Rapid Assessment of Ecosystem Services Provided by Two Mineral Extraction Sites Restored for Nature Conservation in an Agricultural Landscape in Eastern England

Despite growing recognition that mineral sites restored for nature conservation can enhance local biodiversity, the wider societal benefits provided by this type of restoration relative to alternative options are not well understood. This study addresses this research gap by quantifying differences in ecosystem services provision under two common mineral site after-uses: nature conservation and agriculture. Using a combination of site-specific primary field data, benefits transfer and modelling, we show that for our sites restoration for nature conservation provides a more diverse array of ecosystem services than would be delivered under an agricultural restoration scenario. We also explore the effects of addressing different conservation targets, which we find alter the provision of ecosystem services on a service-specific basis. Highly species-focused intervention areas are associated with increased carbon storage and livestock grazing provision, whereas non-intervention areas are important for carbon sequestration, fishing, recreation and flood risk mitigation. The results of this study highlight the wider societal importance of restored mineral sites and may help conservation managers and planners to develop future restoration strategies that provide benefits for both biodiversity and human well-being.     

Novel benzothiophene H1-antihistamines for the treatment of insomnia

SAR of lead benzothiophene H₁-antihistamine 2 was explored to identify backup candidates with suitable pharmacokinetic profiles for an insomnia program. Several potent and selective H₁-antihistamines with a range of projected half-lives in humans were identified. Compound 16d had a suitable human half-life as demonstrated in a human microdose study, but variability in pharmacokinetic profile, attributed to metabolic clearance, prevented further development of this compound. Compound 28b demonstrated lower predicted clearance in preclinical studies, and may represent a more suitable backup compound.     

Identification of a novel selective H1-antihistamine with optimized pharmacokinetic properties for clinical evaluation in the treatment of insomnia

Analogs of the known H₁-antihistamine R-dimethindene with suitable selectivity for key GPCRs, P450 enzymes and hERG channel were assessed for metabolism profile and in vivo properties. Several analogs were determined to exhibit diverse metabolism. One of these compounds, 10a, showed equivalent efficacy in a rat EEG/EMG model to a previously identified clinical candidate and a potentially superior pharmacokinetic profile as determined from a human microdose study.     

Genome-Wide Association of Carbon and Nitrogen Metabolism in the Maize Nested Association Mapping Population

Carbon (C) and nitrogen (N) metabolism are critical to plant growth and development and are at the basis of crop yield and adaptation. We performed high-throughput metabolite analyses on over 12,000 samples from the nested association mapping population to identify genetic variation in C and N metabolism in maize (Zea mays ssp. mays). All samples were grown in the same field and used to identify natural variation controlling the levels of 12 key C and N metabolites, namely chlorophyll a, chlorophyll b, fructose, fumarate, glucose, glutamate, malate, nitrate, starch, sucrose, total amino acids, and total protein, along with the first two principal components derived from them. Our genome-wide association results frequently identified hits with single-gene resolution. In addition to expected genes such as invertases, natural variation was identified in key C₄ metabolism genes, including carbonic anhydrases and a malate transporter. Unlike several prior maize studies, extensive pleiotropy was found for C and N metabolites. This integration of field-derived metabolite data with powerful mapping and genomics resources allows for the dissection of key metabolic pathways, providing avenues for future genetic improvement.Carbon (C) and nitrogen (N) metabolism are the basis for life on Earth. The production, balance, and tradeoffs of C and N metabolism are critical to all plant growth, yield, and local adaptation (Coruzzi and Bush, 2001; Coruzzi et al., 2007). In plants, there is a critical balance between the tissues that are producing energy (sources) and those using it (sinks), as the identities and locations of these vary through time and developmental stage (Smith et al., 2004). While a great deal of research has focused on the key genes and proteins involved in these processes (Wang et al., 1993; Kim et al., 2000; Takahashi et al., 2009), relatively little is known about the natural variation within a species that fine-tunes these processes in individual plants.In addition, a key aspect of core C metabolism involves the nature of plant photosynthesis. While the majority of plants use standard C₃ photosynthetic pathways, some, including maize (Zea mays) and many other grasses, use C₄ photosynthesis to concentrate CO₂ in bundle sheath cells to avoid wasteful photorespiration (Sage, 2004). Under some conditions (such as drought or high temperatures), C₄ photosynthesis is much more efficient than C₃ photosynthesis. Since these conditions are expected to become more prevalent in the near future due to climate change, various research groups are working to convert C₃ crop species to C₄ metabolism in order to boost crop production and food security (Sage and Zhu, 2011). Beyond this, better understanding of both C₃ and C₄ metabolic pathways will aid efforts to breed crops for superior yield, N-use efficiency, and other traits important for global food production.In the last two decades, quantitative trait locus (QTL) mapping, first with linkage analysis and later with association mapping, has been used to dissect C and N metabolism in several species, including Arabidopsis (Arabidopsis thaliana; Mitchell-Olds and Pedersen, 1998; Keurentjes et al., 2008; Lisec et al., 2008; Sulpice et al., 2009), tomato (Solanum lycopersicum; Schauer et al., 2006), and maize (Hirel et al., 2001; Limami et al., 2002; Zhang et al., 2006, 2010a, 2010b). These studies identified key genetic regions underlying variation in core C and N metabolism, many of which include candidate genes known to be involved in these processes.Previous studies of genetic variation for C and N metabolism are limited by the fact that they identified trait loci only through linkage mapping in artificial families or through association mapping across populations of unrelated individuals. Linkage mapping benefits from high statistical power due to many individuals sharing the same genotype at any given location, but it suffers from low resolution due to the limited number of generations (and hence recombination events) since the initial founders. Association mapping, in turn, enjoys high resolution due to the long recombination histories of natural populations but suffers from low power, since most genotypes occur in only a few individuals. In addition, many of these studies focused on C and N in artificial settings (e.g. greenhouses or growth chambers) instead of field conditions, running the risk that important genetic loci could be missed if the conditions do not include important (and potentially unknown) natural environmental variables.To address these issues and improve our understanding of C and N metabolism in maize, we used a massive and diverse germplasm resource, the maize nested association mapping (NAM) population (Buckler et al., 2009; McMullen et al., 2009), to evaluate genetic variation underlying the accumulation of 12 targeted metabolites in maize leaf tissue under field conditions. This population was formed by mating 25 diverse maize lines to the reference line, B73, and creating a 200-member biparental family from each of these crosses. The entire 5,000-member NAM population thus combines the strengths of both linkage and association mapping (McMullen et al., 2009), and it has been used to identify QTLs for important traits such as flowering time (Buckler et al., 2009), disease resistance (Kump et al., 2011; Poland et al., 2011), and plant architecture (Tian et al., 2011; Peiffer et al., 2013). Most importantly, this combination of power and resolution frequently resolves associations down to the single-gene level, even when using field-based data.The metabolites we profiled are key indicators of photosynthesis, respiration, glycolysis, and protein and sugar metabolism in the plant (Sulpice et al., 2009). By taking advantage of a robotized metabolic phenotyping platform (Gibon et al., 2004), we performed more than 100,000 assays across 12,000 samples, with two independent samples per experimental plot. Raw data and the best linear unbiased predictors (BLUPs) of these data were included as part of a study of general functional variation in maize (Wallace et al., 2014), but, to our knowledge, this is the first in-depth analysis of these metabolic data. We find strong correlations among several of the metabolites, and we also find extensive pleiotropy among the different traits. Many of the top QTLs are also near or within candidate genes relating to C and N metabolism, thus identifying targets for future breeding and selection. These results provide a powerful resource for those working with core C and N metabolism in plants and for improving maize performance in particular.     

Effects of intima stiffness and plaque morphology on peak cap stress

Background  

Rupture of the cap of a vulnerable plaque present in a coronary vessel may cause myocardial infarction and death. Cap rupture occurs when the peak cap stress exceeds the cap strength. The mechanical stress within a cap depends on the plaque morphology and the material characteristics of the plaque components. A parametric study was conducted to assess the effect of intima stiffness and plaque morphology on peak cap stress.     

STa and cGMP stimulate CFTR translocation to the surface of villus enterocytes in rat jejunum and is regulated by protein kinase G

The cystic fibrosis transmembrane conductance regulator (CFTR) is critical to cAMP- and cGMP-activated intestinal anion secretion and the pathogenesis of secretory diarrhea. Enterotoxins released by Vibrio cholerae (cholera toxin) and Escherichia coli (heat stable enterotoxin, or STa) activate intracellular cAMP and cGMP and signal CFTR on the apical plasma membrane of small intestinal enterocytes to elicit chloride and fluid secretion. cAMP activates PKA, whereas cGMP signals a cGMP-dependent protein kinase (cGKII) to phosphorylate CFTR in the intestine. In the jejunum, cAMP also regulates CFTR and fluid secretion by insertion of CFTR from subapical vesicles to the surface of enterocytes. It is unknown whether cGMP signaling or phosphorylation regulates the insertion of CFTR associated vesicles from the cytoplasm to the surface of enterocytes. We used STa, cell-permeant cGMP, and cAMP agonists in conjunction with PKG and PKA inhibitors, respectively, in rat jejunum to examine whether 1) cGMP and cGK II regulate the translocation of CFTR to the apical membrane and its relevance to fluid secretion, and 2) PKA regulates cAMP-dependent translocation of CFTR because this intestinal segment is a primary target for toxigenic diarrhea. STa and cGMP induced a greater than fourfold increase in surface CFTR in enterocytes in association with fluid secretion that was inhibited by PKG inhibitors. cAMP agonists induced a translocation of CFTR to the cell surface of enterocytes that was prevented by PKA inhibitors. We conclude that cAMP and cGMP-dependent phosphorylation regulates fluid secretion and CFTR trafficking to the surface of enterocytes in rat jejunum. small intestine; cystic fibrosis transmembrane conductance regulator; membrane traffic; phosphorylation     

The gene for fragrance in rice

The flavour or fragrance of basmati and jasmine rice is associated with the presence of 2-acetyl-1-pyrroline. A recessive gene (fgr) on chromosome 8 of rice has been linked to this important trait. Here, we show that a gene with homology to the gene that encodes betaine aldehyde dehydrogenase (BAD) has significant polymorphisms in the coding region of fragrant genotypes relative to non-fragrant genotypes. The accumulation of 2-acetyl-1-pyrroline in fragrant rice genotypes may be explained by the presence of mutations resulting in a loss of function of the fgr gene product. The allele in fragrant genotypes has a mutation introducing a stop codon upstream of key amino acid sequences conserved in other BADs. The fgr gene corresponds to the gene encoding BAD2 in rice, while BAD1 is encoded by a gene on chromosome 4. BAD has been linked to stress tolerance in plants. However, the apparent loss of function of BAD2 does not seem to limit the growth of fragrant rice genotypes. Fragrance in domesticated rice has apparently originated from a common ancestor and may have evolved in a genetically isolated population, or may be the outcome of a separate domestication event. This is an example of effective human selection for a recessive trait during domestication.     

Neurogenetic interactions and aberrant behavioral co-morbidity of attention deficit hyperactivity disorder (ADHD): dispelling myths

Background

Attention Deficit Hyperactivity Disorder, commonly referred to as ADHD, is a common, complex, predominately genetic but highly treatable disorder, which in its more severe form has such a profound effect on brain function that every aspect of the life of an affected individual may be permanently compromised. Despite the broad base of scientific investigation over the past 50 years supporting this statement, there are still many misconceptions about ADHD. These include believing the disorder does not exist, that all children have symptoms of ADHD, that if it does exist it is grossly over-diagnosed and over-treated, and that the treatment is dangerous and leads to a propensity to drug addiction. Since most misconceptions contain elements of truth, where does the reality lie?

Results

We have reviewed the literature to evaluate some of the claims and counter-claims. The evidence suggests that ADHD is primarily a polygenic disorder involving at least 50 genes, including those encoding enzymes of neurotransmitter metabolism, neurotransmitter transporters and receptors. Because of its polygenic nature, ADHD is often accompanied by other behavioral abnormalities. It is present in adults as well as children, but in itself it does not necessarily impair function in adult life; associated disorders, however, may do so. A range of treatment options is reviewed and the mechanisms responsible for the efficacy of standard drug treatments are considered.

Conclusion

The genes so far implicated in ADHD account for only part of the total picture. Identification of the remaining genes and characterization of their interactions is likely to establish ADHD firmly as a biological disorder and to lead to better methods of diagnosis and treatment.