A theoretical framework for the regulation of Shh morphogen-controlled gene expression.

How morphogen gradients govern the pattern of gene expression in developing tissues is not well understood. Here, we describe a statistical thermodynamic model of gene regulation that combines the activity of a morphogen with the transcriptional network it controls. Using Sonic hedgehog (Shh) patterning of the ventral neural tube as an example, we show that the framework can be used together with the principled parameter selection technique of approximate Bayesian computation to obtain a dynamical model that accurately predicts tissue patterning. The analysis indicates that, for each target gene regulated by Gli, which is the transcriptional effector of Shh signalling, there is a neutral point in the gradient, either side of which altering the Gli binding affinity has opposite effects on gene expression. This explains recent counterintuitive experimental observations. The approach is broadly applicable and provides a unifying framework to explain the temporospatial pattern of morphogen-regulated gene expression

A Sparse Stress Model

Force-directed layout methods constitute the most common approach to draw general graphs. Among them, stress minimization produces layouts of comparatively high quality but also imposes comparatively high computational demands. We propose a speed-up method based on the aggregation of terms in the objective function. It is akin to aggregate repulsion from far-away nodes during spring embedding but transfers the idea from the layout space into a preprocessing phase. An initial experimental study informs a method to select representatives, and subsequent more extensive experiments indicate that our method yields better approximations of minimum-stress layouts in less time than related methods.Comment: Appears in the Proceedings of the 24th International Symposium on Graph Drawing and Network Visualization (GD 2016

Directional collective cell migration emerges as a property of cell interactions.

Collective cell migration is a fundamental process, occurring during embryogenesis and cancer metastasis. Neural crest cells exhibit such coordinated migration, where aberrant motion can lead to fatality or dysfunction of the embryo. Migration involves at least two complementary mechanisms: contact inhibition of locomotion (a repulsive interaction corresponding to a directional change of migration upon contact with a reciprocating cell), and co-attraction (a mutual chemoattraction mechanism). Here, we develop and employ a parameterized discrete element model of neural crest cells, to investigate how these mechanisms contribute to long-range directional migration during development. Motion is characterized using a coherence parameter and the time taken to reach, collectively, a target location. The simulated cell group is shown to switch from a diffusive to a persistent state as the response-rate to co-attraction is increased. Furthermore, the model predicts that when co-attraction is inhibited, neural crest cells can migrate into restrictive regions. Indeed, inhibition of co-attraction in vivo and in vitro leads to cell invasion into restrictive areas, confirming the prediction of the model. This suggests that the interplay between the complementary mechanisms may contribute to guidance of the neural crest. We conclude that directional migration is a system property and does not require action of external chemoattractants

Ptch1 and Gli regulate Shh signalling dynamics via multiple mechanisms.

In the vertebrate neural tube, the morphogen Sonic Hedgehog (Shh) establishes a characteristic pattern of gene expression. Here we quantify the Shh gradient in the developing mouse neural tube and show that while the amplitude of the gradient increases over time, the activity of the pathway transcriptional effectors, Gli proteins, initially increases but later decreases. Computational analysis of the pathway suggests three mechanisms that could contribute to this adaptation: transcriptional upregulation of the inhibitory receptor Ptch1, transcriptional downregulation of Gli and the differential stability of active and inactive Gli isoforms. Consistent with this, Gli2 protein expression is downregulated during neural tube patterning and adaptation continues when the pathway is stimulated downstream of Ptch1. Moreover, the Shh-induced upregulation of Gli2 transcription prevents Gli activity levels from adapting in a different cell type, NIH3T3 fibroblasts, despite the upregulation of Ptch1. Multiple mechanisms therefore contribute to the intracellular dynamics of Shh signalling, resulting in different signalling dynamics in different cell types

Prescribing patterns in premenstrual syndrome

BACKGROUND: Over 300 therapies have been proposed for premenstrual syndrome. To date there has been only one survey conducted in the UK of PMS treatments prescribed by GPs, a questionnaire-based study by the National Association of Premenstrual Syndrome in 1989. Since then, selective serotonin re-uptake inhibitors have been licensed for severe PMS/PMDD, and governmental recommendations to reduce the dosage of vitamin B6 (the first choice over-the-counter treatment for many women with PMS) have been made. This study investigates the annual rates of diagnoses and prescribing patterns for premenstrual syndrome (1993–1998) within a computerised general practitioner database. METHODS: Retrospective survey of prescribing data for premenstrual syndrome between 1993–1998 using the General Practice Research Database for the West Midlands Region which contains information on 282,600 female patients RESULTS: Overall the proportion of women with a prescription-linked diagnosis of premenstrual syndrome has halved over the five years. Progestogens including progesterone were the most commonly recorded treatment for premenstrual syndrome during the whole study period accounting for over 40% of all prescriptions. Selective serotonin-reuptake inhibitors accounted for only 2% of the prescriptions in 1993 but rose to over 16% by 1998, becoming the second most commonly recorded treatment. Vitamin B6 accounted for 22% of the prescriptions in 1993 but dropped markedly between 1997 and 1998 to 11%. CONCLUSIONS: This study shows a yearly decrease in the number of prescriptions linked to diagnoses for premenstrual syndrome. Progestogens including progesterone, is the most widely prescribed treatment for premenstrual syndrome despite the lack of evidence demonstrating their efficacy

Microbial ligand costimulation drives neutrophilic steroid-refractory asthma

Funding: The authors thank the Wellcome Trust (102705) and the Universities of Aberdeen and Cape Town for funding. This research was also supported, in part, by National Institutes of Health GM53522 and GM083016 to DLW. KF and BNL are funded by the Fonds Wetenschappelijk Onderzoek, BNL is the recipient of an European Research Commission consolidator grant and participates in the European Union FP7 programs EUBIOPRED and MedALL. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

Transit Timing and Duration Variations for the Discovery and Characterization of Exoplanets

Transiting exoplanets in multi-planet systems have non-Keplerian orbits which can cause the times and durations of transits to vary. The theory and observations of transit timing variations (TTV) and transit duration variations (TDV) are reviewed. Since the last review, the Kepler spacecraft has detected several hundred perturbed planets. In a few cases, these data have been used to discover additional planets, similar to the historical discovery of Neptune in our own Solar System. However, the more impactful aspect of TTV and TDV studies has been characterization of planetary systems in which multiple planets transit. After addressing the equations of motion and parameter scalings, the main dynamical mechanisms for TTV and TDV are described, with citations to the observational literature for real examples. We describe parameter constraints, particularly the origin of the mass/eccentricity degeneracy and how it is overcome by the high-frequency component of the signal. On the observational side, derivation of timing precision and introduction to the timing diagram are given. Science results are reviewed, with an emphasis on mass measurements of transiting sub-Neptunes and super-Earths, from which bulk compositions may be inferred.Comment: Revised version. Invited review submitted to 'Handbook of Exoplanets,' Exoplanet Discovery Methods section, Springer Reference Works, Juan Antonio Belmonte and Hans Deeg, Eds. TeX and figures may be found at https://github.com/ericagol/TTV_revie

Predictors of isoniazid preventive therapy completion among adults newly diagnosed with HIV in rural Malawi.

SETTING: To reduce the risk of tuberculosis (TB) among individuals with human immunodeficiency virus (HIV) infection, the World Health Organization recommends at least 6 months of isoniazid preventive therapy (IPT). Completion of IPT remains a major challenge in resource-limited settings. OBJECTIVE: To evaluate predictors of IPT completion in individuals newly diagnosed with HIV. DESIGN: Predictors of IPT completion among adults newly diagnosed with HIV in rural Malawi were evaluated using a multilevel logistic regression model. RESULTS: Of 974 participants who screened negative for active TB and were started on IPT, 732 (75%) completed treatment. Only one IPT-eligible individual refused treatment. Participants who were aged <25 years (compared with those aged 45 years, adjusted OR [aOR] 0.33, 95%CI 0.18-0.60) and male (compared to non-pregnant females, aOR 0.57, 95%CI 0.37-0.88) had lower odds of IPT completion. CONCLUSION: IPT provision at the time of initial HIV diagnosis was highly acceptable in rural Malawi; three quarters of those who initiated IPT successfully completed therapy. We observed lower odds of completion among males and among female participants aged <25 years. Additional efforts may be needed to ensure IPT completion among males and young females who have recently been diagnosed with HIV

Predictors of isoniazid preventive therapy completion among adults newly diagnosed with HIV in rural Malawi.

SETTING: To reduce the risk of tuberculosis (TB) among individuals with human immunodeficiency virus (HIV) infection, the World Health Organization recommends at least 6 months of isoniazid preventive therapy (IPT). Completion of IPT remains a major challenge in resource-limited settings. OBJECTIVE: To evaluate predictors of IPT completion in individuals newly diagnosed with HIV. DESIGN: Predictors of IPT completion among adults newly diagnosed with HIV in rural Malawi were evaluated using a multilevel logistic regression model. RESULTS: Of 974 participants who screened negative for active TB and were started on IPT, 732 (75%) completed treatment. Only one IPT-eligible individual refused treatment. Participants who were aged <25 years (compared with those aged 45 years, adjusted OR [aOR] 0.33, 95%CI 0.18-0.60) and male (compared to non-pregnant females, aOR 0.57, 95%CI 0.37-0.88) had lower odds of IPT completion. CONCLUSION: IPT provision at the time of initial HIV diagnosis was highly acceptable in rural Malawi; three quarters of those who initiated IPT successfully completed therapy. We observed lower odds of completion among males and among female participants aged <25 years. Additional efforts may be needed to ensure IPT completion among males and young females who have recently been diagnosed with HIV