Intestinal injury and endotoxemia in children undergoing surgery for congenital heart disease

RATIONALE: Children with congenital heart disease are at risk of gut barrier dysfunction and translocation of gut bacterial antigens into the bloodstream. This may contribute to inflammatory activation and organ dysfunction postoperatively. OBJECTIVES: To investigate the role of intestinal injury and endotoxemia in the pathogenesis of organ dysfunction after surgery for congenital heart disease. METHODS: We analyzed blood levels of intestinal fatty acid binding protein and endotoxin (endotoxin activity assay) alongside global transcriptomic profiling and assays of monocyte endotoxin receptor expression in children undergoing surgery for congenital heart disease. MEASUREMENTS AND MAIN RESULTS: Levels of intestinal fatty acid binding protein and endotoxin were greater in children with duct-dependent cardiac lesions. Endotoxemia was associated with severity of vital organ dysfunction and intensive care stay. We identified activation of pathogen-sensing, antigen-processing, and immune-suppressing pathways at the genomic level postoperatively and down-regulation of pathogen-sensing receptors on circulating immune cells. CONCLUSIONS: Children undergoing surgery for congenital heart disease are at increased risk of intestinal mucosal injury and endotoxemia. Endotoxin activity correlates with a number of outcome variables in this population, and may be used to guide the use of gut-protective strategies.

It was never good world sence minister must have wyves”: clerical celibacy, clerical marriage, and anticlericalism in Reformation England

The impact of the Reformation was felt strongly in the nature and character of the priesthood, and in the function and reputation of the priest. A shift in the understanding of the priesthood was one of the most tangible manifestations of doctrinal change, evident in the physical arrangement of the church, in the language of the liturgy, and in the relaxation of the discipline of celibacy, which had for centuries bound priests in the Latin tradition to a life of perpetual continence. Clerical celibacy, and accusations of clerical incontinence, featured prominently in evangelical criticisms of the Catholic church and priesthood, which made a good deal of polemical capital out of the perceived relationship of the priest and the efficacy of his sacred function. Citing St Paul, Protestant polemicists presented clerical marriage as the only, and appropriate remedy, for priestly immorality. But did the advent of a married priesthood create more problems than it solved? The polemical certainties that informed evangelical writing on sacerdotal celibacy did not guarantee the immediate acceptance of a married priesthood, and the vocabulary that had been used to denounce clergy who failed in their obligation to celibacy was all too readily turned against the married clergy. The anti-clerical lexicon, and its usage, remained remarkably static despite the substantial doctrinal and practical challenges posed to the traditional model of priesthood by the Protestant Reformation.

Can Rachman’s indirect pathways be used to un-learn fear? A prospective paradigm to test whether children’s fears can be reduced using positive information and modelling a non-anxious response

This study investigated whether children’s fears could be un-learned using Rachman’s indirect pathways for learning fear. We hypothesised that positive information and modelling a non-anxious response are effective methods of un-learning fears acquired through verbal information. One hundred and seven children aged 6–8 years received negative information about one animal and no information about another. Fear beliefs and behavioural avoidance were measured. Children were randomised to receive positive verbal information, modelling, or a control task. Fear beliefs and behavioural avoidance were measured again. Positive information and modelling led to lower fear beliefs and behavioural avoidance than the control condition. Positive information was more effective than modelling in reducing fear beliefs and both methods significantly reduced behavioural avoidance. The results support Rachman’s indirect pathways as viable fear un-learning pathways and supports associative learning theories.

Influence of 10 wk of soy consumption on plasma concentrations and excretion of isoflavonoids and on gut microflora metabolism in healthy adults

Although interindividual variation in isoflavone metabolism was high, intraindividual variation was low. Only concentrations of O-DMA in plasma and urine appeared to be influenced by sex. Chronic soy consumption does not appear to induce many significant changes to the gut metabolism of isoflavones other than higher beta-glucosidase activity.

Abiotic drivers and plant traits explain landscape-scale patterns in soil microbial communities

The controls on aboveground community composition and diversity have been extensively studied, but our understanding of the drivers of belowground microbial communities is relatively lacking, despite their importance for ecosystem functioning. In this study, we fitted statistical models to explain landscape-scale variation in soil microbial community composition using data from 180 sites covering a broad range of grassland types, soil and climatic conditions in England. We found that variation in soil microbial communities was explained by abiotic factors like climate, pH and soil properties. Biotic factors, namely community- weighted means (CWM) of plant functional traits, also explained variation in soil microbial communities. In particular, more bacterial-dominated microbial communities were associated with exploitative plant traits versus fungal-dominated communities with resource-conservative traits, showing that plant functional traits and soil microbial communities are closely related at the landscape scale.

Adeno-associated virus-8-Mediated intravenous transfer of myostatin propeptide leads to systemic functional improvements of slow but not fast muscle

Myostatin is a member of the transformating growth factor-_ (TGF-_) superfamily of proteins and is produced almost exclusively in skeletal muscle tissue, where it is secreted and circulates as a serum protein. Myostatin acts as a negative regulator of muscle mass through the canonical SMAD2/3/4 signaling pathway. Naturally occurring myostatin mutants exhibit a ‘double muscling’ phenotype in which muscle mass is dramatically increased as a result of both hypertrophy and hyperplasia. Myostatin is naturally inhibited by its own propeptide; therefore, we assessed the impact of adeno associated virus-8 (AAV8) myostatin propeptide vectors when systemically introduced in MF-1 mice. We noted a significant systemic increase in muscle mass in both slow and fast muscle phenotypes, with no evidence of hyperplasia; however, the nuclei-to- cytoplasm ratio in all myofiber types was significantly reduced. An increase in muscle mass in slow (soleus) muscle led to an increase in force output; however, an increase in fast (extensor digitorum longus [EDL]) muscle mass did not increase force output. These results suggest that the use of gene therapeutic regimens of myostatin inhibition for age-related or disease-related muscle loss may have muscle-specific effects.

Secondary school students’ epistemic insight into the relationships between science and religion – a preliminary enquiry

A number of previous studies have shown that there is a widespread view among young people that science and religion are opposed. In this paper, we suggest that it requires a significant level of what can be termed ‘epistemic insight’ to access the idea that some people see science and religion as compatible while others do not. To explore this further, we draw on previous work to devise a methodology to discover students’ thinking about apparent contradictions between scientific and religious explanations of the origins of the universe. In our discussion of the findings, we highlight that students’ epistemic insight in this context does seem in many cases to be limited and we outline some of the issues emerging from the study that seem to boost or limit students’ progress in this area.

‘These changes and accessions of knowledge’: translation, scientific travel writing and modernity - Alexander von Humboldt's Personal Narrative

A second English translation of Alexander von Humboldt's account of travel to South America, the Relation historique (1814–25), was published between 1852 and 1853. Appearing some 30 years after the first seven-volume translation (1814–29) by Helen Maria Williams, this second rendering of the Personal Narrative by Thomasina Ross was an abridged version that aimed to make Humboldt's travelogue more relevant to the mid-century reader. This translation has largely been overlooked by Humboldt scholars, despite it being a far more affordable, accessible and popular edition. I discuss here how Ross's revisions can be understood within a larger process of rereading and revision that responded to critics’ assessments of the first translation. Emphasising the status of the Personal Narrative as a text in flux, I assess how Ross modernised it to meet the demands of a new readership, recasting the image that Humboldt had constructed of himself as a travelling scientist, scientific writer and member of the international scientific community.

Temporal dynamics of emotional responding: amygdala recovery predicts emotional traits

An individual’s affective style is influenced by many things, including the manner in which an individual responds to an emotional challenge. Emotional response is composed of a number of factors, two of which are the initial reactivity to an emotional stimulus and the subsequent recovery once the stimulus terminates or ceases to be relevant. However, most neuroimaging studies examining emotional processing in humans focus on the magnitude of initial reactivity to a stimulus rather than the prolonged response. In this study, we use functional magnetic resonance imaging to study the time course of amygdala activity in healthy adults in response to presentation of negative images. We split the amygdala time course into an initial reactivity period and a recovery period beginning after the offset of the stimulus. We find that initial reactivity in the amygdala does not predict trait measures of affective style. Conversely, amygdala recovery shows predictive power such that slower amygdala recovery from negative images predicts greater trait neuroticism, in addition to lower levels of likability of a set of social stimuli (neutral faces). These data underscore the importance of taking into account temporal dynamics when studying affective processing using neuroimaging.

A method to diagnose boundary-layer type using Doppler lidar

A new technique for objective classification of boundary layers is applied to ground-based vertically pointing Doppler lidar and sonic anemometer data. The observed boundary layer has been classified into nine different types based on those in the Met Office ‘Lock’ scheme, using vertical velocity variance and skewness, along with attenuated backscatter coefficient and surface sensible heat flux. This new probabilistic method has been applied to three years of data from Chilbolton Observatory in southern England and a climatology of boundary-layer type has been created. A clear diurnal cycle is present in all seasons. The most common boundary-layer type is stable with no cloud (30.0% of the dataset). The most common unstable type is well mixed with no cloud (15.4%). Decoupled stratocumulus is the third most common boundary-layer type (10.3%) and cumulus under stratocumulus occurs 1.0% of the time. The occurrence of stable boundary-layer types is much higher in the winter than the summer and boundary-layer types capped with cumulus cloud are more prevalent in the warm seasons. The most common diurnal evolution of boundary-layer types, occurring on 52 days of our three-year dataset, is that of no cloud with the stability changing from stable to unstable during daylight hours. These results are based on 16393 hours, 62.4% of the three-year dataset, of diagnosed boundary-layer type. This new method is ideally suited to long-term evaluation of boundary-layer type parametrisations in weather forecast and climate models.

Memory as discrimination: what distraction reveals

Recalling information involves the process of discriminating between relevant and irrelevant information stored in memory. Not infrequently, the relevant information needs to be selected from amongst a series of related possibilities. This is likely to be particularly problematic when the irrelevant possibilities are not only temporally or contextually appropriate but also overlap semantically with the target or targets. Here, we investigate the extent to which purely perceptual features which discriminate between irrelevant and target material can be used to overcome the negative impact of contextual and semantic relatedness. Adopting a distraction paradigm, it is demonstrated that when distracters are interleaved with targets presented either visually (Experiment 1) or auditorily (Experiment 2), a within-modality semantic distraction effect occurs; semantically-related distracters impact upon recall more than unrelated distracters. In the semantically-related condition, the number of intrusions in recall is reduced whilst the number of correctly recalled targets is simultaneously increased by the presence of perceptual cues to relevance (color features in Experiment 1 or speaker’s gender in Experiment 2). However, as demonstrated in Experiment 3, even presenting semantically-related distracters in a language and a sensory modality (spoken Welsh) distinct from that of the targets (visual English) is insufficient to eliminate false recalls completely, or to restore correct recall to levels seen with unrelated distracters . Together, the study shows how semantic and non-semantic discriminability shape patterns of both erroneous and correct recall.

Delivery of AAV2/9-microdystrophin genes incorporating helix 1 of the coiled-coil motif in the C-terminal domain of dystrophin improves muscle pathology and restores the level of α1-syntrophin and α-dystrobrevin in skeletal muscles of mdx mice. Level of α1-Syntrophin and α-Dystrobrevin in Skeletal Muscles of mdx Mice

Duchenne muscular dystrophy is a severe X-linked inherited muscle wasting disorder caused by mutations in the dystrophin gene. Adeno-associated virus (AAV) vectors have been extensively used to deliver genes efficiently for dystrophin expression in skeletal muscles. To overcome limited packaging capacity of AAV vectors (<5 kb), truncated recombinant microdystrophin genes with deletions of most of rod and carboxyl-terminal (CT) domains of dystrophin have been developed. We have previously shown the efficiency of mRNA sequence–optimized microdystrophin (ΔR4-23/ΔCT, called MD1) with deletion of spectrin-like repeat domain 4 to 23 and CT domain in ameliorating the pathology of dystrophic mdx mice. However, the CT domain of dystrophin is thought to recruit part of the dystrophin-associated protein complex, which acts as a mediator of signalling between extracellular matrix and cytoskeleton in muscle fibers. In this study, we extended the ΔR4-23/ΔCT microdystrophin by incorporating helix 1 of the coiled-coil motif in the CT domain of dystrophin (MD2), which contains the α1-syntrophin and α-dystrobrevin binding sites. Intramuscular injection of AAV2/9 expressing CT domain–extended microdystrophin showed efficient dystrophin expression in tibialis anterior muscles of mdx mice. The presence of the CT domain of dystrophin in MD2 increased the recruitment of α1-syntrophin and α-dystrobrevin at the sarcolemma and significantly improved the muscle resistance to lengthening contraction–induced muscle damage in the mdx mice compared with MD1. These results suggest that the incorporation of helix 1 of the coiled-coil motif in the CT domain of dystrophin to the microdystrophins will substantially improve their efficiency in restoring muscle function in patients with Duchenne muscular dystrophy.

Preparation and ring-opening reactions of N-diphenylphosphinyl vinyl aziridines

Predominantly (E)-N-diphenylphosphinyl vinyl aziridines are prepared by a reaction of N-diphenylphosphinyl imines with α-bromoallyllithium in the presence of freshly fused ZnCl2. These aziridines undergo a ring-opening reaction with a variety of carbon and heteronucleophiles, in good yield, and generally with good regioselectivity.