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After more than a decade of increasingly widespread clinical use, personalized embryo transfer guided by endometrial receptivity analysis (ERA) remains controversial and unproven. One key element missing from the historical literature is the recognition that potential benefits from personalized embryo transfer are entirely dependent on the accuracy and predictive value of the ERA test. Results from the first comprehensive clinical trial, designed in a way that allowed independent evaluation of both potential benefits of personalized embryo transfer and the predictive value of the ERA test upon which it is based, were recently published. However, the authors failed to conduct an appropriate analysis or recognize the significance of their results. Here, we present a simple reanalysis of data from this otherwise excellent randomized controlled trial, demonstrating for the first time that the ERA was unable to identify the window of implantation as purported and that, as a result, personalized embryo transfer based on the ERA actually reduced rather than increased the birth rates. Based on these results and the lack of any contradictory evidence, it is our opinion that all clinical use of ERA-guided personalized embryo transfer should be discontinued immediately, outside of a controlled experimental setting with appropriate informed consent of all participating patients. [ABSTRACT FROM AUTHOR]

This article discusses a potential safety issue with the connection of Baxter Physioneal, Extraneal, Nutrineal (PEN) and Dianeal solution bags to Fresenius peritoneal dialysis catheter extensions. The authors describe a case where a patient accidentally connected the two systems, resulting in leakage and potential contamination. They recommend that hospitals switch patients back to their previous company's delivery system before discharge to minimize the risk of misconnection and peritonitis. Both Baxter and Fresenius Medical Care were informed of the issue prior to the publication of this article. [Extracted from the article]

In Spain, Holocene deposits are widespread, and although they have been extensively investigated by quaternarists for several decades, their malacological content has remained scarcely studied. In the framework of a German–French–Spanish collaboration, alluvial and tufa sequences in the Baza Basin, Andalusia, Spain are analysed with a multidisciplinary approach, including the analysis of the molluscan successions. Holocene fossil molluscs of the studied sequences reveal a rich assemblage of 53 species, among which 33 are terrestrial. Between 10,000 and 9,000 cal. yr BP, the Galera succession indicates strong river dynamics that prevented the establishment of adjacent terrestrial habitats. The Early to Middle Holocene transition reflects the continuity of humid environments. The Middle Holocene fauna reveals a decrease in humidity accompanied by slight evidence of drier habitats in the near periphery of the floodplain/tufa deposits from 5,900 cal. yr BP onwards. Late Holocene deposits (around 3,000 to 300 cal. yr BP) point to dry and open biotopes indicated by the appearance of xero-resistant and mesophilous gastropods. The palaeoenvironmental reconstruction inferred from the malacocenoses allows discussing local to regional responses of the malacofauna to environmental changes and is consistent with past regional environmental and climatic trends identified in southeastern Spain. The fossil record at Galera offers new evidence to question and clarify the modern range of endemic taxa whose distributions are fragmented. By following a 'conservation paleobiology' approach, the analysis of the mollusc fossil record at Galera provides (1) baselines to determine the natural variability of ecosystems and their response to environmental changes, (2) data to discuss and clarify species distribution evolution and (3) arguments to support conservation priorities. [ABSTRACT FROM AUTHOR]

Quinolin-8-yl 3-(4,4-difluoropiperidine-1-sulfonyl)-4-methylbenzoate (2F-QMPSB) and 3-(4,4-difluoropiperidine-1-sulfonyl)-4-methyl- N -(2-phenylpropan-2-yl)benzamide (SGT-233) belong to a new group of synthetic cannabinoid receptor agonists containing a sulfamoyl benzoate or sulfamoyl benzamide core structure. 2F-QMPSB was identified in herbal material seized in Europe in 2018. The aims of this study were the identification of in vitro Phase I and II metabolites of 2F-QMPSB and SGT-233 to find analytical targets for toxicological screenings. Furthermore, the contribution of different monooxygenases and human carboxylesterases to Phase I metabolism was investigated. Liquid chromatography coupled to high-resolution tandem mass spectrometry was used for analysis. Ester hydrolysis was found to be an important step in the metabolism of 2F-QMPSB, which was catalyzed mainly by human carboxylesterases (hCES)1 isoforms. Additionally, nonenzymatic ester hydrolysis was observed in case of 2F-QMPSB. Notably, the carboxylic acid product derived from ester hydrolysis and metabolites thereof were only detectable in negative ionization mode. In case of SGT-233, mono- and dihydroxy metabolites were identified, as well as glucuronides. The cytochrome P450 (CYP) isozymes CYP2C8, CYP2C9, CYP2C19, CYP3A4 and CYP3A5 were found to be involved in the hydroxylation of both compounds. The results of these in vitro experiments suggest that the ester hydrolysis products of 2F-QMPSB and their glucuronides are suitable targets for toxicological screenings. In the case of SGT-233, the mono- and dihydroxy metabolites were identified as suitable screening targets. The involvement of various CYP isoforms in the metabolism of both substances reduces the likelihood of drug–drug interactions due to CYP inhibition. [ABSTRACT FROM AUTHOR]

This review highlights new advances in the emerging field of 'Fungi-on-a-Chip' microfluidics for single-cell studies on fungi and discusses several future frontiers, where we envisage microfluidic technology development to be instrumental in aiding our understanding of fungal biology. Fungi, with their enormous diversity, bear essential roles both in nature and our everyday lives. They inhabit a range of ecosystems, such as soil, where they are involved in organic matter degradation and bioremediation processes. More recently, fungi have been recognized as key components of the microbiome in other eukaryotes, such as humans, where they play a fundamental role not only in human pathogenesis, but also likely as commensals. In the food sector, fungi are used either directly or as fermenting agents and are often key players in the biotechnological industry, where they are responsible for the production of both bulk chemicals and antibiotics. Although the macroscopic fruiting bodies are immediately recognizable by most observers, the structure, function, and interactions of fungi with other microbes at the microscopic scale still remain largely hidden. Herein, we shed light on new advances in the emerging field of Fungi-on-a-Chip microfluidic technologies for single-cell studies on fungi. We discuss the development and application of microfluidic tools in the fields of medicine and biotechnology, as well as in-depth biological studies having significance for ecology and general natural processes. Finally, a future perspective is provided, highlighting new frontiers in which microfluidic technology can benefit this field. [ABSTRACT FROM AUTHOR]

Open in new tab Download slide OBJECTIVES The purpose of this study was to evaluate the diagnosis of, clinical signs of and strategy for congenital cystic adenomatoid malformations (CCAM). METHODS In this retrospective study, patients who had thoracic surgery for CCAM lesions at the University Hospitals of Leuven from July 1993 to July 2016 were identified. Data on diagnosis, prenatal ultrasound findings, clinical signs, lesion site, CCAM type, associated anomalies, imaging, surgical approach and postoperative morbidity were reviewed. The Fisher exact and Mann–Whitney tests were used as appropriate. RESULTS A total of 55 patients were identified with CCAM. In 65% (n = 36/55), CCAM was detected on prenatal ultrasound scans. Prenatal symptoms due to hydrops or mass effect were present in 22% (n = 8/36), 6 of whom eventually needed prenatal intervention (thoracoamniotic shunting or intrauterine puncture). Elective surgery was performed in 40% of patients (n = 22/55); others developed clinical signs that indicated the need for semi-urgent surgery, with clinical signs of pulmonary infection and respiratory distress being the most common. Most patients had a single lobectomy via a minithoracotomy. Postoperative complications and length of stay were significantly higher in patients with CCAM with preoperative clinical signs. CONCLUSIONS Surgery in asymptomatic patients with CCAM can be performed safely with few postoperative complications and can be planned at a young age in patients with a high risk of developing clinical signs later in life. [ABSTRACT FROM AUTHOR]

Background and Aims ATP-dependent phosphofructokinases (PFKs) catalyse phosphorylation of the carbon-1 position of fructose-6-phosphate, to form fructose-1,6-bisphosphate. In the cytosol, this is considered a key step in channelling carbon into glycolysis. Arabidopsis thaliana has seven genes encoding PFK isoforms, two chloroplastic and five cytosolic. This study focuses on the four major cytosolic isoforms of PFK in vegetative tissues of A. thaliana. Methods We isolated homozygous knockout individual mutants (pfk1 , pfk3 , pfk6 and pfk7) and two double mutants (pfk1/7 and pfk3/6), and characterized their growth and metabolic phenotypes. Key Results In contrast to single mutants and the double mutant pfk3/6 for the hypoxia-responsive isoforms, the double mutant pfk1/7 had reduced PFK activity and showed a clear visual and metabolic phenotype with reduced shoot growth, early flowering and elevated hexose levels. This mutant also has an altered ratio of short/long aliphatic glucosinolates and an altered root–shoot distribution. Surprisingly, this mutant does not show any major changes in short-term carbon flux and in levels of hexose-phosphates. Conclusions We conclude that the two isoforms PFK1 and PFK7 are important for sugar homeostasis in leaf metabolism and apparently in source–sink relationships in A. thaliana , while PFK3 and PFK6 only play a minor role under normal growth conditions. [ABSTRACT FROM AUTHOR]

Sexual selection and sexual conflict play central roles in driving the evolution of male and female traits. Experimental evolution provides a powerful approach to study the operation of these forces under controlled environmental and demographic conditions, thereby allowing direct comparisons of evolutionary trajectories under different treatments such as mating systems. Despite the rapid progress of experimental and statistical techniques that support experimental evolution studies, we still lack clear theoretical predictions on the effects of different mating systems beyond what intuition suggests. For example, polygamy (several males and females in a mating group) and polyandry (one single female and multiple males in a mating group) have each been used as treatments that elevate sexual selection on males and sexual conflict relative to monogamy. However, polygamy and polyandry manipulations sometimes produce different evolutionary outcomes, and the precise reasons why remain elusive. In addition, the softness of selection (i.e., scale of competition within each sex) is known to affect trait evolution, and is an important factor to consider in experimental design. To date, no model has specifically investigated how the softness of selection interacts with different mating systems. Here, we try to fill these gaps by generating clear and readily testable predictions. Our set of models were designed to capture the most important life cycle events in typical experimental evolution studies, and we use simulated changes of sex‐specific gene expression profiles (i.e., feminization or masculinization) to quantify trait evolution under different selection schemes. We show that interactions between the softness of selection and the mating system can produce results that have been identified as counterintuitive in previous empirical work such as polyandry producing stronger feminization than monogamy. We conclude by encouraging a stronger integration of modelling in future experimental evolution studies and pointing out remaining knowledge gaps for future theoretical work. [ABSTRACT FROM AUTHOR]

Summary: Coronavirus 19 (COVID‐19) has been associated with both transient and persistent systemic symptoms that do not appear to be a direct consequence of viral infection. The generation of autoantibodies has been proposed as a mechanism to explain these symptoms. To understand the prevalence of autoantibodies associated with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection, we investigated the frequency and specificity of clinically relevant autoantibodies in 84 individuals previously infected with SARS‐CoV‐2, suffering from COVID‐19 of varying severity in both the acute and convalescent setting. These were compared with results from 32 individuals who were on the intensive therapy unit (ITU) for non‐COVID reasons. We demonstrate a higher frequency of autoantibodies in the COVID‐19 ITU group compared with non‐COVID‐19 ITU disease control patients and that autoantibodies were also found in the serum 3–5 months post‐COVID‐19 infection. Non‐COVID patients displayed a diverse pattern of autoantibodies; in contrast, the COVID‐19 groups had a more restricted panel of autoantibodies including skin, skeletal muscle and cardiac antibodies. Our results demonstrate that respiratory viral infection with SARS‐CoV‐2 is associated with the detection of a limited profile of tissue‐specific autoantibodies, detectable using routine clinical immunology assays. Further studies are required to determine whether these autoantibodies are specific to SARS‐CoV‐2 or a phenomenon arising from severe viral infections and to determine the clinical significance of these autoantibodies. [ABSTRACT FROM AUTHOR]

Background Intake of trans fatty acids (TFAs) increases LDL cholesterol, decreases HDL cholesterol, and increases the risk of heart disease morbidity and mortality. Many food products potentially contain industrially produced or ruminant TFAs. However, little is known about the dietary sources of plasma TFA concentrations. Objective The objective of this study was to examine associations between foods consumed and plasma TFA concentrations using 24-h dietary recall data and plasma TFA measures among adults aged ≥20 y who participated in the NHANES 2009–2010 in the United States. Methods Over 4400 food products in the dietary interview data were categorized into 32 food and beverage groups/subgroups. Four major plasma TFAs (palmitelaidic acid, elaidic acid, vaccenic acid, linolelaidic acid) and the sum of the 4 TFAs (sumTFAs) were analyzed using GC-MS. Multivariable linear regression analyses were conducted to identify associations of plasma TFAs with all 32 food and beverage groups/subgroups, controlling for the potential confounding effects of 11 demographic, socioeconomic, behavioral, lifestyle, and health-related variables. Results Consumption of the following food groups/subgroups was significantly associated with elevated plasma TFA concentrations: cream substitutes (P  < 0.001 for palmitelaidic acid, elaidic acid, vaccenic acid, and sumTFAs); cakes, cookies, pastries, and pies (P  < 0.001 for elaidic acid, vaccenic acid, and sumTFAs; P  < 0.05 for linolelaidic acid); milk and milk desserts (P  < 0.01 for palmitelaidic acid and vaccenic acid; P  < 0.05 for linolelaidic acid and sumTFAs); beef/veal, lamb/goat, and venison/deer (P  < 0.01 for vaccenic acid; P  < 0.05 for sumTFAs); and butters (P  < 0.001 for palmitelaidic acid and vaccenic acid; P  < 0.05 for sumTFAs). Conclusions The findings suggest that the above 5 food groups/subgroups could be the main dietary sources of plasma TFAs among adults in the United States in 2009–2010. [ABSTRACT FROM AUTHOR]

Many plants synchronize their life cycles in response to changing seasons and initiate flowering under favourable environmental conditions to ensure reproductive success. To confer a robust seasonal response, plants use diverse genetic programmes that integrate environmental and endogenous cues and converge on central floral regulatory hubs. Technological advances have allowed us to understand these complex processes more completely. Here, we review recent progress in our understanding of genetic and molecular mechanisms that control flowering in Arabidopsis thaliana. [ABSTRACT FROM AUTHOR]

Objective To quantify the representation of women trainees and faculty and to explore associations between them at Pain Medicine (PM) fellowship programs in the United States. Setting PM fellowship programs accredited by the Accreditation Council for Graduate Medical Education. Methods All PM programs approved for at least four fellows as of December 2017 were identified. Websites of these programs were reviewed to determine the number and gender of current fellows and faculty, and programs were contacted to verify the information. Results A total of 56 PM programs were eligible; of these, 48 PM programs (86%) provided information about the gender distribution of fellows. Women comprised ∼25% of PM fellows. PM programs with a female rather than male fellowship program director (PD) had 2.40 times increased odds of a female trainee. Proportion of female faculty and division chief gender were not significantly associated with trainee gender composition. The adjusted odds of a faculty member being female was 1.99 times greater for PM programs with a female vs male PD and 3.13 times greater for programs with a female vs male division chief. Conclusions Women are underrepresented throughout all levels of academic pain medicine. The presence of women in leadership roles is associated with higher proportions of female trainees and faculty, highlighting the need for more female role models in academic pain medicine. [ABSTRACT FROM AUTHOR]

Motivation Non-coding rare variants (RVs) may contribute to Mendelian disorders but have been challenging to study due to small sample sizes, genetic heterogeneity and uncertainty about relevant non-coding features. Previous studies identified RVs associated with expression outliers, but varying outlier definitions were employed and no comprehensive open-source software was developed. Results We developed Outlier-RV Enrichment (ORE) to identify biologically-meaningful non-coding RVs. We implemented ORE combining whole-genome sequencing and cardiac RNAseq from congenital heart defect patients from the Pediatric Cardiac Genomics Consortium and deceased adults from Genotype-Tissue Expression. Use of rank-based outliers maximized sensitivity while a most extreme outlier approach maximized specificity. Rarer variants had stronger associations, suggesting they are under negative selective pressure and providing a basis for investigating their contribution to Mendelian disorders. Availability and implementation ORE, source code, and documentation are available at https://pypi.python.org/pypi/ore under the MIT license. Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

Background and Aims Bioenergy is central for the future energy mix to mitigate climate change impacts; however, its intricate link with the water cycle calls for an evaluation of the carbon–water nexus in biomass production. The great challenge is to optimize trade-offs between carbon harvest and water use by choosing cultivars that combine low water use with high productivity. Methods Regional scenarios were simulated over a range of willow genotype × environment interactions for the major UK soil × climate variations with the process-based model LUCASS. Soil available water capacity (SAWC) ranged from 51 to 251 mm and weather represented the north-west (wet, cool), north-east (dry, cool), south-west (wet, warm) and south-east (dry, warm) of the UK. Scenario simulations were evaluated for small/open narrow-leaf (NL) versus large/closed broad-leaf (BL) willow canopy phenotypes using baseline (1965–89) and warmer recent (1990–2014) weather data. Key Results The low productivity under baseline climate in the north could be compensated by choosing BL cultivars (e.g. 'Endurance'). Recent warmer climate increased average productivity by 0.5–2.5 t ha−1, especially in the north. The modern NL cultivar 'Resolution' had the smallest and most efficient water use. On marginal soils (SAWC <100 mm), yields remained below an economic threshold of 9 t ha−1 more frequently under baseline than recent climate. In the drought-prone south-east, 'Endurance' yielded less than 'Resolution', which consumed on average 17 mm year−1 less water. Assuming a planting area of 10 000 ha, in droughty years between 1.3 and 4.5 × 106 m3 of water could be saved, with a small yield penalty, for 'Resolution'. Conclusions With an increase in air temperature and occasional water scarcities expected with climate change, high-yielding NL cultivars should be the preferred choice for sustainable use of marginal lands and reduced competition with agricultural food crops. [ABSTRACT FROM AUTHOR]

Motivation To obtain a reliable prediction model for a specific cancer subgroup or cohort is often difficult due to limited sample size and, in survival analysis, due to potentially high censoring rates. Sometimes similar data from other patient subgroups are available, e.g. from other clinical centers. Simple pooling of all subgroups can decrease the variance of the predicted parameters of the prediction models, but also increase the bias due to heterogeneity between the cohorts. A promising compromise is to identify those subgroups with a similar relationship between covariates and target variable and then include only these for model building. Results We propose a subgroup-based weighted likelihood approach for survival prediction with high-dimensional genetic covariates. When predicting survival for a specific subgroup, for every other subgroup an individual weight determines the strength with which its observations enter into model building. MBO (model-based optimization) can be used to quickly find a good prediction model in the presence of a large number of hyperparameters. We use MBO to identify the best model for survival prediction of a specific subgroup by optimizing the weights for additional subgroups for a Cox model. The approach is evaluated on a set of lung cancer cohorts with gene expression measurements. The resulting models have competitive prediction quality, and they reflect the similarity of the corresponding cancer subgroups, with both weights close to 0 and close to 1 and medium weights. Availability and implementation mlrMBO is implemented as an R-package and is freely available at http://github.com/mlr-org/mlrMBO. [ABSTRACT FROM AUTHOR]

Arteriovenous malformation (AVM) is defined as a fast-flow vascular anomaly that shunts blood from arteries directly to veins. This short circuit of blood flow contributes to progressive expansion of draining veins, resulting in ischaemia, tissue deformation and in some severe cases, congestive heart failure. Various medical interventions have been employed to treat AVM, however, management of which remains a huge challenge because of its high recurrence rate and lethal complications. Thus, understanding the underlying mechanisms of AVM development and progression will help direct discovery and a potential cure. Here, we summarize current findings in the field of extracranial AVMs with the aim to provide insight into their aetiology and molecular influences, in the hope to pave the way for future treatment. [ABSTRACT FROM AUTHOR]

FluoroCalins represent novel bifunctional protein reagents derived from engineered lipocalins fused to a fluorescent reporter protein, here the enhanced green fluorescent protein (eGFP). We demonstrate the construction, facile bacterial production and broad applicability of FluoroCalins using two Anticalin® molecules directed against the tumor vasculature-associated extra domain B of fibronectin (ED-B) and the vascular endothelial growth factor receptor 3, a marker of tumor and lymphangiogenesis. FluoroCalins were prepared with two different spacers: (i) a short Ser3Ala linker and (ii) a long hydrophilic and conformationally unstructured PASylation® polypeptide comprising 200 Pro, Ala and Ser residues. These FluoroCalins were applied for direct target quantification in enzyme-linked immunosorbent assay as well as target detection by flow cytometry and fluorescence microscopy of live and fixed cells, respectively, demonstrating high specificity and signal-to-noise ratio. Hence, FluoroCalins offer a promising alternative to antibody-based reagents for state of the art fluorescent in vitro detection and biomolecular imaging. [ABSTRACT FROM AUTHOR]

Background antipsychotic drugs are regularly prescribed as first-line treatment for neuropsychiatric symptoms in persons with dementia although guidelines clearly prioritise non-pharmacological interventions. Objective we investigated a person-centred care approach, which has been successfully evaluated in nursing homes in the UK, and adapted it to German conditions. Design a 2-armed 12-month cluster-randomised controlled trial. Setting nursing homes in East, North and West Germany. Methods all prescribing physicians from both study arms received medication reviews for individual patients and were offered access to 2 h of continuing medical education. Nursing homes in the intervention group received educational interventions on person-centred care and a continuous supervision programme. Primary outcome: proportion of residents receiving at least one antipsychotic prescription after 12 months of follow-up. Secondary outcomes: quality of life, agitated behaviour, falls and fall-related medical attention, a health economics evaluation and a process evaluation. Results the study was conducted in 37 nursing homes with n = 1,153 residents (intervention group: n = 493; control group: n = 660). The proportion of residents with at least one antipsychotic medication changed after 12 months from 44.6% to 44.8% in the intervention group and from 39.8 to 33.3% in the control group. After 12 months, the difference in the prevalence was 11.4% between the intervention and control groups (95% confidence interval: 0.9–21.9; P = 0.033); odds ratio: 1.621 (95% confidence interval: 1.038–2.532). Conclusions the implementation of a proven person-centred care approach adapted to national conditions did not reduce antipsychotic prescriptions in German nursing homes. Trial registration ClinicalTrials.gov NCT02295462. [ABSTRACT FROM AUTHOR]

Grapevine (Vitis vinifera) is a model for the investigation of physiological and biochemical changes during the formation and ripening of nonclimacteric fleshy fruits. However, the order and complexity of the molecular events during fruit development remain poorly understood. To identify the key molecular events controlling berry formation and ripening, we created a highly detailed transcriptomic and metabolomic map of berry development, based on samples collected every week from fruit set to maturity in two grapevine genotypes for three consecutive years, resulting in 219 samples. Major transcriptomic changes were represented by coordinated waves of gene expression associated with early development, veraison (onset of ripening)/midripening, and late-ripening and were consistent across vintages. The two genotypes were clearly distinguished by metabolite profiles and transcriptional changes occurring primarily at the veraison/midripening phase. Coexpression analysis identified a core network of transcripts as well as variations in the within-module connections representing varietal differences. By focusing on transcriptome rearrangements close to veraison, we identified two rapid and successive shared transitions involving genes whose expression profiles precisely locate the timing of the molecular reprogramming of berry development. Functional analyses of two transcription factors, markers of the first transition, suggested that they participate in a hierarchical cascade of gene activation at the onset of ripening. This study defined the initial transcriptional events that mark and trigger the onset of ripening and the molecular network that characterizes the whole process of berry development, providing a framework to model fruit development and maturation in grapevine. [ABSTRACT FROM AUTHOR]

Objectives Vaccinations are an important measure to prevent infections in immunocompromised patients. The knowledge of vaccination coverage and reasons for non-vaccination in patients with SLE is scarce. The aim of this study was to assess coverage rates of selected vaccinations in a representative sample of SLE patients and to identify predictors for non-vaccination. Methods In 2013, information on selected vaccinations (coverage, application and reservations) and on demographics, clinical parameters and health beliefs was assessed by means of a self-reported questionnaire among a representative sample of SLE patients in Germany (LuLa cohort). Results Five hundred and seventy-nine patients participated. Vaccination status was primarily checked by their general practitioner (57.3%). Of all the patients, 24.9% did not get their vaccination status checked at all, 16.1% had generally been advised against the use of vaccinations by a physician, and 37.5% stated that they had rejected vaccinations themselves. Their main reasons were fears of developing a lupus flare (21.8%) or adverse events (13.5%). A greater belief by patients in the doctor controlling one’s health and the general benefit of medication prevented the rejection of vaccines. Vaccination coverage was low for all recorded vaccinations (tetanus 65.8%, influenza 45.2%, pneumococcus 32.2% and meningococcus 6.1%). Older age was predictive of receiving influenza and pneumococcal vaccination. The same applies for CSs >7.5 mg for receiving influenza vaccination. Conclusion Vaccination coverage in SLE patients is poor and reflects insufficient implementation of national and international recommendations. Rheumatologists need to recognize patients’ reservations against vaccinations, to communicate their importance and safety and to give individual recommendations to patients and their health-care providers. Trial registration German Clinical Trials Register, www.germanctr.de , DRKS00011052. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder refers to a neurodevelopmental condition primarily characterized by deficits in social cognition and behavior. Subclinically, autistic features are supposed to be present in healthy humans and can be quantified using the Autism Quotient (AQ). Here, we investigated a potential relationship between AQ and neural correlates of social and monetary reward processing, using functional magnetic resonance imaging in young, healthy participants. In an incentive delay task with either monetary or social reward, reward anticipation elicited increased ventral striatal activation, which was more pronounced during monetary reward anticipation. Anticipation of social reward elicited activation in the default mode network (DMN), a network previously implicated in social processing. Social reward feedback was associated with bilateral amygdala and fusiform face area activation. The relationship between AQ and neural correlates of social reward processing varied in a gender-dependent manner. In women and, to a lesser extent in men, higher AQ was associated with increased posterior DMN activation during social reward anticipation. During feedback, we observed a negative correlation of AQ and right amygdala activation in men only. Our results suggest that social reward processing might constitute an endophenotype for autism-related traits in healthy humans that manifests in a gender-specific way. [ABSTRACT FROM AUTHOR]

In early Alzheimer's disease, which initially presents with progressive loss of short-term memory, neurodegeneration especially affects cholinergic neurons of the basal forebrain. Pharmacotherapy of Alzheimer's disease therefore often targets the cholinergic system. In contrast, cholinergic pharmacotherapy of mild cognitive impairment is debated since its efficacy to date remains controversial. We here investigated the relationship between cholinergic treatment effects and the integrity of the cholinergic system in mild cognitive impairment due to Alzheimer's disease. Fourteen patients with high likelihood of mild cognitive impairment due to Alzheimer's disease and 16 age-matched cognitively normal adults performed an episodic memory task during functional magnetic resonance imaging under three conditions: (i) without pharmacotherapy; (ii) with placebo; and (iii) with a single dose of rivastigmine (3 mg). Cortical acetylcholinesterase activity was measured using PET with the tracer 11C-N-methyl-4-piperidyl acetate (MP4A). Cortical acetylcholinesterase activity was significantly decreased in patients relative to controls, especially in the lateral temporal lobes. Without pharmacotherapy, mild cognitive impairment was associated with less memory-related neural activation in the fusiform gyrus and impaired deactivation in the posterior cingulate cortex, relative to controls. These differences were attenuated under cholinergic stimulation with rivastigmine: patients showed increased neural activation in the right fusiform gyrus but enhanced deactivation of the posterior cingulate cortex under rivastigmine, compared to placebo. Conversely, controls showed reduced activation of the fusiform gyrus and reduced deactivation of the posterior cingulate under rivastigmine, compared to placebo. In both groups, the change in neural activation in response to rivastigmine was negatively associated with local acetylcholinesterase activity. At the behavioural level, an analysis of covariance revealed a significant group × treatment interaction in episodic memory performance when accounting for hippocampal grey matter atrophy and function. Our results indicate that rivastigmine differentially affects memory-related neural activity in patients with mild cognitive impairment and cognitively normal, age-matched adults, depending on acetylcholinesterase activity as a marker for the integrity of the cortical cholinergic system. Furthermore, hippocampal integrity showed an independent association with the response of memory performance to acetylcholinesterase inhibition. [ABSTRACT FROM AUTHOR]

Perturbation of cellulose synthesis in plants triggers stress responses, including growth retardation, mediated by the cell wall integrity-sensing receptor-like kinase (RLK) THESEUS1 (THE1). The analysis of two alleles carrying T-DNA insertions at comparable positions has led to conflicting conclusions concerning the impact of THE1 signaling on growth. Here we confirm that, unlike the1-3 and other the1 alleles in which cellular responses to genetic or pharmacological inhibition of cellulose synthesis are attenuated, the1-4 showed enhanced responses, including growth inhibition, ectopic lignification, and stress gene expression. Both the1-3 and the1-4 express a transcript encoding a predicted membrane-associated truncated protein lacking the kinase domain. However, the1-3, in contrast to the1-4, strongly expresses antisense transcripts, which are expected to prevent the expression of the truncated protein as suggested by the genetic interactions between the two alleles. Seedlings overexpressing such a truncated protein react to isoxaben treatment similarly to the1-4 and the full-length THE overexpressor. We conclude that the1-4 is a hypermorphic allele; that THE1 signaling upon cell wall damage has a negative impact on cell expansion; and that caution is required when interpreting the phenotypic effects of T-DNA insertions in RLK genes. [ABSTRACT FROM AUTHOR]

GENOMES UNCOUPLED 4 (GUN4) is a positive regulator of light-dependent chlorophyll biosynthesis. GUN4 activates Mg chelatase (MgCh) that catalyzes the insertion of an Mg2+ ion into protoporphyrin IX. We show that Arabidopsis (Arabidopsis thaliana) GUN4 is phosphorylated at Ser 264 (S264), the penultimate amino acid residue at the C terminus. While GUN4 is preferentially phosphorylated in darkness, phosphorylation is reduced upon accumulation of Mg porphyrins. Expression of a phosphomimicking GUN4(S264D) results in an incomplete complementation of the white gun4-2 null mutant and a chlorotic phenotype comparable to gun4 knockdown mutants. Phosphorylated GUN4 has a reduced stimulatory effect on MgCh in vitro and in vivo but retains its protein stability and tetrapyrrole binding capacity. Analysis of GUN4 found in oxygenic photosynthetic organisms reveals the evolution of a C-terminal extension, which harbors the phosphorylation site of GUN4 expressed in angiosperms. Homologs of GUN4 from Synechocystis and Chlamydomonas lack the conserved phosphorylation site found in a C-terminal extension of angiosperm GUN4. Biochemical studies proved the importance of the C-terminal extension for MgCh stimulation and inactivation of GUN4 by phosphorylation in angiosperms. An additional mechanism regulating MgCh activity is proposed. In conjunction with the dark repression of 5-aminolevulinic acid synthesis, GUN4 phosphorylation minimizes the flow of intermediates into the Mg branch of the tetrapyrrole metabolic pathway for chlorophyll biosynthesis. [ABSTRACT FROM AUTHOR]

Plant volatiles not only have multiple defense functions against herbivores, fungi, and bacteria, but also have been implicated in signaling within the plant and toward other organisms. Elucidating the function of individual plant volatiles will require more knowledge of their biosynthesis and regulation in response to external stimuli. By exploiting the variation of herbivore-induced volatiles among 26 maize (Zea mays) inbred lines, we conducted a nested association mapping and genome-wide association study (GWAS) to identify a set of quantitative trait loci (QTLs) for investigating the pathways of volatile terpene production. The most significant identified QTL affects the emission of (E)-nerolidol, linalool, and the two homoterpenes (E)-3,8-dimethyl-1,4,7-nonatriene (DMNT) and (E,E)-4,8,12-trimethyltrideca-1,3,7,11-tetraene (TMTT). GWAS associated a single nucleotide polymorphism in the promoter of the gene encoding the terpene synthase TPS2 with this QTL. Biochemical characterization of TPS2 verified that this plastid-localized enzyme forms linalool, (E)-nerolidol, and (E,E)-geranyllinalool. The subsequent conversion of (E)-nerolidol into DMNT maps to a P450 monooxygenase, CYP92C5, which is capable of converting nerolidol into DMNT by oxidative degradation. A QTL influencing TMTT accumulation corresponds to a similar monooxygenase, CYP92C6, which is specific for the conversion of (E,E)-geranyllinalool to TMTT. The DMNT biosynthetic pathway and both monooxygenases are distinct from those previously characterized for DMNT and TMTT synthesis in Arabidopsis thaliana , suggesting independent evolution of these enzymatic activities. [ABSTRACT FROM AUTHOR]

This paper presents a component-level comparison of the polarized v = 1 J = 1-0, v = 2 J = 1-0 and v = 1 J = 2-1 SiO maser emission towards the supergiant star VY CMa at milliarcsecond-scale, as observed using the Very Long Baseline Array at λ = 7 and 3 mm. An earlier paper considered overall maser morphology and constraints on SiO maser excitation and pumping derived from these data. The goal of the current paper is to use the measured polarization properties of individual co-spatial components detected across multiple transitions to provide constraints on several competing theories for the transport of polarized maser emission. This approach minimizes the significant effects of spatial blending. We present several diagnostic tests designed to distinguish key features of competing theoretical models for maser polarization. The number of coincident features is limited by sensitivity however, particularly in the v = 1 J = 2-1 transition at 86 GHz, and deeper observations are needed. Preliminary conclusions based on the current data provide some support for: (i) spin-independent solutions for linear polarization; (ii) the influence of geometry on the distribution of fractional linear polarization with intensity; and, (iii) π/2 rotations in linear polarization position angle arising from transitions across the Van Vleck angle (sin 2θ = 2/3) between the maser line of sight and magnetic field. There is weaker evidence for several enumerated non-Zeeman explanations for circular polarization. The expected 2:1 ratio in circular polarization between J = 1-0 and J = 2-1 predicted by standard Zeeman theory cannot unfortunately be tested conclusively due to insufficient coincident components. [ABSTRACT FROM AUTHOR]

Protein Structure Annotation Tool-plus (ProSAT+) is a newweb server for mapping protein sequence annotations onto a protein structure and visualizing them simultaneously with the structure. ProSAT+ incorporates many of the features of the preceding ProSAT and ProSAT+ tools but also provides new options for the visualization and sharing of protein annotations. Data are extracted from the UniProt KnowledgeBase, the RCSB PDB and the PDBe SIFTS resource, and visualization is performed using JSmol. User-defined sequence annotations can be added directly to the URL, thus enabling visualization and easy data sharing. [ABSTRACT FROM AUTHOR]

Redox regulation is an essential post-translational regulatory mechanism in prokaryotes and eukaryotes. The reversible oxidation and reduction of cysteine residues of proteins is also important in photosynthetic organisms to control enzymatic activities, protein stability and the interaction with other proteins of chloroplast-localized proteins. Several enzymes of the plant tetrapyrrole biosynthesis pathway have been identified to be redox regulated by thioredoxins (TRXs) and NADPH-dependent thioredoxin reductase C (NTRC). Among these proteins, Mg protoporphyrin IX methyltransferase (encoded by CHLM) was identified to be activated and stabilized by interaction with NTRC. CHLM catalyzes a methyl group transfer by using S-adenosylmethionine (SAM). Here we demonstrate that three conserved cysteine residues of Arabidopsis CHLM are essential for catalytic function and redox-dependent activation of the enzyme. In vitro and in planta biochemical assays of recombinant CHLM and the Arabidopsis chlm knockout mutant overexpressing wild-type and cysteine substitution mutants of CHLM revealed modified methyltransferase activity, when the conserved cysteine residues of CHLM are replaced by serine. While C177 is responsible for redox-dependent enzyme activation, exchange of the two cysteine residues, C111 and C115, has a strong impact on enzyme activity. The modified CHLM activity of single and double mutants with cysteine substitution is presented, and the role of each cysteine residue is discussed based on a modeled structure of CHLM. These studies contribute to enhanced understanding of the physiological and enzymatic significance of redoxregulated CHLM. [ABSTRACT FROM AUTHOR]

Identifying key performance traits is essential for elucidating crop growth processes and breeding. In Salix spp., genotypic diversity is being exploited to tailor new varieties to overcome environmental yield constraints. Process-based models can assist these efforts by identifying key parameters of yield formation for different genotype×environment (G×E) combinations. Here, four commercial willow varieties grown in contrasting environments (west and south-east UK) were intensively sampled for growth traits over two 2-year rotations. A sink-source interaction model was developed to parameterize the balance of source (carbon capture/mobilization) and sink formation (morphogenesis, carbon allocation) during growth. Global sensitivity analysis consistently identified day length for the onset of stem elongation as most important factor for yield formation, followed by various 'sink>source' controlling parameters. In coastal climates, the chilling control of budburst ranked higher compared with the more eastern climate. Sensitivity to drought, including canopy size and rooting depth, was potentially growth limiting in the south-east and west of the UK. Potential yields increased from the first to the second rotation, but less so for broad- than for narrow-leaved varieties (20 and 47%, respectively), which had established less well initially (-19%). The establishment was confounded by drought during the first rotation, affecting broad- more than narrow-leaved canopy phenotypes (-29%). The analysis emphasized quantum efficiency at low light intensity as key to assimilation; however, on average, sink parameters were more important than source parameters. The G×E pairings described with this new process model will help to identify parameters of sink-source control for future willow breeding. [ABSTRACT FROM AUTHOR]

Glyceridae (Annelida) are a group of venomous annelids distributed worldwide from intertidal to abyssal depths. To trace the evolutionary history and complexity of glycerid venom cocktails, a solid backbone phylogeny of this group is essential. We therefore aimed to reconstruct the phylogenetic relationships of these annelids using Illumina sequencing technology. We constructed whole-genome shotgun libraries for 19 glycerid specimens and 1 outgroup species (Glycinde armigera). The chosen target genes comprise 13 mitochondrial proteins, 2 ribosomal mitochondrial genes, and 4 nuclear loci (18SrRNA, 28SrRNA, ITS1, and ITS2). Based on partitioned maximum likelihood as well as Bayesian analyses of the resulting supermatrix, we were finally able to resolve a robust glycerid phylogeny and identified three clades comprising the majority of taxa. Furthermore, we detected group II introns inside the cox1 gene of two analyzed glycerid specimens, with two different insertions in one of these species. Moreover, we generated reduced data sets comprising 10 million, 4 million, and 1 million reads from the original data sets to test the influence of the sequencing depth on assembling complete mitochondrial genomes from low coverage genome data. We estimated the coverage of mitochondrial genome sequences in each data set size by mapping the filtered Illumina reads against the respective mitochondrial contigs. By comparing the contig coverage calculated in all data set sizes, we got a hint for the scalability of our genome skimming approach. This allows estimating more precisely the number of reads that are at least necessary to reconstruct complete mitochondrial genomes in Glyceridae and probably non-model organisms in general. [ABSTRACT FROM AUTHOR]

Objective. To compare the 24-month course of health-related quality of life (HRQoL) in patients with longstanding RA treated with a conventional synthetic (cs) or a first, second or third biologic (b) DMARD in daily rheumatological care. Methods. Patients enrolled in the German biologics register RABBIT who were observed over at least 12 months were stratified according to the nth bDMARD started at enrolment. HRQoL was captured by the SF36 health survey. Within strata of sequential bDMARD therapy, we examined patients' HRQoL at baseline and at follow-ups in comparison with the general population, the 24-month course of HRQoL of different bDMARDs and the proportion of patients exceeding the minimal detectable improvement of physical and mental health sum scores. Results. All patients reported remarkably lower scores of physical and mental health than the general population at baseline and month 12. In each stratum of sequential bDMARD therapy, patients improved significantly by month 12 and remained stable until month 24. The improvement of HRQoL was not attributable to a particular bDMARD. The following proportions of patients exceeded the minimal detectable improvement of at least 17.85 Physical Component Scale scores or 22.18 Mental Component Scale score points: csDMARD (n = 1113) 31.1%/22.3%, first bDMARD (n = 1352) 39.9%/29.7%, second bDMARD (n = 730) 37.3%/26.2% and third bDMARD (n = 680) 34.2%/30.9%. Conclusion. Lasting improvement of both physical and mental health is achievable even for severely affected RA patients with a history of more than one bDMARD failure. Nevertheless, impairment of HRQoL in RA patients is enormous compared with the general population. [ABSTRACT FROM AUTHOR]

Although temperature variation is known to cause large-scale adaptive divergence, its potential role as a selective factor over microgeographic scales is less well-understood. Here, we investigated how variation in breeding pond temperature affects divergence in multiple physiological (thermal performance curve and critical thermal maximum [CTmax]) and life-history (thermal developmental reaction norms) traits in a network of Rana arvalis populations. The results supported adaptive responses to face two main constraints limiting the evolution of thermal adaptation. First, we found support for the faster-slower model, indicating an adaptive response to compensate for the thermodynamic constraint of low temperatures in colder environments. Second, we found evidence for the generalist-specialist trade-off with populations from colder and less thermally variable environments exhibiting a specialist phenotype performing at higher rates but over a narrower range of temperatures. By contrast, the local optimal temperature for locomotor performance and CTmax did not match either mean or maximum pond temperatures. These results highlight the complexity of the adaptive multiple-trait thermal responses in natural populations, and the role of local thermal variation as a selective force driving diversity in life-history and physiological traits in the presence of gene flow. [ABSTRACT FROM AUTHOR]

Discusses studies in biodiversity conservation focusing on animal species, populations, ecosystems, landscapes, and other levels of biological organization. Biodiversity on small and large geographic scales; Description of functional conservation areas and how to determine this environmental function; Challenges faced by conservationists; Case study of the Yampa River in Colorado; Conclusions and comments.

The CRISPR (clustered regularly interspaced short palindromic repeats)-Cas (CRISPR-associated) adaptive immune systems use small guide RNAs, the CRISPR RNAs (crRNAs), to mark foreign genetic material, e.g. viral nucleic acids, for degradation. Archaea and bacteria encode a large variety of Cas proteins that bind crRNA molecules and build active ribonucleoprotein surveillance complexes. The evolution of CRISPR-Cas systems has resulted in a diversification of cas genes and a classification of the systems into three types and additional subtypes characterized by distinct surveillance and interfering complexes. Recent crystallographic and biochemical advances have revealed detailed insights into the assembly and DNA/RNA targeting mechanisms of the various complexes. Here, we review our knowledge on the molecular mechanism involved in the DNA and RNA interference stages of type I (Cascade: CRISPR-associated complex for antiviral defense), type II (Cas9) and type III (Csm, Cmr) CRISPR-Cas systems. We further highlight recently reported structural and mechanistic themes shared among these systems. [ABSTRACT FROM AUTHOR]

CRISPR-Cas is an RNA-mediated adaptive immune system that defends bacteria and archaea against mobile genetic elements. Short mature CRISPR RNAs (crRNAs) are key elements in the interference step of the immune pathway. A CRISPR array composed of a series of repeats interspaced by spacer sequences acquired from invading mobile genomes is transcribed as a precursor crRNA (pre-crRNA) molecule. This pre-crRNA undergoes one or two maturation steps to generate the mature crRNAs that guide CRISPR-associated (Cas) protein(s) to cognate invading genomes for their destruction. Different types of CRISPR-Cas systems have evolved distinct crRNA biogenesis pathways that implicate highly sophisticated processing mechanisms. In Types I and III CRISPR-Cas systems, a specific endoribonuclease of the Cas6 family, either standalone or in a complex with other Cas proteins, cleaves the pre-crRNA within the repeat regions. In Type II systems, the trans-acting small RNA (tracrRNA) base pairs with each repeat of the pre-crRNA to form a dual-RNA that is cleaved by the housekeeping RNase III in the presence of the protein Cas9. In this review, we present a detailed comparative analysis of pre-crRNA recognition and cleavage mechanisms involved in the biogenesis of guide crRNAs in the three CRISPR-Cas types. [ABSTRACT FROM AUTHOR]

Our closest neighbours, the Local Group dwarf spheroidal (dSph) galaxies, are extremely quiescent and dim objects, where thermal and non-thermal diffuse emissions lack, so far, of detection. In order to possibly study the dSph interstellar medium, deep observations are required. They could reveal non-thermal emissions associated with the very low level of star formation, or to particle dark matter annihilating or decaying in the dSph halo. In this work, we employ radio observations of six dSphs, conducted with the Australia Telescope Compact Array in the frequency band 1.1-3.1 GHz, to test the presence of a diffuse component over typical scales of few arcmin and at an rms sensitivity below 0.05 mJy beam-1.We observed the dSph fields with both a compact array and long baselines. Short spacings led to a synthesized beam of about 1 arcmin and were used for the extended emission search. The high-resolution data mapped background sources, which in turn were subtracted in the short-baseline maps, to reduce their confusion limit. We found no significant detection of a diffuse radio continuum component. After a detailed discussion on the modelling of the cosmic ray (CR) electron distribution and on the dSph magnetic properties, we present bounds on several physical quantities related to the dSphs, such that the total radio flux, the angular shape of the radio emissivity, the equipartition magnetic field, and the injection and equilibrium distributions of CR electrons. Finally, we discuss the connection to far-infrared and X-ray observations. [ABSTRACT FROM AUTHOR]

Dwarf spheroidal (dSph) galaxies are key objects in near-field cosmology, especially in connection to the study of galaxy formation and evolution at small scales. In addition, dSphs are optimal targets to investigate the nature of dark matter. However, while we begin to have deep optical photometric observations of the stellar population in these objects, little is known so far about their diffuse emission at any observing frequency, and hence on thermal and non-thermal plasma possibly residing within dSphs. In this paper, we present deep radio observations of six local dSphs performed with the Australia Telescope Compact Array (ATCA) at 16 cm wavelength. We mosaicked a region of radius of about 1 deg around three 'classical' dSphs, Carina, Fornax, and Sculptor, and of about half of degree around three 'ultrafaint' dSphs, BootesII, Segue2, and Hercules. The rms noise level is below 0.05 mJy for all the maps. The restoring beams full width at half-maximum ranged from 4.2 arcsec × 2.5 arcsec to 30.0 arcsec × 2.1 arcsec in the most elongated case. A catalogue including the 1392 sources detected in the six dSph fields is reported. The main properties of the background sources are discussed, with positions and fluxes of brightest objects compared with the FIRST, NVSS, and SUMSS observations of the same fields. The observed population of radio emitters in these fields is dominated by synchrotron sources. We compute the associated source number counts at 2 GHz down to fluxes of 0.25 mJy, which prove to be in agreement with AGN count models. [ABSTRACT FROM AUTHOR]

Background: Studies have shown constant or increasing health inequalities in adulthood in the last decades, but less is known about trends in health inequalities among adolescents. The aim is to analyse changes in socioeconomic differences in subjective health complaints from 1994 to 2010 among 11- to 15-year-olds in Europe, North America and Israel. Methods: Data were obtained from the international 'Health Behaviour in School-aged Children' (HBSC) survey. Analyses were based on the HBSC surveys conducted in 1994 (19 countries), 1998 (25 countries), 2002 (32 countries), 2006 (37 countries) and 2010 (36 countries) covering a time period of up to 16 years. Log binomial regression models were used to assess inequalities in multiple health complaints. Socioeconomic position was measured using perceived family wealth. Results: Inequalities in multiple health complaints emerged in almost all countries, in particular since 2002 (RR 1.1-1.7). Trend analyses showed stable (29 countries), increased (5 countries), decreased (one country) and no social inequalities (2 countries) in adolescent health complaints. Conclusion: In almost all countries, social inequalities in health complaints remained constant over a period of up to 16 years. Our findings suggest a need to intensify efforts in social and health policy to tackle existing inequalities. [ABSTRACT FROM AUTHOR]

Objective: Thresholds of 2-20 hounsfield units (HU) in unenhanced computed tomography (CT) are suggested to discriminate benign adrenal tumors (BATs) from malignant adrenal tumors. However, these studies included only low numbers of adrenocortical carcinomas (ACCs). This study defines a HU threshold by inclusion of a large cohort of ACCs. Design: Retrospective, blinded, comparative analysis of CT scans from 51 patients with ACCs (30 females, median age 49 years) and 25 patients with BATs (12 females, median age 64 years) diagnosed during the period of 2005-2010 was performed. Methods: Tumor density was evaluated in unenhanced CT by two blinded investigators. Results: Median tumor size was 9 cm (range 2.0-20) for ACCs vs 4 cm (2.0-7.5) for BATs (P<0.0001). In ACCs, the median unenhanced HU value was 34 (range 14-74) in comparison with 5 (-13 to 40) in BATs (P<0.0001). ROC analysis revealed a HU of 21 as threshold with the best diagnostic accuracy (sensitivity 96%, specificity 80%, and AUC 0.89). However, two ACCs that were 5 and 6 cm in size would have been missed. Setting the threshold to 13.9 allowed for 100% sensitivity, but a lower specificity of 68%. Conclusions: This first large study on ACCs confirmed that the vast majority of ACCs have unenhanced HU >21. However, to avoid misdiagnosing an ACC as benign, a threshold of 13 should be used. [ABSTRACT FROM AUTHOR]

BACKGROUND: Practice guidelines (guidelines) have an increasing role in health care delivery and are being published more frequently. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) is an approach for guideline development. The GRADE approach has been adopted by multiple national and international organizations producing guidelines related to physical therapist care. OBJECTIVE: The purpose of this article is to introduce physical therapists to the GRADE approach for guideline development. RESULTS: GRADE provides a consistent approach for guideline development and transparency in the communication of how the guidelines were developed and how the recommendations were reached, leading to informed choices by patients, clinicians, and policy makers in health care. GRADE leads to a clear distinction between the strength of the evidence and the recommendation. Both the direction (for or against) and the strength (weak or strong) of the recommendation are considered. For determining the strength of the recommendation, GRADE takes into account the quality of evidence, the balance of benefit and harm, uncertainty about or variability in patients' values and preferences, and uncertainty about whether the intervention is a wise use of resources. LIMITATIONS: The GRADE approach has been used primarily with interventions and clinical questions and less often with questions related to diagnosis and prognosis. CONCLUSIONS: The frequency of publication of guidelines is increasing. To make informed choices in the health care system, physical therapists should understand how guidelines are developed. The GRADE approach has been adopted by national and international organizations that produce guidelines relevant to physical therapist practice. Understanding the GRADE approach will enable physical therapists to make informed clinical choices. [ABSTRACT FROM AUTHOR]

Archaea are the least understood members of the microbial community in Antarctic mineral soils. Although their occurrence in Antarctic coastal soils has been previously documented, little is known about their distribution in soils across the Mc Murdo Dry Valleys, Victoria Land. In this study, terminal-restriction fragment length polymorphism (t- RFLP) analysis and 454 pyrosequencing were coupled with a detailed analysis of soil physicochemical properties to characterize archaeal diversity and identify environmental factors that might shape and maintain archaeal communities in soils of the three southern most Mc Murdo Dry Valleys (Garwood, Marshall, and Miers Valley). Archaea were successfully detected in all inland and coastal mineral soils tested, revealing a low overall richness (mean of six operational taxonomic units [ OTUs] per sample site). However, OTU richness was higher in some soils and this higher richness was positively correlated with soil water content, indicating water as a main driver of archaeal community richness. In total, 18 archaeal OTUs were detected, predominately Thaumarchaeota affiliated with Marine Group 1.1b (> 80% of all archaeal sequences recovered). Less abundant OTUs (2% of all archaeal sequences) were loosely related to members of the phylum Euryarchaeota. This is the first comprehensive study showing a widespread presence and distribution of Archaea in inland Antarctic soils. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis is an autoimmunity leading to considerable impairment of quality of life. N-acetyl glucosamine ( GlcNAc) has been described previously as a potent modulator of experimental arthritis in animal models and is used for osteoarthritis treatment in humans, praised for its lack of adverse effects. In this study we present a comprehensive immunological analysis of multivalent GlcNAc-terminated glycoconjugate ( GC) application in the treatment of collagen-induced arthritis ( CIA) and its clinical outcome. We used immunohistochemistry and FACS to describe conditions on the inflammation site. Systemic and clinical effects were evaluated by FACS, cytotoxicity assay, ELISA, cytometric bead array ( CBA), RT-PCR and clinical scoring. We found reduced inflammatory infiltration, NKG2D expression on NK and suppression of T, B and antigen-presenting cells ( APC) in the synovia. On the systemic level, GCs prevented the activation of monocyte- and B cell-derived APCs, the rise of TNF-α and IFN-γ levels, and subsequent type II collagen ( CII)-specific IgG2a formation. Moreover, we detected an increase of anti-inflammatory IL-4 mRNA in the spleen. Similar to the synovia, the GCs caused a significant reduction of NKG2D-expressing NK cells in the spleen without influencing their lytic function. GCs effectively postponed the onset of arthritic symptoms, reduced their severity and in 18% ( GN8P) and 31% ( GN4C) of the cases completely prevented their appearance. Our data prove that GlcNAc glycoconjugates prevent the inflammatory response, involving proinflammatory cytokine rise, APC activation and NKG2D expression, leading to the attenuation of clinical symptoms. These results support the glycobiological approach to the treatment of collagen-induced arthritis/rheumatoid arthritis ( CIA/ RA) as a way of bringing new prospects for more effective therapeutic interventions. [ABSTRACT FROM AUTHOR]

IZI-06.1 is a humanized anti-TNFR1 single-chain fragment variable (scFv) that selectively inhibits binding of tumor necrosis factor (TNF) and lymphotoxin alpha to tumor necrosis factor receptor 1 (TNFR1) but not TNFR2. Recently, IZI-06.1 was converted into a fully human IgG1 antibody (ATROSAB) for the treatment of inflammatory diseases. Here, we compare the bivalent ATROSAB with a monovalent scFv-human serum albumin (HSA) fusion protein lacking any antibody-associated effector functions and possessing approximately only half the molecular mass of an IgG, which should facilitate accumulation in inflamed tissues. Furthermore, the half-life of the scFv should be strongly extended while maintaining monovalent binding, avoiding a possible signal transduction by receptor cross-linking in the absence of TNF. The scFv-HSA fusion protein was produced by stably transfected Chinese hamster ovary cells and purified by affinity chromatography. The fusion protein bound specifically to TNFR1 in enzyme-linked immunosorbent assay and TNFR1-transfected mouse embryonic fibroblasts. Affinity determined by quartz crystal microbalance was reduced compared with ATROSAB, which resulted also in a reduced inhibitory activity. Compared with the scFv fragment, the half-life of the fusion protein was significantly increased, although not reaching the long half-life of ATROSAB. In summary, the scFv-HSA may provide an alternative to the full-length IgG1 with the ability to selectively inhibit TNFR1 and exploiting the pharmacokinetic properties of albumin. [ABSTRACT FROM PUBLISHER]

Much recent progress has been made by assisted reproductive technology (ART) professionals toward minimizing the incidence of multiple pregnancy following ART treatment. While a healthy singleton birth is widely considered to be the ideal outcome of such treatment, a vocal minority continues a campaign to advocate the benefits of multiple embryo transfer as treatment and twin pregnancy as outcome for most ART patients. Proponents of twinning argue four points: that patients prefer twins, that multiple embryo transfer maximizes success rates, that the costs per infant are lower with twins and that one twin pregnancy and birth is associated with no higher risk than two consecutive singleton pregnancies and births. We find fault with the reasoning and data behind each of these tenets. First, we respect the principle of patient autonomy to choose the number of embryos for transfer but counter that it has been shown that better patient education reduces their desire for twins. In addition, reasonable and evidentially supported limits may be placed on autonomy in exchange for public or private insurance coverage for ART treatment, and counterbalancing ethical principles to autonomy exist, especially beneficence (doing good) and non-maleficence (doing no harm). Second, comparisons between success rates following single-embryo transfer (SET) and double-embryo transfers favor double-embryo transfers only when embryo utilization is not comparable; cumulative pregnancy and birth rates that take into account utilization of cryopreserved embryos (and the additional cryopreserved embryo available with single fresh embryo transfer) consistently demonstrate no advantage to double-embryo transfer. Third, while comparisons of costs are system dependent and not easy to assess, several independent studies all suggest that short-term costs per child (through the neonatal period alone) are lower with transfers of one rather than two embryos. And, finally, abundant evidence conclusively demonstrates that the risks to both mother and especially to children are substantially greater with one twin birth compared with two singleton births. Thus, the arguments used by some to promote multiple embryo transfer and twinning are not supported by the facts. They should not detract from efforts to further promote SET and thus reduce ART-associated multiple pregnancy and its inherent risks. [ABSTRACT FROM AUTHOR]

Caveolin-1 (Cav1), a scaffold protein of membrane caveolae and coactivator of peroxisome proliferator-activated receptor gamma (PPARg), inhibits oncogenic signaling through Ras and wingless. However, the in vivo role of Cav1 in colorectal cancer (CRC) remained unknown. To test whether loss of Cav1 accelerates tumorigenesis, we generated a novel mouse model of CRC by crossing C57BL/6 Apcmin/+ with B6129 Cav1 knockout (Cav1−/−) mice. Apcmin/+ Cav1−/− mice developed large, microinvasive and vascularized intraepithelial adenocarcinomas in the distal colon and rectum with higher incidence than Apcmin/+ Cav1+/− and Apcmin/+ Cav1+/+ littermates. Intratumoral gene signatures related to Ras and wingless signaling were elevated, nuclear localization of PPARg protein and expression of PPARg-target genes were reduced independently of Cav1. The PPARg-agonist rosiglitazone prevented tumor formation in mice irrespectively of the Cav1 status and upregulated expression of the Ras-inhibitory protein docking protein-1. Thus, codeficiency of Cav1 and adenomatous polyposis coli facilitated formation of CRC, and activation of PPARg may offer novel strategies for treatment of CRC. [ABSTRACT FROM AUTHOR]

The paralogous and functionally redundant GATA transcription factors GNC (for GATA, NITRATE-INDUCIBLE, CARBOMETABOLISM INVOLVED) and GNL/CGA1 (for GNC-LIKE/CYTOKININ-RESPONSIVE GATA FACTOR1) from Arabidopsis (Arabidopsis thaliana) promote greening and repress flowering downstream from the phytohormone gibberellin. The target genes of GNC and GNL with regard to flowering time control have not been identified as yet. Here, we show by genetic and molecular analysis that the two GATA factors act upstream from the flowering time regulator SUPPRESSOR OF OVEREXPRESSION OF CONSTANS1 (SOC1) to directly repress SOC1 expression and thereby repress flowering. Interestingly, this analysis inversely also reveals that the MADS box transcription factor SOC1 directly represses GNC and GNL expression to control cold tolerance and greening, two further physiological processes that are under the control of SOC1. In summary, these findings support the case of a cross-repressive interaction between the GATA factors GNC and GNL and the MADS box transcription factor SOC1 in flowering time control on the one side and greening and cold tolerance on the other that may be governed by the various signaling inputs that are integrated at the level of SOC1 expression. [ABSTRACT FROM AUTHOR]

Wine has been made for thousands of years. In modern times, as the importance of yeast as an ingredient in winemaking became better appreciated, companies worldwide have collected and marketed specific yeast strains for enhancing positive and minimizing negative attributes in wine. It is generally believed that each yeast strain contributes uniquely to fermentation performance and wine style because of its genetic background; however, the impact of metabolic diversity among wine yeasts on aroma compound production has not been extensively studied. We characterized the metabolic footprints of 69 different commercial wine yeast strains in triplicate fermentations of identical Chardonnay juice, by measuring 29 primary and secondary metabolites; we additionally measured seven attributes of fermentation performance of these strains. We identified up to 1000-fold differences between strains for some of the metabolites and observed large differences in fermentation performance, suggesting significant metabolic diversity. These differences represent potential selective markers for the strains that may be important to the wine industry. Analysis of these metabolic traits further builds on the known genomic diversity of these strains and provides new insights into their genetic and metabolic relatedness. [ABSTRACT FROM AUTHOR]

The NADPH-dependent thioredoxin reductase C (NTRC) is involved in redox-related regulatory processes in chloroplasts and nonphotosynthetic active plastids. Together with 2-cysteine peroxiredoxin, it forms a two-component peroxide-detoxifying system that acts as a reductant under stress conditions. NTRC stimulates in vitro activity of magnesium protoporphyrin IX monomethylester (MgPMME) cyclase, most likely by scavenging peroxides. Reexamination of tetrapyrrole intermediate levels of the Arabidopsis (Arabidopsis thaliana) knockout ntrc reveals lower magnesium protoporphyrin IX (MgP) and MgPMME steady-state levels, the substrate and the product of MgP methyltransferase (CHLM) preceding MgPMME cyclase, while MgP strongly accumulates in mutant leaves after 5-aminolevulinic acid feeding. The ntrc mutant has a reduced capacity to synthesize 5-aminolevulinic acid and reduced CHLM activity compared with the wild type. Although transcript levels of genes involved in chlorophyll biosynthesis are not significantly altered in 2-week-old ntrc seedlings, the contents of glutamyl-transfer RNA reductase1 (GluTR1) and CHLM are reduced. Bimolecular fluorescence complementation assay confirms a physical interaction of NTRC with GluTR1 and CHLM. While ntrc contains partly oxidized CHLM, the wild type has only reduced CHLM. As NTRC also stimulates CHLM activity in vitro, it is proposed that NTRC has a regulatory impact on the redox status of conserved cysteine residues of CHLM. It is hypothesized that a deficiency of NTRC leads to a lower capacity to reduce cysteine residues of GluTR1 and CHLM, affecting the stability and, thereby, altering the activity in the entire tetrapyrrole synthesis pathway. [ABSTRACT FROM AUTHOR]