Genome-wide association study of metabolic traits reveals novel gene-metabolite-disease links.

Metabolic traits are molecular phenotypes that can drive clinical phenotypes and may predict disease progression. Here, we report results from a metabolome- and genome-wide association study on (1)H-NMR urine metabolic profiles. The study was conducted within an untargeted approach, employing a novel method for compound identification. From our discovery cohort of 835 Caucasian individuals who participated in the CoLaus study, we identified 139 suggestively significant (P<5×10(-8)) and independent associations between single nucleotide polymorphisms (SNP) and metabolome features. Fifty-six of these associations replicated in the TasteSensomics cohort, comprising 601 individuals from São Paulo of vastly diverse ethnic background. They correspond to eleven gene-metabolite associations, six of which had been previously identified in the urine metabolome and three in the serum metabolome. Our key novel findings are the associations of two SNPs with NMR spectral signatures pointing to fucose (rs492602, P = 6.9×10(-44)) and lysine (rs8101881, P = 1.2×10(-33)), respectively. Fine-mapping of the first locus pinpointed the FUT2 gene, which encodes a fucosyltransferase enzyme and has previously been associated with Crohn's disease. This implicates fucose as a potential prognostic disease marker, for which there is already published evidence from a mouse model. The second SNP lies within the SLC7A9 gene, rare mutations of which have been linked to severe kidney damage. The replication of previous associations and our new discoveries demonstrate the potential of untargeted metabolomics GWAS to robustly identify molecular disease markers

Comparing the effectiveness of the 0.018-inch versus the 0.022-inch bracket slot system in orthodontic treatment:study protocol for a randomized controlled trial

BACKGROUND: Edgewise fixed orthodontic appliances are available in two different bracket slot sizes (0.018 and 0.022 inch). Both systems are used by clinicians worldwide with some orthodontists claiming the superiority and clinical advantages of one system over the other. However, the scientific evidence supporting this area is scarce and weak. This leaves the clinician’s choice of bracket slot system to clinical preference. We aim to compare the 0.018-inch and 0.022-inch pre-adjusted bracket slot systems in terms of the effectiveness of orthodontic treatment. METHODS/DESIGN: This is a prospective, multicenter, randomized clinical trial, undertaken in the secondary care hospital environment in the NHS Tayside region of Scotland (United Kingdom). A total of 216 orthodontic patients will be recruited in three centers in secondary care hospitals in NHS Tayside. The participants will be randomly allocated to treatment with either the 0.018-inch or 0.022-inch bracket slot systems (n = 108 for each group) using Victory series™ conventional pre-adjusted bracket systems (3 M Unitek, Monrovia, United States). Baseline records and outcome data collected during and at the end of orthodontic treatment will be assessed. The primary outcome measures will be the duration of orthodontic treatment in the maxillary and mandibular arches. The secondary outcome measures will be the number of scheduled appointments for orthodontic treatment in the maxillary and mandibular arches, treatment outcome using Peer Assessment Rating index (PAR), orthodontically induced inflammatory root resorption (as measured using periapical radiographs) and the patient’s perception of wearing orthodontic appliances. DISCUSSION: The results from the current study will serve as evidence to guide the clinician in deciding whether the difference in bracket slot size has a significant impact on the effectiveness of orthodontic treatment. TRIAL REGISTRATION: Registered with ClinicalTrials.gov on 5 March 2014, registration number: NCT02080338

Unusual quasars from the Sloan Digital Sky Survey selected by means of Kohonen self-organising maps

We exploit the spectral archive of the Sloan Digital Sky Survey (SDSS) Data Release 7 to select unusual quasar spectra. The selection method is based on a combination of the power of self-organising maps and the visual inspection of a huge number of spectra. Self-organising maps were applied to nearly 10^5 spectra classified as quasars by the SDSS pipeline. Particular attention was paid to minimise possible contamination by rare peculiar stellar spectral types. We present a catalogue of 1005 quasars with unusual spectra. This large sample provides a useful resource for both studying properties and relations of/between different types of unusual quasars and selecting particularly interesting objects. The spectra are grouped into six types. All these types turn out to be on average more luminous than comparison samples of normal quasars after a statistical correction is made for intrinsic reddening. Both the unusual broad absorption line (BAL) quasars and the strong iron emitters have significantly lower radio luminosities than normal quasars. We also confirm that strong BALs avoid the most radio-luminous quasars. Finally, we create a sample of quasars similar to the two "mysterious" objects discovered by Hall et al. (2002) and briefly discuss the quasar properties and possible explanations of their highly peculiar spectra. (Abstract modified to match the arXiv format)Comment: Added reference to section 6; a few typos corrected; corrections according to the version published in Astronomy and Astrophysic

Rhodococcus opacus B4: a promising bacterium for production of biofuels and biobased chemicals

Bacterial lipids have relevant applications in the production of renewable fuels and biobased oleochemicals. The genus Rhodococcus is one of the most relevant lipid producers due to its capability to accumulate those compounds, mainly triacylglycerols (TAG), when cultivated on different defined substrates, namely sugars, organic acids and hydrocarbons but also on complex carbon sources present in industrial wastes. In this work, the production of storage lipids by Rhodococcus opacus B4 using glucose, acetate and hexadecane is reported for the first time and its productivity compared with Rhodococcus opacus PD630, the best TAG producer bacterium reported. Both strains accumulated mainly TAG from all carbon sources, being influenced by the carbon source itself and by the duration of the accumulation period. R. opacus B4 produced 0.09 and 0.14 g L1 at 24 and 72 h, with hexadecane as carbon source, which was 2 and 3.3 fold higher than the volumetric production obtained by R. opacus PD630. Both strains presented similar fatty acids (FA) profiles in intact cells while in TAG produced fraction, R. opacus B4 revealed a higher variability in fatty acid composition than R. opacus PD630, when both strains were cultivated on hexadecane. The obtained results open new perspectives for the use of R. opacus B4 to produce TAG, in particular using oily (alkane-contaminated) waste and wastewater as cheap raw-materials. Combining TAG production with hydrocarbons degradation is a promising strategy to achieve environmental remediation while producing added value compounds.This work was financially supported by the Portuguese Science Foundation (FCT) and European Social Fund (ESF, POPH-QREN) through the Grant given to A.R. Castro (SFRH/BD/64500/2009), the FCT Strategic Project of UID/BIO/04469/2013 unit and COMPETE 2020 (POCI-01-0145-FEDER-006684) and project RECI/BBB-EBI/0179/2012 (FCOMP-01-0124-FEDER-027462)

Cell-type specific RNA-Seq reveals novel roles and regulatory programs for terminally differentiated Dictyostelium cells

Abstract Background A major hallmark of multicellular evolution is increasing complexity by the evolution of new specialized cell types. During Dictyostelid evolution novel specialization occurred within taxon group 4. We here aim to retrace the nature and ancestry of the novel “cup” cells by comparing their transcriptome to that of other cell types. Results RNA-Seq was performed on purified mature spore, stalk and cup cells and on vegetative amoebas. Clustering and phylogenetic analyses showed that cup cells were most similar to stalk cells, suggesting that they share a common ancestor. The affinity between cup and stalk cells was also evident from promoter-reporter studies of newly identified cell-type genes, which revealed late expression in cups of many stalk genes. However, GO enrichment analysis reveal the unexpected prominence of GTPase mediated signalling in cup cells, in contrast to enrichment of autophagy and cell wall synthesis related transcripts in stalk cells. Combining the cell type RNA-Seq data with developmental expression profiles revealed complex expression dynamics in each cell type as well as genes exclusively expressed during terminal differentiation. Most notable were nine related hssA-like genes that were highly and exclusively expressed in cup cells. Conclusions This study reveals the unique transcriptomes of the mature cup, stalk and spore cells of D. discoideum and provides insight into the ancestry of cup cells and roles in signalling that were not previously realized. The data presented in this study will serve as an important resource for future studies into the regulation and evolution of cell type specialization

Ustekinumab as Induction and Maintenance Therapy for Crohn’s Disease

BACKGROUND Ustekinumab, a monoclonal antibody to the p40 subunit of interleukin-12 and inter-leukin-23, was evaluated as an intravenous induction therapy in two populations with moderately to severely active Crohn’s disease. Ustekinumab was also evaluated as subcutaneous maintenance therapy. METHODS We randomly assigned patients to receive a single intravenous dose of ustekinumab (either 130 mg or approximately 6 mg per kilogram of body weight) or placebo in two induction trials. The UNITI-1 trial included 741 patients who met the criteria for primary or secondary nonresponse to tumor necrosis factor (TNF) antagonists or had unacceptable side effects. The UNITI-2 trial included 628 patients in whom conventional therapy failed or unacceptable side effects occurred. Patients who completed these induction trials then participated in IM-UNITI, in which the 397 patients who had a response to ustekinumab were randomly assigned to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 8 weeks or every 12 weeks) or placebo. The primary end point for the induction trials was a clinical response at week 6 (defined as a decrease from baseline in the Crohn’s Disease Activity Index [CDAI] score of ≥100 points or a CDAI score <150). The primary end point for the maintenance trial was remission at week 44 (CDAI score <150). RESULTS The rates of response at week 6 among patients receiving intravenous ustekinumab at a dose of either 130 mg or approximately 6 mg per kilogram were significantly higher than the rates among patients receiving placebo (in UNITI-1, 34.3%, 33.7%, and 21.5%, respectively, with P≤0.003 for both comparisons with placebo; in UNITI-2, 51.7%, 55.5%, and 28.7%, respectively, with P<0.001 for both doses). In the groups receiving maintenance doses of ustekinumab every 8 weeks or every 12 weeks, 53.1% and 48.8%, respectively, were in remission at week 44, as compared with 35.9% of those receiving placebo (P = 0.005 and P = 0.04, respectively). Within each trial, adverse-event rates were similar among treatment groups. CONCLUSIONS Among patients with moderately to severely active Crohn’s disease, those receiving intravenous ustekinumab had a significantly higher rate of response than did those receiving placebo. Subcutaneous ustekinumab maintained remission in patients who had a clinical response to induction therapy. (Funded by Janssen Research and Development; ClinicalTrials.gov numbers, NCT01369329, NCT01369342, and NCT01369355.

HERMES: Towards an Integrated Toolbox to Characterize Functional and Effective Brain Connectivity

The analysis of the interdependence between time series has become an important field of research in the last years, mainly as a result of advances in the characterization of dynamical systems from the signals they produce, the introduction of concepts such as generalized and phase synchronization and the application of information theory to time series analysis. In neurophysiology, different analytical tools stemming from these concepts have added to the ‘traditional’ set of linear methods, which includes the cross-correlation and the coherency function in the time and frequency domain, respectively, or more elaborated tools such as Granger Causality. This increase in the number of approaches to tackle the existence of functional (FC) or effective connectivity (EC) between two (or among many) neural networks, along with the mathematical complexity of the corresponding time series analysis tools, makes it desirable to arrange them into a unified-easy-to-use software package. The goal is to allow neuroscientists, neurophysiologists and researchers from related fields to easily access and make use of these analysis methods from a single integrated toolbox. Here we present HERMES (http://hermes.ctb.upm.es), a toolbox for the Matlab® environment (The Mathworks, Inc), which is designed to study functional and effective brain connectivity from neurophysiological data such as multivariate EEG and/or MEG records. It includes also visualization tools and statistical methods to address the problem of multiple comparisons. We believe that this toolbox will be very helpful to all the researchers working in the emerging field of brain connectivity analysis

Pitch and duration pattern sequence tests in 7- to 11-year-old children: results depend on response mode

Background: Pitch pattern sequence (PPS) and duration pattern sequence (DPS) tests are frequently used in the assessment of auditory processing disorder. Current recommendations suggest alternate, interchangeable modes for responding to stimuli. Purpose: The objective of the study is to evaluate the influence of response mode (i.e., humming, pointing, and labeling) and age on PPS and DPS performance of 7- to 11-year-old children. Research Design: Laboratory-based testing of school children. Cross-sectional comparison of age, with repeated measures of age, test, ear, and response mode. Study Sample: From 452 children recruited, 228 right-handed children (109 girls) aged 7 years to 11 years 11 months (mean age 9 years 4 months) completed at least one test (PPS: 211, DPS: 198), and 181 children completed both tests. Audiology inclusion criteria include normal hearing thresholds (≤15 dB HL at octave frequencies 250–8000 Hz); word recognition in quiet ≥92%; tympanogram peak compensated static acoustic compliance 0.4–1.6 mmhos; and tympanometric peak pressure −100 to +50 daPa, all in both ears. Other inclusion criteria were Portuguese as first language; right handed; no musical training; no related, known, or observed phonological, learning, neurologic, psychiatric, or behavioral disorder; otologic history; and delayed neuropsychomotor or language development. Data Collection and Analysis: PPS: 30 trials per ear and response condition of three consecutive 500 msec duration intermixed high (1430 Hz) or low (880 Hz) frequency tones presented monaurally at 50 dB HL. The first response condition was humming followed by labeling (naming: high or low). DPS: As per PPS except 1000 Hz tones of intermixed 500 (long) and 250 msec (short) duration. First response was pointing (at a symbolic object) followed by labeling. Trends across age and between tests were assessed using repeated measures generalized linear mixed models. Correlation coefficients were calculated to assess relations among test scores. The two-sided significance level was 0.05. Results: Older children performed better than younger children in all tasks. Humming the tone pattern (PPS humming) produced generally better performance than either articulating the attributes of the tones (labeling) or pointing to objects representing tone duration. PPS humming produced ceiling performance for many children of all ages. For both labeling tasks and DPS pointing, performance was better on the PPS than on the DPS, for stimulation of the right than the left ear, and in boys than girls. Individual performance on the two tasks was highly correlated. Conclusions: Response mode does matter in the PPS and DPS. Results from humming should not be combined with or be a substitute for results obtained from a labeling response. Tasks that rely on labeling a tonal stimulus should be avoided in testing hearing in children or other special populations

Teaching compassion for social accountability: A parallaxic investigation

Background: In an arts integrated interdisciplinary study set to investigate ways to improve social accountability (SA) in medical education, our research team has established a renewed understanding of compassion in the current SA movement. Aim: This paper explores the co-evolution of compassion and SA. Methods: The study used an arts integrated approach to investigate people’s perceptions of SA in four medical schools across Australia, Canada, and the USA. Each school engaged approximately 25 participants who partook in workshops and in-depth interviews. Results: We began with a study of SA and the topic of compassion emerged out of our qualitative data and biweekly meetings within the research team. Content analysis of the data and pedagogical discussion brought us to realize the importance of compassion in the practice of SA. Conclusions: The cultivation of compassion needs to play a significant role in a socially accountable medical educational system. Medical schools as educational institutions may operate themselves with compassion as a driving force in engaging partnership with students and communities. Social accountability without compassion is not SA; compassion humanizes institutional policy by engaging sympathy and care