Learning Computational Models of Video Memorability from fMRI Brain Imaging.
Generally, various visual media are unequally memorable by the human brain. This paper looks into a new direction of modeling the memorability of video clips and automatically predicting how memorable they are by learning from brain functional magnetic resonance imaging (fMRI). We propose a novel computational framework by integrating the power of low-level audiovisual features and brain activity decoding via fMRI. Initially, a user study experiment is performed to create a ground truth database for measuring video memorability and a set of effective low-level audiovisual features is examined in this database. Then, human subjects' brain fMRI data are obtained when they are watching the video clips. The fMRI-derived features that convey the brain activity of memorizing videos are extracted using a universal brain reference system. Finally, due to the fact that fMRI scanning is expensive and time-consuming, a computational model is learned on our benchmark dataset with the objective of maximizing the correlation between the low-level audiovisual features and the fMRI-derived features using joint subspace learning. The learned model can then automatically predict the memorability of videos without fMRI scans. Evaluations on publically available image and video databases demonstrate the effectiveness of the proposed framework.


The mTORC1 signaling repressors REDD1/2 are rapidly induced and activation of p70S6K1 by leucine is defective in skeletal muscle of an immobilized rat hindlimb.
Limb immobilization, limb suspension, and bed rest cause substantial loss of skeletal muscle mass, a phenomenon termed disuse atrophy. To acquire new knowledge that will assist in the development of therapeutic strategies for minimizing disuse atrophy, the present study was undertaken with the aim of identifying molecular mechanisms that mediate control of protein synthesis and mechanistic target of rapamycin complex 1 (mTORC1) signaling. Male Sprague-Dawley rats were subjected to unilateral hindlimb immobilization for 1, 2, 3, or 7 days or served as nonimmobilized controls. Following an overnight fast, rats received either saline or L-leucine by oral gavage as a nutrient stimulus. Hindlimb skeletal muscles were extracted 30 min postgavage and analyzed for the rate of protein synthesis, mRNA expression, phosphorylation state of key proteins in the mTORC1 signaling pathway, and mTORC1 signaling repressors. In the basal state, mTORC1 signaling and protein synthesis were repressed within 24 h in the soleus of an immobilized compared with a nonimmobilized hindlimb. These responses were accompanied by a concomitant induction in expression of the mTORC1 repressors regulated in development and DNA damage responses (REDD) 1/2. The nutrient stimulus produced an elevation of similar magnitude in mTORC1 signaling in both the immobilized and nonimmobilized muscle. In contrast, phosphorylation of 70-kDa ribosomal protein S6 kinase 1 (p70S6K1) on Thr(229) and Thr(389) in response to the nutrient stimulus was severely blunted. Phosphorylation of Thr(229) by PDK1 is a prerequisite for phosphorylation of Thr(389) by mTORC1, suggesting that signaling through PDK1 is impaired in response to immobilization. In conclusion, the results show an immobilization-induced attenuation of mTORC1 signaling mediated by induction of REDD1/2 and defective p70S6K1 phosphorylation.


Do sugar-sweetened beverages cause adverse health outcomes in adults? A systematic review protocol.
Chronic diseases, such as cardiovascular disease and type 2 diabetes, impose significant burden to public health. Most chronic diseases are associated with underlying preventable risk factors, such as elevated blood pressure, blood glucose, and lipids, physical inactivity, excessive sedentary behaviours, overweight and obesity, and tobacco usage. Sugar-sweetened beverages are known to be significant sources of additional caloric intake, and given recent attention to their contribution in the development of chronic diseases, a systematic review is warranted. We will assess whether the consumption of sugar-sweetened beverages in adults is associated with adverse health outcomes and what the potential moderating factors are. Of interest are studies addressing sugar-sweetened beverage consumption, taking a broad perspective. Both direct consumption studies as well as those evaluating interventions that influence consumption (e.g. school policy, educational) will be relevant. Non-specific or multi-faceted behavioural, educational, or policy interventions may also be included subject to the level of evidence that exists for the other interventions/exposures. Comparisons of interest and endpoints of interest are pre-specified. We will include randomized controlled trials, controlled clinical trials, interrupted time series studies, controlled before-after studies, prospective and retrospective comparative cohort studies, case-control studies, and nested case-control designs. The MEDLINE, Embase, The Cochrane Library, CINAHL, ERIC, and PsycINFO databases and grey literature sources will be searched. The processes for selecting studies, abstracting data, and resolving conflicts are described. We will assess risk of bias using design-specific tools. To determine sets of confounding variables that should be adjusted for, we have developed causal directed acyclic graphs and will use those to inform our risk of bias assessments. Meta-analysis will be conducted where appropriate; parameters for exploring statistical heterogeneity and effect modifiers are pre-specified. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach will be used for determining the quality of evidence for outcomes. PROSPERO CRD42014009638.


Desulfotomaculum geothermicum sp. nov., a thermophilic, fatty acid-degrading, sulfate-reducing bacterium isolated with H2 from geothermal ground water.
A strictly anaerobic, thermophilic, fatty acids-degrading, sporulating sulfate-reducing bacterium was isolated from geothermal ground water. The organism stained Gram-negative and formed gas vacuoles during sporulation. Lactate, ethanol, fructose and saturated fatty acids up to C18 served as electron donors and carbon sources with sulfate as external electron acceptor. Benzoate was not used. Stoichiometric measurements revealed a complete oxidation of part of butyrate although growth with acetate as only electron donor was not observed. The rest of butyrate was oxidized to acetate. The strain grew chemolithoautotrophically with hydrogen plus sulfate as energy source and carbon dioxide as carbon source without requirement of additional organic carbon like acetate. The strain contained a c-type cytochrome and presumably a sulfite reductase P582. Optimum temperature, pH and NaCl concentration for growth were 54 degrees C, pH 7.3-7.5 and 25 to 35 g NaCl/l. The G + C content of DNA was 50.4 mol %. Strain BSD is proposed as a new species of the spore-forming sulfate-reducing genus Desulfotomaculum, D. geothermicum.


Clinical applications of microperimetry in RPGR-related retinitis pigmentosa: a review.
Microperimetry, or fundus-tracked perimetry, is a precise static-automated perimetric technique to assess central retinal function. As visual acuity only deteriorates at a late disease stage in RPGR-related retinitis pigmentosa (RP), alternative markers for disease progression are of great utility. Microperimetry assessment has been of critical value as an outcome measure in a recently reported phase I/II gene therapy trial for RPGR-related RP, both in terms of detecting safety and efficacy signals. Here, we performed a review of the literature. We describe the principles of microperimetry before outlining specific parameters that may be useful as outcome measures in clinical trial settings. The current state of structure-function correlations between short-wavelength autofluorescence, optical coherence tomography and adaptive optics in RPGR-related retinitis pigmentosa are also summarized.


National Beef Quality Audit-2016: assessment of cattle hide characteristics, offal condemnations, and carcass traits to determine the quality status of the market cow and bull beef industry.
To continue the series that began in 1994, the National Beef Quality Audit (NBQA) - 2016 was conducted to quantify the quality status of the market cow and bull beef sector, as well as determine improvements made in the beef and dairy industry since 2007. The NBQA-2016 was conducted from March through December of 2016, and assessed hide-on carcasses (n = 5,278), chilled carcasses (n = 4,285), heads (n = 5,720), and offal items (n = 4,800) in 18 commercial processing facilities throughout the United States. Beef cattle were predominantly black-hided; 68.0% of beef cows and 67.2% of beef bulls possessed a black hide. Holstein was the predominant type of dairy animal observed. Just over half (56.0%) of the cattle surveyed had no mud contamination on the hide, and when mud was present, 34.1% of cattle only had small amounts. Harvest floor assessments found 44.6% of livers, 23.1% of lungs, 22.3% of hearts, 20.0% of viscera, 8.2% of heads, and 5.9% of tongues were condemned. Liver condemnations were most frequently due to abscess presence. In contrast, contamination was the primary reason for condemnation of all other offal items. Of the cow carcasses surveyed, 17.4% carried a fetus at the time of harvest. As expected, mean carcass weight and loin muscle area values observed for bulls were heavier and larger than cows. The marbling scores represented by cull animal carcasses were most frequently slight and traces amounts. Cow carcasses manifested a greater amount of marbling on average than bull carcasses. The predominant fat color score showed all carcasses surveyed had some level of yellow fat. Only 1.3% of carcasses exhibited signs of arthritic joints. Results of the NBQA-2016 indicate there are areas in which the beef and dairy industries have improved and areas that still need attention to prevent value loss in market cows and bulls.


Ischemic and Bleeding Events Among Patients With Acute Coronary Syndrome Associated With Low-Dose Prasugrel vs Standard-Dose Clopidogrel Treatment.
Prasugrel was approved at a lower dose in 2014 in Japan than in the West because East Asian patients are considered more susceptible to bleeding than Western patients. However, real-world outcomes with low-dose prasugrel treatment remain unclear. To investigate the association of low-dose prasugrel vs standard-dose clopidogrel administration with short-term outcomes among patients with acute coronary syndrome undergoing percutaneous coronary intervention (PCI). This study used data from the Japan Cardiovascular Database-Keio Interhospital Cardiovascular Studies registry, a large, ongoing, multicenter, retrospective cohort of consecutive patients who underwent PCI. The present cohort study evaluated 2770 patients with acute coronary syndrome who underwent PCI and received either low-dose prasugrel (loading dose, 20 mg; maintenance dose, 3.75 mg) or clopidogrel (loading dose, 300 mg; maintenance dose, 75 mg) in combination with aspirin between 2014 and 2018. Propensity score-matching analysis was conducted to balance the baseline characteristics of patients receiving low-dose prasugrel and those receiving clopidogrel. Data analysis was conducted in June 2019. Prescription of either low-dose prasugrel or standard-dose clopidogrel prior to PCI. Primary ischemic events (in-hospital death, recurrent myocardial infarction, and ischemic stroke) and primary bleeding events, defined as bleeding complications within 72 hours after PCI consistent with the National Cardiovascular Data Registry CathPCI Registry definition. Of 2559 patients included in the study, the mean (SD) age was 67.8 (12.7) years, and 78.2% were male. In total, 1297 patients (50.7%) received low-dose prasugrel, and 1262 patients (49.3%) received clopidogrel. After propensity score matching, primary ischemic events among patients receiving low-dose prasugrel and those receiving clopidogrel were comparable (odds ratio [OR], 1.42; 95% CI, 0.90-2.23), but primary bleeding events were significantly higher among patients receiving prasugrel (OR, 2.91; 95% CI, 1.63-5.18). This increase in bleeding events was associated with the presence of a profile of high-bleeding risk (≥75 years of age, body weight <60 kg, or history of stroke or transient ischemic attack) (OR, 4.08; 95% CI, 1.86-8.97), being female (OR, 3.84; 95% CI, 1.05-14.0), or the presence of ST-segment elevation myocardial infarction (OR, 2.07; 95% CI, 1.05-4.09) or chronic kidney disease (OR, 4.78; 95% CI, 1.95-11.7). Since its approval, low-dose prasugrel has been used by nearly 80% of patients who undergo PCI. Despite the modified dose, bleeding events were higher among patients receiving low-dose prasugrel than among patients receiving clopidogrel, with no difference in ischemic events between the 2 groups. These results suggest the importance of a risk assessment of bleeding prior to selecting a P2Y12 inhibitor, even for the use of a lower approved dose, when treating patients of East Asian descent.


Pigment epithelium-derived factor regulates the vasculature and mass of the prostate and pancreas.
Angiogenesis sustains tumor growth and metastasis, and recent studies indicate that the vascular endothelium regulates tissue mass. In the prostate, androgens drive angiogenic inducers to stimulate growth, whereas androgen withdrawal leads to decreased vascular endothelial growth factor, vascular regression and epithelial cell apoptosis. Here, we identify the angiogenesis inhibitor pigment epithelium-derived factor (PEDF) as a key inhibitor of stromal vasculature and epithelial tissue growth in mouse prostate and pancreas. In PEDF-deficient mice, stromal vessels were increased and associated with epithelial cell hyperplasia. Androgens inhibited prostatic PEDF expression in cultured cells. In vivo, androgen ablation increased PEDF in normal rat prostates and in human cancer biopsies. Exogenous PEDF induced tumor epithelial apoptosis in vitro and limited in vivo tumor xenograft growth, triggering endothelial apoptosis. Thus, PEDF regulates normal pancreas and prostate mass. Its androgen sensitivity makes PEDF a likely contributor to the anticancer effects of androgen ablation.


Mariprofundus ferrooxydans PV-1 the first genome of a marine Fe(II) oxidizing Zetaproteobacterium.
Mariprofundus ferrooxydans PV-1 has provided the first genome of the recently discovered Zetaproteobacteria subdivision. Genome analysis reveals a complete TCA cycle, the ability to fix CO(2), carbon-storage proteins and a sugar phosphotransferase system (PTS). The latter could facilitate the transport of carbohydrates across the cell membrane and possibly aid in stalk formation, a matrix composed of exopolymers and/or exopolysaccharides, which is used to store oxidized iron minerals outside the cell. Two-component signal transduction system genes, including histidine kinases, GGDEF domain genes, and response regulators containing CheY-like receivers, are abundant and widely distributed across the genome. Most of these are located in close proximity to genes required for cell division, phosphate uptake and transport, exopolymer and heavy metal secretion, flagellar biosynthesis and pilus assembly suggesting that these functions are highly regulated. Similar to many other motile, microaerophilic bacteria, genes encoding aerotaxis as well as antioxidant functionality (e.g., superoxide dismutases and peroxidases) are predicted to sense and respond to oxygen gradients, as would be required to maintain cellular redox balance in the specialized habitat where M. ferrooxydans resides. Comparative genomics with other Fe(II) oxidizing bacteria residing in freshwater and marine environments revealed similar content, synteny, and amino acid similarity of coding sequences potentially involved in Fe(II) oxidation, signal transduction and response regulation, oxygen sensation and detoxification, and heavy metal resistance. This study has provided novel insights into the molecular nature of Zetaproteobacteria.


Semi-selective fatty acyl reductases from four heliothine moths influence the specific pheromone composition.
Sex pheromones are essential in moth mate communication. Information on pheromone biosynthetic genes and enzymes is needed to comprehend the mechanisms that contribute to specificity of pheromone signals. Most heliothine moths use sex pheromones with (Z)-11-hexadecenal as the major component in combination with minor fatty aldehydes and alcohols. In this study we focus on four closely related species, Heliothis virescens, Heliothis subflexa, Helicoverpa armigera and Helicoverpa assulta, which use (Z)-11-hexadecenal, (Z)-9-tetradecanal, and (Z)-9-hexadecenal in different ratios in their pheromone blend. The components are produced from saturated fatty acid precursors by desaturation, β-oxidation, reduction and oxidation. We analyzed the composition of fatty acyl pheromone precursors and correlated it to the pheromone composition. Next, we investigated whether the downstream fatty-acyl reduction step modulates the ratio of alcohol intermediates before the final oxidation step. By isolating and functionally characterizing the Fatty Acyl Reductase (pgFAR) from each species we found that the pgFARs were active on a broad set of C8 to C16 fatty acyl substrates including the key pheromone precursors, Z9-14, Z9-16 and Z11-16:acyls. When presenting the three precursors in equal ratios to yeast cultures expressing any of the four pgFARs, all reduced (Z)-9-tetradecenoate preferentially over (Z)-11-hexadecenoate, and the latter over (Z)-9-hexadecenoate. Finally, when manipulating the precursor ratios in vitro, we found that the pgFARs display small differences in the biochemical activity on various substrates. We conclude that a pgFAR with broad specificity is involved in heliothine moth pheromone biosynthesis, functioning as a semi-selective funnel that produces species-specific alcohol product ratios depending on the fatty-acyl precursor ratio in the pheromone gland. This study further supports the key role of these in pheromone biosynthesis and emphasizes the interplay between the pheromone fatty acyl precursors and the Lepidoptera specific pgFARs in shaping the pheromone composition.


Role of MicroRNAs in Pathophysiology of Non-alcoholic Fatty Liver Disease and Non-alcoholic Steatohepatitis.
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder worldwide. It includes wide range of diseases from different subtypes of simple steatosis to non-alcoholic steatohepatitis (NASH), which may be complicated by liver fibrosis, cirrhosis, or hepatocellular carcinoma. Of the epigenetic factors that play a key role in the progression of it, is microRNAs (miRNAs). MiRNAs are short non-coding RNAs of 22-23 nucleotides in length, which regulate a large number of genes that have a critical role in regulation of lipid and cholesterol biosynthesis in hepatocytes. MiRNAs can be used as a very powerful biomarker to diagnosis and follow-up any disorder, such as NAFLD and NASH with a high specificity and sensitivity. The aim of this study was to review the role of different miRNAs in the pathophysiology of NASH and NAFLD.


Structured, intensive education maximising engagement, motivation and long-term change for children and young people with diabetes: a cluster randomised controlled trial with integral process and economic evaluation - the CASCADE study.
Type 1 diabetes (T1D) in children and young people is increasing worldwide with a particular increase in children under the age of 5 years. Fewer than one in six children and young people achieve glycosylated fraction of haemoglobin (HbA1c) values in the range identified as providing best future outcomes. There is an urgent need for clinic-based pragmatic, feasible and effective interventions that improve both glycaemic control and quality of life (QoL). The intervention offers both structured education, to ensure young people know what they need to know, and a delivery model designed to motivate self-management. To assess the feasibility of providing a clinic-based structured educational group programme incorporating psychological approaches to improve long-term glycaemic control, QoL and psychosocial functioning in a diverse range of young people. The study was a pragmatic, cluster randomised control trial with integral process and economic evaluation. Twenty-eight paediatric diabetes services across London, south-east England and the Midlands. Minimised by clinic size, age (paediatric or adolescent) and specialisation (district general hospital clinic or teaching hospital/tertiary clinic). Half of the sites were randomised to the intervention arm and half to the control arm. Allocation was concealed until after clinics had consented and the first participant was recruited. Where possible, families were blind to allocation until recruitment finished. Forty-three health-care practitioners (14 teams) were trained in the intervention. The study recruited 362 children aged 8-16 years, diagnosed with T1D for > 12 months, with a mean 12-month HbA1c level of ≥ 8.5%. Two 1-day workshops taught intervention delivery. A detailed manual and resources were provided. The intervention consists of four group education sessions led by a paediatric diabetes specialist nurse with another team member. The primary outcome was glycaemic control, assessed at the individual level using venous HbA1c values, measured at baseline, 12 and 24 months. Secondary outcomes were directly and indirectly related to diabetes management, including hypoglycaemic episodes, hospital admissions, diabetes regimen, knowledge, skills and responsibility for diabetes management, intervention compliance, clinic utilisation, emotional and behavioural adjustment, and general and diabetes-specific QoL. Questionnaires, semistructured interviews, informal discussion following observation sessions, fieldwork notes and case note review were used to collect qualitative and quantitative data from key stakeholder groups at specific time points in the trial. Primary and secondary analyses were intention-to-treat comparisons of outcomes at 12 and 24 months, using analysis of covariance with a random effect for clinic. Prespecified subgroup analyses based on age, gender, initial HbA1c value and socioeconomic status were estimated from models that included an interaction term. The economic analysis compared long-term costs and predicted quality-adjusted life-years (QALYs). The intervention did not improve HbA1c at 12 months [intervention effect 0.11; 95% confidence interval (CI) -0.28 to 0.50; p = 0.584] or 24 months (intervention effect 0.03; 95% CI -0.36 to 0.41; p = 0.891). A total of 298/362 patients (82.3%) provided blood samples at 12-month follow-up, and 284/362 (78.5%) provided blood samples at 24-month follow-up. Follow-up questionnaires were completed by 307 patients (85.3%) at 12 months and by 295 patients (81.5%) at 24 months. Intervention group parents at 12 months (95% CI 0.74; 0.03 to 1.52) and young people at 24 months (0.85; 95% CI 0.03 to 1.61) had higher scores on the diabetes family responsibility questionnaire. Young people reported reduced happiness with body weight at 12 months (-0.56; 95% CI -1.03 to -0.06). Only 68% of groups were run. Of the 180 families recruited, 96 (53%) attended at least one module. Reasons for low uptake included difficulties organising groups, and work and school commitments. Young people with higher HbA1c levels were less likely to attend. Parents and young people who attended groups described improved family relationships, improved knowledge and understanding, greater confidence and increased motivation to manage diabetes. Twenty-four months after the intervention, nearly half of the young people reported that the groups had made them want to try harder and that they had carried on trying. A high-quality, complex, pragmatic trial of structured education can be delivered alongside standard care in NHS diabetes clinics. Health-care providers benefited from behaviour change skill training and can deliver pragmatic aspects of a National Institute for Health and Care Excellence (NICE)-compliant structured education programme after relatively brief training. The process evaluation provides insight into aspects of the model, and highlights strengths and aspects that may have contributed to the failure to influence primary and secondary outcomes. Current NHS practice dominates CASCADE (Child and Adolescent Structured Competencies Approach to Diabetes Education) in that it achieves the same number of QALYs at a lower cost. The mean cost of providing the intervention was £5098 per site or £683 per child. Members of paediatric diabetes services trained to deliver the CASCADE structured education package using behaviour change techniques did not improve glycaemic control in patients compared with control subjects 1 and 2 years after the intervention. The training workshops for practitioners were well evaluated; however, more intensive training was needed. The intervention cost £683 per patient but was not cost-effective because it did not improve metabolic control. A high-quality, complex, pragmatic trial of structured education can be successfully conducted alongside standard care in NHS diabetes clinics. Pragmatic components of a NICE-compliant structured education programme can be successfully delivered following a relatively brief 2-day training while paediatric health-care professionals benefit from training in behaviour change skills. The study provides invaluable information on barriers and opportunities regarding future, similar interventions. A low dropout rate and good attendance for the subgroup that attended the intervention suggests there might be improved uptake if offered to young people with lower HbA1c. Testing whether this approach can be more successful with a robust ongoing supervisory element should be a target of further research. Current Controlled Trials ISRCTN52537669. This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 18, No. 20. See the NIHR Journals Library website for further project information.


First Report of a New Leaf Spot Caused by Plectosphaerella cucumerina on Field Grown Endive (Cichorium endivia) in Italy.
During summer 2012, symptoms of a new leaf spot disease were observed in several commercial fields in Treviglio (Bergamo, northern Italy) on plants of curly (Cichorium endivia var. crispum) and Bavarian (C. endivia var. latifolium) endive (Asteraceae). This crop is widely grown in the region for fresh market. The first symptoms on leaves of affected plants consisted of small (1 mm) black-brown spots of irregular shape, later coalescing into larger spots, up to 10 to 15 mm diameter. Eventually, spots were surrounded by a yellow halo. Particularly, affected tissues rotted quickly under high moisture. Disease severity was greatest at 75 to 90% RH and air temperature between 23 and 30°C, where affected tissues rotted quickly. This disease resulted in severe production losses. On one farm in particular, three different fields totaling 2 ha, 5 to 13% of the plants were affected. Diseased tissue was excised, immersed in a solution containing 1% sodium hypochlorite for 60 s, rinsed in water, then placed on potato dextrose agar (PDA) medium, containing 25 mg/liter of streptomycin sulphate. After 5 days, a fungus developed producing a whitish-orange mycelium when incubated under 12 h/day of fluorescent light at 23°C. The isolates obtained were purified on PDA. On this medium, they produced hyaline elliptical and ovoid conidia, rarely septate, measuring 5.0 to 9.0 × 1.7 to 3.9 (average 6.0 × 2.9) μm. Conidia were born on phialides, single, clavate, and 2.8 × 1.4 μm. Such characteristics are typical of Plectosphaerella sp. (1,2). The internal transcribed spacer (ITS) region of rDNA was amplified using the primers ITS1/ITS4 (3) and sequenced. BLAST analysis of the 530-bp segment obtained from C. endivia var. crispum isolate PLC28 and of the 527-bp from C. endivia var. latifolium isolate PLC 30, respectively, showed 99% similarity with the sequence of Plectosphaerella cucumerina (anamorph Plectosporium tabacinum), GenBank EU5945566. The nucleotide sequences of isolates PLC 28 and PLC 30 have been assigned the GenBank accession numbers KC293994 and KC293993, respectively. To confirm pathogenicity, tests were conducted on 30-day-old C. endivia plants. C. endivia var. crispum cv Myrna and C. endivia var. latifolium cv. Sardana plants, grown in 2-liter pots (1 plant per pot, 10 plants per treatment) were inoculated by spraying a 106 CFU/ml conidial suspension of the two isolates of P. cucumerina, prepared from 10-day-old cultures, grown on PDA. Inoculated plants were maintained in a growth chamber at 25 ± 1°C and 90% RH for 5 days. Non-inoculated plants, only sprayed with water, served as controls. All plants inoculated with the two isolates, showed typical leaf spots 7 days after the artificial inoculation, similar to those observed in the field. Later, spots enlarged and leaves rotted. Non-inoculated plants remained healthy. P. cucumerina was reisolated from inoculated plants. The pathogenicity tests were conducted twice with identical results. This is, to our knowledge, the first report of P. cucumerina on endive n Italy, as well as worldwide. Due to the importance of the crop in Italy, this disease can cause serious economic losses. References: (1) A. Carlucci et al. Persoonia 28:34, 2012. (2) M. E. Palm et al. Mycologia 87:397, 1995. (3) T. J. White et al. PCR Protocols: A Guide to Methods and Applications. M. A. Innis et al., eds. Academic Press, San Diego, 1990.


The impact of resource valence on children's other-regarding preferences.
Given its importance for the emergence of intergroup conflict, the development of other-regarding preferences toward in-group and out-group members has received increasing attention from various disciplines. The present study investigates children's other-regarding preferences toward in-group and out-group members when allocating resources with positive and negative valence. The 6- and 8-year-olds' (N = 92) task was to allocate resources to themselves versus to an in-group or an out-group member. They demonstrated prosociality more frequently toward in-group than toward out-group recipients and more frequently when positive rather than negative resources were involved. Whereas the importance of the recipient's group membership increased with participants' age, the importance of resource valence decreased. Furthermore, older children, but not younger ones, were more prosocial toward in-group than out-group members in the allocation of negative resources. These findings help to understand the psychological determinants and the ontogenetic origins of other-regarding preferences toward in-group versus out-group members and, hence, individual engagement in intergroup conflict. (PsycINFO Database Record


High-sensitivity blood-based detection of breast cancer by multi photon detection diagnostic proteomics.
We have developed several new methods for blood-based cancer detection by diagnostic proteomics. Ultrasensitive methods of immunoassay using multiphoton-detection (IA/MPD) increase sensitivity by 200- to 1,000-fold (1 femtogram/mL). This has allowed the measurement of cancer biomarkers with very low concentrations in blood that could not be measured for full patient cohorts with conventional immunoassays. Sensitivity and specificity in cancer detection have been found to be potentiated by use of immunoassay panels which include tissue-specific cancer biomarkers as well as cytokines and angiogenic factors. The ultrasensitive immunoassays revealed that patient to patient variations in the concentrations of individual biomarkers in blood can extend over many orders of magnitude (up to six) and that the distributions of biomarker concentrations over patient cohorts are non-Gaussian. New methods of data analysis which correlate abundances of multiple, different biomarkers have been developed to deal with such data sets. Sensitivity and specificity of about 95% have been achieved for blood-based detection of breast cancer in pilot studies on 250 patients and 95 controls. Pilot studies indicate that this methodology may also allow differentiation of malignant breast cancer from benign lesions and can provide similar sensitivity and specificity for other epithelial cancers such as prostate cancer, ovarian cancer and melanoma. The methods developed for selection, application, and evaluation of very high sensitivity biomarker panels are expected to have general relevance for diagnostic proteomics.


Key features of an EU health information system: a concept mapping study.
Despite the acknowledged value of an EU health information system (EU-HISys) and the many achievements in this field, the landscape is still heavily fragmented and incomplete. Through a systematic analysis of the opinions and valuations of public health stakeholders, this study aims to conceptualize key features of an EU-HISys. Public health professionals and policymakers were invited to participate in a concept mapping procedure. First, participants (N = 34) formulated statements that reflected their vision of an EU-HISys. Second, participants (N = 28) rated the relative importance of each statement and grouped conceptually similar ones. Principal Component and cluster analyses were used to condense these results to EU-HISys key features in a concept map. The number of key features and the labelling of the concept map were determined by expert consensus. The concept map contains 10 key features that summarize 93 statements. The map consists of a horizontal axis that represents the relevance of an 'organizational strategy', which deals with the 'efforts' to design and develop an EU-HISys and the 'achievements' gained by a functioning EU-HISys. The vertical axis represents the 'professional orientation' of the EU-HISys, ranging from the 'scientific' through to the 'policy' perspective. The top ranking statement expressed the need to establish a system that is permanent and sustainable. The top ranking key feature focuses on data and information quality. This study provides insights into key features of an EU-HISys. The results can be used to guide future planning and to support the development of a health information system for Europe.


Characterization of nonattaching mutants of Agrobacterium tumefaciens.
The first step in tumor formation by Agrobacterium tumefaciens is the site-specific binding of the bacteria to plant host cells. Transposon mutants of the bacteria which fail to attach to carrot suspension culture cells were isolated. These mutants showed no significant attachment to carrot cells with either microscopic or viable cell count assays of bacterial binding. The nonattaching mutants were all avirulent. When revertants of the mutants were obtained by enriching for bacteria which do bind to carrot cells, the bacteria were found to have regained the ability to bind to carrot cells and virulence simultaneously. These results suggest that the ability of the bacteria to bind to plant cells is required for virulence. Like the parent strain, all of the nonattaching mutants synthesized cellulose, but unlike the parent strain, they failed to aggregate carrot suspension culture cells. The transposon Tn5, which was used to obtain the mutants, was located on a 12-kilobase EcoRI fragment of the bacterial chromosomal DNA in all of the nonattaching mutants from strain C58. That the mutant phenotype was due to the Tn5 insertion was shown by cloning the Tn5-containing DNA fragment from the mutant bacteria and using it to replace the wild-type fragment in the parent strain by marker exchange. The resulting bacteria had the same mutant phenotype as the original Tn5 mutants; they did not attach to carrot cells, they did not cause the aggregation of carrot cells, and they were avirulent. No difference was seen between the parent strain and the nonattaching mutants in hydrophobicity, motility, flagella, fimbriae, beta-2-glucan content, size of lipopolysaccharide, or ability of the lipopolysaccharide to inhibit bacterial attachment to tissue culture cells. Differences were seen between the parent strain and the nonattaching mutants in the polypeptides removed from the bacteria during the preparation of spheroplasts. Three of the mutants were lacking a polypeptide of about 34 kilodaltons (kDa). One mutant was lacking the 34-kDa polypeptide and another polypeptide of about 38 kDa. The fifth mutant was lacking a polypeptide slightly smaller than the 34-kDa polypeptide missing in the other four mutants. These missing polypeptides all reappeared in the revertants of the mutants. Thus, bacterial binding to plant cells appears to require the presence of these polypeptides.


Increasing Attentional Load Boosts Saccadic Adaptation.
Visual exploration relies on saccadic eye movements and attention processes. Saccadic adaptation mechanisms, which calibrate the oculomotor commands to continuously maintain the accuracy of saccades, have been suggested to act at downstream (motor) and upstream (visuoattentional) levels of visuomotor transformation. Conversely, whether attention can directly affect saccadic adaptation remains unknown. To answer this question, we manipulated the level of attention engaged in a visual discrimination task performed during saccadic adaptation. Participants performed low or high attention demanding orientation discrimination tasks on largely or faintly oriented Gabor patches, respectively, which served as targets for reactive saccades. Gabor patches systematically jumped backward during eye motion to elicit an adaptive shortening of saccades, and replaced 50 msec later (100 msec in two subjects) by a mask. Subjects judged whether Gabors' orientation was "nearly horizontal" versus "nearly vertical" (low attention demanding) or "slightly left" versus "slightly right" (high attention demanding), or made no discrimination (control task). We found that the build-up and the retention of adaptation of reactive saccades were larger in the "high attention demanding" condition than in the "low attention demanding" and the no-discrimination control conditions. These results indicate that increasing the level of attention to the perceptual processing of otherwise identical targets boosts saccadic adaptation, and suggest that saccadic adaptation mechanisms and attentional load effects may functionally share common neural substrates.


The tyrosine phosphatase CD148 interacts with the p85 regulatory subunit of phosphoinositide 3-kinase.
CD148 is a transmembrane tyrosine phosphatase that has been implicated in the regulation of cell growth and transformation. However, the signalling mechanisms of CD148 are incompletely understood. To identify the specific intracellular molecules involved in CD148 signalling, we carried out a modified yeast two-hybrid screening assay. Using the substrate-trapping mutant form of CD148 (CD148 D/A) as bait, we recovered the p85 regulatory subunit of PI3K (phosphoinositide 3-kinase). CD148 D/A, but not catalytically active CD148, interacted with p85 in a phosphorylation-dependent manner in vitro and in intact cells. Growth factor receptor and PI3K activity were also trapped by CD148 D/A via p85 from pervanadate-treated cell lysates. CD148 prominently and specifically dephosphorylated p85 in vitro. Co-expression of CD148 reduced p85 phosphorylation induced by active Src, and attenuated the increases in PI3K activity, yet CD148 did not alter the basal PI3K activity. Finally, CD148 knock-down by siRNA (short interfering RNA) increased PI3K activity on serum stimulation. Taken together, these results demonstrate that CD148 may interact with and dephosphorylate p85 when it is phosphorylated and modulate the magnitude of PI3K activity.


CFP and YFP, but not GFP, provide stable fluorescent marking of rat hepatic adult stem cells.
The stable expression of reporter genes in adult stem cells (ASCs) has important applications in stem cell biology. The ability to integrate a noncytotoxic, fluorescent reporter gene into the genome of ASCs with the capability to track ASCs and their progeny is particularly desirable for transplantation studies. The use of fluorescent proteins has greatly aided the investigations of protein and cell function on short-time scales. In contrast, the obtainment of stably expressing cell strains with low variability in expression for studies on longer-time scales is often problematic. We show that this difficulty is partly due to the cytotoxicity of a commonly used reporter, green fluorescent protein (GFP). To avoid GFP-specific toxicity effects during attempts to stably mark a rat hepatic ASC strain and, therefore, obtain stable, long-term fluorescent ASCs, we evaluated cyan fluorescent protein (CFP) and yellow fluorescent protein (YFP), in addition to GFP. Although we were unable to derive stable GFP-expressing strains, stable fluorescent clones (up to 140 doublings) expressing either CFP or YFP were established. When fluorescently marked ASCs were induced to produce differentiated progeny cells, stable fluorescence expression was maintained. This property is essential for studies that track fluorescently marked ASCs and their differentiated progeny in transplantation studies.


The Gut Microbiota in Collagenous Colitis Shares Characteristics With Inflammatory Bowel Disease-Associated Dysbiosis.
In inflammatory bowel disease (IBD), an aberrant immune response to gut microbiota is important, but the role of the microbiota in collagenous colitis (CC) is largely unknown. We aimed to characterize the microbiota of patients with CC compared with that of healthy control and patients with IBD. Fecal samples were collected from patients with CC (n = 29), age- and sex-matched healthy controls (n = 29), patients with Crohn's disease (n = 32), and patients with ulcerative colitis (n = 32). Sequence data were obtained by 454 sequencing of 16S rRNA gene amplicons, and the obtained sequences were subsequently taxonomically classified. Analysis of similarity statistics showed a segregation between patients with CC and healthy controls with increasing taxonomic resolution, becoming significant comparing operational taxonomic unit data (P = 0.006). CC had a lower abundance of 10 different taxa. Taxa-specific analyses revealed a consistent lower abundance of several operational taxonomic units belonging to the Ruminococcaceae family in patients with CC, q < 0.05 after false discovery rate correction. Loss of these taxa was seen in patients with CC with active disease and/or corticosteroid treatment only and resembled the findings in patients with IBD. CC is associated with a specific fecal microbiome seen primarily in patients with active disease or ongoing corticosteroid treatment, whereas the microbiome of CC patients in remission resembled that of healthy controls. Notably, the shift in key taxa, including the Ruminococcaceae family, was also observed in IBD. There may be common mechanisms in the pathogenesis of CC and IBD.


Progressive transforming growth factor beta1-induced lung fibrosis is blocked by an orally active ALK5 kinase inhibitor.
Pulmonary fibrosis is characterized by chronic scar formation and deposition of extracellular matrix, resulting in impaired lung function and respiratory failure. Idiopathic pulmonary fibrosis (IPF) is associated with pronounced morbidity and mortality and responds poorly to known therapeutic interventions; there are no known drugs that effectively block or reverse progressive fibrosis. Transforming growth factor beta (TGF-beta) is known to mediate extracellular matrix gene regulation and appears to be a major player in both the initiation and progression of IPF. TGF-beta mediates its biological effects through members of a family of activin receptor-like kinases (ALK). We have used a gene transfer model of progressive TGF-beta1-induced pulmonary fibrosis in rats to study a newly described orally active small molecular weight drug that is a potent and selective inhibitor of the kinase activity of ALK5, the specific TGF-beta receptor. We show that the drug inhibits the induction of fibrosis when administered at the time of initiation of fibrogenesis and, most important, blocks progressive fibrosis when administered transiently to animals with established fibrosis. These data show promise of the development of an effective therapeutic intervention for IPF and that inhibition of chronic progressive fibrosis may be achieved by blocking TGF-beta receptor activation.


Influenza B outbreak among influenza-vaccinated welfare home residents in Singapore.
Outbreaks of acute respiratory illness occur commonly in long-term care facilities (LTCF), due to the close proximity of residents. Most influenza outbreak reports have been from temperate countries. This study reports an outbreak of influenza B among a highly immunised resident population in a welfare home in tropical Singapore, and discusses vaccine efficacy and the role of acute respiratory illness surveillance for outbreak prevention and control. During the period from 16 to 21 March 2007, outbreak investigations and active case finding were carried out among residents and nursing staff at the welfare home. Interviews and medical notes review were conducted to obtain epidemiological and clinical data. Hospitalised patients were tested for respiratory pathogens. Further genetic studies were also carried out on positive respiratory samples. The overall clinical attack rate was 9.4% (17/180) in residents and 6.7% (2/30) in staff. All infected residents and staff had received influenza immunisation. Fifteen residents were hospitalised, with 2 developing severe complications. Genetic sequencing revealed that the outbreak strain had an 8.2% amino acid difference from B/Malaysia/2506/2004, the 2006 southern hemisphere influenza vaccine strain, which the residents and staff had earlier received. A mismatch between the vaccine and circulating influenza virus strains can result in an outbreak in a highly immunised LTCF resident population. Active surveillance for acute respiratory illness in LTCFs could be implemented for rapid detection of antigenic drift. Enhanced infection control and other preventive measures can then be deployed in a timely manner to mitigate the effect of any outbreaks.


Mixture interpretation: defining the relevant features for guidelines for the assessment of mixed DNA profiles in forensic casework.
Currently in the United States there is little direction for what constitutes sufficient guidelines for DNA mixture interpretation. While a standardized approach is not possible or desirable, more definition is necessary to ensure reliable interpretation of results is carried out. In addition, qualified DNA examiners should be able to review reports and understand the assumptions made by the analyst who performed the interpretation. Interpretation of DNA mixture profiles requires consideration of a number of aspects of a mixed profile, many of which need to be established by on-site, internal validation studies conducted by a laboratory's technical staff, prior to performing casework analysis. The relevant features include: criteria for identification of mixed specimens, establishing detection and interpretation threshold values, defining allele peaks, defining nonallele peaks, identifying artifacts, consideration of tri-allelic patterns, estimating the minimum number of contributors, resolving components of a mixture, determining when a portion of the mixed profile can be treated as a single source profile, consideration of potential additive effects of allele sharing, impact of stutter peaks on interpretation in the presence of a minor contributor, comparison with reference specimens, and some issues related to the application of mixture calculation statistics. Equally important is using sensible judgment based on sound and documented principles of DNA analyses. Assumptions should be documented so that reliable descriptive information is conveyed adequately concerning that mixture and what were the bases for the interpretations that were carried out. Examples are provided to guide the community. Interpretation guidelines also should incorporate strategies to minimize potential bias that could occur by making inferences based on a reference sample. The intent of this paper is to promote more thought, provide assistance on many aspects for consideration, and to support that more formalized mixture interpretation guidelines are developed.


Jaboticaba (Myrciaria cauliflora) Peel Supplementation Prevents Hepatic Steatosis Through Hypolipidemic Effects and Cholesterol Metabolism Modulation in Diet-Induced Nonalcoholic Fatty Liver Disease Rat Model.
Jaboticaba (Myrciaria cauliflora), a Brazilian fruit, is a good source of dietary fiber and phenolic compounds, which are concentrated mainly in the peel. These compounds have been considered promising in prevention and treatment of hypercholesterolemia and hepatic steatosis. In this study, we investigated the effects of 4% jaboticaba peel powder (JPP) supplementation on cholesterol metabolism and hepatic steatosis in livers of rats fed a high-fat (HF) diet. The rats were fed a standard AIN-93M (control) diet or an HF diet containing 32% lard and 1% cholesterol, both with and without 4% JPP. The M. cauliflora peel composition revealed a low-lipid high-fiber content and phenolic compounds. The phenolic compounds in JPP, tentatively identified by high-performance liquid chromatography and mass spectrometry (HPLC-MS/MS) analysis, were confirmed to contain phenolic acids, flavonoids, and anthocyanins. Moreover, JPP presented significant antioxidant activity in vitro and was not cytotoxic to HepG2 cells, as determined by the lactate dehydrogenase (LDH) assay. After 6 weeks of treatment, our results showed that JPP supplementation increased lipid excretion in feces, reduced serum levels of total cholesterol and nonhigh-density lipoprotein cholesterol, decreased serum aspartate aminotransferase (AST) activity, and attenuated hepatic steatosis severity in rats fed the HF diet. Furthermore, JPP treatment downregulated expression of ACAT-1, LXR-α, CYP7A1, and ABCG5 genes. Therefore, jaboticaba peel may represent a viable dietary strategy to prevent nonalcoholic fatty liver disease as the JPP treatment alleviated hepatic steatosis through improvement of serum lipid profiles and modulation of mRNA expression of genes involved in cholesterol metabolism.


Anti-cancer activities of diospyrin, its derivatives and analogues.
Natural products have played a vital role in drug discovery and development process for cancer. Diospyrin, a plant based bisnaphthoquinonoid, has been used as a lead molecule in an effort to develop anti-cancer drugs. Several derivatives/analogues have been synthesized and screened for their pro-apoptotic/anti-cancer activities so far. Our review is focused on the pro-apoptotic/anti-cancer activities of diospyrin, its derivatives/analogues and the different mechanisms potentially involved in the bioactivity of these compounds. Particular focus has been placed on the different mechanisms (both chemical and molecular) thought to underlie the bioactivity of these compounds. A brief bioinformatics analysis at the end of the article provides novel insights into the new potential mechanisms and pathways by which these compounds might exert their effects and lead to a better realization of the full therapeutic potential of these compounds as anti-cancer drugs.


A Duplexed High-Throughput Screen to Identify Allosteric Modulators of the Glucagon-Like Peptide 1 and Glucagon Receptors.
Injectable, degradation-resistant peptide agonists for the glucagon-like peptide 1 (GLP-1) receptor (GLP-1R), such as exenatide and liraglutide, activate the GLP-1R via a complex orthosteric-binding site and are effective therapeutics for glycemic control in type 2 diabetes. Orally bioavailable orthosteric small-molecule agonists are unlikely to be developed, whereas positive allosteric modulators (PAMs) may offer an improved therapeutic profile. We hypothesize that allosteric modulators of the GLP-1R would increase the potency and efficacy of native GLP-1 in a spatial and temporally preserved manner and/or may improve efficacy or side effects of injectable analogs. We report the design, optimization, and initial results of a duplexed high-throughput screen in which cell lines overexpressing either the GLP-1R or the glucagon receptor were coplated, loaded with a calcium-sensitive dye, and probed in a three-phase assay to identify agonists, antagonists, and potentiators of GLP-1, and potentiators of glucagon. 175,000 compounds were initially screened, and progression through secondary assays yielded 98 compounds with a variety of activities at the GLP-1R. Here, we describe five compounds possessing different patterns of modulation of the GLP-1R. These data uncover PAMs that may offer a drug-development pathway to enhancing in vivo efficacy of both endogenous GLP-1 and peptide analogs.


Gene expression and functional annotation of human choroid plexus epithelium failure in Alzheimer's disease.
Alzheimer's disease (AD) is the most common form of dementia. AD has a multifactorial disease etiology and is currently untreatable. Multiple genes and molecular mechanisms have been implicated in AD, including ß-amyloid deposition in the brain, neurofibrillary tangle accumulation of hyper-phosphorylated Tau, synaptic failure, oxidative stress and inflammation. Relatively little is known about the role of the blood-brain barriers, especially the blood-cerebrospinal fluid barrier (BCSFB), in AD. The BCSFB is involved in cerebrospinal fluid (CSF) production, maintenance of brain homeostasis and neurodegenerative disorders. Using an Agilent platform with common reference design, we performed a large scale gene expression analysis and functional annotation of the Choroid Plexus Epithelium (CPE), which forms the BCSFB. We obtained 2 groups of freshly frozen Choroid Plexus (CP) of 7 human donor brains each, with and without AD: Braak stages (0-1) and (5-6). We cut CP cryo-sections and isolated RNA from cresyl-violet stained, laser dissected CPE cells. Gene expression results were analysed with T-tests (R) and the knowledge-database Ingenuity. We found statistically significantly altered gene expression data sets, biological functions, canonical pathways, molecular networks and functionalities in AD-affected CPE. We observed specific cellular changes due to increased oxidative stress, such as the unfolded protein response, E1F2 and NRF2 signalling and the protein ubiquitin pathway. Most likely, the AD-affected BCSFB barrier becomes more permeable due to downregulation of CLDN5. Finally, our data also predicted down regulation of the glutathione mediated detoxification pathway and the urea cycle in the AD CPE, which suggest that the CPE sink action may be impaired. Remarkably, the expression of a number of genes known to be involved in AD, such as APP, PSEN1, PSEN2, TTR and CLU is moderate to high and remains stable in both healthy and affected CPE. Literature labelling of our new functional molecular networks confirmed multiple previous (molecular) observations in the AD literature and revealed many new ones. We conclude that CPE failure in AD exists. Combining our data with those of the literature, we propose the following chronological and overlapping chain of events: increased Aß burden on CPE; increased oxidative stress in CPE; despite continuous high expression of TTR: decreased capability of CPE to process amyloid; (pro-) inflammatory and growth factor signalling by CPE; intracellular ubiquitin involvement, remodelling of CPE tight junctions and, finally, cellular atrophy. Our data corroborates the hypothesis that increased BCSFB permeability, especially loss of selective CLDN5-mediated paracellular transport, altered CSF production and CPE sink action, as well as loss of CPE mediated macrophage recruitment contribute to the pathogenesis of AD.


Multilayer mirrors with high reflectance over an extended spectral region.
The design of mirrors composed of multilayer stacks of dielectric films is considered. High reflectance over an extended spectral range is attained by positioning the stacks so that on a wavelength scale their high-reflectance bands are either contiguous or overlapping. Certain precautions must be taken in the choice of stacks to avoid deep-reflectance minima from developing within the extended high-reflectance region. Some of these are discussed and illustrated with both computional and experimental curves. The techniques of extending the high-reflectance regions are applicable not only to mirrors, but also to low- and high-pass cutoff filters and to multilayer polarizers.


Temporal Tuning of Word- and Face-selective Cortex.
Sensitivity to temporal change places fundamental limits on object processing in the visual system. An emerging consensus from the behavioral and neuroimaging literature suggests that temporal resolution differs substantially for stimuli of different complexity and for brain areas at different levels of the cortical hierarchy. Here, we used steady-state visually evoked potentials to directly measure three fundamental parameters that characterize the underlying neural response to text and face images: temporal resolution, peak temporal frequency, and response latency. We presented full-screen images of text or a human face, alternated with a scrambled image, at temporal frequencies between 1 and 12 Hz. These images elicited a robust response at the first harmonic that showed differential tuning, scalp topography, and delay for the text and face images. Face-selective responses were maximal at 4 Hz, but text-selective responses, by contrast, were maximal at 1 Hz. The topography of the text image response was strongly left-lateralized at higher stimulation rates, whereas the response to the face image was slightly right-lateralized but nearly bilateral at all frequencies. Both text and face images elicited steady-state activity at more than one apparent latency; we observed early (141-160 msec) and late (>250 msec) text- and face-selective responses. These differences in temporal tuning profiles are likely to reflect differences in the nature of the computations performed by word- and face-selective cortex. Despite the close proximity of word- and face-selective regions on the cortical surface, our measurements demonstrate substantial differences in the temporal dynamics of word- versus face-selective responses.


Fluorescence quantum yield rationalized by the magnitude of the charge transfer in π-conjugated terpyridine derivatives.
Terpyridine derivatives are of great interest due to their unique photophysical properties when used as antennas in metallic complexes. Several experimental and theoretical studies indicate strong charge-transfer character of the lowest electronic excited state, which could be exploited for predicting fluorescence quantum yields from the magnitude of the charge separation induced by electronic transitions. Focusing on substituted 4'-phenyl-2,2':6'2''-terpyridyl, we report on two measures of the charge separation obtained from high-level calculations in ground and excited states (length of the change of the dipole moment and the electron-hole distance). Our refined model confirms that the fluorescence quantum yield shows a global S-shape dependence on the magnitude of the charge separation, which can be quantified either by the change in dipole moments between the ground and excited states or by the associated charge-hole distances. This approach provides a remarkable tool for the molecular design of a fluorescent polyaromatic antenna.


Effects of Phytochemicals on Blood Pressure and Neuroprotection Mediated Via Brain Renin-Angiotensin System.
The renin-angiotensin system (RAS) in the brain plays a crucial role in maintaining blood pressure as well as neuroprotection. This study compared the effects of curcumin, quercetin, and saponin on blood pressure, the brain RAS, and cholinergic system using perindopril, an angiotensin converting enzyme inhibitor (ACEI), as a positive control. Five-week-old male mice were stabilized and randomly assigned into a control group (n = 8), three phytochemical-treated groups (curcumin (n = 8), quercetin (n = 8), and saponin (n = 8)), and a positive control group (n = 8). The groups treated with the phytochemical were orally administered daily at a dose of 50 mg/kg body weight of phytochemicals. During the experiments, the weight and dietary intakes were measured regularly. After experiments, the brain tissue was homogenized and centrifuged for an additional assay. The concentrations of ACE, angiotensin II (AngII), and aldosterone levels were measured, and the mRNA expressions of renin and ACE were measured. As biomarkers of neuroprotection, the concentrations of acetylcholine(Ach) as well as the concentration and activity of acetylcholine esterase (AChE) were measured. After 4 weeks of treatment, the perindopril group showed the lowest blood pressure. Among the groups treated with the phytochemicals, treatment with curcumin and saponin significantly reduced blood pressure, although such effect was not as high as that of perindopril. Among phytochemicals, curcumin treatment significantly inhibited the concentration and activity of ACE, concentration of AngII, and mRNA expression of ACE. All phytochemical treatments significantly increased the concentration of ACh. The levels of AChE activity in groups exposed to curcumin or saponin (not quercetin) were significantly inhibited, Conclusion: Curcumin administration in rats reduced blood pressure by blocking the brain RAS components and protected the cholinergic system in brain by inhibiting the activity of AChE.


Evidence for macromolecular protein rings in the absence of bulk water.
We have examined the architecture of a protein complex in the absence of bulk water. By determining collision cross sections of assemblies of the trp RNA binding protein, TRAP, we established that the 11-membered ring topology of the complex can be maintained within a mass spectrometer. We also found that the binding of tryptophan enhances the stability of the ring structure and that addition of a specific RNA molecule increases the size of the complex and prevents structural collapse. These results provide definitive evidence that protein quaternary structure can be maintained in the absence of bulk water and highlight the potential of ion mobility separation for defining shapes of heterogeneous macromolecular assemblies.


Novel missense and truncating mutations in FUS/TLS in familial ALS.
Mutations in the FUS/TLS gene have been associated with familial amyotrophic lateral sclerosis (FALS). We analyzed the presence and frequency of C-terminal FUS/TLS mutations in a German amyotrophic lateral sclerosis (ALS) cohort, including 133 patients with sporadic ALS (SALS) and 58 patients with FALS by sequence analysis of exons 13-15. We identified 2 novel heterozygous FUS/TLS mutations in 4 German ALS families including the novel missense mutation K510R and the truncating mutation R495X. The truncating mutation was associated with an aggressive disease course whereas the K510R mutation showed a mild phenotype with disease duration ranging from 6 to 8 years. No mutation was detected in 133 patients with SALS. Mutations in FUS/TLS account for 7% (4 of 58) of FALS in our German cohort.


RNAseq Analysis of Brain Aging in Wild Specimens of Short-Lived Turquoise Killifish: Commonalities and Differences With Aging Under Laboratory Conditions.
A vast body of studies is available that describe age-dependent gene expression in relation to aging in a number of different model species. These data were obtained from animals kept in conditions with reduced environmental challenges, abundant food, and deprivation of natural sensory stimulation. Here, we compared wild- and captive aging in the short-lived turquoise killifish (Nothobranchius furzeri). These fish inhabit temporary ponds in the African savannah. When the ponds are flooded, eggs hatch synchronously, enabling a precise timing of their individual and population age. We collected the brains of wild fish of different ages and quantified the global age-dependent regulation of transcripts using RNAseq. A major difference between captive and wild populations is that wild populations had unlimited access to food and hence grew to larger sizes and reached asymptotic size more rapidly, enabling the analysis of age-dependent gene expression without the confounding effect of adult brain growth. We found that the majority of differentially expressed genes show the same direction of regulation in wild and captive populations. However, a number of genes were regulated in opposite direction. Genes downregulated in the wild and upregulated in captivity were enriched for terms related to neuronal communication. Genes upregulated in the wild and downregulated in captive conditions were enriched in terms related to DNA replication. Finally, the rate of age-dependent gene regulation was higher in wild animals, suggesting a phenomenon of accelerated aging.


Facial expression recognition in image sequences using geometric deformation features and Support Vector Machines.
In this paper, two novel methods for facial expression recognition in facial image sequences are presented. The user has to manually place some of Candide grid nodes to face landmarks depicted at the first frame of the image sequence under examination. The grid-tracking and deformation system used, based on deformable models, tracks the grid in consecutive video frames over time, as the facial expression evolves, until the frame that corresponds to the greatest facial expression intensity. The geometrical displacement of certain selected Candide nodes, defined as the difference of the node coordinates between the first and the greatest facial expression intensity frame, is used as an input to a novel multiclass Support Vector Machine (SVM) system of classifiers that are used to recognize either the six basic facial expressions or a set of chosen Facial Action Units (FAUs). The results on the Cohn-Kanade database show a recognition accuracy of 99.7% for facial expression recognition using the proposed multiclass SVMs and 95.1% for facial expression recognition based on FAU detection.


A Theoretical Framework and Competency-Based Approach to Training in Guideline Development.
There is increasing requirement to develop guidelines using transparent, standardized, and rigorous methods. Consequently, a better understanding of the knowledge, skills, and expertise necessary for guideline development is needed. The aim of this manuscript is to describe a theoretical framework of knowledge and skills that are required for individuals to serve on a guideline panel in varying capacities. Based on an iterative process and review of published manuscripts focused on guideline development, we identified competencies, subcompetencies, and milestones. Using a competency-based approach to training and the Dreyfus model of skill acquisition, we identified three core competencies: (1) facilitate the development of guideline structure and setup, (2) make judgments about the quality or certainty of the evidence, and (3) transform evidence to a recommendation. Level 1 focuses on recognizing and acknowledging the importance of a specific skill or behavior. Levels 2 and 3 require learners to demonstrate progressive acquisition of knowledge and application to specific behaviors. Level 4 represents the individual who has acquired the requisite knowledge and can function independently, while level 5 represents the mastery/aspirational level. We propose a preliminary competency-based education framework that will (1) help standardize the qualifications needed for individuals to serve on guideline panels in varying capacities or (2) help with curricula development for teaching and training of guideline panel members. This framework can also help enable guideline-producing organizations to identify guideline methodologists with the relevant and appropriate level of knowledge and skills to lead guidelines. Validation of the framework and further refinement of the competencies and milestones will be required before widespread adoption.


Modelling the geographical range of a species with variable life-history.
We show how a climatic niche model can be used to describe the potential geographic distribution of a pest species with variable life-history, and illustrate how to estimate biogeographic pest threats that vary across space. The models were used to explore factors that affect pest risk (irrigation and presences of host plant). A combination of current distribution records and published experimental data were used to construct separate models for the asexual and sexual lineages of Rhopalosiphum padi (Linnaeus) (Hemiptera: Aphididae). The two models were combined with knowledge of host plant presence to classify the global pest risk posed by R. padi. Whilst R. padi has a relatively limited area in which sexual lineages can persist year round, a much larger area is suitable for transient sexual and asexual lineages to exist. The greatest risk of establishment of persistent sexual and asexual populations is in areas with warm temperate climates. At the global scale the models show very little difference in risk patterns between natural rainfall and irrigation scenarios, but in Australia, the amount of land suitable for persistent asexual and transient sexual populations decreases (by 20%) if drought stress is no longer alleviated by irrigation. This approach proved useful for modelling the potential distribution of a species that has a variable life-history. We were able to use the model outputs to examine factors such as irrigation practices and host plant presence that altered the nature (transient or permanent) and extent of pest risk. The composite niche maps indicate pest risk in terms that are useful to both biosecurity agencies and pest managers.


Phylogenetic diversity of ultraplankton plastid small-subunit rRNA genes recovered in environmental nucleic acid samples from the Pacific and Atlantic coasts of the United States.
The scope of marine phytoplankton diversity is uncertain in many respects because, like bacteria, these organisms sometimes lack defining morphological characteristics and can be a challenge to grow in culture. Here, we report the recovery of phylogenetically diverse plastid small-subunit (SSU) rRNA gene (rDNA) clones from natural plankton populations collected in the Pacific Ocean off the mouth of Yaquina Bay, Oreg. (OCS clones), and from the eastern continental shelf of the United States off Cape Hatteras, N.C. (OM clones). SSU rRNA gene clone libraries were prepared by amplifying rDNAs from nucleic acids isolated from plankton samples and cloning them into plasmid vectors. The PCR primers used for amplification reactions were designed to be specific for bacterial SSU rRNA genes; however, plastid genes have a common phylogenetic origin with bacteria and were common in both SSU rRNA gene clone libraries. A combination of restriction fragment length polymorphism analyses, nucleic acid sequencing, and taxon-specific oligonucleotide probe hybridizations revealed that 54 of the 116 OCS gene clones were of plastid origin. Collectively, clones from the OCS and OM libraries formed at least eight unique lineages within the plastid radiation, including gene lineages related to the classes Bacillariophyceae, Cryptophyceae, Prymnesiophyceae, Chrysophyceae, and Prasinophyceae; for a number of unique clones, no close phylogenetic neighbors could be identified with confidence. Only a group of two OCS rRNA gene clones showed close identity to the plastid SSU rRNA gene sequence of a cultured organism [Emiliania huxleyi (Lohmann) Hay and Mohler; 99.8% similar]. The remaining clones could not be identified to the genus or species level. Although cryptic species are not as prevalent among phytoplankton as they are among their bacterial counterparts, this genetic survey nonetheless uncovered significant new information about phytoplankton diversity.


The nature of vertical excited states of dyes containing metals for DSSC applications: insights from TD-DFT and density based indexes.
Transition metal complexes, typically Ru-based complexes, are the most efficient dyes used in dye-sensitized solar cells. The absorption spectra of these molecules generally involve numerous electronic transitions, which are not equivalent for the conversion of the light into electricity. In the present manuscript, an analysis of each electronic transition of selected inorganic complexes is performed based on the variation of the electronic density upon light absorption. To this end, a series of indices recently proposed in the literature is applied. The main conclusions of this work are twofold: from a methodological point of view, global hybrid functionals confirm their robustness for studying the electronic transitions of these compounds and from an application oriented point of view it is clear that the most intense transitions are not necessarily the most efficient ones for the light conversion.


Firearm anticipatory guidance training in psychiatric residency programs.
Most suicides (60%) are committed with firearms, and most (80%) of individuals attempting suicide meet diagnostic criteria for mental illness. This study assessed the prevalence of firearm injury prevention training in psychiatric residency programs. A three-wave mail survey was sent to the directors of 179 psychiatric residency programs. Outcome measures were the portion of programs offering training in anticipatory guidance for firearms safety, the content of training if offered, and the perceived benefits and barriers to providing such training. A total of 115 directors responded, a response rate of 64%. The vast majority (79%) reported they had not seriously thought about providing firearm injury prevention training. However, more than half (55%) reported that they routinely screened patients for firearm ownership. The directors perceived more benefits than barriers to offering such training. Additionally, the majority (62%) thought APA should provide curriculum guidelines regarding firearm injury prevention training. Psychiatrists are uniquely positioned for helping to prevent firearm suicides and homicides among the mentally ill. However, psychiatric residency programs are inadequately training residents and thereby keeping them from maximizing their roles as mental health professionals. Leadership is needed by APA to help reduce firearm violence in the United States.


Applying the net-benefit framework for analyzing and presenting cost-effectiveness analysis of a maternal and newborn health intervention.
Coverage of maternal and newborn health (MNH) interventions is often influenced by important determinants and decision makers are often concerned with equity issues. The net-benefit framework developed and applied alongside clinical trials and in pharmacoeconomics offers the potential for exploring how cost-effectiveness of MNH interventions varies at the margin by important covariates as well as for handling uncertainties around the ICER estimate. We applied the net-benefit framework to analyze cost-effectiveness of the Skilled Care Initiative and assessed relative advantages over a standard computation of incremental cost effectiveness ratios. Household and facility surveys were carried out from January to July 2006 in Ouargaye district (where the Skilled Care Initiative was implemented) and Diapaga (comparison site) district in Burkina Faso. Pregnancy-related and perinatal mortality were retrospectively assessed and data were collected on place of delivery, education, asset ownership, place, and distance to health facilities, costs borne by households for institutional delivery, and cost of standard provision of maternal care. Descriptive and regression analyses were performed. There was a 30% increase in institutional births in the intervention district compared to 10% increase in comparison district, and a significant reduction of perinatal mortality rates (OR 0.75, CI 0.70-0.80) in intervention district. The incremental cost for achieving one additional institutional delivery in Ouargaye district compared to Diapaga district was estimated to be 170 international dollars and varied significantly by covariates. However, the joint probability distribution (net-benefit framework) of the effectiveness measure (institutional delivery), the cost data and covariates indicated distance to health facilities as the single most important determinant of the cost-effectiveness analysis with implications for policy making. The net-benefit framework, the application of which requires household-level effects and cost data, has proven more insightful (than traditional ICER) in presenting and interpreting cost-effectiveness results of the Skilled Care Initiative.


Phase reconstruction from undersampled intensity patterns.
We demonstrate the uniqueness and convergence of phase recovery from high-spatial-frequency and undersampled intensity data. Furthermore, this is accomplished without the ambiguities that arise in phase unwrapping and without the need to employ a priori information. The method incorporates the technique of line integration of the phase gradient to find the first approximation to the phase and the algorithm of synthetic interferograms to find the unknown phase with high accuracy. The method may be used with any experimental method that at a certain data processing step obtains generalized sine and cosine intensity functions.


Genetic locus and structural characterization of the biochemical defect in the O-antigenic polysaccharide of the symbiotically deficient Rhizobium etli mutant, CE166. Replacement of N-acetylquinovosamine with its hexosyl-4-ulose precursor.
The O-antigen polysaccharide (OPS) of Rhizobium etli CE3 lipopolysaccharide (LPS) is linked to the core oligosaccharide via an N-acetylquinovosaminosyl (QuiNAc) residue. A mutant of CE3, CE166, produces LPS with reduced amounts of OPS, and a suppressed mutant, CE166 alpha, produces LPS with nearly normal OPS levels. Both mutants are deficient in QuiNAc production. Characterization of OPS from CE166 and CE166 alpha showed that QuiNAc was replaced by its 4-keto derivative, 2-acetamido-2,6-dideoxyhexosyl-4-ulose. The identity of this residue was determined by NMR and mass spectrometry, and by gas chromatography-mass spectrometry analysis of its 2-acetamido-4-deutero-2,6-dideoxyhexosyl derivatives produced by reduction of the 4-keto group using borodeuteride. Mass spectrometric and methylation analyses showed that the 2-acetamido-2,6-dideoxyhexosyl-4-ulosyl residue was 3-linked and attached to the core-region external Kdo III residue of the LPS, the same position as that of QuiNAc in the CE3 LPS. DNA sequencing revealed that the transposon insertion in strain CE166 was located in an open reading frame whose predicted translation product, LpsQ, falls within a large family of predicted open reading frames, which includes biochemically characterized members that are sugar epimerases and/or reductases. A hypothesis to be tested in future work is that lpsQ encodes UDP-2-acetamido-2,6-dideoxyhexosyl-4-ulose reductase, the second step in the synthesis of UDP-QuiNAc from UDP-GlcNAc.


Crystal structures and new perspectives on Y3Au4 and Y14Au51.
Y3Au4 (triyttrium tetragold) and Y14Au51 (tetradecayttrium henpentacontagold), two binary representatives of Au-rich rare earth (R) systems crystallize with the space groups R-3 and P6/m, adopting the Pu3Pd4 and Gd14Ag51 structure types, respectively (Pearson symbols hR42 and hP65). A variety of binary R-Au compounds have been reported, although only a few have been investigated thoroughly. Many reports lack information or misinterpret known compounds reported elsewhere. The Pu3Pd4 type is fairly common for group 10 elements Ni, Pd, and Pt, while Au representatives are restricted to just five examples, i.e. Ca3Au4, Pr3Au4, Nd3Au4, Gd3Au4, and Th3Au4. Sm6Au7 is suspected to be Sm3Au4 due to identical symmetry and close unit-cell parameters. The Pu3Pd4 structure type allows for full substitution of the position of the rare earth atom by more electronegative and smaller elements, i.e. Ti and Zr. The Gd14Ag51 type instead is more common for the group 11 metals, while rare representatives of group 12 are known. Y3Au4 can be represented as a tunnel structure with encapsulated cations and anionic chains. Though tunnels are present in Y14Au51, this structure is more complex and is best described in terms of polyhedral `pinwheels' around the tunnel forming polyhedra along the c axis.


Delineation of radiation therapy target volumes for patients with postoperative glioblastoma: a review.
Glioblastoma is the most aggressive and lethal primary malignancy of the brain, and radiotherapy (RT) is a fundamental part of its treatment. However, the optimal radiation treatment conditions are still a matter of debate, and there is no clear consensus concerning the inclusion of peritumoral edema in the clinical target volume calculation. Target delineation calculations that use postoperative residual tumor and cavity volumes plus 2 cm margins result in smaller volumes of normal brain receiving high-dose irradiation, compared to calculations that include expanded edema. Smaller RT fields may be more appropriate than larger RT fields, possibly reducing the risk of late neurological deterioration, especially in patients with significant peritumoral edema. This review focuses on the factors influencing target delineation, such as peritumoral edema, failure patterns, and prognostic factors (clinical and pathological characteristics) of patients with glioblastoma. Based on this information, we make three suggestions for radiation oncologists to refer to in daily practice. Further study is necessary to investigate the unresolved problems related to routine clinical application of RT.


Invasive breast cancer and breast cancer mortality after ductal carcinoma in situ in women attending for breast screening in England, 1988-2014: population based observational cohort study.
To evaluate the long term risks of invasive breast cancer and death from breast cancer after ductal carcinoma in situ (DCIS) diagnosed through breast screening. Population based observational cohort study. Data from the NHS Breast Screening Programme and the National Cancer Registration and Analysis Service. All 35 024 women in England diagnosed as having DCIS by the NHS Breast Screening Programme from its start in 1988 until March 2014. Incident invasive breast cancer and death from breast cancer. By December 2014, 13 606 women had been followed for up to five years, 10 998 for five to nine years, 6861 for 10-14 years, 2620 for 15-19 years, and 939 for at least 20 years. Among these women, 2076 developed invasive breast cancer, corresponding to an incidence rate of 8.82 (95% confidence interval 8.45 to 9.21) per 1000 women per year and more than double that expected from national cancer incidence rates (ratio of observed rate to expected rate 2.52, 95% confidence interval 2.41 to 2.63). The increase started in the second year after diagnosis of DCIS and continued until the end of follow-up. In the same group of women, 310 died from breast cancer, corresponding to a death rate of 1.26 (1.13 to 1.41) per 1000 women per year and 70% higher than that expected from national breast cancer mortality rates (observed:expected ratio 1.70, 1.52 to 1.90). During the first five years after diagnosis of DCIS, the breast cancer death rate was similar to that expected from national mortality rates (observed:expected ratio 0.87, 0.69 to 1.10), but it then increased, with values of 1.98 (1.65 to 2.37), 2.99 (2.41 to 3.70), and 2.77 (2.01 to 3.80) in years five to nine, 10-14, and 15 or more after DCIS diagnosis. Among 29 044 women with unilateral DCIS undergoing surgery, those who had more intensive treatment (mastectomy, radiotherapy for women who had breast conserving surgery, and endocrine treatment in oestrogen receptor positive disease) and those with larger final surgical margins had lower rates of invasive breast cancer. To date, women with DCIS detected by screening have, on average, experienced higher long term risks of invasive breast cancer and death from breast cancer than women in the general population during a period of at least two decades after their diagnosis. More intensive treatment and larger final surgical margins were associated with lower risks of invasive breast cancer.


Hysterosalpingosonography for diagnosing tubal occlusion in subfertile women: a systematic review protocol.
Hysterosalpingosonography has been suggested as a less invasive alternative to hysterosalpingography for detecting tubal occlusion among subfertile women. We aim to determine the diagnostic accuracy of hysterosalpingosonography and to compare it to hysterosalpingography. We will conduct a systematic review of diagnostic test accuracy. We will search Medline, Embase, Cochrane Library, Web of Science and Biosis, as well as reference lists of included studies and previous related review articles. Diagnostic studies that compared hysterosalpingosonography ± hysterosalpingography to laparoscopy with chromotubation in women suffering from subfertility will be eligible. Two authors will independently screen for inclusion, data extraction, and quality assessment. Methodological quality will be assessed using the Quality Assessment of Diagnostic Accuracy Study 2 tool (QUADAS-2). We will use SAS 9.3 (SAS Institute Inc., Cary, NC, USA, 2011) to program bivariate random-effects models, estimate pooled sensitivity and specificity with 95% confidence intervals and to generate summary receiver operating characteristics curves. We will perform sensitivity analyses to examine the effect of differences in techniques used for hysterosalpingosonography and in methodological quality of studies. This systematic review will help to determine if hysterosalpingosonography is an adequate alternative screening test for diagnosing tubal occlusion. Accuracy of specific sono-HSG techniques may also be identified. This review has been registered at PROSPERO. The registration number is CRD42013003829.


T CD4+ cells count among patients co-infected with human immunodeficiency virus type 1 (HIV-1) and human T-cell leukemia virus type 1 (HTLV-1): high prevalence of tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM).
HIV positive patients co-infected with HTLV-1 may have an increase in their T CD4+ cell counts, thus rendering this parameter useless as an AIDS-defining event. To study the effects induced by the co-infection of HIV-1 and HTLV-1 upon CD4+ cells. Since 1997, our group has been following a cohort of HTLV-1-infected patients, in order to study the interaction of HTLV-1 with HIV and/or with hepatitis C virus (HCV), as well as HTLV-1-only infected asymptomatic carriers and those with tropical spastic paraparesis/HTLV-1 associated myelopathy (TSP/HAM). One hundred and fifty HTLV-1-infected subjects have been referred to our clinic at the Institute of Infectious Diseases "Emílio Ribas", São Paulo. Twenty-seven of them were also infected with HIV-1 and HTLV-1-infection using two ELISAs and confirmed and typed by Western Blot (WB) or polymerase chain reaction (PCR). All subjects were evaluated by two neurologists, blinded to the patient's HTLV status, and the TSP/HAM diagnostic was based on the World Health Organization (WHO) classification. AIDS-defining events were in accordance with the Centers for Disease Control (CDC) classification of 1988. The first T CD4+ cells count available before starting anti-retroviral therapy are shown compared to the HIV-1-infected subjects at the moment of AIDS defining event. A total of 27 HIV-1/HTLV-1 co-infected subjects were identified in this cohort; 15 already had AIDS and 12 remained free of AIDS. The median of T CD4+ cell counts was 189 (98-688) cells/mm(3) and 89 (53-196) cells/mm(3) for co-infected subjects who had an AIDS-defining event, and HIV-only infected individuals, respectively (p = 0.036). Eight of 27 co-infected subjects (30%) were diagnosed as having a TSP/HAM simile diagnosis, and three of them had opportunistic infections but high T CD4+ cell counts at the time of their AIDS- defining event. Our results indicate that higher T CD4+ cells count among HIV-1/HTLV-1-coinfected subjects was found in 12% of the patients who presented an AIDS-defining event. These subjects also showed a TSP/HAM simile picture when it was the first manifestation of disease; this incidence is 20 times higher than that for HTLV-1-only infected subjects in endemic areas.


Epicardial adipose tissue: far more than a fat depot.
Epicardial adipose tissue (EAT) refers to the fat depot that exists on the surface of the myocardium and is contained entirely beneath the pericardium, thus surrounding and in direct contact with the major coronary arteries and their branches. EAT is a biologically active organ that may play a role in the association between obesity and coronary artery disease (CAD). Given recent advances in non-invasive imaging modalities such a multidetector computed tomography (MDCT), EAT can be accurately measured and quantified. In this review, we focus on the evidence suggesting a role for EAT as a quantifiable risk marker in CAD, as well as describe the role EAT may play in the development and vulnerability of coronary artery plaque.


Changes in prevalence, severity, and recovery in tardive dyskinesia with age.
Advancing age is one of the few factors suggested to predict increased risk of tardive dyskinesias (TDs). By pooling and reanalyzing available epidemiological data, we found strong linear correlations between ages (< 40 to 70 years) and both the prevalences and severity of TD, while neither increased significantly after age 70 years. There was also a strong inverse correlation between rates of spontaneous remission of TD and age (< 30 to > 80 years); TD in those younger than 60 years improved over three times as often as in older patients. These correlations are not readily explained by the duration of previous exposure to neuroleptic drugs and may reflect increased sensitivity of the aging brain to them. These observations support caution in the prolonged use of neuroleptics in patients older than age 50 years but encourage optimism for eventual spontaneous remission of TD in young adults.


[Violence against the elderly: analysis of aspects of mental health care in five Brazilian cities].
This is a research on the aspects of mental health care offered to elderly victims of violence in the cities of Curitiba, Rio de Janeiro, Brasília, Recife and Manaus. It was used the triangulation method that relied on the analysis of secondary data, information from questionnaires and individual and group interviews, defining itself as a target audience of this study, professionals and managers in mental health care. It was investigated the line of practices developed in services regarding policies governing mental health attention and addressed to the elderly who are victims of violence. Among the findings are: the disparity in records between elderly care hospitals (22.3%) and outpatient (0.4%), lack of information on the care of elderly victims of violence; and the incipient perception of professionals regarding the violence as a health intervention. In conclusion, there is a need for greater public investments: in improving the quality of information; the adequacy of the physical structure of services; the training/qualification of professionals to attend for specific elder health issues; under the aspect of violence, it was observed the need to adopt actions of prevention and attention of the most frequent disorders in the elderly.


Targeted reversion of induced pluripotent stem cells from patients with human cleidocranial dysplasia improves bone regeneration in a rat calvarial bone defect model.
Runt-related transcription factor 2 (RUNX2) haploinsufficiency causes cleidocranial dysplasia (CCD) which is characterized by supernumerary teeth, short stature, clavicular dysplasia, and osteoporosis. At present, as a therapeutic strategy for osteoporosis, mesenchymal stem cell (MSC) transplantation therapy is performed in addition to drug therapy. However, MSC-based therapy for osteoporosis in CCD patients is difficult due to a reduction in the ability of MSCs to differentiate into osteoblasts resulting from impaired RUNX2 function. Here, we investigated whether induced pluripotent stem cells (iPSCs) properly differentiate into osteoblasts after repairing the RUNX2 mutation in iPSCs derived from CCD patients to establish normal iPSCs, and whether engraftment of osteoblasts derived from properly reverted iPSCs results in better regeneration in immunodeficient rat calvarial bone defect models. Two cases of CCD patient-derived induced pluripotent stem cells (CCD-iPSCs) were generated using retroviral vectors (OCT3/4, SOX2, KLF4, and c-MYC) or a Sendai virus SeVdp vector (KOSM302L). Reverted iPSCs were established using programmable nucleases, clustered regularly interspaced short palindromic repeats (CRISPR)/Cas-derived RNA-guided endonucleases, to correct mutations in CCD-iPSCs. The mRNA expressions of osteoblast-specific markers were analyzed using quantitative reverse-transcriptase polymerase chain reaction. iPSCs-derived osteoblasts were transplanted into rat calvarial bone defects, and bone regeneration was evaluated using microcomputed tomography analysis and histological analysis. Mutation analysis showed that both contained nonsense mutations: one at the very beginning of exon 1 and the other at the initial position of the nuclear matrix-targeting signal. The osteoblasts derived from CCD-iPSCs (CCD-OBs) expressed low levels of several osteoblast differentiation markers, and transplantation of these osteoblasts into calvarial bone defects created in rats with severe combined immunodeficiency showed poor regeneration. However, reverted iPSCs improved the abnormal osteoblast differentiation which resulted in much better engraftment into the rat calvarial bone defect. Taken together, these results demonstrate that patient-specific iPSC technology can not only provide a useful disease model to elucidate the role of RUNX2 in osteoblastic differentiation but also raises the tantalizing prospect that reverted iPSCs might provide a practical medical treatment for CCD.


Teaching program for the Unified Dyskinesia Rating Scale.
The Unified Dyskinesia Rating Scale (UDysRS) has been introduced as a comprehensive rating tool for the evaluation of dyskinesias in Parkinson's disease (PD). To enhance a uniform application, we developed a DVD-based training program with instructions, patient examples, and a certification exercise. For training on the objective assessment of dyskinesia, seventy PD patients spanning the gamut of dyskinesias (none to severe) were videotaped during four tasks of daily living (speaking, drinking from a cup, putting on a coat, and walking). Dyskinesia severity in seven body parts was rated by 20 international movement disorder specialists using the UDysRS for impairment. Each task was also rated for disability. Inter-rater reliability was assessed with generalized weighted kappa and intraclass correlation coefficients. For the teaching program, examples of each severity level and each body part were selected based on the criterion that they received a uniform rating (+/- 1 point) by at least 75% of the raters. For the certification exercise, four cases were selected to represent the four quartiles of overall objective UDysRS scores to reflect slight, mild, moderate, and severe dyskinesia. Each selection was based on the highest inter-rater reliability score for that quartile (minimum kappa or intraclass correlation coefficient = 0.6). UDysRS ranges for certification were calculated based on the 95% confidence interval. The teaching program lasts 41 min, and the certification exercise requires 10 min (total 51 min). This training program, based on visual examples of dyskinesia and anchored in scores generated by movement disorder experts is aimed at increasing homogeneity of ratings among and within raters and centers. Large-scale multicenter randomized clinical trials of dyskinesia treatment are strengthened by a uniform standard of scale application.


Defining certainty of net benefit: a GRADE concept paper.
Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology is used to assess and report certainty of evidence and strength of recommendations. This GRADE concept article is not GRADE guidance but introduces certainty of net benefit, defined as the certainty that the balance between desirable and undesirable health effects is favourable. Determining certainty of net benefit requires considering certainty of effect estimates, the expected importance of outcomes and variability in importance, and the interaction of these concepts. Certainty of net harm is the certainty that the net effect is unfavourable. Guideline panels using or testing this approach might limit strong recommendations to actions with a high certainty of net benefit or against actions with a moderate or high certainty of net harm. Recommendations may differ in direction or strength from that suggested by the certainty of net benefit or harm when influenced by cost, equity, acceptability or feasibility.