Regulation of B cell fate by chronic activity of the IgE B cell receptor.

IgE can trigger potent allergic responses, yet the mechanisms regulating IgE production are poorly understood. Here we reveal that IgE+ B cells are constrained by chronic activity of the IgE B cell receptor (BCR). In the absence of cognate antigen, the IgE BCR promoted terminal differentiation of B cells into plasma cells (PCs) under cell culture conditions mimicking T cell help. This antigen-independent PC differentiation involved multiple IgE domains and Syk, CD19, BLNK, Btk, and IRF4. Disruption of BCR signaling in mice led to consistently exaggerated IgE+ germinal center (GC) B cell but variably increased PC responses. We were unable to confirm reports that the IgE BCR directly promoted intrinsic apoptosis. Instead, IgE+ GC B cells exhibited poor antigen presentation and prolonged cell cycles, suggesting reduced competition for T cell help. We propose that chronic BCR activity and access to T cell help play critical roles in regulating IgE responses

Adaptation and enslavement in endosymbiont-host associations

The evolutionary persistence of symbiotic associations is a puzzle. Adaptation should eliminate cooperative traits if it is possible to enjoy the advantages of cooperation without reciprocating - a facet of cooperation known in game theory as the Prisoner's Dilemma. Despite this barrier, symbioses are widespread, and may have been necessary for the evolution of complex life. The discovery of strategies such as tit-for-tat has been presented as a general solution to the problem of cooperation. However, this only holds for within-species cooperation, where a single strategy will come to dominate the population. In a symbiotic association each species may have a different strategy, and the theoretical analysis of the single species problem is no guide to the outcome. We present basic analysis of two-species cooperation and show that a species with a fast adaptation rate is enslaved by a slowly evolving one. Paradoxically, the rapidly evolving species becomes highly cooperative, whereas the slowly evolving one gives little in return. This helps understand the occurrence of endosymbioses where the host benefits, but the symbionts appear to gain little from the association.Comment: v2: Correction made to equations 5 & 6 v3: Revised version accepted in Phys. Rev. E; New figure adde

Rock drumming enhances motor and psychosocial skills of children with emotional and behavioral difficulties

Drumming may have therapeutic and learning benefits but there exists little causal evidence regarding the benefits for children with emotional and behavioural difficulties (EBD) such as Autistic Spectrum Disorder. Six EBD pupils (EBD Drum) and 6 peers (Peer Drum) were given 2, 30 minute rock drumming lessons per week, over 5 weeks. Six matched individuals received no drumming instruction (3=EBD Control; 3=Peer Control). An exploratory, mixed-methods analysis was used to explore quantitative changes in skills and qualitative perspectives of the teaching staff. All pupils were tested two times (pretest and posttest) on drumming ability and Motor skills (Movement Assessment Battery for Children, version 2). Teacher’s rating of social behaviour (Strength and Difficulties Questionnaire; SDQ) was tested two times (pretest and retention).Significant differences in total SDQ difficulties between the four groups (χ2(3) = 8.210, p = 0.042) and the hyperactivity subscale (χ2(3) = 10.641, p = 0.014) were observed. The EBD Drum group had greater reductions in total difficulties compared to the Peer Drum (p = 0.009) group and specifically greater reductions in hyperactivity compared to Peer Drum (p = 0.046) and the EBD Control (p = 0.006) group. In follow-up interviews, staff spoke positively about changes in pupil’s attitudes towards learning and social confidence. The positive changes to social and behavioural skills reported in this pilot study are similar to those recorded for other music modalities

A recall-by-genotype study of CHRNA5-A3-B4 genotype, cotinine and smoking topography:study protocol

BACKGROUND: Genome-wide association studies have revealed an association between several loci in the nicotinic acetylcholine receptor gene cluster CHRNA5-A3-B4 and daily cigarette consumption. Recent studies have sought to refine this phenotype, and have shown that a locus within this cluster, marked primarily by rs1051730 and rs16969968, is also associated with levels of cotinine, the primary metabolite of nicotine. This association remains after adjustment for self-reported smoking, which suggests that even amongst people who smoke the same number of cigarettes there is still genetically-influenced variation in nicotine consumption. This is likely to be due to differences in smoking topography, that is, how a cigarette is smoked (e.g., volume of smoke inhaled per puff, number of puffs taken per cigarette). The aim of this study is to determine potential mediation of the relationship between the rs1051730 locus and cotinine levels by smoking topography. METHODS/DESIGN: Adopting a recall-by-genotype design, we will recruit 200 adults from the Avon Longitudinal Study of Parents and Children on the basis of minor or major homozygote status at rs1051730 (100 in each genotype group). All participants will be current, daily smokers. Our primary study outcome measures will be measures of smoking topography: total volume of smoke (ml) inhaled per cigarette, total volume of smoke (ml) inhaled over of the course of one day, and salivary cotinine level (ng/ml). DISCUSSION: This study will extend our understanding of the biological basis of inter-individual variability in heaviness of smoking, and therefore in exposure to smoking-related toxins. The novel recall-by-genotype approach we will use is efficient, maximising statistical power, and enables the collection of extremely precise phenotypic data that are impractical to collect in a larger sample. The methods described within this protocol also hold the potential for wider application in the field of molecular genetics

Eigenvalues of the Schrödinger equation for a periodic potential with nonperiodic boundary conditions: A uniform semiclassical analysis

A uniform semiclassical expression for the eigenvalues of a one dimensional periodic Schrödinger equation with nonperiodic boundary conditions has been derived. The potential energy function can have any number of symmetric or asymmetric barriers and wells. The treatment is uniform in that the classical turning points can come close together, coalesce, and move into the complex plane as the energy passes through a barrier maximum. A detailed application is made to Mathieu functions of integer order; the equations themselves include the case of fractional order. Approximate semiclassical expressions are derived for the widths of the energy bands and the energy gaps of the periodic Mathieu equation when these quantities are small. The semiclassical results give a physical interpretation to formulas present in the mathematical literature and to the decrease in the splitting of a sequence of avoided crossings with increasing quantum numbers in coupled oscillator systems. Numerical calculations are reported to illustrate the high accuracy of the semiclassical formulas

Sonic hedgehog signalling mediates astrocyte crosstalk with neurons to confer neuroprotection

Sonic hedgehog (SHH) is a glycoprotein associated with development that is also expressed in the adult CNS and released after brain injury. Since the SHH receptors patched homolog-1 and Smoothened are highly expressed on astrocytes, we hypothesized that SHH regulates astrocyte function. Primary mouse cortical astrocytes derived from embryonic Swiss mouse cortices, were treated with two chemically distinct agonists of the SHH pathway, which caused astrocytes to elongate and proliferate. These changes are accompanied by decreases in the major astrocyte glutamate transporter-1 and the astrocyte intermediate filament protein glial fibrillary acidic protein. Multisite electrophysiological recordings revealed that the SHH agonist, smoothened agonist suppressed neuronal firing in astrocyte-neuron co-cultures and this was abolished by the astrocyte metabolic inhibitor ethylfluoroacetate, revealing that SHH stimulation of metabolically active astrocytes influences neuronal firing. Using three-dimensional co-culture, MAP2 western blotting and immunohistochemistry, we show that SHH-stimulated astrocytes protect neurons from kainate-induced cell death. Altogether the results show that SHH regulation of astrocyte function represents an endogenous neuroprotective mechanism

Using Regular Languages to Explore the Representational Capacity of Recurrent Neural Architectures

The presence of Long Distance Dependencies (LDDs) in sequential data poses significant challenges for computational models. Various recurrent neural architectures have been designed to mitigate this issue. In order to test these state-of-the-art architectures, there is growing need for rich benchmarking datasets. However, one of the drawbacks of existing datasets is the lack of experimental control with regards to the presence and/or degree of LDDs. This lack of control limits the analysis of model performance in relation to the specific challenge posed by LDDs. One way to address this is to use synthetic data having the properties of subregular languages. The degree of LDDs within the generated data can be controlled through the k parameter, length of the generated strings, and by choosing appropriate forbidden strings. In this paper, we explore the capacity of different RNN extensions to model LDDs, by evaluating these models on a sequence of SPk synthesized datasets, where each subsequent dataset exhibits a longer degree of LDD. Even though SPk are simple languages, the presence of LDDs does have significant impact on the performance of recurrent neural architectures, thus making them prime candidate in benchmarking tasks.Comment: International Conference of Artificial Neural Networks (ICANN) 201

Nebulized heparin is associated with fewer days of mechanical ventilation in critically ill patients: a randomized controlled trial

INTRODUCTION: Prolonged mechanical ventilation has the potential to aggravate or initiate pulmonary inflammation and cause lung damage through fibrin deposition. Heparin may reduce pulmonary inflammation and fibrin deposition. We therefore assessed whether nebulised heparin improved lung function in patients expected to require prolonged mechanical ventilation. METHODS: Fifty patients expected to require mechanical ventilation for more than 48 hours were enrolled in a double-blind randomised placebo-controlled trial of nebulised heparin (25,000 U) or placebo (normal saline) 4 or 6 hourly, depending on patient height. The study drug was continued while the patient remained ventilated to a maximum of 14 days from randomisation. RESULTS: Nebulised heparin was not associated with a significant improvement in the primary end-point, the average daily partial pressure of oxygen to inspired fraction of oxygen ratio while mechanically ventilated, but was associated with improvement in the secondary end-point ventilator free days amongst survivors at day 28 (22.6 4.0 versus 18.0 7.1, treatment difference 4.6 days, 95% CI 0.9 to 8.3, P = 0.02). Heparin administration was not associated with any increase in adverse events. CONCLUSIONS: Nebulised heparin was associated with fewer days of mechanical ventilation in critically ill patients expected to require prolonged mechanical ventilation. Further trials are required to confirm these findings. Trial registration: The Australian Clinical Trials Registry (ACTR-12608000121369

Telling partners about chlamydia: how acceptable are the new technologies?

BACKGROUND Partner notification is accepted as a vital component in the control of chlamydia. However, in reality, many sexual partners of individuals diagnosed with chlamydia are never informed of their risk. The newer technologies of email and SMS have been used as a means of improving partner notification rates. This study explored the use and acceptability of different partner notification methods to help inform the development of strategies and resources to increase the number of partners notified. METHODS Semi-structured telephone interviews were conducted with 40 people who were recently diagnosed with chlamydia from three sexual health centres and two general practices across three Australian jurisdictions. RESULTS Most participants chose to contact their partners either in person (56%) or by phone (44%). Only 17% chose email or SMS. Participants viewed face-to-face as the "gold standard" in partner notification because it demonstrated caring, respect and courage. Telephone contact, while considered insensitive by some, was often valued because it was quick, convenient and less confronting. Email was often seen as less personal while SMS was generally considered the least acceptable method for telling partners. There was also concern that emails and SMS could be misunderstood, not taken seriously or shown to others. Despite these, email and SMS were seen to be appropriate and useful in some circumstances. Letters, both from the patients or from their doctor, were viewed more favourably but were seldom used. CONCLUSION These findings suggest that many people diagnosed with chlamydia are reluctant to use the new technologies for partner notification, except in specific circumstances, and our efforts in developing partner notification resources may best be focused on giving patients the skills and confidence for personal interaction.The study was funded by the Australian Federal Government Department of Health and Ageing Chlamydia Pilot Program of Targeted Grants

G = E:What GWAS Can Tell Us about the Environment

As our understanding of genetics has improved, genome-wide association studies (GWAS) have identified numerous variants associated with lifestyle behaviours and health outcomes. However, what is sometimes overlooked is the possibility that genetic variants identified in GWAS of disease might reflect the effect of modifiable risk factors as well as direct genetic effects. We discuss this possibility with illustrative examples from tobacco and alcohol research, in which genetic variants that predict behavioural phenotypes have been seen in GWAS of diseases known to be causally related to these behaviours. This consideration has implications for the interpretation of GWAS findings