CommWalker: correctly evaluating modules in molecular networks in light of annotation bias.

Motivation: Detecting novel functional modules in molecular networks is an important step in biological research. In the absence of gold standard functional modules, functional annotations are often used to verify whether detected modules/communities have biological meaning. However, as we show, the uneven distribution of functional annotations means that such evaluation methods favor communities of well-studied proteins. Results: We propose a novel framework for the evaluation of communities as functional modules. Our proposed framework, CommWalker, takes communities as inputs and evaluates them in their local network environment by performing short random walks. We test CommWalker's ability to overcome annotation bias using input communities from four community detection methods on two protein interaction networks. We find that modules accepted by CommWalker are similarly co-expressed as those accepted by current methods. Crucially, CommWalker performs well not only in well-annotated regions, but also in regions otherwise obscured by poor annotation. CommWalker community prioritization both faithfully captures well-validated communities and identifies functional modules that may correspond to more novel biology. Availability and implementation: The CommWalker algorithm is freely available at opig.stats.ox.ac.uk/resources or as a docker image on the Docker Hub at hub.docker.com/r/lueckenmd/commwalker/. Contact: deane@stats.ox.ac.uk. Supplementary information: Supplementary data are available at Bioinformatics online.

Study protocol: families and childhood transitions study (FACTS) - a longitudinal investigation of the role of the family environment in brain development and risk for mental health disorders in community based children.

BACKGROUND: Extant research has demonstrated that parenting behaviour can be a significant contributor to the development of brain structure and mental health during adolescence. Nonetheless, there is limited research examining these relationships during late childhood, and particularly in the critical period of brain development occurring between 8 and 10 years of age. The effects of the family environment on the brain during late childhood may have significant implications for later functioning, and particularly mental health. The Families and Childhood Transitions Study (FACTS) is a multidisciplinary longitudinal cohort study of brain development and mental health, with two waves of data collection currently funded, occurring 18-months apart, when child participants are aged approximately 8- and 10-years old. METHODS/DESIGN: Participants are 163 children (M age [SD] = 8.44 [0.34] years, 76 males) and their mothers (M age [SD] = 40.34 [5.43] years). Of the 163 families who consented to participate, 156 completed a video-recorded and observer-coded dyadic interaction task and 153 completed a child magnetic resonance imaging brain scan at baseline. Families were recruited from lower socioeconomic status (SES) areas to maximise rates of social disadvantage and variation in parenting behaviours. All experimental measures and tasks completed at baseline are repeated at an 18-month follow-up, excluding the observer coded family interaction tasks. The baseline assessment was completed in October 2015, and the 18-month follow up will be completed May 2017. DISCUSSION: This study, by examining the neurobiological and mental health consequences of variations in parenting, has the potential to significantly advance our understanding of child development and risk processes. Recruitment of lower SES families will also allow assessment of resilience factors given the poorer outcomes often associated with this population.

WONKA: objective novel complex analysis for ensembles of protein-ligand structures.

WONKA is a tool for the systematic analysis of an ensemble of protein-ligand structures. It makes the identification of conserved and unusual features within such an ensemble straightforward. WONKA uses an intuitive workflow to process structural co-ordinates. Ligand and protein features are summarised and then presented within an interactive web application. WONKA's power in consolidating and summarising large amounts of data is described through the analysis of three bromodomain datasets. Furthermore, and in contrast to many current methods, WONKA relates analysis to individual ligands, from which we find unusual and erroneous binding modes. Finally the use of WONKA as an annotation tool to share observations about structures is demonstrated. WONKA is freely available to download and install locally or can be used online at http://wonka.sgc.ox.ac.uk.

Predicting the response of a long-distance migrant to changing environmental conditions in winter.

Access to high-quality food is critical for long-distance migrants to provide energy for migration and arrival at breeding grounds in good condition. We studied effects of changing abundance and availability of a marine food, common eelgrass (Zostera marina L.), on an arctic-breeding, migratory goose, black brant (Brant bernicla nigricans Lawrence 1846), at a key non-breeding site, Bahía San Quintín, Mexico. Eelgrass, the primary food of brant, is consumed when exposed by the tide or within reach from the water's surface. Using an individual-based model, we predicted effects of observed changes (1991-2013) in parameters influencing food abundance and availability: eelgrass biomass (abundance), eelgrass shoot length (availability, as longer shoots more within reach), brant population size (availability, as competition greater with more birds), and sea level (availability, as less food within reach when sea level higher). The model predicted that the ability to gain enough energy to migrate was most strongly influenced by eelgrass biomass (threshold January biomass for migration = 60 g m-2 dry mass). Conversely, annual variation in population size (except for 1998), was relatively low, and variation in eelgrass shoot length and sea level were not strongly related to ability to migrate. We used observed data on brant body mass at Bahía San Quintín and annual survival to test for effects of eelgrass biomass in the real system. The lowest observed values of body mass and survival were in years when biomass was below 60 g m-2, although in some years of low biomass body mass and/or survival was higher. This suggests that the real birds may have some capacity to compensate to meet their energy demands when eelgrass biomass is low. We discuss consequences for brant population trends and conservation.

Loss of muscle mass in the immediate post-operative period is associated with inadequate dietary protein and energy intake.

Despite the implementation of 'Enhanced Recovery After Surgery' (ERAS) protocols, major abdominal surgery is still associated with significant and detrimental losses of muscle mass and function in the post-operative period. Although ERAS protocols advocate both early mobility and dietary intake, dietary composition in the immediate post-operative period is poorly characterised, despite muscle losses being greatest in this period. Herein, we show in 15 patients (66 ± 6 y, 12:3 M:F) who lost ~10% m. vastus lateralis muscle mass in the 5 days after open colorectal resective surgery, mean energy intake was only ~25% of the minimum ESPEN recommendation of 25 kcal/kg/d and daily dietary protein intake was only ~12% of the ESPEN recommended guidelines of 1.5 g/kg/d. Given the known importance of nutrition for muscle mass maintenance, innovative dietary interventions are needed in the immediate post-operative period, accounting for specific patient dietary preference to maximise compliance (e.g., soft-textured foods).

Reduced amounts and abnormal forms of phospholipase C zeta (PLCzeta) in spermatozoa from infertile men.

BACKGROUND: In mammals, oocyte activation at fertilization is thought to be induced by the sperm-specific phospholipase C zeta (PLCzeta). However, it still remains to be conclusively shown that PLCzeta is the endogenous agent of oocyte activation. Some types of human infertility appear to be caused by failure of the sperm to activate and this may be due to specific defects in PLCzeta. METHODS AND RESULTS: Immunofluorescence studies showed PLCzeta to be localized in the equatorial region of sperm from fertile men, but sperm deficient in oocyte activation exhibited no specific signal in this same region. Immunoblot analysis revealed reduced amounts of PLCzeta in sperm from infertile men, and in some cases, the presence of an abnormally low molecular weight form of PLCzeta. In one non-globozoospermic case, DNA analysis identified a point mutation in the PLCzeta gene that leads to a significant amino acid change in the catalytic region of the protein. Structural modelling suggested that this defect may have important effects upon the structure and function of the PLCzeta protein. cRNA corresponding to mutant PLCzeta failed to induce calcium oscillations when microinjected into mouse oocytes. Injection of infertile human sperm into mouse oocytes failed to activate the oocyte or trigger calcium oscillations. Injection of such infertile sperm followed by two calcium pulses, induced by assisted oocyte activation, activated the oocytes without inducing the typical pattern of calcium oscillations. CONCLUSIONS: Our findings illustrate the importance of PLCzeta during fertilization and suggest that mutant forms of PLCzeta may underlie certain types of human male infertility.

Antibody H3 Structure Prediction.

Antibodies are proteins of the immune system that are able to bind to a huge variety of different substances, making them attractive candidates for therapeutic applications. Antibody structures have the potential to be useful during drug development, allowing the implementation of rational design procedures. The most challenging part of the antibody structure to experimentally determine or model is the H3 loop, which in addition is often the most important region in an antibody's binding site. This review summarises the approaches used so far in the pursuit of accurate computational H3 structure prediction.

Development of educational image databases and e-books for medical physics training.

Medical physics education and training requires the use of extensive imaging material and specific explanations. These requirements provide an excellent background for application of e-Learning. The EU projects Consortia EMERALD and EMIT developed five volumes of such materials, now used in 65 countries. EMERALD developed e-Learning materials in three areas of medical physics (X-ray diagnostic radiology, nuclear medicine and radiotherapy). EMIT developed e-Learning materials in two further areas: ultrasound and magnetic resonance imaging. This paper describes the development of these e-Learning materials (consisting of e-books and educational image databases). The e-books include tasks helping studying of various equipment and methods. The text of these PDF e-books is hyperlinked with respective images. The e-books are used through the readers' own Internet browser. Each Image Database (IDB) includes a browser, which displays hundreds of images of equipment, block diagrams and graphs, image quality examples, artefacts, etc. Both the e-books and IDB are engraved on five separate CD-ROMs. Demo of these materials can be taken from www.emerald2.net.

CODA: a combined algorithm for predicting the structurally variable regions of protein models.

CODA, an algorithm for predicting the variable regions in proteins, combines FREAD a knowledge based approach, and PETRA, which constructs the region ab initio. FREAD selects from a database of protein structure fragments with environmentally constrained substitution tables and other rule-based filters. FREAD was parameterized and tested on over 3000 loops. The average root mean square deviation ranged from 0.78 A for three residue loops to 3.5 A for eight residue loops on a nonhomologous test set. CODA clusters the predictions from the two independent programs and makes a consensus prediction that must pass a set of rule-based filters. CODA was parameterized and tested on two unrelated separate sets of structures that were nonhomologous to one another and those found in the FREAD database. The average root mean square deviation in the test set ranged from 0.76 A for three residue loops to 3.09 A for eight residue loops. CODA shows a general improvement in loop prediction over PETRA and FREAD individually. The improvement is far more marked for lengths six and upward, probably as the predictive power of PETRA becomes more important. CODA was further tested on several model structures to determine its applicability to the modeling situation. A web server of CODA is available at http://www-cryst.bioc.cam.ac.uk/~charlotte/Coda/search_coda.html.

HOMSTRAD: a database of protein structure alignments for homologous families.

We describe a database of protein structure alignments for homologous families. The database HOMSTRAD presently contains 130 protein families and 590 aligned structures, which have been selected on the basis of quality of the X-ray analysis and accuracy of the structure. For each family, the database provides a structure-based alignment derived using COMPARER and annotated with JOY in a special format that represents the local structural environment of each amino acid residue. HOMSTRAD also provides a set of superposed atomic coordinates obtained using MNYFIT, which can be viewed with a graphical user interface or used for comparative modeling studies. The database is freely available on the World Wide Web at: http://www-cryst.bioc.cam. ac.uk/-homstrad/, with search facilities and links to other databases.

Transplant renal artery stenosis in 77 patients--does it have an immunological cause?

Transplant renal artery stenosis (TRAS) is a common complication after transplantation and is an important cause of graft dysfunction. Damage from graft rejection, trauma, and atherosclerosis have been implicated as possible causes. We reviewed all 917 patients transplanted in our unit since 1978 to study the prevalence, clinical features, and possible causes of TRAS. Seventy-seven patients with TRAS were identified. The detected incidence was 2.4% before the introduction of color doppler ultrasonography (CDU) and rose to 12.4% after CDU was introduced in 1985, giving an overall incidence of 8.4% during a mean follow-up period of 6.9 years. The TRAS group was compared with a control group of 77 transplanted patients matched for age, year of transplant, sex, and number of previous grafts. Mean ages for the study and control groups were 43.6 +/- 15 and 44.8 +/- 13.7 yr. A total of 25% of cases of TRAS were diagnosed within the first 8 wk of transplantation and in 60% within the first 30 wk (median = 23 wk). All patients were treated with angioplasty, 28 patients had recurrence of TRAS requiring multiple angioplasties (maximum 5) and 1 went on to have surgery. Angioplasty resulted in a significant fall in plasma creatinine. Patient and graft survival were significantly worse in the TRAS group: 69% vs. 83% (P < 0.05) and 56% vs. 74% (P < 0.05) (TRAS vs. Control), respectively. There was a significantly higher incidence of rejection, especially cellular rejection in the TRAS group, 0.67 vs. 0.35 episodes per patient (P < 0.01) (TRAS vs. Control). Recurrence but not occurrence of TRAS was associated with the use of cyclosporine.

Reproducibility of plasma and extracellular fluid volume measurements in critically ill patients.

Plasma and extracellular fluid (ECF) volume measurements may provide valuable complementary data to the hemodynamic measurements currently used to compare fluid infusions in critically ill patients. To assess the reproducibility of plasma and extracellular fluid volume measurements in critically ill patients, we injected 131I-labeled albumin (10 microCi) and 35S-sodium sulfate (50 microCi), respectively, into 15 stable patients on two occasions 150 min apart. Plasma was sampled at 20, 30, and 40 min after each injection and the volume of distribution of each radioisotope was calculated from the extrapolated zero time counts. We found that plasma and ECF volume did not differ significantly between the first (42.4 +/- 4.7 ml/kg and 186 +/- 39 ml/kg) and second (42.8 +/- 5.5 ml/kg and 193 +/- 48 ml/kg) measurements. Specifically, the mean difference between the two measurements was 0.4 +/- 3.2 ml/kg and 7 +/- 17 ml/kg respectively. We conclude that measurements of plasma and ECF volume are reproducible over 150 min in stable critically ill patients.

The effect of the nitric oxide donor glyceryl trinitrate on global and regional cerebral blood flow in man.

Despite their potential use as cerebral vasodilatory agents there are few studies of the effect of nitric oxide (NO) donors on the cerebral circulation in non-anaesthetised man. We determined the effect of the NO donor glyceryl trinitrate (GTN) at clinically relevant doses on global and regional cerebral blood flow (CBF) in healthy non-anaesthetised volunteers, using H(2)(15)O PET, ultrasonic colour velocity flow imaging of carotid artery flow, and transcranial Doppler (TCD) of middle cerebral artery velocities (MCAv). Three rates of GTN infusion (0.1, 0.4, 1.0 microg/kg/min) were used. There was no significant change in common or internal carotid artery flow following GTN administration although a dose dependent fall in MCAv post GTN was observed. There was no significant change in either global or regional CBF following GTN. Thus intravenous GTN at therapeutic doses in awake humans does not alter global or regional CBF. However it does produce basal cerebral artery vasodilatation as evidenced by a fall in MCAv in the absence of a change in internal carotid artery flow.

A structural model of the human thrombopoietin receptor complex.

Thrombopoietin (TPO) is a glycoprotein hormone that regulates red blood cell production. Presented here is a modeling study of the extracellular region of the human thrombopoietin receptor complex, in particular the TPO-receptor interface. The models were developed from structural homology to other cytokines and their receptors. Experimental evidence suggests that the receptor is homodimeric and it was modeled accordingly. Key interactions are shown that correlate with previous cytokine receptor complexes, and the pattern of cysteine bonding (Cys7-Cys151 and Cys29-Cys85) agrees with that experimentally determined for thrombopoietin. These models pave the way for possible mutagenesis experimentation and the design of (ant)agonists.

Colour velocity flow measurement: in vitro validation and application to human carotid arteries.

Ultrasound measurement of volume blood flow is potentially useful for many clinical situations, yet practical implementation and use are restricted by the many instrumentation and blood flow limitations that can arise. Colour velocity imaging offers a number of theoretical advantages over methods based on duplex imaging. We evaluated a colour velocity flow measurement system (CVI-Q, Philips) both in a flow phantom and in vivo in the extracranial carotid arteries of normal volunteers. Over a range of constant (50-1200 ml/min) and pulsatile (92-366 ml/min) flows and using both steered and unsteered beams with beam angles of 30 degrees and 40 degrees, errors usually within 5% were obtained for constant flow and within 10% for pulsatile flow. However, with a beam angle of 70 degrees, higher errors of 20% were obtained for pulsatile flow. The reproducibility of flow measurements made using both anterior and posterior-lateral scanning approaches was determined in the common (CCA), internal (ICA) and external carotid (ECA) arteries of 18 volunteers. A greater reproducibility was found using the posterior-lateral approach (CCA 6.27%; ICA 9.8%), and mean (SD) flow values were 376 ml/min in the CCA and 255 ml/min in the ICA. The ratio of (ICA + ECA)/CCA flow calculated for each subject individually was mean (SD) 0.95 (0.11). Insonation from an anterior approach resulted in lower reproducibility and lower flow values. In conclusion, colour flow velocity imaging allows repeatable reproducible measurements of CCA and ICA flow, but results are optimal if a posterior-lateral scanning approach is used.

Patient and hospital delays in acute ischaemic stroke in a Dublin teaching hospital.

A limiting factor for thrombolysis in ischaemic stroke is delayed presentation to hospital. Prolonged A&E stay and delayed rehabilitation affects care. We evaluated the delay in presentation, A&E stay and rehabilitation delivery in 117 consecutive stroke patients. The mean presentation delay was 16.0 +/- 23.7 hours. A prior history of TIA or stroke, a reduced Glascow Coma Scale and larger strokes were associated with shorter delays to presentation. Longer delays occurred in patients living alone. The mean time spent in A&E was 11 hours, those with larger strokes spent shorter time. There were significant delays in referral to, and assessment by certain rehabilitation disciplines. Delayed presentation in stroke is a barrier to thrombolysis. Increasing public awareness may reduce this delay. In addition, prolonged A&E stay and delayed rehabilitation may adversely affect management, outcome and duration of hospital stay. Further study is required to investigate the reasons and possible solutions for such deficiencies.

ABangle: characterising the VH-VL orientation in antibodies.

The binding site of an antibody is formed between the two variable domains, VH and VL, of its antigen binding fragment (Fab). Understanding how VH and VL orientate with respect to one another is important both for studying the mechanisms of antigen specificity and affinity and improving antibody modelling, docking and engineering. Different VH-VL orientations are commonly described using relative measures such as root-mean-square deviation. Recently, the orientation has also been characterised using the absolute measure of a VH-VL packing angle. However, a single angle cannot fully describe all modes of orientation. Here, we present a method which fully characterises VH-VL orientation in a consistent and absolute sense using five angles (HL, HC1, LC1, HC2 and LC2) and a distance (dc). Additionally, we provide a computational tool, ABangle, to allow the VH-VL orientation for any antibody to be automatically calculated and compared with all other known structures. We compare previous studies and show how the modes of orientation being identified relate to movements of different angles. Thus, we are able to explain why different studies identify different structural clusters and different residues as important. Given this result, we then identify those positions and their residue identities which influence each of the angular measures of orientation. Finally, by analysing VH-VL orientation in bound and unbound forms, we find that antibodies specific for protein antigens are significantly more flexible in their unbound form than antibodies specific for hapten antigens. ABangle is freely available at http://opig.stats.ox.ac.uk/webapps/abangle.