Too many roads not taken

Edwards, A.M.; Isserlin, Ruth; Bader, Gary D.; Frye, Stephen V.; Willson, Timothy M.; Yu, Frank H.

doi:10.1038/470163a

Cited by 365 publications

(349 citation statements)

References 7 publications

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“…As discussed in a recent commentary, there are 'too many roads not taken' 165 . We propose that discovery proteomics has provided candidates that may allow us to understand the disease pathogenesis from different angle, that of CME.…”

Section: Resultsmentioning

confidence: 99%

Hypothesis review: are clathrin-mediated endocytosis and clathrin-dependent membrane and protein trafficking core pathophysiological processes in schizophrenia and bipolar disorder?

et al. 2011

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Clathrin mediated endocytosis (CME) is the best characterized mechanism governing cellular membrane-and protein trafficking. In this hypothesis review, we integrate recent evidence implicating CME and related cellular trafficking mechanisms in the pathophysiology of psychotic disorders such as schizophrenia and bipolar disorder. The evidence includes proteomic and genomic findings implicating proteins and genes of the CME interactome. Additionally, several important candidate genes for schizophrenia, such as dysbindin, are involved in processes closely linked to CME and membrane trafficking. We discuss that key aspects of psychosis neuropathology such as synaptic dysfunction, white matter changes, and aberrant neurodevelopment are all influenced by CME, and that other cellular trafficking mechanisms previously linked to psychoses interact with CME in important ways. Furthermore, many antipsychotic drugs have been shown to affect clathrin-interacting proteins. We propose that the targeted pharmacological manipulation of CME may offer fruitful opportunities for novel treatments of schizophrenia.

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Section: Resultsmentioning

confidence: 99%

Hypothesis review: are clathrin-mediated endocytosis and clathrin-dependent membrane and protein trafficking core pathophysiological processes in schizophrenia and bipolar disorder?

et al. 2011

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“…In their pivotal kinome studies Harlow and Knapp showed that most of the interest is focused to a relatively small set of protein kinases in both the scientific 45 and the patent literature, 46 respectively. As an extension of this work Edwards et al 47 recently found that most protein research focuses on proteins known prior to the sequencing of the human genome. Investigating three classes of proteins with pharmaceutical relevance they found that research groups favoured the most well-known fraction of kinases, ion channels and nuclear receptors.…”

Section: Can We Reach the Maximum Synthetic Output?mentioning

confidence: 99%

Anthropogenic reaction parameters – the missing link between chemical intuition and the available chemical space

2014

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How do skilled synthetic chemists develop such a good intuitive expertise? Why can we only access such a small amount of the available chemical space -both in terms of the reactions used and the chemical scaffolds we make? We argue here that these seemingly unrelated questions have a common root and are strongly interdependent. We performed a comprehensive analysis of organic reaction parameters dating back to 1771 and discovered that there are several anthropogenic factors that limit the reaction parameters and thus the scope of synthetic chemistry. Nevertheless, many of the anthropogenic limitations such as the narrow parameter space and the opportunity of the rapid and clear feedback on the progress of reactions appear to be crucial for the acquisition of valid and reliable chemical intuition. In parallel, however, all of these same factors represent limitations for the exploration of available chemistry space and we argue that these are thus at least partly responsible for limited access to new chemistries. We advocate, therefore, that the present anthropogenic boundaries can be expanded by a more conscious exploration of "off-road" chemistry that would also extend the intuitive knowledge of trained chemists.

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“…This bias parallels the effect seen when predicting gene-disease relationships via MeSHOPs, where the most popular genes are more likely to be linked to diseases, and vice-versa [24]. It is important to be aware of biases and trends in research that may influence the results of text analysis, and to correct for these biases to better direct research efforts [25,26]. …”

Section: Introductionmentioning

confidence: 98%

Compensating for literature annotation bias when predicting novel drug-disease relationships through Medical Subject Heading Over-representation Profile (MeSHOP) similarity

2013

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BackgroundUsing annotations to the articles in MEDLINE®/PubMed®, over six thousand chemical compounds with pharmacological actions have been tracked since 1996. Medical Subject Heading Over-representation Profiles (MeSHOPs) quantitatively leverage the literature associated with biological entities such as diseases or drugs, providing the opportunity to reposition known compounds towards novel disease applications.MethodsA MeSHOP is constructed by counting the number of times each medical subject term is assigned to an entity-related research publication in the MEDLINE database and calculating the significance of the count by comparing against the count of the term in a background set of publications. Based on the expectation that drugs suitable for treatment of a disease (or disease symptom) will have similar annotation properties to the disease, we successfully predict drug-disease associations by comparing MeSHOPs of diseases and drugs.ResultsThe MeSHOP comparison approach delivers an 11% improvement over bibliometric baselines. However, novel drug-disease associations are observed to be biased towards drugs and diseases with more publications. To account for the annotation biases, a correction procedure is introduced and evaluated.ConclusionsBy explicitly accounting for the annotation bias, unexpectedly similar drug-disease pairs are highlighted as candidates for drug repositioning research. MeSHOPs are shown to provide a literature-supported perspective for discovery of new links between drugs and diseases based on pre-existing knowledge.

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Too many roads not taken

Cited by 365 publications

References 7 publications

Hypothesis review: are clathrin-mediated endocytosis and clathrin-dependent membrane and protein trafficking core pathophysiological processes in schizophrenia and bipolar disorder?

Hypothesis review: are clathrin-mediated endocytosis and clathrin-dependent membrane and protein trafficking core pathophysiological processes in schizophrenia and bipolar disorder?

Anthropogenic reaction parameters – the missing link between chemical intuition and the available chemical space

Compensating for literature annotation bias when predicting novel drug-disease relationships through Medical Subject Heading Over-representation Profile (MeSHOP) similarity

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