Identifying therapeutic targets by combining transcriptional data with ordinal clinical measurements

The immense and growing repositories of transcriptional data may contain critical insights for developing new therapies. Current approaches to mining these data largely rely on binary classifications of disease vs. control, and are not able to incorporate measures of disease severity. We report an analytical approach to integrate ordinal clinical information with transcriptomics. We apply this method to public data for a large cohort of Huntington's disease patients and controls, identifying and prioritizing phenotype-associated genes. We verify the role of a high-ranked gene in dysregulation of sphingolipid metabolism in the disease and demonstrate that inhibiting the enzyme, sphingosine-1-phosphate lyase 1 (SPL), has neuroprotective effects in Huntington's disease models. Finally, we show that one consequence of inhibiting SPL is intracellular inhibition of histone deacetylases, thus linking our observations in sphingolipid metabolism to a well-characterized Huntington's disease pathway. Our approach is easily applied to any data with ordinal clinical measurements, and may deepen our understanding of disease processes

Information is Power? Transparency and fetishism in International Relations

International actors, state and non-state, have embraced transparency as a solution to all manner of political problems. Theoretical analyses of these processes present transparency in a fetishtic manner, in which the social relations that generate transparency are misrecognized as the product of information itself. This paper will outline the theoretical problems that arise when transparency promotion is fetishized in International Relations theory. Examining the fetishism of transparency, we will note problematic conception of politics, the public sphere, and rationality they articulate. Confusing the relationship between data, information and knowledge, fetishized treatments of transparency muddy the historical dynamics responsible for the emergence of transparency as a political practice. This alters our understanding of the relationship between global governance institutions, their constituents, and the nature of knowledge production itself. Realizing the normative promise of transparency requires a reorientation of theoretical practice towards sociologically and historically sensitive approaches to the politics of knowledge

CRISPR/Cas9 recombineering-mediated deep mutational scanning of essential genes in Escherichia coli

Deep mutational scanning can provide significant insights into the function of essential genes in bacteria. Here, we developed a high-throughput method for mutating essential genes of Escherichia coli in their native genetic context. We used Cas9-mediated recombineering to introduce a library of mutations, created by error-prone PCR, within a gene fragment on the genome using a single gRNA pre-validated for high efficiency. Tracking mutation frequency through deep sequencing revealed biases in the position and the number of the introduced mutations. We overcame these biases by increasing the homology arm length and blocking mismatch repair to achieve a mutation efficiency of 85% for non-essential genes and 55% for essential genes. These experiments also improved our understanding of poorly characterized recombineering process using dsDNA donors with single nucleotide changes. Finally, we applied our technology to target rpoB, the beta subunit of RNA polymerase, to study resistance against rifampicin. In a single experiment, we validate multiple biochemical and clinical observations made in the previous decades and provide insights into resistance compensation with the study of double mutants.</p

The ordinary city trap

The paper is a critique of a critique, it explains why the most salient and influential critiques of the neo-Marxist world city and global city concepts, made by those arguing to further postcolonialize urban studies through such suppositions that all cities are ‘ordinary’, are misguided. First, it is explained how the charges of economism and ethnocentrism against the world city and global city concepts are ignoratio elenchi: they do not even begin to address or critique their neo-Marxist argument that, across the difference and diversity of the world’s cities, a few major cities have the necessary economic specialization and therefore extraordinary function of commanding and controlling neoliberal globalization. Second, the error made by advocates of ordinary cities of supposing that world-systems analysis and the world city concept are forms of developmentalism is understood as the source for a wider postcolonial mistake of conflating the neo-Marxist world city and global city literatures with the very neoliberal practices toward urban development that they have long attempted to disclose and counter. Finally, the charges against the world city and global city concepts as paradigmatic, peripheralizing, and normative are also rebutted, not only to highlight how those critiques are consequentialist and dependent on the respective charges of economism, ethnocentrism, and developmentalism having veracity, but to demonstrate how an acceptance of the ordinary cities argument for an idiographic, provincial, nominalist, and comparative approach to urban studies, as an alternative to the two neo-Marxist concepts, is only to fall into the trap of making the mistake of confusing evidence of absence for absence of evidence

Employment in the Ecuadorian cut-flower industry and the risk of spontaneous abortion

<p>Abstract</p> <p>Background</p> <p>Research on the potentially adverse effects of occupational pesticide exposure on risk of spontaneous abortion (SAB) is limited, particularly among female agricultural workers residing in developing countries.</p> <p>Methods</p> <p>Reproductive histories were obtained from 217 Ecuadorian mothers participating in a study focusing on occupational pesticide exposure and children's neurobehavioral development. Only women with 2+ pregnancies were included in this study (n = 153). Gravidity, parity and frequency of SAB were compared between women with and without a history of working in the cut-flower industry in the previous 6 years. Logistic regression analysis was conducted to assess the relation between SAB and employment in the flower industry adjusting for maternal age.</p> <p>Results</p> <p>In comparison to women not working in the flower industry, women working in the flower industry were significantly younger (27 versus 32 years) and of lower gravidity (3.3 versus 4.5) and reported more pregnancy losses. A 2.6 (95% CI: 1.03-6.7) fold increase in the odds of pregnancy loss among exposed women was observed after adjusting for age. Odds of reporting an SAB increased with duration of flower employment, increasing to 3.4 (95% CI: 1.3, 8.8) among women working 4 to 6 years in the flower industry compared to women who did not work in the flower industry.</p> <p>Conclusion</p> <p>This exploratory analysis suggests a potential adverse association between employment in the cut-flower industry and SAB. Study limitations include the absence of a temporal relation between exposure and SAB, no quantification of specific pesticides, and residual confounding such as physical stressors (i.e., standing). Considering that approximately half of the Ecuadorian flower laborers are women, our results emphasize the need for an evaluating the reproductive health effects of employment in the flower industry on reproductive health in this population.</p

Error determination in the photogrammetric assessment of shoreline changes

The evaluation of error or uncertainty in shoreline change studies is an issue of prime importance for providing an adequate framework for calculated rates of change and to allow the establishment of threshold values above which the rates would be significant. In this note, a practical, easy-to-use method is presented to estimate error involved in the calculation of shoreline changes on aerial photographs, including the three most used types of shoreline indicators: high water line, dune/cliff toe and cliff top. This approach takes into account the specific characteristics of each shoreline proxy, such as relief in the case of the cliff top or tidal oscillations in the case of the high water line. At the same time it includes the error components that are independent from the proxy, basically related to the technical aspects of the process such as photo scanning and georeferencing. A practical example of application of the method is provided for several types of data inputs, based on shoreline changes around the Bay of Cádiz (SW Spain)

Attitudes towards 12-step groups and referral practices in a 12-step naive treatment culture; a survey of addiction professionals in Norway

<p>Abstract</p> <p>Background</p> <p>Addressing substance use disorders effectively requires a long-term approach. Substance abuse treatment is typically of short duration; referring patients to Twelve Step based self-help groups (TSGs) – e.g. Narcotics Anonymous, represents a promising complementary recovery resource. Clinicians' attitudes and referral practices towards the TSGs have mainly been studied in countries with high integration of the 12-step philosophy in their substance abuse services and where the TSGs are widely available, such as the US. In Norway, there are currently 294 weekly TSG meetings (6 per 100,000 inhabitants). This study describes clinicians' attitudes and referral practices to TSGs in Norway where health authorities seek to promote self-help participation, but where the treatment culture is unfamiliar with 12-step fellowships.</p> <p>Methods</p> <p>Data collected by a self-administered questionnaire, adapted from established US and UK instruments. Information covered the attitudes, knowledge and referral practices towards TSGs among addiction treatment professionals in Norway in mid 2008.</p> <p>Results</p> <p>The return rate was 79.7% (n = 291). Participants had moderately positive attitude scores towards TSGs, but referral to these groups among Norwegian addiction professionals was low, as was the level of knowledge about TSGs. More than six out of ten did not refer any patients to TSGs in the previous week. Local variation with more referrals to TSGs in the county with the one established 12-step treatment facility was observed. Respondents' integration of the 12-steps in their own treatment work, higher self-efficacy for making a successful referral, and greater TSG knowledge were associated with referring patients.</p> <p>Conclusion</p> <p>Low referral rates to TSGs point to the need for education and training to raise the awareness and knowledge about it among addiction professionals unfamiliar with these 12-step fellowships. Training should focus on the usefulness of these groups for all types of treatment models regardless of therapeutic orientation. Increased knowledge is expected to lead to higher referral rates, which in turn would maximize the likelihood of positive long-term patient outcomes.</p

Docking of Secretory Vesicles Is Syntaxin Dependent

Secretory vesicles dock at the plasma membrane before they undergo fusion. Molecular docking mechanisms are poorly defined but believed to be independent of SNARE proteins. Here, we challenged this hypothesis by acute deletion of the target SNARE, syntaxin, in vertebrate neurons and neuroendocrine cells. Deletion resulted in fusion arrest in both systems. No docking defects were observed in synapses, in line with previous observations. However, a drastic reduction in morphologically docked secretory vesicles was observed in chromaffin cells. Syntaxin-deficient chromaffin cells showed a small reduction in total and plasma membrane staining for the docking factor Munc18-1, which appears insufficient to explain the drastic reduction in docking. The sub-membrane cortical actin network was unaffected by syntaxin deletion. These observations expose a docking role for syntaxin in the neuroendocrine system. Additional layers of regulation may have evolved to make syntaxin redundant for docking in highly specialized systems like synaptic active zones

Semi-supervised segmentation of ultrasound images based on patch representation and continuous min cut.

Ultrasound segmentation is a challenging problem due to the inherent speckle and some artifacts like shadows, attenuation and signal dropout. Existing methods need to include strong priors like shape priors or analytical intensity models to succeed in the segmentation. However, such priors tend to limit these methods to a specific target or imaging settings, and they are not always applicable to pathological cases. This work introduces a semi-supervised segmentation framework for ultrasound imaging that alleviates the limitation of fully automatic segmentation, that is, it is applicable to any kind of target and imaging settings. Our methodology uses a graph of image patches to represent the ultrasound image and user-assisted initialization with labels, which acts as soft priors. The segmentation problem is formulated as a continuous minimum cut problem and solved with an efficient optimization algorithm. We validate our segmentation framework on clinical ultrasound imaging (prostate, fetus, and tumors of the liver and eye). We obtain high similarity agreement with the ground truth provided by medical expert delineations in all applications (94% DICE values in average) and the proposed algorithm performs favorably with the literature