HETEROGENEITY IN VIRUS EXPRESSION, TUMORIGENICITY, AND IN VITRO GROWTH PROPERTIES OF DRUG-RESISTANT CLONES OF AN RIII MOUSE MAMMARY TUMOR CELL LINE

Four 8-azaguanine (AG)-resistant and 5-bromodeoxyuridine (BUdR)-resistant clones of a mouse mammary adenocarcinoma cell line, RIII 7387, were developed and analyzed for their tumorigenic properties, in vitro characteristics, and virus expression. These characteristics were analyzed for relationships of any of the cellular parameters and the ability of these lines to produce tumors in syngeneic animals.^ The results of this study demonstrated that the parental line consists of a heterogeneous population of cells. Doubling times, saturation densities, and 2-deoxy-D-glucose uptake varied between sublines. In addition, while all sublines were found to express both B-type and C-type viral antigenic markers, levels of the major B-type and C-type viral proteins varied in the subclones. The sublines also differed markedly in their response to the presence of dexamethasone, glutathione, and insulin in the tissue culture medium.^ Variations in retrovirus expression were convirmed by electron microscopy. Budding and extracellular virus particles were seen in the majority of the cell lines. Virus particles in one of the BUdR-resistant lines, BUD9, were found however, only in inclusions and vacuoles. The AG-resistant subline AGE11 was observed to be rich in intracytoplasmic A particles. The examination of these cell lines for the presence of retroviral RNA-dependent DNA polymerase (RT) activity revealed that some B-type RT activity could be found in the culture fluid of most of the cell lines but that little C-type RT activity could be found suggesting that the C-type virus particles expressed by these RIII clones contain a defective RT.^ Tumor clones also varied in their ability to form tumors in syngeneic RIII mice. Tumor incidence ranged from 50% to 100%. The majority of the tumors regressed within 30 days post infection.^ Statistical analysis indicated that while these clones varied in their characteristics, there was no correlation between the ability of these cell lines to form tumors in syngeneic mice and any of the other characteristics examined.^ These studies have confirmed and extended the growing evidence that tumors, regardless of their natural origin, consist of heterogeneous subpopulations of cells which may vary widely in their in vitro growth behavior, their antigenic expression, and their malignant properties. ^

The genetic basis of thoracic aortic aneurysms and dissections: Genetic heterogeneity and mapping of TAAD1 and TAAD2 loci

Thoracic aortic aneurysms leading to aortic dissections (TAAD) are a major cause of morbidity and mortality in the United States. TAAD is a complication of some known genetic disorders, such as Marfan syndrome and Turner syndrome, but the majority of familial cases are not due to a known genetic syndrome. Previous studies by our group have established that nonsyndromic, familial TAAD is inherited in an autosomal dominant manner with decreased penetrance and variable expression. Using one large family with multiple members with TAAD for the genome wide scan, a major locus for familial TAAD was mapped to 5q13–14 (TAAD1). Nine out of 15 families studied were linked to this locus, establishing that TAAD1 was a major locus, and that there was genetic heterogeneity for the condition. Mapping of TAAD2 locus was accomplished using a single large family with multiple members with TAAD not linked to known loci of aneurysm formation. This established a second novel locus for familial TAAD on 3p24–25 (LOD score of 4.3), termed the TAAD2 locus. Two putative loci with suggestive LOD scores were mapped on 4q and 12q through a genome scan carried out using three families. TAAD phenotype in 12 families did not segregate with known loci, indicating further genetic heterogeneity. An STS-tagged BAC based contig was constructed for 7.8Mb and 25Mb critical interval of TAAD1 and TAAD2 respectively and characterized to identify the defective gene. The hypothesis that the defective genes responsible for the TAAD1 and TAAD2 encoded extracellular matrix (ECM) proteins, the major components of the elastic fiber system in the aortic media was tested. Four genes encoding ECM proteins, versican, thrombospondin-3, CRTL1, on TAAD1 and FBLN2 at TAAD2 were sequenced, but no disease-causing mutations were identified. Studies to identify the defective gene are initiated through the positional candidate gene approach using combination of bioinformatics and expression studies. The identification of the TAAD susceptibility genes will allow for presymptomatic diagnosis of individuals at risk for this life threatening disease. The identification of the molecular defects that contribute to TAAD will also further our understanding of the proteins that provide structural integrity to the aortic wall. ^

Wage Premia in Employment Clusters: Agglomeration Economies or Worker Heterogeneity?

The correlation between wage premia and concentrations of firm activity may arise due to agglomeration economies or workers sorting by unobserved productivity. A worker's residential location is used as a proxy for their unobservable productivity attributes in order to test whether estimated work location wage premia are robust to the inclusion of these controls. Further, in a locational equilibrium, identical workers must receive equivalent compensation so that after controlling for residential location (housing prices) and commutes workers must be paid the same wages and only wage premia arising from unobserved productivity differences should remain unexplained. The models in this paper are estimated using a sample of male workers residing in 33 large metropolitan areas drawn from the 5% Public Use Microdata Sample (PUMS) from the 2000 U.S. Decennial Census. We find that wages are higher when an individual works in a location that has more workers or a greater density of workers. These agglomeration effects are robust to the inclusion of residential location controls and disappear with the inclusion of commute time suggesting that the effects are not caused by unobserved differences in worker productivity. Extended model specifications suggest that wages increase with the education level of nearby workers and the concentration of workers in an individual's own industry or occupation.

Tumor heterogeneity dictates sensitivity to gefitinib (Iressa(TM)/ZD1839) in solid tumor models

The epidermal growth factor receptor (EGFR) and its ligands are overexpressed in many human tumors, including bladder and pancreas, correlating with a more aggressive tumor phenotype and poor patient prognosis. We initiated the present study to characterize the heterogeneity of gefitinib responsiveness in a panel of human bladder and pancreatic cancer cell lines in order to identify the biological characteristics of EGFR-dependent proliferation that could be used to prospectively identify drug-sensitive tumors. A second objective was to elucidate how to best exploit these results by utilizing gefitinib in combination therapy. To these ends, we examined the effects of the EGFR antagonist gefitinib on proliferation and apoptosis in a panel of 18 human bladder cancer cell lines and 9 human pancreatic cancer cell lines. Our data confirmed the existence of marked heterogeneity in Iressa responsiveness with less than half of the cell lines displaying significant growth inhibition by clinically relevant concentrations of the drug. Gefitinib responsiveness was found to be p27 kip1 dependent as DNA synthesis was restored following exposure to p27siRNA. Unfortunately, Iressa responsiveness was not closely linked to surface EGFR or TGF-α expression in the bladder cancer cells, however, cellular TGF-α expression correlated directly with Iressa sensitivity in the pancreatic cancer cell lines. These findings provide the potential for prospectively identifying patients with drug-sensitive tumors. ^ Further studies aimed at exploiting gefitinib-mediated cell cycle effects led us to investigate if gefitinib-mediated TRAIL sensitization correlated with increased p27kip1 accumulation. We observed that increased TRAIL sensitivity following gefitinib exposure was not dependent on p27 kip1 expression. Additional studies initiated to examine the role(s) of Akt and Erk signaling demonstrated that exposure to PI3K or MEK inhibitors significantly enhanced TRAIL-induced apoptosis at concentrations that block target phosphorylation. Furthermore, combinations of TRAIL and the PI3K or MEK inhibitors increased procaspase-8 processing above levels observed with TRAIL alone, indicating that the effects were exerted at the level of caspase-8 activation, considered the earliest step in the TRAIL pathway. ^

The epidemiology of left ventricular outflow tract obstruction defects in Texas, 2002-2008: An update and assessment of effect heterogeneity

Left ventricular outflow tract (LVOT) defects are an important group of congenital heart defects (CHDs) because of their associated mortality and long-term complications. LVOT defects include aortic valve stenosis (AVS), coarctation of aorta (CoA), and hypoplastic left heart syndrome (HLHS). Despite their clinical significance, their etiology is not completely understood. Even though the individual component phenotypes (AVS, CoA, and HLHS) may have different etiologies, they are often "lumped" together in epidemiological studies. Though "lumping" of component phenotypes may improve the power to detect associations, it may also lead to ambiguous findings if these defects are etiologically distinct. This is due to potential for effect heterogeneity across component phenotypes. ^ This study had two aims: (1) to identify the association between various risk factors and both the component (i.e., split) and composite (i.e., lumped) LVOT phenotypes, and (2) to assess the effect heterogeneity of risk factors across component phenotypes of LVOT defects. ^ This study was a secondary data analysis. Primary data were obtained from the Texas Birth Defect Registry (TBDR). TBDR uses an active surveillance method to ascertain birth defects in Texas. All cases of non complex LVOT defects which met our inclusion criteria during the period of 2002–2008 were included in the study. The comparison groups included all unaffected live births for the same period (2002–2008). Data from vital statistics were used to evaluate associations. Statistical associations between selected risk factors and LVOT defects was determined by calculating crude and adjusted prevalence ratio using Poisson regression analysis. Effect heterogeneity was evaluated using polytomous logistic regression. ^ There were a total of 2,353 cases of LVOT defects among 2,730,035 live births during the study period. There were a total of 1,311 definite cases of non-complex LVOT defects for analysis after excluding "complex" cardiac cases and cases associated with syndromes (n=168). Among infant characteristics, males were at a significantly higher risk of developing LVOT defects compared to females. Among maternal characteristics, significant associations were seen with maternal age > 40 years (compared to maternal age 20–24 years) and maternal residence in Texas-Mexico border (compared to non-border residence). Among birth characteristics, significant associations were seen with preterm birth and small for gestation age LVOT defects. ^ When evaluating effect heterogeneity, the following variables had significantly different effects among the component LVOT defect phenotypes: infant sex, plurality, maternal age, maternal race/ethnicity, and Texas-Mexico border residence. ^ This study found significant associations between various demographic factors and LVOT defects. While many findings from this study were consistent with results from previous studies, we also identified new factors associated with LVOT defects. Additionally, this study was the first to assess effect heterogeneity across LVOT defect component phenotypes. These findings contribute to a growing body of literature on characteristics associated with LVOT defects. ^

Spatial compartmentalization of free radical formation and mitochondrial heterogeneity in bivalve gills revealed by live-imaging techniques, supplementary material

Live-imaging techniques (LIT) utilize target-specific fluorescent dyes to visualize biochemical processes using confocal and multiphoton scanning microscopy, which are increasingly employed as non-invasive approach to physiological in-vivo and ex-vivo studies. Here we report application of LIT to bivalve gills for ex-vivo analysis of gill physiology and mapping of reactive oxygen (ROS) and nitrogen (RNS) species formation in the living tissue. Our results indicate that H2O2, HOO. and ONOO- radicals (assessed through C-H2DFFDA staining) are mainly formed within the blood sinus of the filaments and are likely to be produced by hemocytes as defense against invading pathogens. The oxidative damage in these areas is controlled by enhanced CAT (catalase) activities recorded within the filaments. The outermost areas of the ciliated epithelial cells composing the filaments, concentrated the highest mitochondrial densities (MTK Deep Red 633 staining) and the most acidic pH values (as observed with ageladine-a). These mitochondria have low (depolarized) membrane potentials (D psi m) (JC-1 staining), suggesting that the high amounts of ATP required for ciliary beating may be in part produced by non-mitochondrial mechanisms, such as the enzymatic activity of an ATP-regenerating kinase. Nitric oxide (NO, DAF-2DA staining) produced in the region of the peripheral mitochondria may have an effect on mitochondrial electron transport and possibly cause the low membrane potential. High DAF-2DA staining was moreover observed in the muscle cells composing the wall of the blood vessels where NO may be involved in regulating blood vessel diameter. On the ventral bend of the gills, subepithelial mucus glands (SMG) contain large mucous vacuoles showing higher fluorescence intensities for O2.- (DHE staining) than the rest of the tissue. Given the antimicrobial properties of superoxide, release of O2.- into the mucus may help to avoid the development of microbial biofilms on the gill surface. However, cells of the ventral bends are paying a price for this antimicrobial protection, since they show significantly higher oxidative damage, according to the antioxidant enzyme activities and the carbonyl levels, than the rest of the gill tissue. This study provides the first evidence that one single epithelial cell may contain mitochondria with significantly different membrane potentials. Furthermore, we provide new insight into ROS and RNS formation in ex-vivo gill tissues which opens new perspectives for unraveling the different ecophysiological roles of ROS and RNS in multifunctional organs such as gills.

Complex Vertical FDI and Firm Heterogeneity: Evidence from East Asia

In this paper we statistically test the validity of the mechanics of complex VFDI in Japanese machinery FDI to East Asia; we do this by estimating a multiple-spatial lag model. From the theoretical point of view, in complex VFDI, the production activity of affiliates in a given country is positively related to that in neighboring countries which have large differences in factor prices with the given country. Our empirical results show that such mechanics of complex VFDI work in Japanese FDI to East Asia, and that they work more strongly in the MNEs with higher productivity. These results have an important implication for the policies of developing countries in attracting FDI.

Export platform FDI and firm heterogeneity

This paper investigates theoretically and empirically firms' productivity ranking among traditional horizontal foreign direct investment (HFDI), pure platform FDI (PFDI), and complex platform FDI (CFDI). Using data on Japanese outward FDI, we define firms conducting HFDI or PFDI as those Japanese firms that maintain production affiliates only in the U.S. or Mexico, respectively. The firms for CFDI are defined as having production affiliates in both the U.S. and Mexico. The theoretical illustration shows that the CFDI firms should have the highest productivity when trade costs between the U.S. and Mexico are low. By carefully disentangling firms' self-selection effects from learning-by-investing effects, we find some evidence consistent with this hypothesis for a period of relatively low trade costs. Our results indicate the importance of trade costs in developing countries with neighboring markets in attracting foreign investment by highly productive multinational firms.

Stability of complementarity between Japanese FDI and import of intermediate goods : agglomeration effects and parent-firm heterogeneity

This paper examines the duration of intermediate goods imports and its determinants for Japanese affiliates in China. Our estimations, using a unique parent-affiliate-transaction matched panel dataset for a discrete-time hazard model over the 2000–2006 period, reveal that products with a higher upstreamness index, differentiated goods, and goods traded under processing trade are less likely to be substituted with local procurement. Firms located in more agglomerated regions with more foreign affiliates tend to shorten the duration of imports from the home country. For parent-firm characteristics, multinational enterprises that have many foreign affiliates or longer foreign production experience import intermediate goods for a longer duration.

How does firm heterogeneity information impact the estimation of embodied carbon emissions in Chinese exports?

Using an augmented Chinese input–output table in which information about firm ownership and type of traded goods are explicitly reported, we show that ignoring firm heterogeneity causes embodied CO2 emissions in Chinese exports to be overestimated by 20% at the national level, with huge differences at the sector level, for 2007. This is because different types of firm that are allocated to the same sector of the conventional Chinese input–output table vary greatly in terms of market share, production technology and carbon intensity. This overestimation of export-related carbon emissions would be even higher if it were not for the fact that 80% of CO2 emissions embodied in exports of foreign-owned firms are, in fact, emitted by Chinese-owned firms upstream of the supply chain. The main reason is that the largest CO2 emitter, the electricity sector located upstream in Chinese domestic supply chains, is strongly dominated by Chinese-owned firms with very high carbon intensity.

Dealing with Semantic Heterogeneity Issues on the Web

The Semantic Web is an extension of the traditional Web in which meaning of information is well defined, thus allowing a better interaction between people and computers. To accomplish its goals, mechanisms are required to make explicit the semantics of Web resources, to be automatically processed by software agents (this semantics being described by means of online ontologies). Nevertheless, issues arise caused by the semantic heterogeneity that naturally happens on the Web, namely redundancy and ambiguity. For tackling these issues, we present an approach to discover and represent, in a non-redundant way, the intended meaning of words in Web applications, while taking into account the (often unstructured) context in which they appear. To that end, we have developed novel ontology matching, clustering, and disambiguation techniques. Our work is intended to help bridge the gap between syntax and semantics for the Semantic Web construction

The Risk of Using the Q Heterogeneity Estimator for Software Engineering Experiments

All meta-analyses should include a heterogeneity analysis. Even so, it is not easy to decide whether a set of studies are homogeneous or heterogeneous because of the low statistical power of the statistics used (usually the Q test). Objective: Determine a set of rules enabling SE researchers to find out, based on the characteristics of the experiments to be aggregated, whether or not it is feasible to accurately detect heterogeneity. Method: Evaluate the statistical power of heterogeneity detection methods using a Monte Carlo simulation process. Results: The Q test is not powerful when the meta-analysis contains up to a total of about 200 experimental subjects and the effect size difference is less than 1. Conclusions: The Q test cannot be used as a decision-making criterion for meta-analysis in small sample settings like SE. Random effects models should be used instead of fixed effects models. Caution should be exercised when applying Q test-mediated decomposition into subgroups.

Semantic Heterogeneity Issues on the Web

The Semantic Web is an extension of the traditional Web in which meaning of information is well defined, thus allowing a better interaction between people and computers. To accomplish its goals, mechanisms are required to make explicit the semantics of Web resources, to be automatically processed by software agents (this semantics being described by means of online ontologies). Nevertheless, issues arise caused by the semantic heterogeneity that naturally happens on the Web, namely redundancy and ambiguity. For tackling these issues, we present an approach to discover and represent, in a non-redundant way, the intended meaning of words in Web applications, while taking into account the (often unstructured) context in which they appear. To that end, we have developed novel ontology matching, clustering, and disambiguation techniques. Our work is intended to help bridge the gap between syntax and semantics for the Semantic Web construction.

Flexibility, innovation and sustainability in business models as determinants of firm performance heterogeneity.

La comprensión actual de la heterogeneidad de las empresas académico rendimiento en el entorno entra industria necesita un mayor desarrollo. Gestión estratégica y el discurso sobre la literatura empresarial necesita mayor explicación de por qué los modelos de negocio aparentemente similares en el mismo sector actúan de forma diferente. También qué factores del entorno sectorial y operativo determina el surgimiento y funcionamiento de los modelos de negocio sostenibles e innovadoras permanecen sin explorar. Un marco se conceptualiza acompañado de estudios de caso sobre la compañía aérea y las industrias de energía renovable. El estudio lleva a una visión basada en los recursos de los modelos de negocio que las empresas alcancen posiciones heterogéneas de recursos. Una explicación para la heterogeneidad firme desempeño que se busca por intermediación conocimiento que genera valor a partir de la utilización eficaz de los recursos de conocimientos adquiridos a entornos entra y inter-empresa. Un marco para la aparición de nuevos modelos de negocios verdes se conceptualiza y deducciones se obtienen mediante un estudio de caso sobre la base de la industria de biocombustibles de energías renovables para explicar la dinámica de los mercados verdes y cómo se puede crear valor sostenible y capturó e innovadora de los modelos de negocios verdes. El marco desarrollado proporciona una visión cíclica de la flexibilidad del modelo de negocio en la que se propaga la acumulación de recursos basada en el conocimiento del modelo de negocio a través de los ambientes dentro y inter-empresa. Estrategias de conocimiento de corretaje del resultado ambientes inter e dentro-firma en un mejor desempeño del modelo de negocio. La flexibilidad del modelo de negocio que adquiere está determinada por la eficiencia con la acumulación de recursos está alineado con su ambiente externo. Las características de la que el modelo de negocio alcanza ventajas competitivas, como la innovación y la flexibilidad se atribuyen a la heterogeneidad de los recursos. La investigación se extiende a la literatura orientación de servicio al conceptualizar y medir la orientación a servicios como un requisito clave para la innovación del modelo de negocio, mientras que aboga por la necesidad de identificar correctamente las competencias básicas de la empresa, especialmente relevante en el contexto de la empresa orientada a los servicios, donde la creación de valor requiere recursos y la prestación eficiente de los servicios. La investigación trata de llegar a una descripción de los modelos de negocio sostenibles verdes y argumenta que la innovación, la flexibilidad y la sostenibilidad son los tres habilitadores básicos de los cuales el concepto de modelo de negocio verde puede evolucionar la explotación de nuevos mecanismos de mercado y los mercados para crear y capturar valor en el mantenimiento de su innovadora ambiente externo. La investigación integra efectivamente los conceptos de corretaje de conocimientos y modelos de negocio a partir de un recurso basado en la acumulación de vista y al mismo tiempo llega a la heterogeneidad rendimiento de los modelos de negocio aparentemente similares dentro de la misma industria. La investigación indica cómo se producen perturbaciones del mercado en una industria como resultado de modelos de negocio innovador y flexible, y cómo los nuevos modelos de negocio evolucionan en base a estos trastornos. Avanza la comprensión de cómo la estrategia de núcleo competencia y la innovación del modelo de negocio construcciones se comportan en el esfuerzo de la empresa de servicios para obtener una ventaja competitiva sostenible. Los resultados tienen implicaciones en el rendimiento de las empresas que empiezan sin recursos distintos de los suyos, o que utilizan un modelo de negocio imitado, para lograr un mejor rendimiento a través de la evolución del modelo de negocio alineado con las exitosas estrategias de conocimiento de corretaje. Dicho marco puede permitir a las empresas a evaluar y elegir un modelo de negocio basado en la innovación, la flexibilidad, la sostenibilidad y las opciones para el cambio. La investigación se suma a la literatura acumulación de recursos, explicando cómo los recursos pueden ser efectivamente adquirida para crear valor. La investigación también se suma a la literatura empresarial verde, explicando cómo las empresas crear y capturar valor en los nuevos mecanismos dinámicos de mercado.

Impact of knowledge brokering on performance heterogeneity among business models

Purpose – The strategic management literature lacks a comprehensive explanation as to why seemingly similar business models in the same industry perform differently. This paper strives to explain this phenomenon. Design/methodology/approach – The model is conceptualized and accompanied by a case study on the airline industry to explain knowledge brokerage that creates value from the effective utilization of knowledge resources acquired from intra- and inter-firm environments. Findings – The model explains a cyclical view of business model flexibility in which the knowledge-based resource accumulation of the business model is spread across the intra- and inter-firm environments. Knowledge brokerage strategies from the inter- and intra-firm environments result in improved performance of the business model. The flexibility that the business model acquires is determined by how efficiently resource accumulation is aligned with its external environment. Originality/value – The paper effectively integrates the concepts of knowledge brokerage and business models from a resource accumulation-based view and simultaneously arrives at the performance heterogeneity of seemingly similar business models within the same industry. It has performance implications for firms that start out without any distinct resources of their own, or that use an imitated business model, to attain better performance through business model evolution aligned with successful knowledge brokerage strategies. It adds to the resource accumulation literature by explaining how resources can be effectively acquired to create value.