Recent studies suggest that most cases of myelodysplastic syndrome (MDS) are clonally heterogeneous, with a founding clone and multiple subclones. It is not known whether specific gene mutations ...typically occur in founding clones or subclones. We screened a panel of 94 candidate genes in a cohort of 157 patients with MDS or secondary acute myeloid leukemia (sAML). This included 150 cases with samples obtained at MDS diagnosis and 15 cases with samples obtained at sAML transformation (8 were also analyzed at the MDS stage). We performed whole-genome sequencing (WGS) to define the clonal architecture in eight sAML genomes and identified the range of variant allele frequencies (VAFs) for founding clone mutations. At least one mutation or cytogenetic abnormality was detected in 83% of the 150 MDS patients and 17 genes were significantly mutated (false discovery rate ≤0.05). Individual genes and patient samples displayed a wide range of VAFs for recurrently mutated genes, indicating that no single gene is exclusively mutated in the founding clone. The VAFs of recurrently mutated genes did not fully recapitulate the clonal architecture defined by WGS, suggesting that comprehensive sequencing may be required to accurately assess the clonal status of recurrently mutated genes in MDS.
Throughout the nineteenth century, federal Indian policy oscillated between two extreme positions: assimilation versus isolation. While scholars have often been interested in the impact of past ...federal policy on current levels of economic development among American Indian tribes, none have explicitly examined the influence of federal assimilation policy on long-run economic development. In this paper, I take advantage of tribal-level variation in the application of federal policies to estimate the effect of assimilation on long-run economic performance. To quantify the impact of such policies, I introduce a novel measure of cultural assimilation: the prevalence of traditional indigenous names relative to common American first names. To calculate the distribution of name types, I have gathered the names and locations for all American Indians enumerated in the 1900 United States census. After classifying each name, I calculated the reservation-specific share of non-indigenous names. I estimate the relationship between cultural assimilation in 1900 and per capita income from 1970 through 2020. I find that historical levels of assimilation are consistently associated with higher levels of per capita income in all census years. The results are robust to the inclusion of a variety of cultural and institutional controls and regional fixed effects.
Networks of person-to-person contacts form the substrate along which infectious diseases spread. Most network-based studies of this spread focus on the impact of variations in degree (the number of ...contacts an individual has). However, other effects such as clustering, variations in infectiousness or susceptibility, or variations in closeness of contacts may play a significant role. We develop analytic techniques to predict how these effects alter the growth rate, probability and size of epidemics, and validate the predictions with a realistic social network. We find that (for a given degree distribution and average transmissibility) clustering is the dominant factor controlling the growth rate, heterogeneity in infectiousness is the dominant factor controlling the probability of an epidemic and heterogeneity in susceptibility is the dominant factor controlling the size of an epidemic. Edge weights (measuring closeness or duration of contacts) have impact only if correlations exist between different edges. Combined, these effects can play a minor role in reinforcing one another, with the impact of clustering the largest when the population is maximally heterogeneous or if the closer contacts are also strongly clustered. Our most significant contribution is a systematic way to address clustering in infectious disease models, and our results have a number of implications for the design of interventions.
Upregulation of the immune response may be involved in the pathogenesis of schizophrenia with changes occurring in both peripheral blood and brain tissue. To date, microarray technology has provided ...a limited view of specific inflammatory transcripts in brain perhaps due to sensitivity issues. Here we used SOLiD Next Generation Sequencing to quantify neuroimmune mRNA expression levels in the dorsolateral prefrontal cortex of 20 individuals with schizophrenia and their matched controls. We detected 798 differentially regulated transcripts present in people with schizophrenia compared with controls. Ingenuity pathway analysis identified the inflammatory response as a key change. Using quantitative real-time PCR we confirmed the changes in candidate cytokines and immune modulators, including interleukin (IL)-6, IL-8, IL-1β and SERPINA3. The density of major histocompatibility complex-II-positive cells morphologically resembling microglia was significantly increased in schizophrenia and correlated with IL-1β expression. A group of individuals, most of whom had schizophrenia, were found to have increased inflammatory mRNA expression. In summary, we have demonstrated changes in an inflammatory response pathway that are present in ∼40% of people diagnosed with schizophrenia. This suggests that therapies aimed at immune system attenuation in schizophrenia may be of direct benefit in the brain.
Individuals and institutions seeking to reduce travel-related carbon dioxide (CO
) emissions by changing travel modes need information on the amount of CO
that can be saved by rail travel rather than ...air travel. This study uses flight emissions data from the International Civil Aviation Organization (ICAO) to estimate average per-passenger CO
emissions saved by using rail travel between selected city pairs in the northeastern U.S. Trend lines are developed from the ICAO data for different aircraft types to facilitate comparison with CO
emissions from rail travel. Separate rail emission factors are calculated for portions of Amtrak's system operating electric and diesel locomotives. An adjustment factor is estimated to account for longer rail distances than flight distances. Results show rail travel has generally lower CO
emissions than air travel, with substantially lower emissions for electrified segments of the Amtrak system. At flight distances of over 700 miles, air travel using single-aisle jets can have lower per-passenger CO
emissions compared to diesel-powered rail travel, accounting for the longer distances by rail.
: Savings in per-passenger CO
emissions using rail rather than air travel in the northeastern U.S. Travel by rail in the northeastern U.S. results in lower CO
emissions compared to travel by air between the same city pairs using existing airline and passenger rail infrastructure. Savings are higher for cities connected by electrified rail.
The Myth of Firm Performance Miller, C. Chet; Washburn, Nathan T.; Glick, William H.
Organization science (Providence, R.I.),
05/2013, Volume:
24, Issue:
3
Journal Article
Peer reviewed
Firm performance is one of the most prominent concepts in organizational research. Despite its importance, and despite the many developmental critiques that have appeared over the years, performance ...continues to be a difficult concept to apply in a scientifically rigorous way. After surfacing three potentially viable approaches for conceptualizing performance, we find that most studies are internally inconsistent in their use of these approaches, a situation that creates substantial difficulty in effectively interpreting research. The primary source of inconsistency lies in the use of a generalized abstract conceptualization of performance in theory building (the latent multidimensional approach) coupled with the adoption of one or two narrow aspects of performance in the empirical work (the separate constructs approach). Follow-up analyses designed to determine the best path for resolving these mismatches indicate that our field's heavy use of abstract performance in theorizing is not scientifically grounded and should be replaced with more specific aspects of performance to match existing practices in empirical work. Although this change would profoundly affect the field and would be resisted by many, it offers a concrete path away from indefensible practices. We offer several explanations for current practices but emphasize forces related to institutional theory. From an institutional perspective, it appears that firm performance is treated in a general fashion in many areas of our academic lives because it has been embraced as an instrument of legitimacy rather than as a scientific tool that facilitates dialogue and the accumulation of knowledge. We recommend and begin a conversation designed to highlight the long-run dangers of focusing our attention on an abstract concept of performance and suggest a set of specific steps that could help to move all of us in a new direction as we attempt to enhance the scientific rigor of our field.
A proline to serine substitution at position 56 in the gene encoding vesicle-associated membrane protein-associated protein B (VAPB) causes some dominantly inherited familial forms of motor neuron ...disease including amyotrophic lateral sclerosis (ALS) type-8. VAPB is an integral endoplasmic reticulum (ER) protein whose amino-terminus projects into the cytosol. Overexpression of ALS mutant VAPBP56S disrupts ER structure but the mechanisms by which it induces disease are not properly understood. Here we show that VAPB interacts with the outer mitochondrial membrane protein, protein tyrosine phosphatase-interacting protein 51 (PTPIP51). ER and mitochondria are both stores for intracellular calcium (Ca(2+)) and Ca(2+) exchange between these organelles occurs at regions of ER that are closely apposed to mitochondria. These are termed mitochondria-associated membranes (MAM). We demonstrate that VAPB is a MAM protein and that loss of either VAPB or PTPIP51 perturbs uptake of Ca(2+) by mitochondria following release from ER stores. Finally, we demonstrate that VAPBP56S has altered binding to PTPIP51 and increases Ca(2+) uptake by mitochondria following release from ER stores. Damage to ER, mitochondria and Ca(2+) homeostasis are all seen in ALS and we discuss the implications of our findings in this context.
OBJECTIVE:--To systematically tabulate published and unpublished sources of reliable glycemic index (GI) values. RESEARCH DESIGN AND METHODS--A literature search identified 205 articles published ...between 1981 and 2007. Unpublished data were also included where the data quality could be verified. The data were separated into two lists: the first representing more precise data derived from testing healthy subjects and the second primarily from individuals with impaired glucose metabolism. RESULTS:--The tables, which are available in the online-only appendix, list the GI of over 2,480 individual food items. Dairy products, legumes, and fruits were found to have a low GI. Breads, breakfast cereals, and rice, including whole grain, were available in both high and low GI versions. The correlation coefficient for 20 staple foods tested in both healthy and diabetic subjects was r = 0.94 (P < 0.001). CONCLUSIONS:--These tables improve the quality and quantity of GI data available for research and clinical practice.
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