A Novel Unsupervised Method to Identify Genes Important in the Anti-viral Response: Application to Interferon/Ribavirin in Hepatitis C Patients

Background: Treating hepatitis C with interferon/ribavirin results in a varied response in terms of decrease in viral titer and ultimate outcome. Marked responders have a sharp decline in viral titer within a few days of treatment initiation, whereas in other patients there is no effect on the virus (poor responders). Previous studies have shown that combination therapy modifies expression of hundreds of genes in vitro and in vivo. However, identifying which, if any, of these genes have a role in viral clearance remains challenging. Aims: The goal of this paper is to link viral levels with gene expression and thereby identify genes that may be responsible for early decrease in viral titer. Methods: Microarrays were performed on RNA isolated from PBMC of patients undergoing interferon/ribavirin therapy. Samples were collected at pre-treatment (day 0), and 1, 2, 7, 14 and 28 days after initiating treatment. A novel method was applied to identify genes that are linked to a decrease in viral titer during interferon/ribavirin treatment. The method uses the relationship between inter-patient gene expression based proximities and inter-patient viral titer based proximities to define the association between microarray gene expression measurements of each gene and viral-titer measurements. Results: We detected 36 unique genes whose expressions provide a clustering of patients that resembles viral titer based clustering of patients. These genes include IRF7, MX1, OASL and OAS2, viperin and many ISG's of unknown function. Conclusion: The genes identified by this method appear to play a major role in the reduction of hepatitis C virus during the early phase of treatment. The method has broad utility and can be used to analyze response to any group of factors influencing biological outcome such as antiviral drugs or anti-cancer agents where microarray data are available. © 2007 Brodsky et al

The limit of N=(2,2) superconformal minimal models

The limit of families of two-dimensional conformal field theories has recently attracted attention in the context of AdS/CFT dualities. In our work we analyse the limit of N=(2,2) superconformal minimal models when the central charge approaches c=3. The limiting theory is a non-rational N=(2,2) superconformal theory, in which there is a continuum of chiral primary fields. We determine the spectrum of the theory, the three-point functions on the sphere, and the disc one-point functions.Comment: 37 pages, 3 figures; v2: minor corrections in section 5.3, version to be published in JHE

Timor Este

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The Distances of the Magellanic Clouds

The present status of our knowledge of the distances to the Magellanic Clouds is evaluated from a post-Hipparcos perspective. After a brief summary of the effects of structure, reddening, age and metallicity, the primary distance indicators for the Large Magellanic Cloud are reviewed: The SN 1987A ring, Cepheids, RR Lyraes, Mira variables, and Eclipsing Binaries. Distances derived via these methods are weighted and combined to produce final "best" estimates for the Magellanic Clouds distance moduli.Comment: Invited review article to appear in ``Post Hipparcos Cosmic Candles'', F. Caputo & A. Heck (Eds.), Kluwer Academic Publ., Dordrecht, in pres

A tool for functional brain imaging with lifespan compliance

The human brain undergoes significant functional and structural changes in the first decades of life, as the foundations for human cognition are laid down. However, non-invasive imaging techniques to investigate brain function throughout neurodevelopment are limited due to growth in head-size with age and substantial head movement in young participants. Experimental designs to probe brain function are also limited by the unnatural environment typical brain imaging systems impose. However, developments in quantum technology allowed fabrication of a new generation of wearable magnetoencephalography (MEG) technology with the potential to revolutionise electrophysiological measures of brain activity. Here we demonstrate a lifespan-compliant MEG system, showing recordings of high fidelity data in toddlers, young children, teenagers and adults. We show how this system can support new types of experimental paradigm involving naturalistic learning. This work reveals a new approach to functional imaging, providing a robust platform for investigation of neurodevelopment in health and disease

Weakened magnetic braking as the origin of anomalously rapid rotation in old field stars

A knowledge of stellar ages is crucial for our understanding of many astrophysical phenomena, and yet ages can be difficult to determine. As they become older, stars lose mass and angular momentum, resulting in an observed slowdown in surface rotation. The technique of 'gyrochronology' uses the rotation period of a star to calculate its age. However, stars of known age must be used for calibration, and, until recently, the approach was untested for old stars (older than 1 gigayear, Gyr). Rotation periods are now known for stars in an open cluster of intermediate age (NGC 6819; 2.5 Gyr old), and for old field stars whose ages have been determined with asteroseismology. The data for the cluster agree with previous period-age relations, but these relations fail to describe the asteroseismic sample. Here we report stellar evolutionary modelling, and confirm the presence of unexpectedly rapid rotation in stars that are more evolved than the Sun. We demonstrate that models that incorporate dramatically weakened magnetic braking for old stars can---unlike existing models---reproduce both the asteroseismic and the cluster data. Our findings might suggest a fundamental change in the nature of ageing stellar dynamos, with the Sun being close to the critical transition to much weaker magnetized winds. This weakened braking limits the diagnostic power of gyrochronology for those stars that are more than halfway through their main-sequence lifetimes.Comment: 25 pages, 3 figures in main paper, 6 extended data figures, 1 table. Published in Nature, January 2016. Please see https://youtu.be/O6HzYgP5uyc for a video description of the resul

The influence of 'significant others' on persistent back pain and work participation: a qualitative exploration of illness perceptions

Background Individual illness perceptions have been highlighted as important influences on clinical outcomes for back pain. However, the illness perceptions of 'significant others' (spouse/partner/close family member) are rarely explored, particularly in relation to persistent back pain and work participation. The aim of this study was to initiate qualitative research in this area in order to further understand these wider influences on outcome. Methods Semi-structured interviews based on the chronic pain version of the Illness Perceptions Questionnaire-Revised were conducted with a convenience sample of UK disability benefit claimants, along with their significant others (n=5 dyads). Data were analysed using template analysis. Results Significant others shared, and perhaps further reinforced, claimants' unhelpful illness beliefs including fear of pain/re-injury associated with certain types of work and activity, and pessimism about the likelihood of return to work. In some cases, significant others appeared more resigned to the permanence and negative inevitable consequences of the claimant's back pain condition on work participation, and were more sceptical about the availability of suitable work and sympathy from employers. In their pursuit of authenticity, claimants were keen to stress their desire to work whilst emphasising how the severity and physical limitations of their condition prevented them from doing so. In this vein, and seemingly based on their perceptions of what makes a 'good' significant other, significant others acted as a 'witness to pain', supporting claimants' self-limiting behaviour and statements of incapacity, often responding with empathy and assistance. The beliefs and responses of significant others may also have been influenced by their own experience of chronic illness, thus participants lives were often intertwined and defined by illness. Conclusions The findings from this exploratory study reveal how others and wider social circumstances might contribute both to the propensity of persistent back pain and to its consequences. This is an area that has received little attention to date, and wider support of these findings may usefully inform the design of future intervention programmes aimed at restoring work participation

Access to Artemisinin-Based Anti-Malarial Treatment and its Related Factors in Rural Tanzania.

Artemisinin-based combination treatment (ACT) has been widely adopted as one of the main malaria control strategies. However, its promise to save thousands of lives in sub-Saharan Africa depends on how effective the use of ACT is within the routine health system. The INESS platform evaluated effective coverage of ACT in several African countries. Timely access within 24 hours to an authorized ACT outlet is one of the determinants of effective coverage and was assessed for artemether-lumefantrine (Alu), in two district health systems in rural Tanzania. From October 2009 to June 2011we conducted continuous rolling household surveys in the Kilombero-Ulanga and the Rufiji Health and Demographic Surveillance Sites (HDSS). Surveys were linked to the routine HDSS update rounds. Members of randomly pre-selected households that had experienced a fever episode in the previous two weeks were eligible for a structured interview. Data on individual treatment seeking, access to treatment, timing, source of treatment and household costs per episode were collected. Data are presented on timely access from a total of 2,112 interviews in relation to demographics, seasonality, and socio economic status. In Kilombero-Ulanga, 41.8% (CI: 36.6-45.1) and in Rufiji 36.8% (33.7-40.1) of fever cases had access to an authorized ACT provider within 24 hours of fever onset. In neither of the HDSS site was age, sex, socio-economic status or seasonality of malaria found to be significantly correlated with timely access. Timely access to authorized ACT providers is below 50% despite interventions intended to improve access such as social marketing and accreditation of private dispensing outlets. To improve prompt diagnosis and treatment, access remains a major bottle neck and new more innovative interventions are needed to raise effective coverage of malaria treatment in Tanzania

Predicting progression of mild cognitive impairment to dementia using neuropsychological data: a supervised learning approach using time windows

Background: Predicting progression from a stage of Mild Cognitive Impairment to dementia is a major pursuit in current research. It is broadly accepted that cognition declines with a continuum between MCI and dementia. As such, cohorts of MCI patients are usually heterogeneous, containing patients at different stages of the neurodegenerative process. This hampers the prognostic task. Nevertheless, when learning prognostic models, most studies use the entire cohort of MCI patients regardless of their disease stages. In this paper, we propose a Time Windows approach to predict conversion to dementia, learning with patients stratified using time windows, thus fine-tuning the prognosis regarding the time to conversion. Methods: In the proposed Time Windows approach, we grouped patients based on the clinical information of whether they converted (converter MCI) or remained MCI (stable MCI) within a specific time window. We tested time windows of 2, 3, 4 and 5 years. We developed a prognostic model for each time window using clinical and neuropsychological data and compared this approach with the commonly used in the literature, where all patients are used to learn the models, named as First Last approach. This enables to move from the traditional question "Will a MCI patient convert to dementia somewhere in the future" to the question "Will a MCI patient convert to dementia in a specific time window". Results: The proposed Time Windows approach outperformed the First Last approach. The results showed that we can predict conversion to dementia as early as 5 years before the event with an AUC of 0.88 in the cross-validation set and 0.76 in an independent validation set. Conclusions: Prognostic models using time windows have higher performance when predicting progression from MCI to dementia, when compared to the prognostic approach commonly used in the literature. Furthermore, the proposed Time Windows approach is more relevant from a clinical point of view, predicting conversion within a temporal interval rather than sometime in the future and allowing clinicians to timely adjust treatments and clinical appointments.FCT under the Neuroclinomics2 project [PTDC/EEI-SII/1937/2014, SFRH/BD/95846/2013]; INESC-ID plurianual [UID/CEC/50021/2013]; LASIGE Research Unit [UID/CEC/00408/2013

Molecular Characterization of the Gastrula in the Turtle Emys orbicularis: An Evolutionary Perspective on Gastrulation

Due to the presence of a blastopore as in amphibians, the turtle has been suggested to exemplify a transition form from an amphibian- to an avian-type gastrulation pattern. In order to test this hypothesis and gain insight into the emergence of the unique characteristics of amniotes during gastrulation, we have performed the first molecular characterization of the gastrula in a reptile, the turtle Emys orbicularis. The study of Brachyury, Lim1, Otx2 and Otx5 expression patterns points to a highly conserved dynamic of expression with amniote model organisms and makes it possible to identify the site of mesoderm internalization, which is a long-standing issue in reptiles. Analysis of Brachyury expression also highlights the presence of two distinct phases, less easily recognizable in model organisms and respectively characterized by an early ring-shaped and a later bilateral symmetrical territory. Systematic comparisons with tetrapod model organisms lead to new insights into the relationships of the blastopore/blastoporal plate system shared by all reptiles, with the blastopore of amphibians and the primitive streak of birds and mammals. The biphasic Brachyury expression pattern is also consistent with recent models of emergence of bilateral symmetry, which raises the question of its evolutionary significance