Potential conservation of circadian clock proteins in the phylum Nematoda as revealed by bioinformatic searches

Although several circadian rhythms have been described in C. elegans, its molecular clock remains elusive. In this work we employed a novel bioinformatic approach, applying probabilistic methodologies, to search for circadian clock proteins of several of the best studied circadian model organisms of different taxa (Mus musculus, Drosophila melanogaster, Neurospora crassa, Arabidopsis thaliana and Synechoccocus elongatus) in the proteomes of C. elegans and other members of the phylum Nematoda. With this approach we found that the Nematoda contain proteins most related to the core and accessory proteins of the insect and mammalian clocks, which provide new insights into the nematode clock and the evolution of the circadian system.Fil: Romanowski, Andrés. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; ArgentinaFil: Garavaglia, Matías Javier. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Ing.genética y Biolog.molecular y Celular. Area Virus de Insectos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Goya, María Eugenia. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Ghiringhelli, Pablo Daniel. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Ing.genética y Biolog.molecular y Celular. Area Virus de Insectos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Golombek, Diego Andres. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Cost-utility analysis of repetitive transcranial magnetic stimulation as add-on therapy to standard care for the treatment of hallucinations in schizophrenia

Abstract Background This research evaluates the cost-effectiveness of repetitive transcranial magnetic stimulation (rTMS) as add-on therapy to standard care for adults with schizophrenia from an Australian health system perspective. Methods A Markov model estimated costs in 2021 Australian dollars and Disability-Adjusted Life-Years (DALYs) averted with rTMS added to standard care compared to standard care alone over 12-months for adults aged 25-65 years with hallucinations in schizophrenia refractory to other therapies. rTMS effect size was sourced from a meta-analysis and converted to a relative risk using the Cochrane conversion method. Probabilistic sensitivity analysis evaluated uncertainty in effect size and disability weights. One-way sensitivity analyses varied rTMS session cost and effectiveness, time horizon and inpatient costs. Results The base-case average incremental cost-effectiveness ratio (ICER) was $87,310/DALY averted (95$10,157-$97,877). Reducing rTMS session cost to$100 lowered the ICER to $9,127/DALY (95$50,699). A 4-year time horizon resulted in rTMS being less costly and more effective (Dominant) than standard care. Decreasing the 3-month probability of relapse with rTMS to 4.6% resulted in a 71% probability of rTMS being cost-effective. Conclusions Using a threshold of $50,000/ DALY averted, rTMS as add-on therapy to standard care for the treatment of refractory hallucinations in schizophrenia would not be considered a cost-effective treatment option compared to standard care alone. However, given the refractory nature of this condition and the relatively small size of this population, it may be reasonable for decision-makers to adopt a higher ICER threshold

Measurement of the inclusive and dijet cross-sections of b-jets in pp collisions at sqrt(s) = 7 TeV with the ATLAS detector

The inclusive and dijet production cross-sections have been measured for jets containing b-hadrons (b-jets) in proton-proton collisions at a centre-of-mass energy of sqrt(s) = 7 TeV, using the ATLAS detector at the LHC. The measurements use data corresponding to an integrated luminosity of 34 pb^-1. The b-jets are identified using either a lifetime-based method, where secondary decay vertices of b-hadrons in jets are reconstructed using information from the tracking detectors, or a muon-based method where the presence of a muon is used to identify semileptonic decays of b-hadrons inside jets. The inclusive b-jet cross-section is measured as a function of transverse momentum in the range 20 < pT < 400 GeV and rapidity in the range |y| < 2.1. The bbbar-dijet cross-section is measured as a function of the dijet invariant mass in the range 110 < m_jj < 760 GeV, the azimuthal angle difference between the two jets and the angular variable chi in two dijet mass regions. The results are compared with next-to-leading-order QCD predictions. Good agreement is observed between the measured cross-sections and the predictions obtained using POWHEG + Pythia. MC@NLO + Herwig shows good agreement with the measured bbbar-dijet cross-section. However, it does not reproduce the measured inclusive cross-section well, particularly for central b-jets with large transverse momenta.Comment: 10 pages plus author list (21 pages total), 8 figures, 1 table, final version published in European Physical Journal

Characterization of primary human hepatocyte spheroids as a model system for drug-induced liver injury, liver function and disease

Liver biology and function, drug-induced liver injury (DILI) and liver diseases are difficult to study using current in vitro models such as primary human hepatocyte (PHH) monolayer cultures, as their rapid de-differentiation restricts their usefulness substantially. Thus, we have developed and extensively characterized an easily scalable 3D PHH spheroid system in chemically-defined, serum-free conditions. Using whole proteome analyses, we found that PHH spheroids cultured this way were similar to the liver in vivo and even retained their inter-individual variability. Furthermore, PHH spheroids remained phenotypically stable and retained morphology, viability, and hepatocyte-specific functions for culture periods of at least 5 weeks. We show that under chronic exposure, the sensitivity of the hepatocytes drastically increased and toxicity of a set of hepatotoxins was detected at clinically relevant concentrations. An interesting example was the chronic toxicity of fialuridine for which hepatotoxicity was mimicked after repeated-dosing in the PHH spheroid model, not possible to detect using previous in vitro systems. Additionally, we provide proof-of-principle that PHH spheroids can reflect liver pathologies such as cholestasis, steatosis and viral hepatitis. Combined, our results demonstrate that the PHH spheroid system presented here constitutes a versatile and promising in vitro system to study liver function, liver diseases, drug targets and long-term DILI

Brazilian adolescents' knowledge and beliefs about abortion methods: A school-based internet inquiry

Background: Internet surveys that draw from traditionally generated samples provide the unique conditions to engage adolescents in exploration of sensitive health topics.Methods: We examined awareness of unwanted pregnancy, abortion behaviour, methods, and attitudes toward specific legal indications for abortion via a school-based internet survey among 378 adolescents aged 12-21 years in three Rio de Janeiro public schools.Results: Forty-five percent knew peers who had undergone an abortion. Most students (66.0%) did not disclose abortion method knowledge. However, girls (aOR 4.2, 95% CI 2.4-7.2), those who had experienced their sexual debut (aOR1.76, 95% CI 1.1-3.0), and those attending a prestigious magnet school (aOR 2.7 95% CI 1.4-6.3) were more likely to report methods. Most abortion methods (79.3%) reported were ineffective, obsolete, and/or unsafe. Herbs (e.g. marijuana tea), over-the-counter medications, surgical procedures, foreign objects and blunt trauma were reported. Most techniques (85.2%) were perceived to be dangerous, including methods recommended by the World Health Organization. A majority (61.4%) supported Brazil's existing law permitting abortion in the case of rape. There was no association between gender, age, sexual debut, parental education or socioeconomic status and attitudes toward legal abortion. However, students at the magnet school supported twice as many legal indications (2.7, SE.27) suggesting a likely role of peers and/or educators in shaping abortion views.Conclusions: Abortion knowledge and attitudes are not driven simply by age, religion or class, but rather a complex interplay that includes both social spaces and gender. Prevention of abortion morbidity and mortality among adolescents requires comprehensive sexuality and reproductive health education that includes factual distinctions between safe and unsafe abortion methods

Quantitative imaging of concentrated suspensions under flow

We review recent advances in imaging the flow of concentrated suspensions, focussing on the use of confocal microscopy to obtain time-resolved information on the single-particle level in these systems. After motivating the need for quantitative (confocal) imaging in suspension rheology, we briefly describe the particles, sample environments, microscopy tools and analysis algorithms needed to perform this kind of experiments. The second part of the review focusses on microscopic aspects of the flow of concentrated model hard-sphere-like suspensions, and the relation to non-linear rheological phenomena such as yielding, shear localization, wall slip and shear-induced ordering. Both Brownian and non-Brownian systems will be described. We show how quantitative imaging can improve our understanding of the connection between microscopic dynamics and bulk flow.Comment: Review on imaging hard-sphere suspensions, incl summary of methodology. Submitted for special volume 'High Solid Dispersions' ed. M. Cloitre, Vol. xx of 'Advances and Polymer Science' (Springer, Berlin, 2009); 22 pages, 16 fig

Plume Characterization of a Typical South African Braai

To braai is part of the South African heritage that transcends ethnic barriers and socio-economic groups. In this paper, a comprehensive analysis of atmospheric gaseous and aerosol species within a plume originating from a typical South African braai is presented. Braai experiments were conducted at Welgegund – a comprehensively equipped regional background atmospheric air quality and climate change monitoring station. Five distinct phases were identified during the braai. Sulphur dioxide (SO2), nitrogen oxides(NOx) and carbonmonoxide (CO) increased significantly, while ozone (O3) did not increase notably. Aromatic and alkane volatile organic compounds were determined, with benzene exceeding the 2015 South African one-year ambient air quality limit. A comparison of atmospheric PM10 (particulate matter of an aerodynamic diameter ≤10 μm) concentrations with the 24-hour ambient limit indicated that PM10 is problematic during the meat grilling phase. From a climatic point of view, relatively high single scattering albedo (ωo) indicated a cooling aerosol direct effect, while periods with lowerωo coincided with peak black carbon (BC) emissions. The highest trace metal concentrations were associated with species typically present in ash. The lead (Pb) concentration was higher than the annual ambient air quality limit. Sulphate (SO4 2–), calcium (Ca2+) and magnesium (Mg2+) were the dominant water-soluble species present in the aerosols. The largest number of organic aerosol compounds was in the PM 2.5–1 fraction, which also had the highest semi-quantified concentration. The results indicated that a recreational braai does not pose significant health risks. However, the longer exposure periods that are experienced by occupational vendors, will significantly increase health risks.KEYWORDS Braai (barbeque), atmospheric gaseous species, aerosols, atmospheric organic compounds, optical properties, chemical properties

Luteinizing hormone and androstendione are independent predictors of ovulation after laparoscopic ovarian drilling: a retrospective cohort study

<p>Abstract</p> <p>Background</p> <p>Our objective was to investigate luteinizing hormone, follicle-stimulating hormone, testosterone, and androstenedione as predicitve markers for ovulation after laparoscopic ovarian drilling.</p> <p>Methods</p> <p>We retrospectively analyzed 100 clompihen-resistant patients with the polycystic ovary syndrome who underwent laparoscopic ovarian drilling at our department. The main outcome measure was spontaneous postoperative ovulation within three months after laparoscopic ovarian drilling. In order to predict spontaneous ovulation, we tested the following parameters by use of a univariate followed by a multivariate regression model: Preoperative serum levels of LH, FSH, testosterone, and androstenedione as well as patients' age and body mass index. In addition, we focused on pregnancy and life birth rates.</p> <p>Results</p> <p>Spontaneous ovulation was documented in 71/100 patients (71.0%). In a univariate and multivariate analysis, luteinizing hormone (OR 1.58, 95%CI: 1.30-1.92) and androstenedione (OR 3.03, 95%CI: 1.20-7.67), but not follicle-stimulating hormone and testosterone were independent predictors of ovulation. Using a cut-off for luteinizing hormone and androstenedione of 12.1 IU/l and 3.26 ng/ml, respectively, spontaneous ovulation was observed in 63/70 (90.0%) and 36/42 patients (85.7%) with elevated and in 8/30 (26.7%) and 35/58 (60.3%) patients with low luteinizing hormone and androstenedione levels, respectively. The sensitivity, specificity, positive and negatvie predictive values for luteinizing hormone and androstendione as predictors of spontaneous ovulation after ovarian drilling were 88.7% (95%CI: 79.0-95.0%), 75.9% (95%CI: 56.5-89.7%), 90.0% (95%CI: 80.5-95.8%), and 73.3% (95%CI: 54.1-87.7%) for luteinizing hormone, and 50.7% (95%CI: 38.6-62.8%), 79.3% (95%CI: 60.3-92.0%), 85.7% (95%CI: 71.5-94.6%), and 39.7% (95%CI: 27.0-53.4%) for androstenedione, respectively. Complete one-year follow-up was available for 74/100 patients (74%). We observed a one-year pregnancy rate and a resulting life-birth rate of 61% and 51%, respectively.</p> <p>Conclusions</p> <p>Luteinizing hormone and androstenedione prior to laparoscopic ovarian drilling are independent predictors of spontaneous ovulation within three months of surgery. We suggest to preferentially performing laparoscopic ovarian drilling in patients with high luteinizing hormone and androstenedione levels.</p

A Bioinformatics Classifier and Database for Heme-Copper Oxygen Reductases

Background: Heme-copper oxygen reductases (HCOs) are the last enzymatic complexes of most aerobic respiratory chains, reducing dioxygen to water and translocating up to four protons across the inner mitochondrial membrane (eukaryotes) or cytoplasmatic membrane (prokaryotes). The number of completely sequenced genomes is expanding exponentially, and concomitantly, the number and taxonomic distribution of HCO sequences. These enzymes were initially classified into three different types being this classification recently challenged. Methodology:We reanalyzed the classification scheme and developed a new bioinformatics classifier for the HCO and Nitric oxide reductases (NOR), which we benchmark against a manually derived gold standard sequence set. It is able to classify any given sequence of subunit I from HCO and NOR with a global recall and precision both of 99.8%. We use this tool to classify this protein family in 552 completely sequenced genomes. Conclusions: We concluded that the new and broader data set supports three functional and evolutionary groups of HCOs. Homology between NORs and HCOs is shown and NORs closest relationship with C Type HCOs demonstrated. We established and made available a classification web tool and an integrated Heme-Copper Oxygen reductase and NOR protein database (www.evocell.org/hco)

Selective APRIL Blockade Delays Systemic Lupus Erythematosus in Mouse

SLE pathogenesis is complex, but it is now widely accepted that autoantibodies play a key role in the process by forming excessive immune complexes; their deposits within tissues leading to inflammation and functional damages. A proliferation inducing ligand (APRIL) is a member of the tumor necrosis factor (TNF) superfamily mediating antibody-producing plasma cell (PC)-survival that may be involved in the duration of pathogenic autoantibodies in lupus. We found significant increases of APRIL at the mRNA and protein levels in bone marrow but not spleen cells from NZB/W lupus mice, as compared to control mice. Selective antibody-mediated APRIL blockade delays disease development in this model by preventing proteinuria, kidney lesions, and mortality. Notably, this was achieved by decreasing anti-DNA and anti-chromatin autoantibody levels, without any perturbation of B- and T- cell homeostasis. Thus, anti-APRIL treatment may constitute an alternative therapy in SLE highly specific to PCs compared to other B-cell targeting therapies tested in this disease, and likely to be associated with less adverse effects than any anti-inflammatory and immunosuppressant agents previously used