Metabolic profiling of follistatin overexpression: a novel therapeutic strategy for metabolic diseases.

Background: Follistatin (Fst) promotes brown adipocyte characteristics in adipose tissues. Methods: Abdominal fat volume (CT scan), glucose clearance (GTT test), and metabolomics analysis (mass spectrometry) of adipose tissues from Fst transgenic (Fst-Tg) and wild type (WT) control mice were analyzed. Oxygen consumption (Seahorse Analyzer) and lipidomics (gas chromatography) was analyzed in 3T3-L1 cells. Results: Fst-Tg mice show significant decrease in abdominal fat content, increased glucose clearance, improved plasma lipid profiles and significant changes in several conventional metabolites compared to the WT mice. Furthermore, overexpression of Fst in 3T3-L1 cells resulted in up regulation of key brown/beige markers and changes in lipidomics profiles. Conclusion: Fst modulates key factors involved in promoting metabolic syndrome and could be used for therapeutic intervention. Diabetes Metab Syndr Obes 2018 Mar 26; 11:65-84

EXTUBATE: A randomised controlled trial of nasal biphasic positive airway pressure vs. nasal continuous positive airway pressure following extubation in infants less than 30 weeks' gestation: study protocol for a randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>Respiratory distress syndrome remains a significant problem among premature infants. Mechanical ventilation through an endotracheal tube remains the mainstay of respiratory support but may be associated with lung injury and the development of chronic lung disease of prematurity. Efforts are needed to reduce the duration of mechanical ventilation in favour of less invasive forms of respiratory support and to improve rates of successful extubation.</p> <p>Non-invasive respiratory support has been demonstrated to be less injurious to the premature lung. Standard practice is to use nasal continuous positive airway pressure (n-CPAP) following extubation to support the baby's breathing. Many clinicians also use nasal biphasic positive airway pressure (n-BiPAP) in efforts to improve rates of successful extubation. However, there is currently no evidence that this confers any advantage over conventional nasal continuous positive airway pressure.</p> <p>Methods</p> <p>We propose an unblinded multi-centre randomised trial comparing n-CPAP with n-BiPAP in babies born before 30 weeks' gestation and less than two weeks old. Babies with congenital abnormalities and severe intra-ventricular haemorrhage will be excluded. 540 babies admitted to neonatal centres in England will be randomised at the time of first extubation attempt. The primary aim of this study is to compare the rate of extubation failure within 48 hours following the first attempt at extubation. The secondary aims are to compare the effect of n-BiPAP and n-CPAP on the following outcomes:</p> <p>1. Maintenance of successful extubation for 7 days post extubation</p> <p>2. Oxygen requirement at 28 days of age and at 36 weeks' corrected gestational age</p> <p>3. Total days on ventilator, n-CPAP/n-BiPAP</p> <p>4. Number of ventilator days following first extubation attempt</p> <p>5. pH and partial pressure of carbon dioxide in the first post extubation blood gas</p> <p>6. Duration of hospital stay</p> <p>7. Rate of abdominal distension requiring cessation of feeds</p> <p>8. Rate of apnoea and bradycardia</p> <p>9. The age at transfer back to referral centre in days</p> <p>The trial will determine whether n-BiPAP is safe and superior to n-CPAP in preventing extubation failure in babies born before 30 weeks' gestation and less than two weeks old.</p> <p>Trial registration number</p> <p>ISRCTN: <a href="http://www.controlled-trials.com/ISRCTN18921778">ISRCTN18921778</a></p

Competing for the Platform: How Organized Interests affect Party Positioning in the United States

What explains which groups are included in a party coalition in any given election cycle? Recent advances in political party theory suggest that policy demanders comprise parties, and that the composition of a party coalition varies from election to election. We theorize three conditions under which parties articulate an interest group?s preferred positions in its quadrennial platform: when groups are ideologically proximate to the party median, when groups display party loyalty, and when groups are flush with resources. Using computer-assisted content analysis on a unique and rich data source, we examine three cycles of testimony that 80 organized groups provided to the Democratic Party. The analysis compares group requests with the content of Democratic and Republican National Committee platforms in 1996, 2000, and 2004. Results show that parties reward loyal groups and those that are ideologically proximate to the party, but offer no confirmation of a resource effect

A transcriptomic snapshot of early molecular communication between Pasteuria penetrans and Meloidogyne incognita

© The Author(s). 2018Background: Southern root-knot nematode Meloidogyne incognita (Kofoid and White, 1919), Chitwood, 1949 is a key pest of agricultural crops. Pasteuria penetrans is a hyperparasitic bacterium capable of suppressing the nematode reproduction, and represents a typical coevolved pathogen-hyperparasite system. Attachment of Pasteuria endospores to the cuticle of second-stage nematode juveniles is the first and pivotal step in the bacterial infection. RNA-Seq was used to understand the early transcriptional response of the root-knot nematode at 8 h post Pasteuria endospore attachment. Results: A total of 52,485 transcripts were assembled from the high quality (HQ) reads, out of which 582 transcripts were found differentially expressed in the Pasteuria endospore encumbered J2 s, of which 229 were up-regulated and 353 were down-regulated. Pasteuria infection caused a suppression of the protein synthesis machinery of the nematode. Several of the differentially expressed transcripts were putatively involved in nematode innate immunity, signaling, stress responses, endospore attachment process and post-attachment behavioral modification of the juveniles. The expression profiles of fifteen selected transcripts were validated to be true by the qRT PCR. RNAi based silencing of transcripts coding for fructose bisphosphate aldolase and glucosyl transferase caused a reduction in endospore attachment as compared to the controls, whereas, silencing of aspartic protease and ubiquitin coding transcripts resulted in higher incidence of endospore attachment on the nematode cuticle. Conclusions: Here we provide evidence of an early transcriptional response by the nematode upon infection by Pasteuria prior to root invasion. We found that adhesion of Pasteuria endospores to the cuticle induced a down-regulated protein response in the nematode. In addition, we show that fructose bisphosphate aldolase, glucosyl transferase, aspartic protease and ubiquitin coding transcripts are involved in modulating the endospore attachment on the nematode cuticle. Our results add new and significant information to the existing knowledge on early molecular interaction between M. incognita and P. penetrans.Peer reviewedFinal Published versio

Metabolic constraints on the evolution of antibiotic resistance

Despite our continuous improvement in understanding antibiotic resistance, the interplay between natural selection of resistance mutations and the environment remains unclear. To investigate the role of bacterial metabolism in constraining the evolution of antibiotic resistance, we evolved Escherichia coli growing on glycolytic or gluconeogenic carbon sources to the selective pressure of three different antibiotics. Profiling more than 500 intracellular and extracellular putative metabolites in 190 evolved populations revealed that carbon and energy metabolism strongly constrained the evolutionary trajectories, both in terms of speed and mode of resistance acquisition. To interpret and explore the space of metabolome changes, we developed a novel constraint‐based modeling approach using the concept of shadow prices. This analysis, together with genome resequencing of resistant populations, identified condition‐dependent compensatory mechanisms of antibiotic resistance, such as the shift from respiratory to fermentative metabolism of glucose upon overexpression of efflux pumps. Moreover, metabolome‐based predictions revealed emerging weaknesses in resistant strains, such as the hypersensitivity to fosfomycin of ampicillin‐resistant strains. Overall, resolving metabolic adaptation throughout antibiotic‐driven evolutionary trajectories opens new perspectives in the fight against emerging antibiotic resistance.ISSN:1744-429

The UK Biobank imaging enhancement of 100,000 participants: rationale, data collection, management and future directions

UK Biobank is a population-based cohort of half a million participants aged 40–69 years recruited between 2006 and 2010. In 2014, UK Biobank started the world’s largest multi-modal imaging study, with the aim of re-inviting 100,000 participants to undergo brain, cardiac and abdominal magnetic resonance imaging, dual-energy X-ray absorptiometry and carotid ultrasound. The combination of large-scale multi-modal imaging with extensive phenotypic and genetic data offers an unprecedented resource for scientists to conduct health-related research. This article provides an in-depth overview of the imaging enhancement, including the data collected, how it is managed and processed, and future direction

Limits of effective nutrient management in dairy farming: analyses of experimental farm De Marke

Key words: nutrient management, dairy, prototyping, organic matter, soil fertility, nitrogen, phosphor. Intensive dairy production in the Netherlands is associated with high farm nutrient (N and P) inputs and high losses to the environment. The Dutch government and the dairy sector stimulate farmers to reduce losses through more efficient use of N and P inputs on their farms. This study explores for a dairy farm on dry sandy soil with average Dutch production intensity (12,000 kg milk per ha) the possibilities to meet strict environmental standards related to N and P by maximizing N and P use efficiency at the level of the farm and of the soil. Moreover, the study addresses the effects of efficient nutrient management on soil fertility. The research was conducted on experimental dairy farm De Marke, that is designed to meet strict environmental standards, implemented in practice in 1989 and modified continuously to meet its targets by prototyping, i.e. a cyclic procedure of designing, implementing, testing and evaluating measures. The thesis evaluates system development since 2000, while results from 1993-1999 were used to analyse long-term developments. After implementation of the farming system in 1989, the nitrate concentration in groundwater ‘stabilized’ at a level exceeding the environmental standard: 55 mg l-1. Causes of excessive nitrate leaching were examined by relating measured nitrate concentrations to management. Grazing was associated with higher leaching in spite of careful management with rotational grazing. Leaching under permanent grassland was similar to the overall leaching in crop rotations in which grass was alternated with maize and grains. Spatial and temporal patterns of soil N mineralization were explored to improve the synchronization of N application and crop N requirements. This study indicated that fertilizing a 1st year maize crop, following grassland, is not necessary. Measures implemented since 2000 to improve nutrient efficiency, included reduced grazing, adoption of anaerobic digestion, application of manure in the rows of maize, growing spring barley as the last crop in the arable phase, and, since 2004, the abolishment of fertilizer N. These measures contributed to an increase in the manure-N utilization and to an increase in the farm-N use efficiency up to 2008 to values exceeding the value of 33% that was realized in the period 1993-1999. Farm-N use efficiency was 35% in 2000-2003, 43% in 2004-2008 and 37% in 2009-2010. Farm-P use efficiency also increased as compared to the 87% that was realized in 1993-1999, i.e., it was 103% in 2000-2003 and 91% in 2004-2008. In 2009-2010, however, the farm-P use efficiency decreased to 69%, lower than the value realized in 1993-1999. The lower N and P use efficiency in 2009-2010 can be attributed to the lower N and P yields in grassland as a delayed effect of N limitation resulting from the abolishment of fertilizer N in grassland since 2004. Hence, despite the increase in manure-N utilization, mineral-N use is not yet completely redundant. P-equilibrium fertilization seems to be compatible with highly efficient crop production, in the short and in the long term. Soil organic matter (SOM) percentage in the upper topsoil decreased by 0.03 yr-1 (average across all land uses) at a constant rate over the last 20 years. The possibilities to stop this decline by higher organic matter inputs to the soil seem conflicting with efficient nutrient use. Hence, the long term dynamics of SOM may become critical for future farm performance. It was concluded that N and P use efficiency can be enhanced substantially by on-farm nutrient management, but that efficient nutrient management may conflict with maintenance of SOM.</p

An evaluation of crude palm oil (CPO) and tocotrienol rich fraction (TRF) of palm oil as percutaneous permeation enhancers using full-thickness human skin

The drawbacks associated with chemical skin permeation enhancers such as skin irritation and toxicity necessitated the research to focus on potential permeation enhancers with a perceived lower toxicity. Crude palm oil (CPO) is obtained by direct compression of the mesocarp of the fruit of the oil palm belonging to the genus Elaeis. In this research, CPO and tocotrienol-rich fraction (TRF) of palm oil were evaluated for the first time as skin permeation enhancers using full-thickness human skin. The in vitro permeation experiments were conducted using excised human skin mounted in static upright ‘Franz-type’ diffusion cells. The drugs selected to evaluate the enhancing effects of these palm oil derivatives were 5-fluorouracil, lidocaine and ibuprofen: compounds covering a wide range of Log p values. It was demonstrated that CPO and TRF were capable of enhancing the percutaneous permeation of drugs across full-thickness human skin in vitro. Both TRF and CPO were shown to significantly enhance the permeation of ibuprofen with flux values of 30.6 µg/cm2 h and 23.0 µg/cm2 h respectively, compared to the control with a flux of 16.2 µg/cm2 h. The outcome of this research opens further scope for investigation on the transdermal penetration enhancement activity of pure compounds derived from palm oil