Problem-driven scenario generation:an analytical approach for stochastic programs with tail risk measure

Scenario generation is the construction of a discrete random vector to represent parameters of uncertain values in a stochastic program. Most approaches to scenario generation are distribution-driven, that is, they attempt to construct a random vector which captures well in a probabilistic sense the uncertainty. On the other hand, a problem-driven approach may be able to exploit the structure of a problem to provide a more concise representation of the uncertainty. There have been only a few problem-driven approaches proposed, and these have been heuristic in nature. In this paper we propose what is, as far as we are aware, the first analytic approach to problem-driven scenario generation. This approach applies to stochastic programs with a tail risk measure, such as conditional value-at-risk. Since tail risk measures only depend on the upper tail of a distribution, standard methods of scenario generation, which typically spread there scenarios evenly across the support of the solution, struggle to adequately represent tail risk well

Problem-driven scenario generation:an analytical approach for stochastic programs with tail risk measure

Scenario generation is the construction of a discrete random vector to represent parameters of uncertain values in a stochastic program. Most approaches to scenario generation are distribution-driven, that is, they attempt to construct a random vector which captures well in a probabilistic sense the uncertainty. On the other hand, a problem-driven approach may be able to exploit the structure of a problem to provide a more concise representation of the uncertainty. In this paper we propose an analytic approach to problem-driven scenario generation. This approach applies to stochastic programs where a tail risk measure, such as conditional value-at-risk, is applied to a loss function. Since tail risk measures only depend on the upper tail of a distribution, standard methods of scenario generation, which typically spread their scenarios evenly across the support of the random vector, struggle to adequately represent tail risk. Our scenario generation approach works by targeting the construction of scenarios in areas of the distribution corresponding to the tails of the loss distributions. We provide conditions under which our approach is consistent with sampling, and as proof-of-concept demonstrate how our approach could be applied to two classes of problem, namely network design and portfolio selection. Numerical tests on the portfolio selection problem demonstrate that our approach yields better and more stable solutions compared to standard Monte Carlo sampling

Oral colistin sulfate in pigs: pharmacokinetics and effect on fecal Escherichia coli excretion of weaned pigs challenged with Escherichia coli F4 (K88)

Colistin sulfate (CS), a polymyxin antibiotic, is used in Canada for the treatment of post-weaning diarrhea in pigs as an alternative to neomycin. The aim of the present study was to evaluate some pharmcokinetics parameters of CS and its effect on the evolution of the intestinal Escherichia coli population in pigs challenged with enterotoxigenic E. coli (ETEC): F4

Impacts of colistin sulfate on fecal Escherichia coli resistance and on growth performance of piglets in a post-weaning diarrhea model

Colistin sulfate (CS) is used in Canada for the treatment of post weaning diarrhea (PWD), to overcome conventional therapeutic antibiotics failures. The aim of the present study was to determine the effect of a conventional oral regimen of CS for the treatment of PWD, on the development of E. coli CS resistance and to evaluate the effect of ETEC: F4 infection on CS intestinal absorption. A total of 48 pigs were used, challenge was carried out by oral administration of 109CFU of a hemolytic ETEC: F4 strain resistant to nalidixic acid. CS was administered at a dose of 50.000 UI/kg twice a day for 5 days. Feces were examined clinically and bacteriologically before and after challenge to evaluate presence of diarrhea and E. coli fecal excretion. ETEC: F4 virulence factors were monitored and CS plasma concentrations were quantified by an HPLC-MS/MS. From one until six days after CS administration, a significant reduction in the fecal excretion of ETEC: F4, total E. coli, ETEC: F4 virulence factors and in diarrhea scores was observed in the challenged treated group compared to the challenged untreated group (p\u3c0.0001). No significant difference in growth performances was observed in treated compared to non-treated pigs (p\u3e0.71). A significant selection pressure on E. coli total population was observed following CS treatment (p\u3c0.0001). Challenge with ETEC: F4 resulted in an increase in intestinal absorption of CS. Our study is the first to demonstrate in an experimental model of PWD, that CS at a dose of 50,000 IU/kg is effective in reducing fecal excretion of E. coli. However, this regimen was associated with a selection pressure on E. coli CS resistance, and did not improve growth performance in challenged pigs. Thus, the use of this antibiotic in pig should be revised

RESCUE-ESE identifies candidate exonic splicing enhancers in vertebrate exons.

ABSTRACT A typical gene contains two levels of information: a sequence that encodes a particular protein and a host of other signals that are necessary for the correct expression of the transcript. While much attention has been focused on the effects of sequence variation on the amino acid sequence, variations that disrupt gene processing signals can dramatically impact gene function. A variation that disrupts an exonic splicing enhancer (ESE), for example, could cause exon skipping which would result in the exclusion of an entire exon from the mRNA transcript. RESCUE-ESE, a computational approach used in conjunction with experimental validation, previously identified 238 candidate ESE hexamers in human genes. The RESCUE-ESE method has recently been implemented in three additional species: mouse, zebrafish and pufferfish. Here we describe an online ESE analysis tool (http://genes.mit.edu/burgelab/ rescue-ese/) that annotates RESCUE-ESE hexamers in vertebrate exons and can be used to predict splicing phenotypes by identifying sequence changes that disrupt or alter predicted ESEs

Challenging school reform from below: is leadership the missing link in mobilization theory?

This article presents research relating to the experiences of union and community-based campaigns that have sought to challenge the establishment of academy and free schools in England. Such schools are removed from local government control and are seen as a defining element of the neoliberal restructuring of public education. The research draws on social-movement literature, and particularly mobilization theory, to better understand the dynamics of such campaigns and the contexts in which they can either thrive or wither. In the article, I argue that mobilization theory provides a useful framework for such analysis but that it fails to adequately reflect the importance of individual agency and the role of leadership at a local level. Leadership of such campaigns is often assumed by individuals reluctantly, and often defies traditional descriptions of “leadership,” but must be recognized if mobilization theory is to avoid being overly deterministic

Alternative Splicing of RNA Triplets Is Often Regulated and Accelerates Proteome Evolution

Thousands of human genes contain introns ending in NAGNAG (N any nucleotide), where both NAGs can function as 3′ splice sites, yielding isoforms that differ by inclusion/exclusion of three bases. However, few models exist for how such splicing might be regulated, and some studies have concluded that NAGNAG splicing is purely stochastic and nonfunctional. Here, we used deep RNA-Seq data from 16 human and eight mouse tissues to analyze the regulation and evolution of NAGNAG splicing. Using both biological and technical replicates to estimate false discovery rates, we estimate that at least 25% of alternatively spliced NAGNAGs undergo tissue-specific regulation in mammals, and alternative splicing of strongly tissue-specific NAGNAGs was 10 times as likely to be conserved between species as was splicing of non-tissue-specific events, implying selective maintenance. Preferential use of the distal NAG was associated with distinct sequence features, including a more distal location of the branch point and presence of a pyrimidine immediately before the first NAG, and alteration of these features in a splicing reporter shifted splicing away from the distal site. Strikingly, alignments of orthologous exons revealed a ~15-fold increase in the frequency of three base pair gaps at 3′ splice sites relative to nearby exon positions in both mammals and in Drosophila. Alternative splicing of NAGNAGs in human was associated with dramatically increased frequency of exon length changes at orthologous exon boundaries in rodents, and a model involving point mutations that create, destroy, or alter NAGNAGs can explain both the increased frequency and biased codon composition of gained/lost sequence observed at the beginnings of exons. This study shows that NAGNAG alternative splicing generates widespread differences between the proteomes of mammalian tissues, and suggests that the evolutionary trajectories of mammalian proteins are strongly biased by the locations and phases of the introns that interrupt coding sequences.Damon Runyon Cancer Research Foundation (DRG 2032-09)National Science Foundation (U.S.). (no. 0821391)United States. National Institutes of Healt

Shop stewards’ leadership, left-wing activism and collective workplace union organisation

Providing an account of the dynamic interrelationship between shop steward leadership and membership interaction, Ralph Darlington focuses particular attention on the much-neglected crucial role that left-wing political activists can play in shaping the nature of collective workplace relations

Functional genomics provide key insights to improve the diagnostic yield of hereditary ataxia

Improvements in functional genomic annotation have led to a critical mass of neurogenetic discoveries. This is exemplified in hereditary ataxia, a heterogeneous group of disorders characterised by incoordination from cerebellar dysfunction. Associated pathogenic variants in more than 300 genes have been described, leading to a detailed genetic classification partitioned by age-of-onset. Despite these advances, up to 75% of patients with ataxia remain molecularly undiagnosed even following whole genome sequencing, as exemplified in the 100,000 Genomes Project. This study aimed to understand whether we can improve our knowledge of the genetic architecture of hereditary ataxia by leveraging functional genomic annotations, and as a result, generate insights and strategies that raise the diagnostic yield. To achieve these aims, we used publicly-available multi-omics data to generate 294 genic features, capturing information relating to a gene's structure, genetic variation, tissue-specific, cell-type-specific and temporal expression, as well as protein products of a gene. We studied these features across genes typically causing childhood-onset, adult-onset or both types of disease first individually, then collectively. This led to the generation of testable hypotheses which we investigated using whole genome sequencing data from up to 2,182 individuals presenting with ataxia and 6,658 non-neurological probands recruited in the 100,000 Genomes Project. Using this approach, we demonstrated a high short tandem repeat (STR) density within childhood-onset genes suggesting that we may be missing pathogenic repeat expansions within this cohort. This was verified in both childhood- and adult-onset ataxia patients from the 100,000 Genomes Project who were unexpectedly found to have a trend for higher repeat sizes even at naturally-occurring STRs within known ataxia genes, implying a role for STRs in pathogenesis. Using unsupervised analysis, we found significant similarities in genomic annotation across the gene panels, which suggested adult- and childhood-onset patients should be screened using a common diagnostic gene set. We tested this within the 100,000 Genomes Project by assessing the burden of pathogenic variants among childhood-onset genes in adult-onset patients and vice versa. This demonstrated a significantly higher burden of rare, potentially pathogenic variants in conventional childhood-onset genes among individuals with adult-onset ataxia. Our analysis has implications for the current clinical practice in genetic testing for hereditary ataxia. We suggest that the diagnostic rate for hereditary ataxia could be increased by removing the age-of-onset partition, and through a modified screening for repeat expansions in naturally-occurring STRs within known ataxia-associated genes, in effect treating these regions as candidate pathogenic loci

Benefits, Barriers and Enablers of Breastfeeding: Factor Analysis of Population Perceptions in Western Australia

Objective: The objective of this study was to investigate knowledge and community perceptions of breastfeeding in Western Australia using a factor analysis approach. Methods: Data were pooled from five Nutrition Monitoring Survey Series which included information on breastfeeding from 4,802 Western Australian adults aged 18–64 years. Tetrachoric factor analysis was conducted for data reduction and significant associations identified using logistic, ordinal and poisson regression analyses. Results: Four factors were derived for benefits (it’s natural, good nutrition, good for the baby, and convenience), barriers (breastfeeding problems, poor community acceptability, having to go back to work, and inconvenience) and for enablers (breastfeeding education, community support, family support and not having to work).As assessed by standardized odds ratios the most important covariates across benefit factors were: importance of breastfeeding (ORs range from 1.22–1.44),female gender (ORs range from 0.80 to 1.46), being able to give a time for how long a baby should be breastfed (ORs range from 0.96 to 1.27) and education (less than high school to university completion) (ORs range from 0.95 to 1.23); the most important covariate across barrier factors was being able to give a time for how long a baby should be breastfed (ORs range from 0.89 to 1.93); and the most important covariates across all enabling factors were education (ORs range from 1.14 to1.32) and being able to give a time for how long a baby should be breastfed (ORs range from 1.17 to 1.42).Conclusions: Being female, rating breastfeeding as important, believing that babies should be breastfed for a period of time and education accounted for most of the statistically significant associations. The differences between male and female perceptions require investigation particularly in relation to returning to work