A long-held assumption in entrepreneurship research is that normal (i.e., Gaussian) distributions characterize variables of interest for both theory and practice. We challenge this assumption by ...examining more than 12,000 nascent, young, and hyper-growth firms. Results reveal that variables which play central roles in resource-, cognition-, action-, and environment-based entrepreneurship theories exhibit highly skewed power law distributions, where a few outliers account for a disproportionate amount of the distribution's total output. Our results call for the development of new theory to explain and predict the mechanisms that generate these distributions and the outliers therein. We offer a research agenda, including a description of non-traditional methodological approaches, to answer this call.
•We examine more than 12,000 nascent, young, and hyper-growing firms.•We examine the distribution of key variables in entrepreneurship theories.•Forty eight of 49 variables are power law rather than normally distributed.•Variables should be assumed as power law distributed unless proven otherwise.•Power law distributions challenge and offer opportunities for entrepreneurship research.
Candidate gene and genome-wide association studies (GWAS) have identified genetic variants that modulate risk for human disease; many of these associations require further study to replicate the ...results. Here we report the first large-scale application of the phenome-wide association study (PheWAS) paradigm within electronic medical records (EMRs), an unbiased approach to replication and discovery that interrogates relationships between targeted genotypes and multiple phenotypes. We scanned for associations between 3,144 single-nucleotide polymorphisms (previously implicated by GWAS as mediators of human traits) and 1,358 EMR-derived phenotypes in 13,835 individuals of European ancestry. This PheWAS replicated 66% (51/77) of sufficiently powered prior GWAS associations and revealed 63 potentially pleiotropic associations with P < 4.6 × 10⁻⁶ (false discovery rate < 0.1); the strongest of these novel associations were replicated in an independent cohort (n = 7,406). These findings validate PheWAS as a tool to allow unbiased interrogation across multiple phenotypes in EMR-based cohorts and to enhance analysis of the genomic basis of human disease.
DOCK8 mutations result in an inherited combined immunodeficiency characterized by increased susceptibility to skin and other infections. We show that when DOCK8-deficient T and NK cells migrate ...through confined spaces, they develop cell shape and nuclear deformation abnormalities that do not impair chemotaxis but contribute to a distinct form of catastrophic cell death we term cytothripsis. Such defects arise during lymphocyte migration in collagen-dense tissues when DOCK8, through CDC42 and p21-activated kinase (PAK), is unavailable to coordinate cytoskeletal structures. Cytothripsis of DOCK8-deficient cells prevents the generation of long-lived skin-resident memory CD8 T cells, which in turn impairs control of herpesvirus skin infections. Our results establish that DOCK8-regulated shape integrity of lymphocytes prevents cytothripsis and promotes antiviral immunity in the skin.
We challenge a stream of thought that focuses on drawing what we see as a frivolous contrast between creation and discovery view of entrepreneurship. Its detachment from the empirical world is ...tantamount to theoretical “fetishism”. We see opportunities as emergent structures, with ontologically real components, epistemologically real functional relationships, and requiring real human actions and interactions to come to fruition. This calls for building theory based on the strengths of both discovery and creation assumptions.
ECG QRS duration, a measure of cardiac intraventricular conduction, varies ≈2-fold in individuals without cardiac disease. Slow conduction may promote re-entrant arrhythmias.
We performed a ...genome-wide association study to identify genomic markers of QRS duration in 5272 individuals without cardiac disease selected from electronic medical record algorithms at 5 sites in the Electronic Medical Records and Genomics (eMERGE) network. The most significant loci were evaluated within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium QRS genome-wide association study meta-analysis. Twenty-three single-nucleotide polymorphisms in 5 loci, previously described by CHARGE, were replicated in the eMERGE samples; 18 single-nucleotide polymorphisms were in the chromosome 3 SCN5A and SCN10A loci, where the most significant single-nucleotide polymorphisms were rs1805126 in SCN5A with P=1.2×10(-8) (eMERGE) and P=2.5×10(-20) (CHARGE) and rs6795970 in SCN10A with P=6×10(-6) (eMERGE) and P=5×10(-27) (CHARGE). The other loci were in NFIA, near CDKN1A, and near C6orf204. We then performed phenome-wide association studies on variants in these 5 loci in 13859 European Americans to search for diagnoses associated with these markers. Phenome-wide association study identified atrial fibrillation and cardiac arrhythmias as the most common associated diagnoses with SCN10A and SCN5A variants. SCN10A variants were also associated with subsequent development of atrial fibrillation and arrhythmia in the original 5272 "heart-healthy" study population.
We conclude that DNA biobanks coupled to electronic medical records not only provide a platform for genome-wide association study but also may allow broad interrogation of the longitudinal incidence of disease associated with genetic variants. The phenome-wide association study approach implicated sodium channel variants modulating QRS duration in subjects without cardiac disease as predictors of subsequent arrhythmias.
This research has met the following four objectives within the broader research topic of characterizing and quantifying success in brownfield revitalization: (1) to define 40 total indicators that ...define and determine the success of brownfield redevelopments in four categories: environment-health, finance, livability, and social-economic; (2) to use these indicators to develop a partially automated tool that stakeholders in brownfield redevelopment may use to more easily assess and communicate success (or failures) in these projects; (3) to integrate “green” building as an important aspect of successful brownfield redevelopments; and (4) to develop this tool within the framework of a specific multi-attribute decision method (MADM), the analytical hierarchical process (AHP). Future research should include the operationalization and application of this tool to specific sites.
Currently, no such indicator framework or automated tool is known to exist or be in use. Indicators were chosen because of their ability to reduce data into comprehensible measurements and to systematically measure success in a standardized fashion. Appropriate indicators were selected based on (1) interviews with prominent private developers and national leaders in brownfield redevelopment, (2) a review of the relevant literature, (3) objective hierarchies created in this project, and (4) the ability for each indicator to serve goals in more than one of the four categories described above. These were combined to form the Sustainable Brownfields Redevelopment (SBR) Tool.
A survey was conducted to serve as a preliminary assessment and proposed methodology for judging the validity of the SBR Tool. Professionals in the academic, private, and public sector were asked to provide an evaluation of the management tool and a weighting of the relative importance of each indicator and each of the four categories listed previously. Experts rated the tool at 7.68 out of 10 suggesting that this framework will be useful in evaluating these redevelopments upon completion and in formulating initial site plans and building design.
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Bromodomain-containing protein 9 (BRD9), an epigenetic “reader” of acetylated lysines on post-translationally modified histone proteins, is upregulated in multiple cancer cell lines. ...To assess the functional role of BRD9 in cancer cell lines, we identified a small-molecule inhibitor of the BRD9 bromodomain. Starting from a pyrrolopyridone lead, we used structure-based drug design to identify a potent and highly selective in vitro tool compound 11, (GNE-375). While this compound showed minimal effects in cell viability or gene expression assays, it showed remarkable potency in preventing the emergence of a drug tolerant population in EGFR mutant PC9 cells treated with EGFR inhibitors. Such tolerance has been linked to an altered epigenetic state, and 11 decreased BRD9 binding to chromatin, and this was associated with decreased expression of ALDH1A1, a gene previously shown to be important in drug tolerance. BRD9 inhibitors may therefore show utility in preventing epigenetically-defined drug resistance.
The biological role played by non-BET bromodomains remains poorly understood, and it is therefore imperative to identify potent and highly selective inhibitors to effectively explore the biology of ...individual bromodomain proteins. A ligand-efficient nonselective bromodomain inhibitor was identified from a 6-methyl pyrrolopyridone fragment. Small hydrophobic substituents replacing the N-methyl group were designed directing toward the conserved bromodomain water pocket, and two distinct binding conformations were then observed. The substituents either directly displaced and rearranged the conserved solvent network, as in BRD4(1) and TAF1(2), or induced a narrow hydrophobic channel adjacent to the lipophilic shelf, as in BRD9 and CECR2. The preference of distinct substituents for individual bromodomains provided selectivity handles useful for future lead optimization efforts for selective BRD9, CECR2, and TAF1(2) inhibitors.
Whereas our understanding of corporate entrepreneurship (CE) and corporate entrepreneurship strategy (CES) continues to expand, there has been little theoretical development to support the most ...extensive framework to date: the integrative model of CES as proposed by Ireland et al. (Entrep Theory Pract 33(1): 19-46, 2009). According to the model, CES is built upon the "three foundational elements of an entrepreneurial strategic vision, a pro-entrepreneurship organizational architecture, and entrepreneurial processes and behaviors as exhibited throughout the organization" (Ireland et al. 2009, p. 38). The purpose of this study is to present a broad, overarching theory—complexity science—to examine the key elements and propositions of the CES model. Complexity science—founded on assumptions of interdependent heterogeneous agents and nonlinear interactions, as well as non-deterministic and potentially extreme outcomes—offers established multilevel concepts, theoretical boundary conditions, and methodological guidance for scholars to build and test future studies on CE and CES. Though our complexity perspective draws extensively from conceptual work on complex adaptive systems and agent-based models, we ground our arguments on the empirical ubiquity of power law distributions in all constructs and levels of analysis within the CES model. We conclude with a detailed research agenda, as well as a prescriptive discussion related to theory development, quantitative analysis, and practical applications to guide future studies on CE.
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