ATP hydrolysis-driven gating in cystic fibrosis transmembrane conductance regulator

Proteins belonging to the ATP-binding cassette superfamily couple ATP binding and hydrolysis at conserved nucleotide-binding domains (NBDs) to diverse cellular functions. Most superfamily members are transporters, while cystic fibrosis transmembrane conductance regulator (CFTR), alone, is an ion channel. Despite this functional difference, recent results have suggested that CFTR shares a common molecular mechanism with other members. ATP binds to partial binding sites on the surface of the two NBDs, which then associate to form a NBD dimer, with complete composite catalytic sites now buried at the interface. ATP hydrolysis and γ-phosphate dissociation, with the loss of molecular contacts linking the two sides of the composite site, trigger dimer dissociation. The conformational signals generated by NBD dimer formation and dissociation are transmitted to the transmembrane domains where, in transporters, they drive the cycle of conformational changes that translocate the substrate across the membrane; in CFTR, they result in opening and closing (gating) of the ion-permeation pathway

Caudal analgesia with buprenorphine for postoperative pain relief in children

Caudal buprenorphine was investigated as a postoperative analgesic in a randomized double blind study in thirty children aged 5-12 years undergoing lower abdominal and lower limb surgery. Comparison was made between two groups of patients, one group receiving plain bupivacaine and the other a combination of plain bupivacaine with buprenorphine. Postoperative analgesia was assessed using a linear analogue scale, and by the response to direct questioning of children using an illustration of sequence of faces. Any untoward side effects and the need for additional analgesics were recorded. The degree and duration of analgesia was far superior in the buprenorphine group and there was a highly significant difference in the requirement of postoperative analgesia between the two groups. There were no major adverse side effects and no motor weakness in either groups, however the incidence of nausea and vomiting was higher in the buprenorphine group. It is concluded that a combination of bupivacaine with buprenorphine administered through the caudal epidural space is a safe and reliable means of providing postoperative pain relief in children for up to 24 h

An Adaptive and Memory Efficient Algorithm for Genotype Imputation

Genome wide association studies have proven to be a highly successful method for identification of genetic loci for complex phenotypes in both humans and model organisms. These large scale studies rely oil the collection of hundreds of thousands of single nucleotide polymorphisms (SNPs) across the genome. Standard high-throughput genotyping technologies capture only a fraction of the total genetic variation. Recent efforts have shown that it is possible to "impute" with high accuracy the genotypes of SNPs that are not collected ill the study provided that they are present in a reference data set which contains both SNPs collected in the Study as well as other SNPs. We here introduce a novel HMM based technique to solve the imputation problem that addresses several shortcomings of existing methods. First, our method is adaptive which lets it estimate population genetic parameters from the data and be applied to model organisms that have very different evolutionary histories. Compared to traditional methods. Our method is tip to tell times more accurate on model organisms such as mouse. Second, our algorithm scales in memory usage in the number of collected markers as opposed to the number of known SNPs. This issue is very relevant due to the size of the reference data sets currently being generated. We compare our method over mouse and human data sets to existing methods and show that each has either comparable or better performance and much lower memory usage. The method is available for download at http://genetics.cs.ucla.edu/eminim.N

eALPS: Estimating Abundance Levels in Pooled Sequencing Using Available Genotyping Data

The recent advances in high-throughput sequencing technologies bring the potential of a better characterization of the genetic variation in humans and other organisms. In many occasions, either by design or by necessity, the sequencing procedure is performed on a pool of DNA samples with different abundances, where the abundance of each sample is unknown. Such a scenario is naturally occurring in the case of metagenomics analysis where a pool of bacteria is sequenced, or in the case of population studies involving DNA pools by design. Particularly, various pooling designs were recently suggested that can identify carriers of rare alleles in large cohorts, dramatically reducing the cost of such large-scale sequencing projects. A fundamental problem with such approaches for population studies is that the uncertainly of DNA proportions from different individuals in the pools might lead to spurious associations. Fortunately, it is often the case that the genotype data of at least some of the individuals in the pool is known. Here, we propose a method (eALPS) that uses the genotype data in conjunction with the pooled sequence data in order to accurately estimate the proportions of the samples in the pool, even in cases where not all individuals in the pool were genotyped (eALPS-LD). Using real data from a sequencing pooling study of Non-Hodgkin's Lymphoma, we demonstrate that the estimation of the proportions is crucial, since otherwise there is a risk for false discoveries. Additionally, we demonstrate that our approach is also applicable to the problem of quantification of species in metagenomics samples (eALPS-BCR), and is particularly suitable for metagenomic quantification of closely-related species. © 2013 Springer-Verlag