Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Pre clinical and clinical studies of the effects of resveratrol, a phytochemical with potential chemopreventive efficacy

Resveratrol, found in grape skins and red wine, has potential chemopreventive activity in vitro at concentrations ≥5μM. This project explored the tolerability, pharmacokinetics and pharmacodynamics of resveratrol in two clinical phase 1 studies. In vivo data were supported by in vitro studies designed to mimic the daily dosing protocol, using concentrations observed clinically. Forty healthy volunteers received 29 oral daily doses of 0.5, 1.0, 2.5 and 5.0g resveratrol and 20 colorectal cancer patients 8 oral daily doses of 0.5 and 1.0g prior to surgical resection. The pharmacodynamics of resveratrol were assessed by measuring changes in plasma levels of proteins involved in the IGF system, oxidative DNA damage in whole blood and colorectal tissue (M1dG), effects on inflammatory pathways in plasma (PGE2) and colorectal tissue (COX-2), as well as colorectal tissue proliferation (Ki-67). No serious adverse events were reported. In volunteers, mean peak plasma levels of resveratrol across the dose groups ranged from 44.7-954ng/mL (0.20-4.20μM), and for the main metabolite, resveratrol-3-sulfate, were 4-13 fold-higher. Despite low systemic bioavailability, resveratrol concentrations associated with potential chemopreventive efficacy were observed in colorectal tumour tissue with a mean of 44.0nmol/g detected in patients receiving the 1.0g dose (range 0.30-195nmol/g). Post dosing, IGF-1 levels were reduced by 8% (P=0.03) in volunteers and by 33% (P<0.001) in colorectal cancer patients. In tissue, a reduction in cell proliferation of 5.5% (P=0.05) was observed, whilst there was an increase in COX-2 staining (P=0.004). Apart from the 2.5g dose in volunteers, where a significant increase was observed in blood M1dG (21.6%, P=0.02), resveratrol did not significantly affect plasma PGE2 or markers of DNA damage in either study. In cultured colon cancer cells, daily exposure to resveratrol was associated with increased antiproliferative activity compared to an equivalent single dose, supporting the indication that chronic administration may cause pharmacodynamic changes in humans. The work presented here suggests resveratrol has potential as a cancer chemopreventive agent and controlled clinical trials are now warranted.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Protein homeostasis and synaptic plasticity

The Schuman lab provides an overview of the importance of mRNA localization, spatially restricted mRNA translation and protein degradation within neuronal synapses in modulating local synaptic plasticit

Correlations between physical and chemical defences in plants: tradeoffs, syndromes, or just many different ways to skin a herbivorous cat?

� Most plant species have a range of traits that deter herbivores. However, understanding of how different defences are related to one another is surprisingly weak. Many authors argue that defence traits trade off against one another, while others argue that they form coordinated defence syndromes. � We collected a dataset of unprecedented taxonomic and geographic scope (261 species spanning 80 families, from 75 sites across the globe) to investigate relationships among four chemical and six physical defences. � Five of the 45 pairwise correlations between defence traits were significant and three of these were tradeoffs. The relationship between species’ overall chemical and physical defence levels was marginally nonsignificant (P = 0.08), and remained nonsignificant after accounting for phylogeny, growth form and abundance. Neither categorical principal component analysis (PCA) nor hierarchical cluster analysis supported the idea that species displayed defence syndromes. � Our results do not support arguments for tradeoffs or for coordinated defence syndromes. Rather, plants display a range of combinations of defence traits. We suggest this lack of consistent defence syndromes may be adaptive, resulting from selective pressure to deploy a different combination of defences to coexisting species

Surgical bypass vs. endoscopic stenting for pancreatic ductal adenocarcinoma

AbstractBackgroundThe majority of patients with pancreatic cancer are non-resectable and jaundiced at presentation. Methods of palliation in such patients with locally advanced disease comprise endoscopic placement of a biliary endoprosthesis or surgical bypass.MethodsThis retrospective study compared morbidity, mortality, hospital stay, readmission rate and survival in consecutive patients with incurable locally advanced pancreatic ductal adenocarcinoma.ResultsWe identified a total of 56 patients, of whom 33 underwent endoscopic stenting and 23 underwent a surgical bypass consisting of a hepaticojejunostomy-en-Y and a gastrojejunostomy. There were no significant differences in complication or mortality rates between patients undergoing palliative stenting and those undergoing palliative surgery. However, after excluding admissions for chemotherapy-related problems, the number of readmissions expressed as a percentage of the group population size was greater in stented patients compared with biliary bypass patients (39.4% vs. 13.0%, respectively; P < 0.05). Overall survival amongst patients undergoing palliative bypass was significantly greater than in stented patients (382 days vs. 135 days, respectively; P < 0.05).ConclusionsOn analysis of these data and the published literature, we conclude that surgical bypass represents an effective method of palliation for patients with locally advanced pancreatic cancer. Patients need to be carefully selected with regard to both operative risk and perceived overall survival