Flavin-containing monooxygenases: mutations, disease and drug response

NOTICE: this is the author’s version of a work that was accepted for publication in Trends in Pharmacological Sciences. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Trends in Pharmacological Sciences, [VOL 29, ISSUE 6, (2008)] DOI: 10.1016/j.tips.2008.03.00

Integrated breathing and relaxation training (the Papworth method) for adults with asthma in primary care: a randomised controlled trial

Background: An integrated breathing and relaxation technique known as the Papworth method has been implemented by physiotherapists since the 1960s for patients with asthma and dysfunctional breathing, but no controlled trials have been reported. This study evaluated the effectiveness of the Papworth method in a randomised controlled trial.Methods: Eighty-five patients (36 men) were individually randomised to the control group (n = 46) or to the intervention group receiving five sessions of treatment by the Papworth method (n = 39). Both groups received usual medical care. Assessments were undertaken at baseline, post-treatment (6 months after baseline) and at 12 months. The primary outcome measure was the St George's Respiratory Symptoms Questionnaire (SGRQ). Secondary outcome measures included the Hospital Anxiety and Depression Scale (HADS), the Nijmegen dysfunctional breathing questionnaire and objective measures of respiratory function.Results: Post-treatment and 12 month data were available for 78 and 72 patients, respectively. At the post-treatment assessment the mean (SD) score on the SGRQ Symptom subscale was 21.8 (18.1) in the intervention group and 32.8 (20.1) in the control group (p = 0.001 for the difference). At the 12 month follow-up the corresponding figures were 24.9 (17.9) and 33.5 (15.9) (p = 0.007 for the difference). SGRQ Total scores and HADS and Nijmegen scores were similarly significantly lower in the intervention group than in the control group. The groups did not differ significantly following the treatment on objective measures of respiratory function except for relaxed breathing rate.Conclusions: The Papworth method appears to ameliorate respiratory symptoms, dysfunctional breathing and adverse mood compared with usual care. Further controlled trials are warranted to confirm this finding, assess the effect in other patient groups and determine whether there is some effect on objective measures of respiratory function

Methodology and calibration for continuous measurements of biogeochemical trace gas and O2 concentrations from a 300-m tall tower in central Siberia

We present an integrated system for measuring atmospheric concentrations of CO2, O2, CH4, CO, and N2O in central Siberia. Our project aims to demonstrate the feasibility of establishing long-term, continuous, high precision atmospheric measurements to elucidate greenhouse gas processes from a very remote, mid-continental boreal environment. Air is sampled from five heights on a custom-built 300-m tower. Common features to all species' measurements include air intakes, an air drying system, flushing procedures, and data processing methods. Calibration standards are shared among all five measured species by extending and optimising a proven methodology for long-term O2 calibration. Our system achieves the precision and accuracy requirements specified by the European Union's "CarboEurope" and "ICOS" (Integrated Carbon Observing System) programmes in the case of CO2, O2, and CH4, while CO and N2O require some further improvements. It was found that it is not possible to achieve these high precision measurements without skilled technical assistance on-site, primarily because of 2–3 month delays in access to data and diagnostic information. We present results on the stability of reference standards in high pressure cylinders. It was also found that some previous methods do not mitigate fractionation of O2 in a sample airstream to a satisfactory level

The evaluation of the far-field integral in the Green's function representation for steady Oseen flow

Consider the Green's function representation of an exterior problem in steady Oseen flow. The far-field integral in the formulation is shown to be zero

Activated T cells induce expression of B7/BB1 on normal or leukemic B cells through a CD40-dependent signal.

Cognate interactions between antigen-presenting B and T cells play crucial roles in immunologic responses. T cells that have been activated via the crosslinking of CD3 are able to induce B cell proliferation and immunoglobulin secretion in a major histocompatibility complex-unrestricted and contact-dependent manner. We find that such activated human CD4+ T cells, but not control Ig-treated T cells, may induce normal or leukemic B cells to express B7/BB1 and significantly higher levels of CD54 intercellular adhesion molecule 1 via a process that also requires direct cell-cell contact. To discern what cell surface molecule(s) may be responsible for signalling B cells to express B7/BB1, we added various monoclonal antibodies (mAbs) specific for T or B cell accessory molecules or control mAbs to cocultures of alpha-CD3-activated T cells and resting B cells. We find that only alpha-CD40 mAbs can significantly inhibit the increased expression of B7/BB1, suggesting that the ligand for CD40 expressed on activated T cells may be an important inducer of B7/BB1 expression. Subsequent experiments in fact demonstrate that alpha-CD40 mAbs, but not control mAbs, induce changes in B cell phenotype similar to those induced by activated T cells when the mAbs are presented on Fc gamma RII (CDw32)-expressing L cells. These phenotypic changes have significant effects on B cell function. Whereas chronic lymphocytic leukemia (CLL) B cells normally are very poor stimulators in allogeneic mixed lymphocyte reactions (MLRs), CLL-B cells preactivated via CD40 crosslinking are significantly better presenters of alloantigen, affecting up to 30-fold-greater stimulation of T cell proliferation than that induced by control treated or nontreated CLL-B cells. Similarly, the MLR of T cells stimulated by allogeneic nonleukemic B cells can be enhanced significantly if the stimulator B cells are preactivated via CD40 crosslinking. The enhanced MLR generated by such preactivated B cells may be inhibited by blocking B7/BB1-CD28 interaction with CTLA4Ig. These studies demonstrate a novel, CD40-dependent pathway for inducing B cell expression of B7/BB1 and enhancing B cell antigen-presenting cell activity that can be initiated via cell-cell contact with alpha-CD3-stimulated CD4+ T cells

Fast, Simple Calcium Imaging Segmentation with Fully Convolutional Networks

Calcium imaging is a technique for observing neuron activity as a series of images showing indicator fluorescence over time. Manually segmenting neurons is time-consuming, leading to research on automated calcium imaging segmentation (ACIS). We evaluated several deep learning models for ACIS on the Neurofinder competition datasets and report our best model: U-Net2DS, a fully convolutional network that operates on 2D mean summary images. U-Net2DS requires minimal domain-specific pre/post-processing and parameter adjustment, and predictions are made on full $512\times512$ images at $\approx$9K images per minute. It ranks third in the Neurofinder competition ($F_1=0.569$) and is the best model to exclusively use deep learning. We also demonstrate useful segmentations on data from outside the competition. The model's simplicity, speed, and quality results make it a practical choice for ACIS and a strong baseline for more complex models in the future.Comment: Accepted to 3rd Workshop on Deep Learning in Medical Image Analysis (http://cs.adelaide.edu.au/~dlmia3/

Take care of yourself

This article focuses on how compassion focused techniques that encourage self-reflection can help student practitioners to promote self-car

Regulation of NF-κB activity through lysine monomethylation of p65

NF-κB is a key activator of inflammatory and immune responses with important pathological roles in cancer, heart disease, and autoimmune diseases. Transcriptional activity of NF-κB is regulated by different posttranslational modifications. Here, we report a novel mechanism of NF-κB regulation through lysine monomethylation by SET9 methyltransferase. Set9 specifically methylates p65 at lysine 37. Both TNFα and IL-1β treatments induced methylation of p65. Methylated p65 is restricted to the nucleus and this modification regulates the promoter binding of p65. Moreover, Set9 mediated methylation of p65 is required for the expression of a subset of NF-κB target genes in response to TNFα stimulation

Integrins alpha v beta 3 and alpha v beta 5 contribute to cell attachment to vitronectin but differentially distribute on the cell surface.

We investigated the role of the integrins alpha v beta 3 and alpha v beta 5 in mediating vitronectin adhesion of three phenotypically distinct cell types. M21 human melanoma cells and H2981 lung carcinoma cells use both alpha v-containing integrins in adhering to vitronectin while UCLA-P3 lung carcinoma cells adhere exclusively with alpha v beta 5. Specifically, monoclonal antibodies directed to functional epitopes on both receptors were required to block adhesion of M21 or H2981 cells while adhesion of UCLA-P3 cells to vitronectin could be blocked with a monoclonal antibody to alpha v beta 5. Although both receptors are involved in M21 and H2981 cell adhesion to vitronectin, only alpha v beta 3 can be detected in focal contacts, colocalizing with vinculin, talin, and the ends of actin filaments, while alpha v beta 5 shows a distinct, nonfocal contact, distribution on the cell surface. These results provide the first evidence that two homologous integrins that recognize the same ligand distribute differentially on the cell surface