Carotenoid metabolic profiling and transcriptome-genome mining reveal functional equivalence among blue-pigmented copepods and appendicularia.
The tropical oligotrophic oceanic areas are characterized by high water transparency and annual solar radiation. Under these conditions, a large number of phylogenetically diverse mesozooplankton species living in the surface waters (neuston) are found to be blue pigmented. In the present study, we focused on understanding the metabolic and genetic basis of the observed blue phenotype functional equivalence between the blue-pigmented organisms from the phylum Arthropoda, subclass Copepoda (Acartia fossae) and the phylum Chordata, class Appendicularia (Oikopleura dioica) in the Red Sea. Previous studies have shown that carotenoid-protein complexes are responsible for blue coloration in crustaceans. Therefore, we performed carotenoid metabolic profiling using both targeted and nontargeted (high-resolution mass spectrometry) approaches in four different blue-pigmented genera of copepods and one blue-pigmented species of appendicularia. Astaxanthin was found to be the principal carotenoid in all the species. The pathway analysis showed that all the species can synthesize astaxanthin from β-carotene, ingested from dietary sources, via 3-hydroxyechinenone, canthaxanthin, zeaxanthin, adonirubin or adonixanthin. Further, using de novo assembled transcriptome of blue A. fossae (subclass Copepoda), we identified highly expressed homologous β-carotene hydroxylase enzymes and putative carotenoid-binding proteins responsible for astaxanthin formation and the blue phenotype. In blue O. dioica (class Appendicularia), corresponding putative genes were identified from the reference genome. Collectively, our data provide molecular evidences for the bioconversion and accumulation of blue astaxanthin-protein complexes underpinning the observed ecological functional equivalence and adaptive convergence among neustonic mesozooplankton.


Early and late stage of neurodegeneration induced by trimethyltin in hippocampus and cortex of male Wistar rats.
Trimethyltin (TMT), a potent neurotoxicant, elicits neuronal death in the limbic system and causes damage particularly in the hippocampus. Current interest relates to the opportunity to use TMT as an experimental model of neurodegeneration in the study of Alzheimer-like diseases. In light of recently found species-specific and strain-specific differences in TMT intoxication, the aim of this study was to characterise the model of TMT-induced neurodegeneration in the brain of Wistar rats during early (days 1-3) and late (days 22-24) stage of neuronal damage. Reduced neurotransmission at the CA3-CA1 synapse and reduced number of cells accompanied with reduced width of CA1 pyramidal cell layer were observed at the late stage of TMT intoxication (7 mg/kg, i.p.). Long-term potentiation of excitatory postsynaptic potential, elicited by train stimulation (100 Hz, 1s), was not impaired by the dose of TMT tested. Activation of pro-apoptotic caspase-3 suggests involvement of apoptosis in neuronal cell death in the hippocampus at the late stage of TMT intoxication. Increased protein carbonyl formation was proved in the cortex at the early stage of TMT intoxication compared both to controls in the early and late stage and to the late stage of TMT action. TMT-induced neurodegeneration was proved in the brain of Wistar rats. Changes found in the parameters examined may be reliable indicators of neurodegeneration. The increased level of carbonyls in the cortex at the early stage indicates that particularly at the onset of progressive neurodegeneration compounds with antioxidative properties may be effective in slowing down brain injury.


A study of Ca(2+)-heparin complex-formation by polarimetry.
Possible inflexions in isothermal binding plots derived from equilibrium-dialysis measurements and in equivalent plots obtained by polarimetric measurements accord with the possibility that discrete Ca(2+)-heparin-water complexes/phases may exist, the nature and proportions of which depend on the conditions under which the interaction occurs. Analysis of the plots obtained by polarimetric study of chemically modified heparins suggests, for individual substituents groups, an order of importance of carboxylate greater than N-sulphonate greater than N-acetyl greater than O-sulphate for the Ca(2+)-heparin interaction occurring at [Ca2+]/[heparin disaccharide] ratios of less than 0.5. At higher ratios, transitions occur that eventually lead to the formation of a complex in which the stoichiometry of association is 1 Ca2+ ion/heparin disaccharide unit.


Phlebotomine sand flies (Diptera: Psychodidae) in the municipality of Várzea Grande: an area of transmission of visceral leishmaniasis in the state of Mato Grosso, Brazil.
Visceral leishmaniasis (VL) has been naturally transmitted in periurban areas due to the emergence and reemergence of its vectors in such areas. Aimed to further knowledge on ecological aspects affecting the occurrence of phlebotomine sand flies in VL transmission areas in the municipality of Várzea Grande, state of Mato Grosso (MT), Brazil, sand fly captures were carried out. Monthly collections of sand flies were undertaken with CDC light-traps, which were left in both intradomiciliary and peridomiciliary areas of ten residences during four consecutive days between January 2004 and June 2006. Twenty-two species of genus Lutzomyia and one of Brumptomyia were captured. The most abundant species was Lutzomyia longipalpis (65.23%), followed by L. evandroi (16.26%), L. lenti (7.69%), L. whitmani (4.92%), L. sallesi (2.34%) and L. termitophila (1.32%). The highest density of the main VL vector, L. longipalpis, was found in peridomiciliary areas, mostly males. No significant correlation was found between environment (temperature, air relative humidity and rain fall) and phlebotomine density; although a slight increase in sand fly density has been observed in the period following rainfalls, particularly L. longipalpis. No correlation was observed between distribution and density of L. longipalpis, prevalence of human VL cases and the presence of serologically positive dogs. The presence of infected dogs, increased vector density, susceptibility rate and interruption of epidemiological surveillance may raise the risk of VL transmission to man in Várzea Grande.


The geographical distribution of fossil fuels unused when limiting global warming to 2 °C.
Policy makers have generally agreed that the average global temperature rise caused by greenhouse gas emissions should not exceed 2 °C above the average global temperature of pre-industrial times. It has been estimated that to have at least a 50 per cent chance of keeping warming below 2 °C throughout the twenty-first century, the cumulative carbon emissions between 2011 and 2050 need to be limited to around 1,100 gigatonnes of carbon dioxide (Gt CO2). However, the greenhouse gas emissions contained in present estimates of global fossil fuel reserves are around three times higher than this, and so the unabated use of all current fossil fuel reserves is incompatible with a warming limit of 2 °C. Here we use a single integrated assessment model that contains estimates of the quantities, locations and nature of the world's oil, gas and coal reserves and resources, and which is shown to be consistent with a wide variety of modelling approaches with different assumptions, to explore the implications of this emissions limit for fossil fuel production in different regions. Our results suggest that, globally, a third of oil reserves, half of gas reserves and over 80 per cent of current coal reserves should remain unused from 2010 to 2050 in order to meet the target of 2 °C. We show that development of resources in the Arctic and any increase in unconventional oil production are incommensurate with efforts to limit average global warming to 2 °C. Our results show that policy makers' instincts to exploit rapidly and completely their territorial fossil fuels are, in aggregate, inconsistent with their commitments to this temperature limit. Implementation of this policy commitment would also render unnecessary continued substantial expenditure on fossil fuel exploration, because any new discoveries could not lead to increased aggregate production.


Phytochemical Characterization, In Vitro Anti-Inflammatory, Anti-Diabetic, and Cytotoxic Activities of the Edible Aromatic Plant; Pulicaria jaubertii.
Pulicaria jaubertii is a medicinal herb that alleviates inflammations and fever. Chromatographic separation, phytochemical characterization, and in vitro biological activities of the plant n-hexane extract were conducted for the first time in this study. Six compounds were isolated for the first time from the n-hexane fraction of Pulicaria jaubertii aerial parts and were identified on the bases of NMR and MS analyses as pseudo-taraxaterol (1), pseudo-taraxasterol acetate (2), 3β-acetoxytaraxaster-20-en-30-aldehyde (3), calenduladiol-3-O-palmitate (4), stigmasterol (5), and α-tocospiro B (6). Compound (6) was a rare tocopherol-related compound and was isolated for the first time from family Asteraceae, while compound (3) was isolated for the first time from genus Pulicaria. The total alcoholic extract and n-hexane fraction were tested for their anti-inflammatory, antidiabetic, and cytotoxic activities. The n-hexane fraction has dose dependent red blood cells (RBCs) membrane stabilization and inhibition of histamine release activities with IC50: 60.8 and 72.9 µg/mL, respectively. As antidiabetic activity, the alcoholic extract exerted the most inhibition on the activity of yeast α-glucosidase, with an IC50: 76.8 µg/mL. The n-hexane fraction showed cytotoxic activity against hepatocarcinoma (HepG-2), breast carcinoma (MCF-7), and prostate carcinoma (PC-3) cell lines with IC50: 51.8, 90.8 and 62.2 µg/mL, respectively. In conclusion, the anti-inflammatory effect of Pulicaria jaubertii might be attributed to the triterpenoid constituents of the n-hexane extract of the plant.


Use of ultra-thin window detectors for biological microanalysis.
Films and bulk samples of Nylon, gelatin, Makrofol, epoxy resin, aminoplastic resin and sodium acetate have been used as models of biological samples. It is shown that the use of ultrathin window (UTW) detectors in scanning transmission and scanning electron microsopes permits the quantitative analysis of light elements, yielding a total element analysis with hydrogen estimated by difference or "guesstimated". Comparison with known concentrations of concentrations obtained by chemical analysis shows that X-ray microanalysis of selections by the peak to continuum ratio model and bulk samples by the phi(pz) model gives sufficiently accurate results for biological purposes. It is also shown that sections may be analysed by the standardless ratio model. The application of UTW detectors to total element analysis by quantitative elemental imaging is demonstrated of bulk biological samples. which have been freeze-substituted, embedded in epoxy resin and surface polished. The possibility of imaging the oxygen content of frozen-hydrated bulk tissue samples which have been surface polished is also demonstrated. This may lead to the imaging of water distribution in frozen-hydrated bulk samples of biological tissues. UTW detectors are also useful for detecting mass loss in organic samples by monitoring the decrease in oxygen counts and for detecting contamination by monitoring the increase in carbon counts. It is also shown that changes in carbon counts are good indicators of folds in sections.


Consuming sex: the association between modern goods, lifestyles and sexual behaviour among youth in Madagascar.
Ethnographic evidence suggests that transactional sex is sometimes motivated by youth's interest in the consumption of modern goods as much as it is in basic survival. There are very few quantitative studies that examine the association between young people's interests in the consumption of modern goods and their sexual behaviour. We examined this association in two regions and four residence zones of Madagascar: urban, peri-urban and rural Antananarivo, and urban Antsiranana. We expected risky sexual behaviour would be associated with interests in consuming modern goods or lifestyles; urban residence; and socio-cultural characteristics. We administered a population-based survey to 2, 255 youth ages 15-24 in all four residence zones. Focus group discussions guided the survey instrument which assessed socio-demographic and economic characteristics, consumption of modern goods, preferred activities and sexual behaviour. Our outcomes measures included: multiple sexual partners in the last year (for men and women); and ever practicing transactional sex (for women). Overall, 7.3% of women and 30.7% of men reported having had multiple partners in the last year; and 5.9% of women reported ever practicing transactional sex. Bivariate results suggested that for both men and women having multiple partners was associated with perceptions concerning the importance of fashion and a series of activities associated with modern lifestyles. A subset of lifestyle characteristics remained significant in multivariate models. For transactional sex bivariate results suggested perceptions around fashion, nightclub attendance, and getting to know a foreigner were key determinants; and all remained significant in multivariate analysis. We found peri-urban residence more associated with transactional sex than urban residence; and ethnic origin was the strongest predictor of both outcomes for women. While we found indication of an association between sexual behaviour and interest in modern goods, or modern lifestyles, such processes did not single-handedly explain risky sexual behaviour among youth; these behaviours were also shaped by culture and conditions of economic uncertainty. These determinants must all be accounted for when developing interventions to reduce risky transactional sex and vulnerability to HIV.


Joint Modeling of Chest Radiographs and Radiology Reports for Pulmonary Edema Assessment.
We propose and demonstrate a novel machine learning algorithm that assesses pulmonary edema severity from chest radiographs. While large publicly available datasets of chest radiographs and free-text radiology reports exist, only limited numerical edema severity labels can be extracted from radiology reports. This is a significant challenge in learning such models for image classification. To take advantage of the rich information present in the radiology reports, we develop a neural network model that is trained on both images and free-text to assess pulmonary edema severity from chest radiographs at inference time. Our experimental results suggest that the joint image-text representation learning improves the performance of pulmonary edema assessment compared to a supervised model trained on images only. We also show the use of the text for explaining the image classification by the joint model. To the best of our knowledge, our approach is the first to leverage free-text radiology reports for improving the image model performance in this application. Our code is available at: https://github.com/RayRuizhiLiao/joint_chestxray.


Learning at large conferences: from the 'sage on the stage' to contemporary models of learning.
To explore and evaluate the affordances of a flipped classroom model applied to a research paper session within the professional development opportunity of a large conference setting. Authors were invited to present their research papers in a flipped classroom presentation format at two large, multi-national conferences. Before the session, authors and moderators met online to clarify features of the session, and preparation of the material. The research material was then posted online before the conference, to allow access by meeting attendees. During the sessions, moderators encouraged the audience to actively participate. An evaluation form was collected from the audience at the end of each session. Participants found the session valuable, and appreciated the opportunity to engage in a meaningful dialogue with colleagues. However, the majority of the audience did not access the materials in advance. Lack of time, or technology-related issues were mentioned as potential challenges to such format. In the context of a large conference, a 'flipped session' format can facilitate active learning and a participatory culture of inquiry. However, to change the nature of how individuals learn collaboratively at large conferences means a change in the culture of continuous professional learning.


Assessing Uncertainty and Reliability of Connective Field Estimations From Resting State fMRI Activity at 3T.
Connective Field (CF) modeling estimates the local spatial integration between signals in distinct cortical visual field areas. As we have shown previously using 7T data, CF can reveal the visuotopic organization of visual cortical areas even when applied to BOLD activity recorded in the absence of external stimulation. This indicates that CF modeling can be used to evaluate cortical processing in participants in which the visual input may be compromised. Furthermore, by using Bayesian CF modeling it is possible to estimate the co-variability of the parameter estimates and therefore, apply CF modeling to single cases. However, no previous studies evaluated the (Bayesian) CF model using 3T resting-state fMRI data. This is important since 3T scanners are much more abundant and more often used in clinical research compared to 7T scanners. Therefore in this study, we investigate whether it is possible to obtain meaningful CF estimates from 3T resting state (RS) fMRI data. To do so, we applied the standard and Bayesian CF modeling approaches on two RS scans, which were separated by the acquisition of visual field mapping data in 12 healthy participants. Our results show good agreement between RS- and visual field (VF)- based maps using either the standard or Bayesian CF approach. In addition to quantify the uncertainty associated with each estimate in both RS and VF data, we applied our Bayesian CF framework to provide the underlying marginal distribution of the CF parameters. Finally, we show how an additional CF parameter, beta, can be used as a data-driven threshold on the RS data to further improve CF estimates. We conclude that Bayesian CF modeling can characterize local functional connectivity between visual cortical areas from RS data at 3T. Moreover, observations obtained using 3T scanners were qualitatively similar to those reported for 7T. In particular, we expect the ability to assess parameter uncertainty in individual participants will be important for future clinical studies.


Parathyroid hormone and teriparatide for the treatment of osteoporosis: a review of the evidence and suggested guidelines for its use.
All therapies currently recommended for the management of osteoporosis act mainly to inhibit bone resorption and reduce bone remodeling. PTH and its analog, teriparatide [recombinant human PTH(1-34)], represent a new class of anabolic therapies for the treatment of severe osteoporosis, having the potential to improve skeletal microarchitecture. Significant reductions in both vertebral and appendicular fracture rates have been demonstrated in the phase III trial of teriparatide, involving elderly women with at least one prevalent vertebral fracture before the onset of therapy. However, there is as yet no evidence that the antifracture efficacy of PTH will be superior to the bisphosphonates, whereas cost-utility estimates suggest that teriparatide is significantly more expensive. Teriparatide should be considered as treatment for postmenopausal women and men with severe osteoporosis, as well as for patients with established glucocorticoid-induced osteoporosis who require long-term steroid treatment. Teriparatide should also be considered for the management of individuals at particularly high risk for fractures, including subjects who are younger than age 65 and who have particularly low bone mineral density measurements (T scores < or = 3.5). Teriparatide therapy is not recommended for more than 2 yr, based, in part, on the induction of osteosarcoma in a rat model of carcinogenicity. Total daily calcium intake from both supplements and dietary sources should be limited to 1500 mg together with adequate vitamin D intake (< or =1000 U/d). Monitoring of serum calcium may be safely limited to measurement after 1 month of treatment; mild hypercalcemia may be treated by withdrawing dietary calcium supplements, reducing the dosing frequency of PTH, or both. At present, concurrent therapy with antiresorptive therapy, particularly bisphosphonates, should be avoided, although sequential therapy with such agents may consolidate the beneficial effects upon the skeleton after PTH is discontinued.


Terpene synthases in disguise: enzymology, structure, and opportunities of non-canonical terpene synthases.
Covering: up to July 2019 Terpene synthases (TSs) are responsible for generating much of the structural diversity found in the superfamily of terpenoid natural products. These elegant enzymes mediate complex carbocation-based cyclization and rearrangement cascades with a variety of electron-rich linear and cyclic substrates. For decades, two main classes of TSs, divided by how they generate the reaction-triggering initial carbocation, have dominated the field of terpene enzymology. Recently, several novel and unconventional TSs that perform TS-like reactions but do not resemble canonical TSs in sequence or structure have been discovered. In this review, we identify 12 families of non-canonical TSs and examine their sequences, structures, functions, and proposed mechanisms. Nature provides a wide diversity of enzymes, including prenyltransferases, methyltransferases, P450s, and NAD+-dependent dehydrogenases, as well as completely new enzymes, that utilize distinctive reaction mechanisms for TS chemistry. These unique non-canonical TSs provide immense opportunities to understand how nature evolved different tools for terpene biosynthesis by structural and mechanistic characterization while affording new probes for the discovery of novel terpenoid natural products and gene clusters via genome mining. With every new discovery, the dualistic paradigm of TSs is contradicted and the field of terpene chemistry and enzymology continues to expand.


Herbal Teas and their Health Benefits: A Scoping Review.
Herbal teas are used as therapeutic vehicles in many forms of traditional medicine and are a popular global beverage. The purpose of this scoping review was to examine the evidence relating to the clinical efficacy and safety of herbal teas, and to identify the main research themes and gaps in knowledge to inform further work. A scoping review methodology was followed that set out the research question and described the sourcing, selection and analysis of studies. Overall, a total of 145 research publications were retrieved from global bibliographic databases, and after applying exclusion criteria, 21 remained. These studies looked at herbal tea use in female health, diabetes, heart disease and weight loss, with plant species including lavender, chamomile, fenugreek, stinging nettle, spearmint, hibiscus, yerba maté, echinacea and combinations of herbs. Observational studies explored associations between herbal tea consumption and cancer risk, liver health, and the risks linked to the consumption of environmental contaminants in the plant material. Despite plant materials being the basis for drug discovery, and the popularity of herbal teas, the number of articles exploring clinical efficacy and safety is small. In this review we discuss how herbal teas may be beneficial in some areas of clinical and preventative health, and what further research is required to understand whether regular consumption can contribute to healthy living more generally.


Peptidases and amino acid catabolism in lactic acid bacteria.
The conversion of peptides to free amino acids and their subsequent utilization is a central metabolic activity in prokaryotes. At least 16 peptidases from lactic acid bacteria (LAB) have been characterized biochemically and/or genetically. Among LAB, the peptidase systems of Lactobacillus helveticus and Lactococcus lactis have been examined in greatest detail. While there are homologous enzymes common to both systems, significant differences exist in the peptidase complement of these organisms. The characterization of single and multiple peptidase mutants indicate that these strains generally exhibit reduced specific growth rates in milk compared to the parental strains. LAB can also catabolize amino acids produced by peptide hydrolysis. While the catabolism of amino acids such as Arg, Thr, and His is well understood, few other amino acid catabolic pathways from lactic acid bacteria have been characterized in significant detail. Increasing research attention is being directed toward elucidating these pathways as well as characterizing their physiological and industrial significance.


Correlation between Thyroid Stimulating Hormone and Renal Function in Euthyroid Residents of Japan: Results from the Kyushu and Okinawa Population Study (KOPS).
The present large-scale Japanese population study was performed to evaluate the relation between the serum thyroid stimulating hormone (TSH) level and renal function. Out of 1,374 residents who participated in a free public physical examination between 2010 and 2011, we evaluated the data of 888 participants for whom the serum TSH level and estimated glomerular filtration rate (eGFR) were successfully measured. The participants were categorized into three groups based on TSH levels (normal TSH, ≤2.4; high-normal TSH, 2.5-4.4; and subclinical hypothyroid, ≥4.5 μIU/mL). Multiple linear regression analysis adjusted for cardiovascular risk factors was performed to determine the relationship between serum TSH level and renal function. The mean±SD TSH level was 2.0±1.4 μIU/mL, and 75.9% (n=674) of the participants had normal, 17.9% (n=159) had high-normal, and 6.2% (n=55) had subclinical hypothyroid TSH levels. The mean eGFR significantly decreased with increased TSH levels (normal TSH, 79.3±14.1; high-normal TSH, 77.4±13.0; and subclinical hypothyroid, 72.3±12.2 mL/min/1.73 m2: P for trend <0.01). Multiple linear regression analysis extracted log-transformed TSH level as an independent factor correlated with eGFR in the high-normal TSH group (beta=-0.18, P=0.02). Our findings demonstrated a significant correlation between serum TSH levels and eGFR in high-normal TSH participants. In healthy individuals, high-normal TSH levels indicate increased the risk of chronic kidney disease.


Effects of Coffee and Tea Consumption on Glucose Metabolism: A Systematic Review and Network Meta-Analysis.
Prospective cohort studies have described an association between coffee or tea consumption and the risk of developing diabetes. However, whether coffee or tea improves glucose metabolism remains uncertain. We investigated the effect of coffee and tea on glucose metabolism by conducting a systematic review and meta-analysis of randomized controlled trials. Electronic databases were searched for articles published up 19 February 2017. The primary endpoint was the mean difference in post-intervention fasting blood glucose (FBG) levels between the groups. Of 892 citations screened, 27 studies (1898 participants) were included in our meta-analysis. A network meta-analysis suggested that green tea, but not caffeinated/decaffeinated coffee or black tea, may reduce FBG levels, compared with placebo/water (-2.10 mg/dL; 95% confidence interval (CI), -3.96 to -0.24 mg/dL; p = 0.03; moderate quality of evidence). In a subgroup analysis, the effect of green tea on FBG levels was statistically significant only in studies with a mean age of < 55-years-old or Asian-based studies. The oolong tea group also showed a significant decrease in FBG, but the quality of evidence was very low. In conclusion, green tea consumption might decrease FBG levels, especially in < 55-year-olds or Asian-based populations.


Dissecting Long-Term Glucose Metabolism Identifies New Susceptibility Period for Metabolic Dysfunction in Aged Mice.
Metabolic disorders, like diabetes and obesity, are pathogenic outcomes of imbalance in glucose metabolism. Nutrient excess and mitochondrial imbalance are implicated in dysfunctional glucose metabolism with age. We used conplastic mouse strains with defined mitochondrial DNA (mtDNA) mutations on a common nuclear genomic background, and administered a high-fat diet up to 18 months of age. The conplastic mouse strain B6-mtFVB, with a mutation in the mt-Atp8 gene, conferred β-cell dysfunction and impaired glucose tolerance after high-fat diet. To our surprise, despite of this functional deficit, blood glucose levels adapted to perturbations with age. Blood glucose levels were particularly sensitive to perturbations at the early age of 3 to 6 months. Overall the dynamics consisted of a peak between 3-6 months followed by adaptation by 12 months of age. With the help of mathematical modeling we delineate how body weight, insulin and leptin regulate this non-linear blood glucose dynamics. The model predicted a second rise in glucose between 15 and 21 months, which could be experimentally confirmed as a secondary peak. We therefore hypothesize that these two peaks correspond to two sensitive periods of life, where perturbations to the basal metabolism can mark the system for vulnerability to pathologies at later age. Further mathematical modeling may perspectively allow the design of targeted periods for therapeutic interventions and could predict effects on weight loss and insulin levels under conditions of pre-diabetic obesity.


Differentiating Pathway-Specific From Nonspecific Effects in High-Throughput Toxicity Data: A Foundation for Prioritizing Adverse Outcome Pathway Development.
The U.S. Environmental Protection Agency's ToxCast program has screened thousands of chemicals for biological activity, primarily using high-throughput in vitro bioassays. Adverse outcome pathways (AOPs) offer a means to link pathway-specific biological activities with potential apical effects relevant to risk assessors. Thus, efforts are underway to develop AOPs relevant to pathway-specific perturbations detected in ToxCast assays. Previous work identified a "cytotoxic burst" (CTB) phenomenon wherein large numbers of the ToxCast assays begin to respond at or near test chemical concentrations that elicit cytotoxicity, and a statistical approach to defining the bounds of the CTB was developed. To focus AOP development on the molecular targets corresponding to ToxCast assays indicating pathway-specific effects, we conducted a meta-analysis to identify which assays most frequently respond at concentrations below the CTB. A preliminary list of potentially important, target-specific assays was determined by ranking assays by the fraction of chemical hits below the CTB compared with the number of chemicals tested. Additional priority assays were identified using a diagnostic-odds-ratio approach which gives greater ranking to assays with high specificity but low responsivity. Combined, the two prioritization methods identified several novel targets (e.g., peripheral benzodiazepine and progesterone receptors) to prioritize for AOP development, and affirmed the importance of a number of existing AOPs aligned with ToxCast targets (e.g., thyroperoxidase, estrogen receptor, aromatase). The prioritization approaches did not appear to be influenced by inter-assay differences in chemical bioavailability. Furthermore, the outcomes were robust based on a variety of different parameters used to define the CTB.


Evolution of bird genomes-a transposon's-eye view.
Birds, the most species-rich monophyletic group of land vertebrates, have been subject to some of the most intense sequencing efforts to date, making them an ideal case study for recent developments in genomics research. Here, we review how our understanding of bird genomes has changed with the recent sequencing of more than 75 species from all major avian taxa. We illuminate avian genome evolution from a previously neglected perspective: their repetitive genomic parasites, transposable elements (TEs) and endogenous viral elements (EVEs). We show that (1) birds are unique among vertebrates in terms of their genome organization; (2) information about the diversity of avian TEs and EVEs is changing rapidly; (3) flying birds have smaller genomes yet more TEs than flightless birds; (4) current second-generation genome assemblies fail to capture the variation in avian chromosome number and genome size determined with cytogenetics; (5) the genomic microcosm of bird-TE "arms races" has yet to be explored; and (6) upcoming third-generation genome assemblies suggest that birds exhibit stability in gene-rich regions and instability in TE-rich regions. We emphasize that integration of cytogenetics and single-molecule technologies with repeat-resolved genome assemblies is essential for understanding the evolution of (bird) genomes.


Accuracy of Elastic Fusion of Prostate Magnetic Resonance and Transrectal Ultrasound Images under Routine Conditions: A Prospective Multi-Operator Study.
To evaluate in unselected patients imaged under routine conditions the co-registration accuracy of elastic fusion between magnetic resonance (MR) and ultrasound (US) images obtained by the Koelis Urostation™. We prospectively included 15 consecutive patients referred for placement of intraprostatic fiducials before radiotherapy and who gave written informed consent by signing the Institutional Review Board-approved forms. Three fiducials were placed in the prostate under US guidance in standardized positions (right apex, left mid-gland, right base) using the Koelis Urostation™. Patients then underwent prostate MR imaging. Four operators outlined the prostate on MR and US images and an elastic fusion was retrospectively performed. Fiducials were used to measure the overall target registration error (TRE3D), the error along the antero-posterior (TREAP), right-left (TRERL) and head-feet (TREHF) directions, and within the plane orthogonal to the virtual biopsy track (TRE2D). Median TRE3D and TRE2D were 3.8-5.6 mm, and 2.5-3.6 mm, respectively. TRE3D was significantly influenced by the operator (p = 0.013), fiducial location (p = 0.001) and 3D axis orientation (p<0.0001). The worst results were obtained by the least experienced operator. TRE3D was smaller in mid-gland and base than in apex (average difference: -1.21 mm (95% confidence interval (95%CI): -2.03; -0.4) and -1.56 mm (95%CI: -2.44; -0.69) respectively). TREAP and TREHF were larger than TRERL (average difference: +1.29 mm (95%CI: +0.87; +1.71) and +0.59 mm (95%CI: +0.1; +0.95) respectively). Registration error values were reasonable for clinical practice. The co-registration accuracy was significantly influenced by the operator's experience, and significantly poorer in the antero-posterior direction and at the apex.


Someone to count on: social support as an effect modifier of viral load suppression in a prospective cohort study.
Though functional social support has been shown to serve as a protective factor for HIV viral load suppression in other populations, scant research has examined this relationship among men who have sex with men (MSM) in the United States. We assessed characteristics of social support, effects of social support on HIV viral load, and moderation by social support of the relationship between psychosocial indicators of a synergistic epidemic (syndemic) and HIV viral load. We analyzed longitudinal data from HIV-positive MSM using antiretroviral therapy who were enrolled in the Multicenter AIDS Cohort Study between 2002 and 2009 (n = 712). First, we conducted reliability assessments of a one-item social support measure. Then, we conducted a series of generalized longitudinal mixed models to assess our research questions. Moderation was assessed using an interaction term. A three-level (low/medium/high) social support variable demonstrated high reliability (intraclass correlation coefficients = 0.72; 95% CI: 0.70, 0.75). Black and Hispanic MSM reported lower social support than their White counterparts (p < .0001). Recent sero-conversion was associated with higher social support (p < .05). Higher numbers of concomitant syndemic indicators (depression, polysubstance use, and condomless anal sex) were associated with lower social support (p < .0001). Medium and high social support levels were associated with greater viral load suppression and lower viral load means (p < .0001). Social support moderated the relationships between syndemic and HIV viral load (p < .05). HIV-positive MSM, particularly those of color, may benefit greatly from interventions that can successfully boost functional social support. Creating strengths-based interventions may also have particularly high impact among HIV-positive MSM with the highest psychosocial burdens.


Regulation of oxidative DNA damage repair by DNA polymerase λ and MutYH by cross-talk of phosphorylation and ubiquitination.
It is of pivotal importance for genome stability that repair DNA polymerases (Pols), such as Pols λ and β, which all exhibit considerably reduced fidelity when replicating undamaged DNA, are tightly regulated, because their misregulation could lead to mutagenesis. Recently, we found that the correct repair of the abundant and highly miscoding oxidative DNA lesion 7,8-dihydro-8-oxo-2'-deoxyguanine (8-oxo-G) is performed by an accurate repair pathway that is coordinated by the MutY glycosylase homologue (MutYH) and Pol λ in vitro and in vivo. Pol λ is phosphorylated by Cdk2/cyclinA in late S and G2 phases of the cell cycle, promoting Pol λ stability by preventing it from being targeted for proteasomal degradation by ubiquitination. However, it has remained a mystery how the levels of Pol λ are controlled, how phosphorylation promotes its stability, and how the engagement of Pol λ in active repair complexes is coordinated. Here, we show that the E3 ligase Mule mediates the degradation of Pol λ and that the control of Pol λ levels by Mule has functional consequences for the ability of mammalian cells to deal with 8-oxo-G lesions. Furthermore, we demonstrate that phosphorylation of Pol λ by Cdk2/cyclinA counteracts its Mule-mediated degradation by promoting recruitment of Pol λ to chromatin into active 8-oxo-G repair complexes through an increase in Pol λ's affinity to chromatin-bound MutYH. Finally, MutYH appears to promote the stability of Pol λ by binding it to chromatin. In contrast, Pol λ not engaged in active repair on chromatin is subject for proteasomal degradation.


Word recognition for temporally and spectrally distorted materials: the effects of age and hearing loss.
The purpose of Experiment 1 was to measure word recognition in younger adults with normal hearing when speech or babble was temporally or spectrally distorted. In Experiment 2, older listeners with near-normal hearing and with hearing loss (for pure tones) were tested to evaluate their susceptibility to changes in speech level and distortion types. The results across groups and listening conditions were compared to assess the extent to which the effects of the distortions on word recognition resembled the effects of age-related differences in auditory processing or pure-tone hearing loss. In Experiment 1, word recognition was measured in 16 younger adults with normal hearing using Northwestern University Auditory Test No. 6 words in quiet and the Words-in-Noise test distorted by temporal jittering, spectral smearing, or combined jittering and smearing. Another 16 younger adults were evaluated in four conditions using the Words-in-Noise test in combinations of unaltered or jittered speech and unaltered or jittered babble. In Experiment 2, word recognition in quiet and in babble was measured in 72 older adults with near-normal hearing and 72 older adults with hearing loss in four conditions: unaltered, jittered, smeared, and combined jittering and smearing. For the listeners in Experiment 1, word recognition was poorer in the distorted conditions compared with the unaltered condition. The signal to noise ratio at 50% correct word recognition was 4.6 dB for the unaltered condition, 6.3 dB for the jittered, 6.8 dB for the smeared, 6.9 dB for the double-jitter, and 8.2 dB for the combined jitter-smear conditions. Jittering both the babble and speech signals did not significantly reduce performance compared with jittering only the speech. In Experiment 2, the older listeners with near-normal hearing and hearing loss performed best in the unaltered condition, followed by the jitter and smear conditions, with the poorest performance in the combined jitter-smear condition in both quiet and noise. Overall, listeners with near-normal hearing performed better than listeners with hearing loss by ~30% in quiet and ~6 dB in noise. In the quiet distorted conditions, when the level of the speech was increased, performance improved for the hearing loss group, but decreased for the older group with near-normal hearing. Recognition performance of younger listeners in the jitter-smear condition and the performance of older listeners with near-normal hearing in the unaltered conditions were similar. Likewise, the performance of older listeners with near-normal hearing in the jitter-smear condition and the performance of older listeners with hearing loss in the unaltered conditions were similar. The present experiments advance our understanding regarding how spectral or temporal distortions of the fine structure of speech affect word recognition in older listeners with and without clinically significant hearing loss. The Speech Intelligibility Index was able to predict group differences, but not the effects of distortion. Individual differences in performance were similar across all distortion conditions with both age and hearing loss being implicated. The speech materials needed to be both spectrally and temporally distorted to mimic the effects of age-related differences in auditory processing and hearing loss.


Induction of NANOG expression by targeting promoter sequence with small activating RNA antagonizes retinoic acid-induced differentiation.
RNAa (RNA activation) is a mechanism by which small dsRNA (double-stranded RNA), termed saRNA (small activating RNA), target promoter sequences to induce gene expression. This technique represents a novel approach to gene overexpression without the use of exogenous DNA. In the present study, we investigated whether RNAa can modulate expression of the development-related gene NANOG and manipulate cell fate. Using a lentivirus-based reporter system as a screening tool, we identified synthetic saRNAs that stimulate NANOG expression in human NCCIT embryonic carcinoma cells. Mismatch mutations to saRNA duplexes define sequence requirement for gene activation. Functional analysis of NANOG induction reveals saRNA treatment predictably modulates the expression of several known downstream target genes, including FOXH1 (forkhead box H1), REST (RE1-silencing transcription factor), OCT4 (octamer-binding protein 4) and REX1 (reduced expression protein 1). Treatment with RA (retinoic acid) triggers NCCIT cell differentiation, reducing NANOG and OCT4 expression and up-regulating several neural markers [i.e. ASCL1 (achaete-scute complex homologue 1), NEUROD1 (neuronal differentiation 1) and PAX6 (paired box 6)]. However, co-treatment with saRNA antagonizes NANOG down-regulation and RA-induced differentiation. Ectopic overexpression of NANOG via lentiviral transduction further recapitulates saRNA results, providing proof-of-concept that RNAa may be utilized to activate development-related genes and manipulate cell fate.


Contraceptive effect of sperm-agglutinating monoclonal antibodies in rabbits.
Immune infertility in humans correlates clinically with the presence of anti-sperm antibodies that trap (agglutinate) sperm in semen and cervical mucus. To test whether sperm-agglutinating antibodies can be effective contraceptive agents, several mouse anti-rabbit sperm (MARS) sperm-agglutinating monoclonal antibodies (mAbs) were developed that rapidly and completely agglutinate sperm: MARS-M3 (IgM), MARS-G16 (IgG3), and MARS-G17 (IgG3). Contraceptive efficacy of these mAbs was tested by mixing the mAb with 0.1 ml semen (approximately 1/5 of a whole ejaculate) immediately before artificially inseminating rabbits paracervically. This paracervical dose of semen provided a rigorous test since it delivered several thousand times more fertilizing doses than does a human ejaculate. All of the mAbs were contraceptively effective, and MARS-G16 reduced the number of fetuses per animal by 88% and 95% with doses of 150 microg and 2 mg, respectively. The contraceptive efficacy of the MARS mAbs in the rabbit suggests that human sperm-agglutinating mAbs may be effective agents for vaginal contraception in humans.


Expression of a plasmid gene of Chlamydia trachomatis encoding a novel 28 kDa antigen.
Plasmid pCT is present in essentially all isolates of Chlamydia trachomatis and may encode factors important for survival in the natural environment. However, no pCT-associated phenotype has been described so far. With the purpose of investigating the possibility of a role of pCT in C. trachomatis pathogenicity we examined the expression of an ORF (ORF3), potentially encoding a 28 kDa polypeptide (pgp3). Analysis of RNA extracted from chlamydia-infected Vero cells detected ORF3-specific transcripts, from 20 h post-infection onwards, mainly as discrete RNA species of 1390 nucleotides comprising the downstream ORF4 sequence. ORF3 DNA was cloned and expressed in Escherichia coli as a 39 kDa fusion protein (MS2/pgp3). Antibodies raised against purified MS2/pgp3, specifically recognized a 28 kDa protein on Western blots of protein from purified chlamydial elementary bodies (EBs). The same antibodies detected chlamydial inclusions in methanol-fixed infected cells by immunofluorescence. Western blot analysis of EBs extracted with 2% Sarkosyl, showed that a large proportion of the 28 kDa antigen is associated with the detergent-insoluble ('membrane') fraction. Antibodies recognizing pgp3 epitopes were detected in sera from patients with chlamydial infections, but not in sero-negative control sera. The finding support the hypothesis that pCT may provide a function related to chlamydial cell physiology.


Thermodynamic modeling of PCDD/Fs formation in thermal processes.
Three thermodynamic databases of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), derived using the Group Additivity approach and two computational molecular modeling methods, Modified Neglect of Diatomic Overlap (MNDO) and Parametrized Model 3 (PM3), respectively, combined with the Scientific Group Thermodata Europe (SGTE) database have been used to model the formation of PCDD/Fs in thermal processes, such as iron ore sintering process. The predictions using the three different databases are compared, and similar thermodynamic conditions of PCDD/Fs formation are found. The comparison of the calculated values with measured results obtained from industrial iron ore sinter plant indicates that the PCDDs and PCDFs found in practice are not in equilibrium with each other. While within each dioxin and furan homologue equilibrium between the isomers appears to be established in industrial processes, reactions between dioxins and furans seem to be kinetically inhibited. This view has been supported by assuming no reaction at all between PCDFs and PCDDs in the simulation. With this assumption, both PCDFs and PCDDs reached partial pressures between 600 and 800 K in the order of magnitude actually found in practice. Taking this restriction into account, the conditions for PCDD/Fs formation were calculated as a function of oxygen partial pressure; temperature; concentrations of carbon, hydrogen, and chlorine; and C/H ratio.


Long-range clustered connections within extrastriate visual area V5/MT of the rhesus macaque.
Visual area V5/MT in the rhesus macaque has a distinct functional organization, where neurons with specific preferences for direction of motion and binocular disparity are co-organized in columns or clusters. Here, we analyze the pattern of intrinsic connectivity within cortical area V5/MT in both parasagittal sections of the intact brain and tangential sections from flatmounted cortex using small injections of the retrograde tracer cholera toxin subunit b. Labeled cells were predominantly found in cortical layers 2, 3, and 6. Going along the cortical layers, labeled cells were concentrated in regularly spaced clusters. The clusters nearest to the injection site were approximately 2 mm from its center. In flatmounted cortex, along the dorsoventral axis of V5/MT, we identified further clusters of labeled cells up to 10 mm from the injection site. Quantitative analysis of parasagittal sections estimated average cluster spacing at 2.2 mm; in cortical flatmounts, spacing was 2.3 mm measured radially from the injection site. The results suggest a regular pattern of intrinsic connectivity within V5/MT, which is consistent with connectivity between sites with a common preference for both direction of motion and binocular depth. The long-range connections can potentially account for the large suppressive surrounds of V5/MT neurons.


Six weeks of home enteral nutrition versus standard care after esophagectomy or total gastrectomy for cancer: study protocol for a randomized controlled trial.
Each year approximately 3000 patients in the United Kingdom undergo surgery for esophagogastric cancer. Jejunostomy feeding tubes, placed at the time of surgery for early postoperative nutrition, have been shown to have a positive impact on clinical outcomes in the short term. Whether feeding out of hospital is of benefit is unknown. Local experience has identified that between 15 and 20% of patients required 'rescue' jejunostomy feeding for nutritional problems and weight loss while at home. This weight loss and poor nutrition may contribute to the detrimental effect on the overall quality of life (QoL) reported in these patients. This randomized pilot and feasibility study will provide preliminary information on the routine use of jejunostomy feeding after hospital discharge in terms of clinical benefits and QoL. Sixty participants undergoing esophagectomy or total gastrectomy will be randomized to receive either a planned program of six weeks of home jejunostomy feeding after discharge from hospital (intervention) or treatment-as-usual (control). The intention of this study is to inform a multi-centre randomized controlled trial. The primary outcome measures will be recruitment and retention rates at six weeks and six months. Secondary outcome measures will include disease specific and general QoL measures, nutritional parameters, total and oral nutritional intake, hospital readmission rates, and estimates of healthcare costs. Up to 20 participants will also be enrolled in a qualitative sub-study that will explore participants' and carers' experiences of home tube feeding.The results will be disseminated by presentation at surgical, gastroenterological and dietetic meetings and publication in appropriate peer review journals. A patient-friendly lay summary will be made available on the University of Leicester and the University Hospitals of Leicester NHS Trust websites. The study has full ethical and institutional approval and started recruitment in July 2012. UKClinical Research Network ID #12447 (Main study); UKCRN ID#13361 (Qualitative sub study); ClinicalTrials.gov #NCT01870817 (First registered 28 May 2013).


Effects of chronic consumption of specific fruit (berries, citrus and cherries) on CVD risk factors: a systematic review and meta-analysis of randomised controlled trials.
This review aims to compare the magnitude of the effects of chronic consumption of fruits; specifically berries, citrus and cherries on cardiovascular disease (CVD) risk factors. PubMed, Web of Science, Scopus, and psycARTICLES were searched from inception until January 2020. Forty-five chronic (≥ 1 week) randomised controlled trials assessing CVD risk factors including endothelial (dys)function, blood pressure (BP), blood lipids and inflammatory biomarkers were included. Investigated interventions reported improvements in endothelial function (n = 8), inflammatory biomarkers and lipid status (n = 14), and BP (n = 10). Berries including juice of barberry, cranberry, grape, pomegranate, powder of blueberry, grape, raspberry and freeze-dried strawberry significantly reduced SBP by 3.68 mmHg (95% CI - 6.79 to - 0.58; P = 0.02) and DBP by 1.52 mmHg (95% CI - 2.87 to - 0.18, P = 0.04). In subgroup analysis, these associations were limited to cranberry juice (SBP by 1.52 mmHg [95% CI - 2.97 to - 0.07; P = 0.05], DBP by 1.78 mmHg [95% CI - 3.43 to - 0.12, P = 0.04] and cherry juice (SBP by 3.11 mmHg [95% CI - 4.06 to - 2.15; P = 0.02]). Berries also significantly elevated sVCAM-1 levels by 14.57 ng/mL (85% CI 4.22 to 24.93; P = 0.02). These findings suggest that supplementing cranberry or cherry juice might contribute to an improvement in blood pressure. No other significant improvements were observed for other specified fruits. More research is warranted comparing different classes of fruit and exploring the importance of fruit processing on their cardiovascular-protective effects.


Lipids and the immune response: from molecular mechanisms to clinical applications.
This review critically evaluates recent studies investigating the effects of fatty acids on immune and inflammatory responses in both healthy individuals and in patients with inflammatory diseases, with some reference to animal studies where relevant. It examines recent findings describing the cellular and molecular basis for the modulation of immune function by fatty acids. The newly emerging area of diet-genotype interactions will also be discussed, with specific reference to the anti-inflammatory effects of fish oil. Fatty acids are participants in many intracellular signalling pathways. They act as ligands for nuclear receptors regulating a host of cell responses, they influence the stability of lipid rafts, and modulate eicosanoid metabolism in cells of the immune system. Recent findings suggest that some or all of these mechanisms may be involved in the modulation of immune function by fatty acids. Human studies investigating the relationship between dietary fatty acids and some aspects of the immune response have been disappointingly inconsistent. This review presents the argument that most studies have not been adequately powered to take into account the influence of variation (genotypic or otherwise) on parameters of immune function. There is well-documented evidence that fatty acids modulate T lymphocyte activation, and recent findings describe a range of potential cellular and molecular mechanisms. However, there are still many questions remaining, particularly with respect to the roles of nuclear receptors, for which fatty acids act as ligands, and the modulation of eicosanoid synthesis, for which fatty acids act as precursors.


An Ethics Toolkit to Support Animal-Centered Research and Design.
Designers and researchers who work with animals need to employ an array of ethical competencies to guarantee the welfare of animals taking part in animal-centered research. The emerging field of Animal-Computer Interaction (ACI), which deals with the design of animal-centered interactive systems, considers ethics a fundamental concern when working with animals, and ACI researchers have proposed ethics frameworks in response to these concerns. Ethical approaches proposed within the field tend to be normative but, on their own, norms may not be sufficient to support designers who will inevitably face unexpected and ethically charged situations as the research progresses. During a research project, focused on the design of dog-friendly controls for Mobility Assistance Dogs (MADs), these limitations came to the fore. Drawing from situated ethics approaches, developed to support researchers' ethical engagement with vulnerable populations such as children and differently abled adults, this paper presents an ethics toolkit that aims to support animal-centered research and design by enabling researchers to make ethically sound situated decisions as their work progresses. The toolkit comprises three templates, each of which asks a series of questions aiming to articulate the ethical baselines of individual team members and of their research project, and to inform the development of a series of ethical guiding statements to better prepare designers to make ethical situated decisions. The application of the toolkit during the research with MADs helped the field researcher to clearly and systematically articulate the project's ethos and understand the ethical stance that guided the research team's interactions with the dogs, their trainers, and their human partners throughout the project. It also fostered a practice of active reflection within the team, which helped them to maintain their commitment to the project's ethos in the face of unexpected ethical challenges. We propose that, beyond supporting ACI research, the toolkit could support the ethical engagement of researchers and practitioners who work for and with animals in many other settings.


Reconstructing 3D Face Model with Associated Expression Deformation from a Single Face Image via Constructing a Low-Dimensional Expression Deformation Manifold.
Facial expression modeling is central to facial expression recognition and expression synthesis for facial animation. In this work, we propose a manifold-based 3D face reconstruction approach to estimating the 3D face model and the associated expression deformation from a single face image. With the proposed robust weighted feature map (RWF), we can obtain the dense correspondences between 3D face models and build a nonlinear 3D expression manifold from a large set of 3D facial expression models. Then a Gaussian mixture model in this manifold is learned to represent the distribution of expression deformation. By combining the merits of morphable neutral face model and the low-dimensional expression manifold, a novel algorithm is developed to reconstruct the 3D face geometry as well as the facial deformation from a single face image in an energy minimization framework. Experimental results on simulated and real images are shown to validate the effectiveness and accuracy of the proposed algorithm.


Using the Flipped Classroom to Bridge the Gap to Generation Y.
The flipped classroom is a student-centered approach to learning that increases active learning for the student compared to traditional classroom-based instruction. In the flipped classroom model, students are first exposed to the learning material through didactics outside of the classroom, usually in the form of written material, voice-over lectures, or videos. During the formal teaching time, an instructor facilitates student-driven discussion of the material via case scenarios, allowing for complex problem solving, peer interaction, and a deep understanding of the concepts. A successful flipped classroom should have three goals: (1) allow the students to become critical thinkers, (2) fully engage students and instructors, and (3) stimulate the development of a deep understanding of the material. The flipped classroom model includes teaching and learning methods that can appeal to all four generations in the academic environment. During the 2015 academic year, we implemented the flipped classroom in the obstetrics and gynecology clerkship for the Ochsner Clinical School in New Orleans, LA. Voice-over presentations of the lectures that had been given to students in prior years were recorded and made available to the students through an online classroom. Weekly problem-based learning sessions matched to the subjects of the traditional lectures were held, and the faculty who had previously presented the information in the traditional lecture format facilitated the problem-based learning sessions. The knowledge base of students was evaluated at the end of the rotation via a multiple-choice question examination and the Objective Structured Clinical Examination (OSCE) as had been done in previous years. We compared demographic information and examination scores for traditional teaching and flipped classroom groups of students. The traditional teaching group consisted of students from Rotation 2 and Rotation 3 of the 2014 academic year who received traditional classroom-based instruction. The flipped classroom group consisted of students from Rotation 2 and Rotation 3 of the 2015 academic year who received formal didactics via voice-over presentation and had the weekly problem-based learning sessions. When comparing the students taught by traditional methods to those taught in the flipped classroom model, we saw a statistically significant increase in test scores on the multiple-choice question examination in both the obstetrics and gynecology sections in Rotation 2. While the average score for the flipped classroom group increased in Rotation 3 on the obstetrics section of the multiple-choice question examination, the difference was not statistically significant. Unexpectedly, the average score on the gynecology portion of the multiple-choice question examination decreased among the flipped classroom group compared to the traditional teaching group, and this decrease was statistically significant. For both the obstetrics and the gynecology portions of the OSCE, we saw statistically significant increases in the scores for the flipped classroom group in both Rotation 2 and Rotation 3 compared to the traditional teaching group. With the exception of the gynecology portion of the multiple-choice question examination in Rotation 3, we saw improvement in scores after the implementation of the flipped classroom. The flipped classroom is a feasible and useful alternative to the traditional classroom. It is a method that embraces Generation Y's need for active learning in a group setting while maintaining a traditional classroom method for introducing the information. Active learning increases student engagement and can lead to improved retention of material as demonstrated on standard examinations.


The effect of puerperal uterine disease on histopathologic findings and mRNA expression of proinflammatory cytokines of the endometrium in dairy cows.
The aim of this study was to investigate the effect of puerperal uterine disease on histopathologic findings and gene expression of proinflammatory cytokines in the endometrium of postpuerperal dairy cows; 49 lactating Holstein-Friesian cows were divided into two groups, one without (UD-; n = 29) and one with uterine disease (UD+; n = 21), defined as retained fetal membranes and/or clinical metritis. General clinical examination, vaginoscopy, transrectal palpation, and transrectal B-mode sonography were conducted on days 8, 11, 18, and 25 and then every 10 days until Day 65 (Day 0 = day of calving). The first endometrial sampling (ES1; swab and biopsy) was done during estrus around Day 42 and the second endometrial sampling (ES2) during the estrus after synchronization (cloprostenol between days 55 and 60 and GnRH 2 days later). The prevalence of histopathologic evidence of endometritis, according to the categories used here, and positive bacteriologic cultures was not affected by group (P > 0.05), but cows with uterine disease had a higher prevalence of chronic purulent endometritis (ES1; P = 0.07) and angiosclerosis (ES2; P ≤ 0.05) than healthy cows. Endometrial gene expression of IL1α (ES2), IL1β (ES2), and TNFα (ES1 and ES2) was higher (P ≤ 0.05) in the UD+ group than in the UD- group. In conclusion, puerperal uterine disease had an effect on histopathologic parameters and on gene expression of proinflammatory cytokines in the endometrium of postpuerperal cows, indicating impaired clearance of uterine inflammation in cows with puerperal uterine disease.


Assessment of NS1 protein as an early diagnostic marker for Kyasanur forest disease virus.
Due to the emergence of Kyasanur forest disease (KFD) virus to new regions in India, there is an urgent need to develop an early diagnostic system, which is cost-effective and can be efficiently used with minimum paraphernalia. The non-structural-1 (NS1) protein is known to be an early diagnostic marker for flaviviruses. Furthermore, NS1 antigen capture ELISA kits developed using bacterially expressed dengue NS1 protein are commercially available. Based on the data available on dengue virus, West Nile virus and other flaviviruses, bacterially expressed Kyasanur forest disease virus (KFDV) NS1 protein and polyclonal serum raised against the NS1 protein in mice and rabbit were used to develop an antigen capture ELISA for early diagnosis of the virus. The feasibility of this ELISA was further tested using in silico predictions. KFDV NS1 gene was cloned, expressed and confirmed by SDS-PAGE and western blotting. An antigen detection ELISA was standardized and sensitivity and specificity was tested with other flaviviruses. KFDV acute phase 43 samples were tested and only two were found to be positive for KFDV NS1 antigen. Superimposition of KFDV NS1 and TBEV NS1 revealed a root mean square distance (RMSD) of ~0.79 Å covering 1220 backbone atoms. This implies that the structures are very similar in terms of 3D fold. The identity of amino acid composition between these proteins was 73.4% and similarity was 92.9%, as revealed from the pairwise comparison. The study points out that the half-life, expression and secretion levels of KFDV NS1 protein are not sufficient enough for its use as early diagnostic marker. The protein may have to be expressed in eukaryotic host to counter the lack of glycosylation in bacterial plasmid based expression of proteins. Hence, bacterially expressed KFDV NS1 protein may not be an ideal early diagnostic marker for the virus.


Picturing Polarized Myeloid Phagocytes and Regulatory Cells by Mass Cytometry.
The immune monocyte/phagocyte system (MPS) includes numerous cell subsets of the myeloid lineage including monocyte, macrophage, and dendritic cell (DC) populations that are heterogeneous both phenotypically and functionally. Previously, we characterized these diverse MPS phenotypes with multi-parametric mass cytometry (CyTOF). In order to expansively characterize monocytes, macrophages, and dendritic cells, a CyTOF panel was designed to measure 35 identity-, activation-, and polarization-markers. Here we provide a protocol to define a reference map for the myeloid compartment, including sample preparation, to produce reference cell subsets from the monocyte/phagocyte system. In particular, we focused on monocyte-derived macrophages that were further polarized in vitro with cytokine stimulation (i.e., M-CSF, GM-CSF, IL-4, IL-10, IFNγ, and LPS), as well as monocyte-derived DCs, and myeloid-derived suppressor cells (MDSCs), generated in vitro from human bone marrow and/or peripheral blood.


Bcl-2 associates with the ras-related protein R-ras p23.
Apoptosis is an important but poorly understood mechanism of cell regulation. Growth factor deprivation can trigger apoptosis in a variety of cells, suggesting the existence of a signal transduction pathway responding to external signals and leading to apoptosis. Overexpression of the proto-oncogene bcl-2 can override these signals and block apoptosis, indicating that the bcl-2 protein (Bcl-2) is an important component of the apoptotic response. The identification of Bcl-2-binding proteins might help explain how Bcl-2 acts to regulate apoptosis. Here we use the yeast two-hybrid system to show that the human ras-related protein R-ras p23 (ref 16-18) binds to Bcl-2. This association is also detected in immunoprecipitates from human cell extracts. The association requires full-length Bcl-2 but the C-terminal 60 amino acids of R-ras p23 are sufficient for the interaction. These results provide evidence of a putative component of a signal transduction pathway involved in the regulation of apoptosis.


Increased oxidation of extracellular glutathione by bronchoalveolar inflammatory cells in diffuse fibrosing alveolitis.
An unbalanced oxidative stress is thought to be an important element in the pathogenesis of diffuse fibrosing alveolitis (DFA). The purpose of our study was to investigate the role of reactive oxygen metabolites (ROMs) released from cultured bronchoalveolar inflammatory cells (BA-cells) on glutathione oxidation. We studied bronchoalveolar lavage samples from 10 healthy controls and from 20 patients with diffuse fibrosing alveolitis (all were nonsmokers). BA-cells obtained by bronchoalveolar lavage (BAL) were incubated with 50 microM of reduced glutathione (GSH). Oxidation of GSH to glutathione disulphide (GSSG) by BA-cell derived oxidants was detected as a decline of GSH in the supernatants. Total glutathione (GSHtot = GSH + 2 GSSG) and GSSG in the epithelial lining fluid (ELF), and methionine sulphoxide (Met(O)) content of BAL proteins were determined. In diffuse fibrosing alveolitis the oxidative activity of BA-cells was enhanced, GSHtot and GSH were decreased, whereas the GSSG:GSH ratio was increased. The oxidative activity of BA-cells correlated positively with the GSSG:GSH ratio, but not with the methionine sulphoxide content. The methionine sulphoxide content was elevated in diffuse fibrosing alveolitis and inversely correlated with GSHtot. The methionine sulphoxide content also correlated positively with the percentage of BAL neutrophils. We conclude that BA-cell-derived reactive oxygen species are capable of oxidizing extracellular GSH in vitro. The positive correlation between the BA-cell oxidative activity in vitro and GSSG:GSH ratio in ELF suggests that a similar oxidative effect on extracellular GSH may also occur in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)


A single amino acid substitution, Gly117His, confers phosphotriesterase (organophosphorus acid anhydride hydrolase) activity on human butyrylcholinesterase.
The G117H mutant of human butyrylcholinesterase (EC 220.127.116.11) was expressed in Chinese hamster ovary cells. Substitution of Gly 117 with His to make the G117H mutant endowed butyrylcholinesterase with the ability to catalyze the hydrolysis of organophosphate esters. G117H was still able to hydrolyze butyrylthiocholine, benzoylcholine, and o-nitrophenyl butyrate, but in addition it had acquired the ability to hydrolyze the antiglaucoma drug echothiophate and the pesticide paraoxon. Wild-type butyrylcholinesterase was irreversibly inhibited by echothiophate and paraoxon, but G117H regained 100% activity within 2-3 min following reaction with these compounds. On a polyacrylamide gel, the same bands that stained for activity with butyrylthiocholine also stained for activity with echothiophate. G117H is the only enzyme known that hydrolyzes echothiophate. Diethoxyphosphorylated G117H aged with a half-time of 5.5 h, a rate 600 times slower than the rate of hydrolysis. Echothiophate and paraoxon were hydrolyzed with the same kcat of 0.75 min-1. This calculates to a rate acceleration of 100,000-fold for hydrolysis of echothiophate and paraoxon by the G117H mutant compared to the nonenzymatic rate.


Hybrid Printing Using Cellulose Nanocrystals Reinforced GelMA/HAMA Hydrogels for Improved Structural Integration.
3D printing of soft-tissue like cytocompatible single material constructs with appropriate mechanical properties remains a challenge. Hybrid printing technology provides an attractive alternative as it combines a cell-free ink for providing mechanical support with a bioink for housing embedded cells. Several hybrid printed structures have been developed, utilizing thermoplastic polymers such as polycaprolactone as structural support. These thermoplastics demonstrated limited structural integration with the cell-laden components, and this may compromise the overall performance. In this work, a hybrid printing platform is presented using two distinct hydrogel inks that share the same photo-crosslinking chemistry to enable simple fabrication and seamless structural integration. A mechanically reinforced hydrogel ink is developed comprising cellulose nanocrystals and gelatin methacryloyl/hyaluronic acid methacrylate (GelMA/HAMA) as the structural component, and GelMA/HAMA as the cytogel containing a mouse chondrogenic cell line, ATDC5. Hybrid printed constructs with encapsulated cells are fabricated using the two optimized inks, and the structural integration of the constructs is evaluated by cyclic mechanical compression. Finally, the cell viability of encapsulated ATDC5 cells in the hybrid printed structures is evaluated.


Inflammation and elevation of C-reactive protein: does magnesium play a key role?
The adverse role played by inflammation in the etiology of humankind's most prevalent chronic diseases compels researchers to work diligently to explore its biologic basis. Recent research supports the concept of an important relationship between dietary factors and inflammation, and in particular the role of magnesium deficiency, however, the specifics of this association are not completely understood. Recent findings from epidemiologic studies support that magnesium intake is inversely associated with C-reactive protein concentration, an important marker of inflammation strongly associated with cardiovascular disease risk. Animal studies have provided many mechanistic possibilities to explain the link between magnesium and inflammation. Further research is needed to understand more completely the role of magnesium in inflammation.


The STM bias voltage-dependent polymorphism of a binary supramolecular network.
A Scanning Tunneling Microscope (STM) is used to induce a reversible transition between different polymorphs in a binary supramolecular network at the liquid/solid interface. The transition is driven externally by switching the polarity of the sample by positive or negative sample bias potentials. We demonstrate that by mixing bias-sensitive and non-sensitive molecules, we gain access to a variety of binary porous structures that can be prepared and reliably actuated for each relative concentration.


Hospital-reported data on the pneumonia quality measure "Time to First Antibiotic Dose" are not associated with inpatient mortality: results of a nationwide cross-sectional analysis.
Significant controversy exists regarding the Centers for Medicare & Medicaid Services (CMS) "time to first antibiotics dose" (TFAD) quality measure. The objective of this study was to determine whether hospital performance on the TFAD measure for patients admitted from the emergency department (ED) for pneumonia is associated with decreased mortality. This was a cross-sectional analysis of 95,704 adult ED admissions with a principal diagnosis of pneumonia from 530 hospitals in the 2007 Nationwide Inpatient Sample. The sample was merged with 2007 CMS Hospital Compare data, and hospitals were categorized into TFAD performance quartiles. Univariate association of TFAD performance with inpatient mortality was evaluated by chi-square test. A population-averaged logistic regression model was created with an exchangeable working correlation matrix of inpatient mortality adjusted for age, sex, comorbid conditions, weekend admission, payer status, income level, hospital size, hospital location, teaching status, and TFAD performance. Patients had a mean age of 69.3 years. In the adjusted analysis, increasing age was associated with increased mortality with odds ratios (ORs) of >2.3. Unadjusted inpatient mortality was 4.1% (95% confidence interval [CI] = 3.9% to 4.2%). Median time to death was 5 days (25th-75th interquartile range = 2-11). Mean TFAD quality performance was 77.7% across all hospitals (95% CI = 77.6% to 77.8%). The risk-adjusted OR of mortality was 0.89 (95% CI = 0.77 to 1.02) in the highest performing TFAD quartile, compared to the lowest performing TFAD quartile. The second highest performing quartile OR was 0.94 (95% CI = 0.82 to 1.08), and third highest performing quartile was 0.91 (95% CI = 0.79 to 1.05). In this nationwide heterogeneous 2007 sample, there was no association between the publicly reported TFAD quality measure performance and pneumonia inpatient mortality.


Warming your heart: the energy solution.
Citron (2002) probably sums it up best when he states that generosity is the best strategy for corporate prosperity. He believes that the love you get from others as a person and a corporation is equal to the love you extend to others. It's really about creating communities of caring and missions of inclusiveness. And the way to make this all happen is to continually recharge our batteries by staying close to the beautiful stories of our organization that will undeniably warm our hearts and give us the energy to be generous.


Arsenic biogeochemical cycling in paddy soil-rice system: Interaction with various factors, amendments and mineral nutrients.
Arsenic (As) contamination is a well-recognized environmental and health issue, threatening over 200 million people worldwide with the prime cases in South and Southeast Asian and Latin American countries. Rice is mostly cultivated under flooded paddy soil conditions, where As speciation and accumulation by rice plants is controlled by various geo-environmental (biotic and abiotic) factors. In contrast to other food crops, As uptake in rice has been found to be substantially higher due to the prevalence of highly mobile and toxic As species, arsenite (As(III)), under paddy soil conditions. In this review, we discussed the biogeochemical cycling of As in paddy soil-rice system, described the influence of critical factors such as pH, iron oxides, organic matter, microbial species, and pathways affecting As transformation and accumulation by rice. Moreover, we elucidated As interaction with organic and inorganic amendments and mineral nutrients. The review also elaborates on As (im)mobilization processes and As uptake by rice under the influence of different mineral nutrients and amendments in paddy soil conditions, as well as their role in mitigating As transfer to rice grain. This review article provides critical information on As contamination in paddy soil-rice system, which is important to develop suitable strategies and mitigation programs for limiting As exposure via rice crop, and meet the UN's key Sustainable Development Goals (SDGs: 2 (zero hunger), 3 (good health and well-being), 12 (responsible consumption and production), and 13 (climate action)).


A suppressive oligodeoxynucleotide enhances the efficacy of myelin cocktail/IL-4-tolerizing DNA vaccination and treats autoimmune disease.
Targeting pathogenic T cells with Ag-specific tolerizing DNA vaccines encoding autoantigens is a powerful and feasible therapeutic strategy for Th1-mediated autoimmune diseases. However, plasmid DNA contains abundant unmethylated CpG motifs, which induce a strong Th1 immune response. We describe here a novel approach to counteract this undesired side effect of plasmid DNA used for vaccination in Th1-mediated autoimmune diseases. In chronic relapsing experimental autoimmune encephalomyelitis (EAE), combining a myelin cocktail plus IL-4-tolerizing DNA vaccine with a suppressive GpG oligodeoxynucleotide (GpG-ODN) induced a shift of the autoreactive T cell response toward a protective Th2 cytokine pattern. Myelin microarrays demonstrate that tolerizing DNA vaccination plus GpG-ODN further decreased anti-myelin autoantibody epitope spreading and shifted the autoreactive B cell response to a protective IgG1 isotype. Moreover, the addition of GpG-ODN to tolerizing DNA vaccination therapy effectively reduced overall mean disease severity in both the chronic relapsing EAE and chronic progressive EAE mouse models. In conclusion, suppressive GpG-ODN effectively counteracted the undesired CpG-induced inflammatory effect of a tolerizing DNA vaccine in a Th1-mediated autoimmune disease by skewing both the autoaggressive T cell and B cell responses toward a protective Th2 phenotype. These results demonstrate that suppressive GpG-ODN is a simple and highly effective novel therapeutic adjuvant that will boost the efficacy of Ag-specific tolerizing DNA vaccines used for treating Th1-mediated autoimmune diseases.


Fruit Juice in Infants, Children, and Adolescents: Current Recommendations.
Historically, fruit juice was recommended by pediatricians as a source of vitamin C and as an extra source of water for healthy infants and young children as their diets expanded to include solid foods with higher renal solute load. It was also sometimes recommended for children with constipation. Fruit juice is marketed as a healthy, natural source of vitamins and, in some instances, calcium. Because juice tastes good, children readily accept it. Although juice consumption has some benefits, it also has potential detrimental effects. High sugar content in juice contributes to increased calorie consumption and the risk of dental caries. In addition, the lack of protein and fiber in juice can predispose to inappropriate weight gain (too much or too little). Pediatricians need to be knowledgeable about juice to inform parents and patients on its appropriate uses.


Associations between dietary flavonoid intakes and bone health in a Scottish population.
Flavonoids are bioactive polyphenols found particularly in fruit and vegetables, but little is known about their role in bone health in humans. The aim of this observational study was to investigate whether dietary flavonoid intake was associated with bone mineral density (BMD) and bone resorption in a large group of perimenopausal Scottish women. Over 3000 women completed a food frequency questionnaire as part of an osteoporosis screening study. The diets were analyzed for flavonoid intake using a food composition database. BMD was measured at the femoral neck (FN) and lumbar spine (LS) by dual-energy X-ray absorptiometry (DXA). Free pyridinoline (PYD) and deoxypyridinoline (DPD) were measured by high-performance liquid chromatography (HPLC) in second early morning fasted urine samples. The mean flavonoid intake of the diet was 307 ±199 mg/d. The catechin family contributed the most to flavonoid intakes (55%), and the flavones the least (<1%). Associations were found between energy-adjusted total flavonoid intakes and BMD at the FN and LS (FN r = 0.054, LS r = 0.036, p ≤ .05). Annual percent change in BMD was associated with intakes of procyanidins and catechins (p ≤ .05), and flavanones were negatively associated with bone-resorption markers (PYD r = -0.049, DPD r = -0.057, p ≤ .001). These associations were still seen after adjusting for confounders. It is concluded that dietary flavonoid intakes are associated with BMD, supporting the evidence from animal and cellular studies.


Deposition of (236)U from atmospheric nuclear testing in Washington state (USA) and the Pechora region (Russian Arctic).
Stratospheric fallout-derived (236)U has been detected by sector field ICPMS at two field locations for which our laboratory possessed available archived samples: A) four soil cores from Washington state (northwestern USA) and B) sediment cores from three small lakes in the Pechora region (Russian Arctic). Four Washington state soil cores exhibit (236)U inventories of 8.1 ± 1.3, 11.1 ± 0.9, 18 ± 2, and 30.2 ± 3.9 Tatoms/m(2); the respective (239)Pu contents are 52.9 ± 3.5, 67 ± 3, 71 ± 2, and 151 ± 2 Tatoms/m(2). A (236)U/(239)Pu atom ratio of 0.19 ± 0.04 (1 SD) has been determined from the Washington state soil cores. The three Pechora region lake cores each exhibit coincident maxima in their (236)U and (239)Pu atom concentration profiles. The (236)U/(238)U atom ratios are controlled by two independent factors; (236)U is from fallout deposition and (238)U concentrations are a property of the geochemical distribution of naturally occurring U. A (236)U/(238)U atom ratio as high as 8.9 × 10(-6) has been observed for acid-leached soils containing Pu solely derived from bomb-test fallout. Accordingly, a non-zero (236)U background from stratospheric fallout must be recognized and taken into account when detectable (236)U is used to infer specific local or regional influences of reactor-irradiated U.


Discovery of a Potent Inhibitor Class with High Selectivity toward Clostridial Collagenases.
Secreted virulence factors like bacterial collagenases are conceptually attractive targets for fighting microbial infections. However, previous attempts to develop potent compounds against these metalloproteases failed to achieve selectivity against human matrix metalloproteinases (MMPs). Using a surface plasmon resonance-based screening complemented with enzyme inhibition assays, we discovered an N-aryl mercaptoacetamide-based inhibitor scaffold that showed sub-micromolar affinities toward collagenase H (ColH) from the human pathogen Clostridium histolyticum. Moreover, these inhibitors also efficiently blocked the homologous bacterial collagenases, ColG from C. histolyticum, ColT from C. tetani, and ColQ1 from the Bacillus cereus strain Q1, while showing negligible activity toward human MMPs-1, -2, -3, -7, -8, and -14. The most active compound displayed a more than 1000-fold selectivity over human MMPs. This selectivity can be rationalized by the crystal structure of ColH with this compound, revealing a distinct non-primed binding mode to the active site. The non-primed binding mode presented here paves the way for the development of selective broad-spectrum bacterial collagenase inhibitors with potential therapeutic application in humans.


Arthropod diversity in two Historic Gardens in the Azores, Portugal.
The aim of our study was to characterise and compare the richness and composition of endemic, native (non-endemic) and introduced arthropod assemblages of two Azorean Historic Gardens with contrasting plant species composition. We hypothesised that Faial Botanic Garden would hold higher arthropod diversity and abundance of native and endemic arthropod species due to its larger native plant community. Species were collected using several arthropod standardised techniques between April 2017 and June 2018. We used the alpha diversity metrics (Hill series) and the partitioning of total beta diversity (βtotal) into its replacement (βrepl) and richness (βrich) components, to analyse the adult and total arthropod community. The orders Araneae, Coleoptera and Hemiptera were also studied separately. Our results show that the number of exotic arthropod species exceeds the number of native and/or the endemic species in both gardens, but the arthropod community of Faial Botanic Garden exhibited a higher density of endemic and native species. Despite some minor exceptions, the geographic origins of plant communities largely influenced the arthropod species sampled in each garden. This study improves our knowledge about urban arthropod diversity in the Azores and shows how well-designed urban garden management and planning contribute to the conservation of native and endemic Azorean species.


High speed adaptive liquid microlens array.
Liquid microlenses are attractive for adaptive optics because they offer the potential for both high speed actuation and parallelization into large arrays. Yet, in conventional designs, resonances of the liquid and the complexity of driving mechanisms and/or the device architecture have hampered a successful integration of both aspects. Here we present an array of up to 100 microlenses with synchronous modulation of the focal length at frequencies beyond 1 kHz using electrowetting. Our novel concept combines pinned contact lines at the edge of each microlens with an electrowetting controlled regulation of the pressure that actuates all microlenses in parallel. This design enables the development of various shapes of microlenses. The design presented here has potential applications in rapid parallel optical switches, artificial compound eye and three dimensional imaging.


[The relationship between maternal emotional symptoms during pregnancy and emotional and behavioral problems in preschool children: a birth cohort study].
To investigate the related influencing factors of preschool children's emotional and behavioral problems in early life and explore the associations between the symptoms of depression or anxiety during pregnancy and emotional and behavioral problems in preschool children. Based on the Ma'anshan Birth Cohort Study of the China-Anhui Birth Cohort Study (C-ABCS), women were recruited at their first clinical visit between October 2008 and October 2010 in four municipal medical and health institutions of Ma'anshan City, a total of 5 084 pregnant women and 4 669 singletons live births were included in the birth cohort. Women completed measures of depressive (Self-Rating Anxiety scale) and anxious (Center for Epidemiologic Studies Depression) symptoms in pregnancy. By the age of 3-6 follow-up, 3 653 children were followed with completed information between April 2014 and April 2015, strengths and difficulties questionnaires were used to assessed offspring emotional and behavioral problems. Logistics regression was used to investigate the relationship between the symptoms of depression or anxiety during pregnancy and emotional and behavioral problems in preschool children. The detected rates of emotional symptoms, conduct problems, hyperactivity and peer problems in preschool children were 6.3% (229/3 653), 7.5% (274/3 653), 7.6% (278/3 653) and 2.8% (103/3 653), while 7.6% (277/3 653) for total difficulties, 10.9%(398/3 653) for prosocial behavior and 27.4%(981/3 557) for impact respectively. Prevalence of anxiety and depression in the first trimester was 2.7%(100/3 653) and 4.7%(171/3 653) respectively, and in the second trimester was 2.0%(66/3 375) and 3.6%(122/3 375) respectively. After we controlled the confoundings of gestation age, place of residence, family income, maternal education, paternal education, premature birth and folic acid supplement before pregnancy, multinomial logistic regression analysis showed that the risk of children's emotional symptoms in maternal anxiety in both first-trimester and second-trimester group was higher than the group of no depression and anxiety symptoms, and OR(95%CI) was 5.90(2.00-17.48). Compared with whose mother no depression in both first-trimester and second-trimester, the risk of children's emotional symptoms in maternal depression in both first-trimester and second-trimester group was higher, and OR(95% CI) was 3.07 (1.30-7.28). And the risk of children's total difficulties of maternal anxiety in second-trimester was 2.27 (95%CI: 1.10-4.71) times of no anxiety in second-trimester. While the risk of children's total difficulties of maternal depression in second-trimester was 2.20 (95%CI: 1.24-3.93) times of no depression in second-trimester. Maternal emotional symptoms were not significant associations with conduct problems, hyperactivity, peer problems and prosocial behaviors (P> 0.05). There was a negative impact of maternal anxiety and depression symptoms during pregnancy on emotional and behavioral problems in preschool children. These findings highlight the need for additional clinical and research attention to both maternal depression and anxiety in pregnancy, which may be helpful to reduce the incidence of children's emotional and behavioral problems and act as an important measure in prevention.


European consensus on the concepts and measurement of the pathophysiological neuromuscular responses to passive muscle stretch.
To support clinical decision-making in central neurological disorders, a physical examination is used to assess responses to passive muscle stretch. However, what exactly is being assessed is expressed and interpreted in different ways. A clear diagnostic framework is lacking. Therefore, the aim was to arrive at unambiguous terminology about the concepts and measurement around pathophysiological neuromuscular response to passive muscle stretch. During two consensus meetings, 37 experts from 12 European countries filled online questionnaires based on a Delphi approach, followed by plenary discussion after rounds. Consensus was reached for agreement ≥75%. The term hyper-resistance should be used to describe the phenomenon of impaired neuromuscular response during passive stretch, instead of for example 'spasticity' or 'hypertonia'. From there, it is essential to distinguish non-neural (tissue-related) from neural (central nervous system related) contributions to hyper-resistance. Tissue contributions are elasticity, viscosity and muscle shortening. Neural contributions are velocity dependent stretch hyperreflexia and non-velocity dependent involuntary background activation. The term 'spasticity' should only be used next to stretch hyperreflexia, and 'stiffness' next to passive tissue contributions. When joint angle, moment and electromyography are recorded, components of hyper-resistance within the framework can be quantitatively assessed. A conceptual framework of pathophysiological responses to passive muscle stretch is defined. This framework can be used in clinical assessment of hyper-resistance and will improve communication between clinicians. Components within the framework are defined by objective parameters from instrumented assessment. These parameters need experimental validation in order to develop treatment algorithms based on the aetiology of the clinical phenomena.


No overall damage progression despite persistent inflammation in adalimumab-treated psoriatic arthritis patients: results from an investigator-initiated 48-week comparative magnetic resonance imaging, computed tomography and radiography trial.
In a comparative conventional MRI, dynamic contrast-enhanced (DCE)-MRI, CT and radiography study, the authors aimed to monitor whether inflammation is reduced or even eliminated and damage halted in PsA patients receiving anti-TNF therapy. A 48-week prospective open-label investigator-initiated trial of 41 biologic-naive patients treated with 40 mg adalimumab every other week. Hand CT, MRI (according to the PsA MRI scoring system method) and radiography (Sharp-van der Heijde method) were obtained at weeks 0, 6 (only MRI), 24 and 48. Clinical response was assessed by the PsA Response Criteria (PsARC). In the 23 PsARC responders at week 48, significant decreases from baseline in MRI synovitis (mean -2.0, P < 0.05), bone marrow oedema (BMO) (-1.3, P < 0.05), flexor tenosynovitis (-2.1, P < 0.05) and total inflammation (-6.0, P < 0.005) were observed. However, MRI signs of inflammation remained present (week 48 total inflammation score median = 9). Several DCE-MRI parameters also decreased (P < 0.05) and were correlated (ρ = 0.62) with conventional MRI total inflammation score. No statistically significant changes in bone erosion or proliferation scores were observed. With CT as the standard reference for detecting bone erosions/proliferations, sensitivity, specificity and accuracy were 100%/40%, 83%/93% and 84%/86%, respectively, for MRI, whereas corresponding values for radiography were 17%/26%, 98%/96%, and 93%/87%, respectively. Erosive progression as assessed by CT was found in 6 of 480 joints and baseline BMO was predictive (relative risk 10, 95% CI 2.1, 49). MRI signs of inflammation decrease, but do not disappear, during anti-TNF-α therapy. No overall changes in bone erosions or proliferations were observed. On joint-level baseline MRI, BMO was related to subsequent erosive progression detected by CT. ClinicalTrials.gov, http://clinicaltrials.gov/, NCT01465438.


Testing the effect of tACS over parietal cortex in modulating endogenous alpha rhythm and temporal integration windows in visual perception.
Neural oscillations in the alpha band (8-12 Hz) have been proposed as a key mechanism for the temporal resolution of visual perception. Higher alpha frequencies have been related to improved segregation of visual events over time, whereas lower alpha frequencies have been related to improved temporal integration. Similarly, also the phase of ongoing alpha has been shown to correlate with temporal integration/segregation. To test a causal relationship between alpha oscillations and perception, we here employed multi-channel transcranial alternating current stimulation (mc-tACS) over the right parietal cortex, whereas participants performed a visual temporal integration/segregation task that used identical stimuli with different instructions. Before and after mc-tACS we recorded the resting-state electroencephalogram (EEG) to extract the individual alpha frequency (IAF) and delivered electrical stimulation at slightly slower and faster frequencies (IAF±2 Hz). We hypothesized that this would not only drive endogenous alpha rhythms, but also affect temporal integration and segregation in an opposite way. However, the mc-tACS protocol used here did not consistently increase or decrease the IAF after the stimulation and did not affect temporal integration/segregation accuracy as expected. Although we found some preliminary evidence for an influence of tACS phase on temporal integration accuracy, the ongoing phase of mc-tACS oscillations did not reliably modulate temporal integration/segregation accuracy in a sinusoidal way as would have been predicted by an effective entrainment of brain oscillations. These findings may guide future studies using different stimulation montages for investigating the role of cortical alpha oscillations for human vision.