the NEMO 3 data. After the analysis of 8024 h of data the half-life for the two-neutrino double beta decay of 100Mo to the excited 0^+_1 state is measured to be T^(2nu)_1/2 = [5.7^{+1.3}_{-0.9}(stat)+/-0.8(syst)]x 10^20 y. The signal-to-background ratio is equal to 3. Information about energy and angular distributions of emitted electrons is also obtained. No evidence for neutrinoless double beta decay to the excited 0^+_1 state has been found. The corresponding half-life limit is T^(0nu)_1/2(0^+ --> 0^+_1) > 8.9 x 10^22 y (at 90% C.L.). The search for the double beta decay to the 2^+_1 excited state has allowed the determination of limits on the half-life for the two neutrino mode T^(2nu)_1/2(0^+ --> 2^+_1) > 1.1 x 10^21 y (at 90% C.L.) and for the neutrinoless mode T^(0nu)_1/2(0^+ --> 2^+_1) > 1.6 x 10^23 y (at 90% C.L.).Comment: 23 pages, 7 figures, 4 tables, submitted to Nucl. Phy

Comparison of breast and bowel cancer screening uptake patterns in a common cohort of South Asian women in England

Background: Inequalities in uptake of cancer screening by ethnic minority populations are well documented in a number of international studies. However, most studies to date have explored screening uptake for a single cancer only. This paper compares breast and bowel cancer screening uptake for a cohort of South Asian women invited to undertake both, and similarly investigates these women's breast cancer screening behaviour over a period of fifteen years. Methods: Screening data for rounds 1, 2 and 5 (1989-2004) of the NHS breast cancer screening programme and for round 1 of the NHS bowel screening pilot (2000-2002) were obtained for women aged 50-69 resident in the English bowel screening pilot site, Coventry and Warwickshire, who had been invited to undertake breast and bowel cancer screening in the period 2000-2002. Breast and bowel cancer screening uptake levels were calculated and compared using the chi-squared test. Results: 72,566 women were invited to breast and bowel cancer screening after exclusions. Of these, 3,539 were South Asian and 69,027 non-Asian; 18,730 had been invited to mammography over the previous fifteen years (rounds 1 to 5). South Asian women were significantly less likely to undertake both breast and bowel cancer screening; 29.9% (n = 1,057) compared to 59.4% (n = 40,969) for non-Asians (p < 0.001). Women in both groups who consistently chose to undertake breast cancer screening in rounds 1, 2 and 5 were more likely to complete round 1 bowel cancer screening. However, the likelihood of completion of bowel cancer screening was still significantly lower for South Asians; 49.5% vs. 82.3% for non-Asians, p < 0.001. South Asian women who undertook breast cancer screening in only one round were no more likely to complete bowel cancer screening than those who decided against breast cancer screening in all three rounds. In contrast, similar women in the non-Asian population had an increased likelihood of completing the new bowel cancer screening test. The likelihood of continued uptake of mammography after undertaking screening in round 1 differed between South Asian religio-linguistic groups. Noticeably, women in the Muslim population were less likely to continue to participate in mammography than those in other South Asian groups. Conclusions: Culturally appropriate targeted interventions are required to reduce observed disparities in cancer screening uptakes

The clinical features of the piriformis syndrome: a systematic review

Piriformis syndrome, sciatica caused by compression of the sciatic nerve by the piriformis muscle, has been described for over 70 years; yet, it remains controversial. The literature consists mainly of case series and narrative reviews. The objectives of the study were: first, to make the best use of existing evidence to estimate the frequencies of clinical features in patients reported to have PS; second, to identify future research questions. A systematic review was conducted of any study type that reported extractable data relevant to diagnosis. The search included all studies up to 1 March 2008 in four databases: AMED, CINAHL, Embase and Medline. Screening, data extraction and analysis were all performed independently by two reviewers. A total of 55 studies were included: 51 individual and 3 aggregated data studies, and 1 combined study. The most common features found were: buttock pain, external tenderness over the greater sciatic notch, aggravation of the pain through sitting and augmentation of the pain with manoeuvres that increase piriformis muscle tension. Future research could start with comparing the frequencies of these features in sciatica patients with and without disc herniation or spinal stenosis

High-speed fixed-target serial virus crystallography

We report a method for serial X-ray crystallography at X-ray free-electron lasers (XFELs), which allows for full use of the current 120-Hz repetition rate of the Linear Coherent Light Source (LCLS). Using a micropatterned silicon chip in combination with the high-speed Roadrunner goniometer for sample delivery, we were able to determine the crystal structures of the picornavirus bovine enterovirus 2 (BEV2) and the cytoplasmic polyhedrosis virus type 18 polyhedrin, with total data collection times of less than 14 and 10 min, respectively. Our method requires only micrograms of sample and should therefore broaden the applicability of serial femtosecond crystallography to challenging projects for which only limited sample amounts are available. By synchronizing the sample exchange to the XFEL repetition rate, our method allows for most efficient use of the limited beam time available at XFELs and should enable a substantial increase in sample throughput at these facilities

Limits on different Majoron decay modes of 100^{100}Mo and 82^{82}Se for neutrinoless double beta decays in the NEMO-3 experiment

The NEMO-3 tracking detector is located in the Fr\'ejus Underground Laboratory. It was designed to study double beta decay in a number of different isotopes. Presented here are the experimental half-life limits on the double beta decay process for the isotopes $^{100}$Mo and $^{82}$Se for different Majoron emission modes and limits on the effective neutrino-Majoron coupling constants. In particular, new limits on "ordinary" Majoron (spectral index 1) decay of $^{100}$Mo ($T_{1/2} > 2.7\cdot10^{22}$ y) and $^{82}$Se ($T_{1/2} > 1.5\cdot10^{22}$ y) have been obtained. Corresponding bounds on the Majoron-neutrino coupling constant are $< (0.4-1.9) \cdot 10^{-4}$ and $< (0.66-1.7) \cdot 10^{-4}$.Comment: 23 pages includind 4 figures, to be published in Nuclear Physics