/pdf/molecular-evolutionary-genetics-analysis-1uvpbl4lte.pdf

Molecular Evolutionary Genetics Analysis

The article reports a field study which examined the mental models of 80 undergraduates seeking information for either a history or psychology course essay when they were in an early, exploration stage of researching their essay. This group is presently at a disadvantage when using thesaurus-type schemes in indexes and online search engines because there is a disconnect between how domain novice users of IR systems represent a topic space and how this space is represented in the standard IR system thesaurus. The study attempted to (a) ascertain the coding language used by the 80 undergraduates in the study to mentally represent their topic and then (b) align the mental models with the hierarchical structure found in many thesauri. The intervention focused the undergraduates' thinking about their topic from a topic statement to a thesis statement. The undergraduates were asked to produce three mental model diagrams for their real-life course essay at the beginning, middle, and end of the interview, for a total of 240 mental model diagrams, from which we created a 12-category mental model classification scheme. Findings indicate that at the end of the intervention, (a) the percentage of vertical mental models increased from 24 to 35p of all mental models; but that (b) 3rd-year students had fewer vertical mental models than did 1st-year undergraduates in the study, which is counterintuitive. The results indicate that there is justification for pursuing our research based on the hypothesis that rotating a domain novice's mental model into a vertical position would make it easier for him or her to cognitively connect with the thesaurus's hierarchical representation of the topic area. © 2007 Wiley Periodicals, Inc.

A classification of mental models of undergraduates seeking information for a course essay in history and psychology: Preliminary investigations into aligning their mental models with online thesauri

Genome-wide association studies suggest that common genetic variants explain only a modest fraction of heritable risk for common diseases, raising the question of whether rare variants account for a significant fraction of unexplained heritability. Although DNA sequencing costs have fallen markedly, they remain far from what is necessary for rare and novel variants to be routinely identified at a genome-wide scale in large cohorts. We have therefore sought to develop second-generation methods for targeted sequencing of all protein-coding regions ('exomes'), to reduce costs while enriching for discovery of highly penetrant variants. Here we report on the targeted capture and massively parallel sequencing of the exomes of 12 humans. These include eight HapMap individuals representing three populations, and four unrelated individuals with a rare dominantly inherited disorder, Freeman-Sheldon syndrome (FSS). We demonstrate the sensitive and specific identification of rare and common variants in over 300 megabases of coding sequence. Using FSS as a proof-of-concept, we show that candidate genes for Mendelian disorders can be identified by exome sequencing of a small number of unrelated, affected individuals. This strategy may be extendable to diseases with more complex genetics through larger sample sizes and appropriate weighting of non-synonymous variants by predicted functional impact.

Targeted capture and massively parallel sequencing of 12 human exomes

On autopsy, a patient is found to have hypertrophic cardiomyopathy The patient’s family pursues genetic testing that shows a “likely pathogenic” variant for the condition on the basis of a study in an original research publication Given the dominant inheritance of the condition and the risk of sudden cardiac death, other family members are tested for the genetic variant to determine their risk Several family members test negative and are told that they are not at risk for hypertrophic cardiomyopathy and sudden cardiac death, and those who test positive are told that they need to be regularly monitored for cardiomyopathy on echocardiography Five years later, during a routine clinic visit of one of the genotype-positive family members, the cardiologist queries a database for current knowledge on the genetic variant and discovers that the variant is now interpreted as “likely benign” by another laboratory that uses more recently derived population-frequency data A newly available testing panel for additional genes that are implicated in hypertrophic cardiomyopathy is initiated on an affected family member, and a different variant is found that is determined to be pathogenic Family members are retested, and one member who previously tested negative is now found to be positive for this new variant An immediate clinical workup detects evidence of cardiomyopathy, and an intracardiac defibrillator is implanted to reduce the risk of sudden cardiac death

https://www.nejm.org/doi/pdf/10.1056/NEJMsr1406261

ClinGen — The Clinical Genome Resource

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDA) is characterised by stromal desmoplasia and vascular dysfunction, which critically impair drug delivery. This study examines the role of an abundant extracellular matrix component, the megadalton glycosaminoglycan hyaluronan (HA), as a novel therapeutic target in PDA. METHODS: Using a genetically engineered mouse model of PDA, the authors enzymatically depleted HA by a clinically formulated PEGylated human recombinant PH20 hyaluronidase (PEGPH20) and examined tumour perfusion, vascular permeability and drug delivery. The preclinical utility of PEGPH20 in combination with gemcitabine was assessed by short-term and survival studies. RESULTS: PEGPH20 rapidly and sustainably depleted HA, inducing the re-expansion of PDA blood vessels and increasing the intratumoral delivery of two chemotherapeutic agents, doxorubicin and gemcitabine. Moreover, PEGPH20 triggered fenestrations and interendothelial junctional gaps in PDA tumour endothelia and promoted a tumour-specific increase in macromolecular permeability. Finally, combination therapy with PEGPH20 and gemcitabine led to inhibition of PDA tumour growth and prolonged survival over gemcitabine monotherapy, suggesting immediate clinical utility. CONCLUSIONS: The authors demonstrate that HA impedes the intratumoral vasculature in PDA and propose that its enzymatic depletion be explored as a means to improve drug delivery and response in patients with pancreatic cancer.

pdf/hyaluronan-impairs-vascular-function-and-drug-delivery-in-a-2bjlsydi7n.pdf

Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer

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