The enteric nervous system in gastrointestinal disease etiology

A highly conserved but convoluted network of neurons and glial cells, the enteric nervous system (ENS), is positioned along the wall of the gut to coordinate digestive processes and gastrointestinal homeostasis. Because ENS components are in charge of the autonomous regulation of gut function, it is inevitable that their dysfunction is central to the pathophysiology and symptom generation of gastrointestinal disease. While for neurodevelopmental disorders such as Hirschsprung, ENS pathogenesis appears to be clear-cut, the role for impaired ENS activity in the etiology of other gastrointestinal disorders is less established and is often deemed secondary to other insults like intestinal inflammation. However, mounting experimental evidence in recent years indicates that gastrointestinal homeostasis hinges on multifaceted connections between the ENS, and other cellular networks such as the intestinal epithelium, the immune system, and the intestinal microbiome. Derangement of these interactions could underlie gastrointestinal disease onset and elicit variable degrees of abnormal gut function, pinpointing, perhaps unexpectedly, the ENS as a diligent participant in idiopathic but also in inflammatory and cancerous diseases of the gut. In this review, we discuss the latest evidence on the role of the ENS in the pathogenesis of enteric neuropathies, disorders of gut–brain interaction, inflammatory bowel diseases, and colorectal cancer.

     

Maize HapMap2 identifies extant variation from a genome in flux

Whereas breeders have exploited diversity in maize for yield improvements, there has been limited progress in using beneficial alleles in undomesticated varieties. Characterizing standing variation in this complex genome has been challenging, with only a small fraction of it described to date. Using a population genetics scoring model, we identified 55 million SNPs in 103 lines across pre-domestication and domesticated Zea mays varieties, including a representative from the sister genus Tripsacum. We find that structural variations are pervasive in the Z. mays genome and are enriched at loci associated with important traits. By investigating the drivers of genome size variation, we find that the larger Tripsacum genome can be explained by transposable element abundance rather than an allopolyploid origin. In contrast, intraspecies genome size variation seems to be controlled by chromosomal knob content. There is tremendous overlap in key gene content in maize and Tripsacum, suggesting that adaptations from Tripsacum (for example, perennialism and frost and drought tolerance) can likely be integrated into maize.     

Vitamin K-dependent blood coagulation proteins form hetero-dimers

The later stages of the blood coagulation cascade are characterized by the presence of vitamin K-dependent proteins and their involvement in membrane-bound, multi-protein converting complexes with an essential requirement for calcium ions. Specific interactions between zymogens and activating enzymes have not yet been identified. Here we describe a crystallographic study of prothrombin fragment 1 (residues 1-156 of prothrombin) which indicates that vitamin K-dependent coagulation proteins have specific association sites that allow them to form hetero-dimers. The calcium-induced formation of a hetero-dimer between fragment 1 and factor X is demonstrated by cross-linking. Such hetero-dimers of vitamin K-dependent proteins could be significant in the coagulation system.     

The antilipolytic effects of 3,5-dimethylisoxazole and possible carboxylic acid metabolites

Zusammenfassung Von allen möglichen Isoxazolcarbonsäurenstoffwechselprodukten von 3,5-Dimethylisoxazol (3,5-DMI), die untersucht wurden, war nur die 3-Methylisoxazol-5-carbonsäure wirksam genug, um die auffallende Wirkung von 3,5-DMI auf unveresterte Fettsäurespiegel in normalen Hunden zu erklären.     

In vitro effects of high molecular weight forms of ACTH on the fetal sheep adrenal

The direct involvement of the pituitary-adrenal axis in birth has been well established, at least in sheep, and its removal prolongs pregnancy. As part of the process the fetal sheep adrenal grows rapidly during the 10-15 d prepartum and is associated with a large rise in the plasma corticosteroid concentration. This does not seem to result from an increased ACTH secretion. The fetal adrenal in vivo seems refractory to circulating ACTH and shows poor response to elevation of plasma concentration. Thus the signal for the adrenal hypertrophy and the initiation of parturition remains unclear. The responsiveness of the fetal adrenal to ACTH has been re-examined using isolated adrenal cells. The study shows that in the fetal sheep these are not inherently unresponsive to ACTH, but that high-molecular-weight forms of ACTH block the action of ACTH. These peptides may be responsible for controlling the activity of the adrenal in situ.     

Genome-wide association study of leaf architecture in the maize nested association mapping population

US maize yield has increased eight-fold in the past 80 years, with half of the gain attributed to selection by breeders. During this time, changes in maize leaf angle and size have altered plant architecture, allowing more efficient light capture as planting density has increased. Through a genome-wide association study (GWAS) of the maize nested association mapping panel, we determined the genetic basis of important leaf architecture traits and identified some of the key genes. Overall, we demonstrate that the genetic architecture of the leaf traits is dominated by small effects, with little epistasis, environmental interaction or pleiotropy. In particular, GWAS results show that variations at the liguleless genes have contributed to more upright leaves. These results demonstrate that the use of GWAS with specially designed mapping populations is effective in uncovering the basis of key agronomic traits.     

Genome-wide association study identifies a new melanoma susceptibility locus at 1q21.3

We performed a genome-wide association study of melanoma in a discovery cohort of 2,168 Australian individuals with melanoma and 4,387 control individuals. In this discovery phase, we confirm several previously characterized melanoma-associated loci at MC1R, ASIP and MTAP-CDKN2A. We selected variants at nine loci for replication in three independent case-control studies (Europe: 2,804 subjects with melanoma, 7,618 control subjects; United States 1: 1,804 subjects with melanoma, 1,026 control subjects; United States 2: 585 subjects with melanoma, 6,500 control subjects). The combined meta-analysis of all case-control studies identified a new susceptibility locus at 1q21.3 (rs7412746, P = 9.0 × 10(-11), OR in combined replication cohorts of 0.89 (95% CI 0.85-0.95)). We also show evidence suggesting that melanoma associates with 1q42.12 (rs3219090, P = 9.3 × 10(-8)). The associated variants at the 1q21.3 locus span a region with ten genes, and plausible candidate genes for melanoma susceptibility include ARNT and SETDB1. Variants at the 1q21.3 locus do not seem to be associated with human pigmentation or measures of nevus density.