Negative skill sorting across production chains

Previous literature generally predicts that individuals with higher skills work in industries with longer production chains. However, the opposite skill-sorting pattern, a "negative skill-sorting" phenomenon, is also observed in reality. This paper proposes a possible mechanism by which both cases can happen and shows that negative skill sorting is more likely to occur when the quality of intermediate inputs degrade rapidly (or improves slowly) along the production chain. We empirically confirm our theoretical prediction by using country-industry panel data. The results are robust regardless of estimation method, control variables, and industry coverage. This study has important implications for understanding countries' comparative advantages and development patterns.

Negative responses of highland pines to anthropogenic activities in inland Spain: a palaeoecological perspective

Palaeoecological evidence indicates that highland pines were dominant in extensive areas of the mountains of Central and Northern Iberia during the first half of the Holocene. However, following several millennia of anthropogenic pressure, their natural ranges are now severely reduced. Although pines have been frequently viewed as first-stage successional species responding positively to human disturbance, some recent palaeobotanical work has proposed fire disturbance and human deforestation as the main drivers of this vegetation turnover. To assess the strength of the evidence for this hypothesis and to identify other possible explanations for this scenario, we review the available information on past vegetation change in the mountains of northern inland Iberia. We have chosen data from several sites that offer good chronological control, including palynological records with microscopic charcoal data and sites with plant macro- and megafossil occurrence. We conclude that although the available long-term data are still fragmentary and that new methods are needed for a better understanding of the ecological history of Iberia, fire events and human activities (probably modulated by climate) have triggered the pine demise at different locations and different temporal scales. In addition, all palaeoxylological, palynological and charcoal results obtained so far are fully compatible with a rapid human-induced ecological change that could have caused a range contraction of highland pines in western Iberia.

Negative ternary set-sharing

The Set-Sharing domain has been widely used to infer at compiletime interesting properties of logic programs such as occurs-check reduction, automatic parallelization, and flnite-tree analysis. However, performing abstract uniflcation in this domain requires a closure operation that increases the number of sharing groups exponentially. Much attention has been given to mitigating this key inefflciency in this otherwise very useful domain. In this paper we present a novel approach to Set-Sharing: we define a new representation that leverages the complement (or negative) sharing relationships of the original sharing set, without loss of accuracy. Intuitively, given an abstract state sh\> over the finite set of variables of interest V, its negative representation is p(V) \ shy. Using this encoding during analysis dramatically reduces the number of elements that need to be represented in the abstract states and during abstract uniflcation as the cardinality of the original set grows toward 2 . To further compress the number of elements, we express the set-sharing relationships through a set of ternary strings that compacts the representation by eliminating redundancies among the sharing sets. Our experiments show that our approach can compress the number of relationships, reducing signiflcantly the memory usage and running time of all abstract operations, including abstract uniflcation.

Lateral orbitofrontal cortex involvement in initial negative aesthetic impression formation

It is well established that aesthetic appreciation is related with activity in several different brain regions. The identification of the neural correlates of beauty or liking ratings has been the focus of most prior studies. Not much attention has been directed towards the fact that humans are surrounded by objects that lead them to experience aesthetic indifference or leave them with a negative aesthetic impression. Here we explore the neural substrate of such experiences. Given the neuroimaging techniques that have been used, little is known about the temporal features of such brain activity. By means of magnetoencephalography we registered the moment at which brain activity differed while participants viewed images they considered to be beautiful or not. Results show that the first differential activity appears between 300 and 400 ms after stimulus onset. During this period activity in right lateral orbitofrontal cortex (lOFC) was greater while participants rated visual stimuli as not beautiful than when they rated them as beautiful. We argue that this activity is associated with an initial negative aesthetic impression formation, driven by the relative hedonic value of stimuli regarded as not beautiful. Additionally, our results contribute to the understanding of the nature of the functional roles of the lOFC.

Analysis of Super Imaging Properties of Spherical Geodesic Waveguide Using COMSOL Multyphisics

Negative Refractive Lens (NRL) has shown that an optical system can produce images with details below the classic Abbe diffraction limit using materials of negative dielectric and magnetic constants. Recently, two devices with positive refraction, the Maxwell Fish Eye lens (MFE) (Leonhardt et al 2000) and the Spherical Geodesic Waveguide (SGW)(Minano et all 2011) have been claimed to break the diffraction limit using positive refraction with a different meaning. In these cases, it has been considered the power transmission from a point source to a point receptor, which falls drastically when the receptor is displaced from the focus by a distance much smaller than the wavelength. Moreover, recent analysis of the SGW with defined object and image surfaces, which are both conical sections of the sphere, has shown that the system transmits images bellow diffraction limit. The key assumption is the use of a perfectly absorbing receptor called perfect drain. This receptor is capable to absorb all the radiation without reflection or scattering. Here, it is presented the COMSOL analysis of the SGW using a perfect drain that absorbs perfectly two modes. The design procedure for PD capable to absorb k modes is proposed, as well.

Super-resolution for a point source using positive refraction

Leonhardt demonstrated (2009) that the 2D Maxwell Fish Eye lens (MFE) can focus perfectly 2D Helmholtz waves of arbitrary frequency, i.e., it can transport perfectly an outward (monopole) 2D Helmholtz wave field, generated by a point source, towards a receptor called "perfect drain" (PD) located at the corresponding MFE image point. The PD has the property of absorbing the complete radiation without radiation or scattering and it has been claimed as necessary to obtain super-resolution (SR) in the MFE. However, a prototype using a "drain" different from the PD has shown λ/5 resolution for microwave frequencies (Ma et al, 2010). Recently, the SR properties of a device equivalent to the MFE, called the Spherical Geodesic Waveguide (SGW) (Miñano et al, 2012) have been analyzed. The reported results show resolution up to λ /3000, for the SGW loaded with the perfect drain, and up to λ /500 f for the SGW without perfect drain. The perfect drain was realized as a coaxial probe loaded with properly calculated impedance. The SGW provides SR only in a narrow band of frequencies close to the resonance Schumann frequencies. Here we analyze the SGW loaded with a small "perfect drain region" (González et al, 2011). This drain is designed as a region made of a material with complex permittivity. The comparative results show that there is no significant difference in the SR properties for both perfect drain designs.

Perfect imaging analysis of the spherical geodesic waveguide

Negative Refractive Lens (NRL) has shown that an optical system can produce images with details below the classic Abbe diffraction limit. This optical system transmits the electromagnetic fields, emitted by an object plane, towards an image plane producing the same field distribution in both planes. In particular, a Dirac delta electric field in the object plane is focused without diffraction limit to the Dirac delta electric field in the image plane. Two devices with positive refraction, the Maxwell Fish Eye lens (MFE) and the Spherical Geodesic Waveguide (SGW) have been claimed to break the diffraction limit using positive refraction with a different meaning. In these cases, it has been considered the power transmission from a point source to a point receptor, which falls drastically when the receptor is displaced from the focus by a distance much smaller than the wavelength. Although these systems can detect displacements up to ?/3000, they cannot be compared to the NRL, since the concept of image is different. The SGW deals only with point source and drain, while in the case of the NRL, there is an object and an image surface. Here, it is presented an analysis of the SGW with defined object and image surfaces (both are conical surfaces), similarly as in the case of the NRL. The results show that a Dirac delta electric field on the object surface produces an image below the diffraction limit on the image surface.

Perfect imaging of point sources with positive refraction

The capability of a device called the Spherical Geodesic Waveguide (SGW) to produce images with details below the classic Abbe diffraction limit (super-resolution) is analyzed here. The SGW is an optical system equivalent (by means of Transformation Optics) to the Maxwell Fish Eye (MFE) refractive index distribution. Recently, it has been claimed that the necessary condition to get super-resolution in the MFE and the SGW is the use of a Perfect Point Drain (PPD). The PPD is a punctual receptor placed in the focal point that absorbs the incident wave, without reflection or scattering. A microwave circuit comprising three elements, the SGW, the source and the drain (two coaxial lines loaded with specific impedances) is designed and simulated in COMSOL. The super-resolution properties have been analyzed for different position of the source and drain and for two different load impedances: the PPD and the characteristic line impedance. The results show that in both cases super-resolution occurs only for discrete number of frequencies. Out of these frequencies, the SGW does not show SR in the analysis carried out.

Electrodynamic Tethers For Planetary And De-orbiting Missions

Nuevas aplicaciones tecnológicas y científicas mediante amarras electrodinámicas son analizadas para misiones planetarias. i) Primero, se considera un conjunto de amarras cilíndricas en paralelo (veleros electrosolares) para una misión interplanetaria. Los iones provenientes del viento solar son repelidos por el alto potencial de dichas amarras generando empuje sobre el velero. Para conocer el intercambio de momento que provocan los iones sobre las amarras se ha considerado un modelo de potencial estacionario. Se ha analizado la transferencia orbital de la Tierra a Júpiter siguiendo un método de optimización de trayectoria indirecto. ii) Una vez que el velero se encuentra cerca de Júpiter, se ha considerado el despliegue de una amarra para diferentes objetivos científicos. iia) Una amarra podría ser utilizada para diagnóstico de plasmas, al ser una fuente efectiva de ondas, y también como un generador de auroras artificiales. Una amarra conductora que orbite en la magnetosfera jovial es capaz de producir ondas. Se han analizado las diferentes ondas radiadas por un conductor por el que circula una corriente constante que sigue una órbita polar de alta excentricidad y bajo apoápside, como ocurre en la misión Juno de la NASA. iib) Además, se ha estudiado una misión tentativa que sigue una órbita ecuatorial (LJO) por debajo de los intensos cinturones de radiación. Ambas misiones requiren potencia eléctrica para los sistemas de comunicación e instrumentos científicos. Las amarras pueden generar potencia de manera más eficiente que otros sistemas que utlizan paneles solares o sistemas de potencia de radioisótopos (RPS). La impedancia de radiación es necesaria para determinar la corriente que circula por todo el circuito de la amarra. En un modelo de plasma frío, la radiación ocurre principalmente en los modos de Alfven y magnetosónica rápida, mostrando un elevado índice de refracción. Se ha estudiado la impedancia de radiación en amarras con recubrimiento aislante para los dos modos de radiación y cada una de las misiones. A diferencia del caso ionosférico terrestre, la baja densidad y el intenso campo magnético que aparecen en el entorno de Júpiter consiguen que la girofrecuencia de los electrones sea mucho mayor que la frecuencia del plasma; esto hace que el espectro de potencia para cada modo se modifique substancialmente, aumentando la velocidad de Alfven. Se ha estimado también la impedancia de radiación para amarras sin aislante conductor. En la misión LJO, un vehículo espacial bajando lentamente la altitud de su órbita permitiría estudiar la estructura del campo magnético y composición atmosférica para entender la formación, evolución, y estructura de Júpiter. Adicionalmente, si el contactor (cátodo) se apaga, se dice que la amarra flota eléctricamente, permitiendo emisión de haz de electrones que generan auroras. El continuo apagado y encendido produce pulsos de corriente dando lugar a emisiones de señales, que pueden ser utilizadas para diagnóstico del plasma jovial. En Órbita Baja Jovial, los iones que impactan contra una amarra polarizada negativamente producen electrones secundarios, que, viajando helicoidalmente sobre las líneas de campo magnético de Júpiter, son capaces de alcanzar su atmósfera más alta, y, de esta manera, generar auroras. Se han identificado cuáles son las regiones donde la amarra sería más eficiente para producir auroras. iic) Otra aplicación científica sugerida para la misión LJO es la detección de granos cargados que orbitan cerca de Júpiter. Los electrones de alta energía en este ambiente pueden ser modelados por una distribucción no Maxwelliana conocida como distribución kappa. En escenarios con plasmas complejos, donde los campos eléctricos en Júpiter pueden acelerar las cargas hasta velocidades que superen la velocidad térmica, este tipo de distribuciones son muy útiles. En este caso las colas de las distribuciones de electrones siguen una ley de potencias. Se han estudiado las fluctuaciones de granos cargados para funciones de distribución kappa. iii) La tesis concluye con el análisis para deorbitar satélites con amarras electrodinámicas que siguen una Órbita Baja Terrestre (LEO). Una amarra debe presentar una baja probabilidad de corte por pequeño debris y además debe ser suficientemente ligero para que el cociente entre la masa de la amarra y el satélite sea muy pequeño. En este trabajo se estiman las medidas de la longitud, anchura y espesor que debe tener una amarra para minimizar el producto de la probabilidad de corte por el cociente entre las masas de la amarra y el satélite. Se presentan resultados preliminares del diseño de una amarra con forma de cinta para deorbitar satélites relativamente ligeros como Cryosat y pesados como Envisat. Las misiones espaciales a planetas exteriores y en el ámbito terrestre plantean importantes retos científico-tecnológicos que deben ser abordados y solucionados. Por ello, desde el inicio de la era espacial se han diseñando novedosos métodos propulsivos, sistemas de guiado, navegación y control más robustos, y nuevos materiales para mejorar el rendimiento de los vehículos espaciales (SC). En un gran número de misiones interplanetarias y en todas las misiones a planetas exteriores se han empleado sistemas de radioisótopos (RPS) para generar potencia eléctrica en los vehículos espaciales y en los rovers de exploración. Estos sistemas emplean como fuente de energía el escaso y costoso plutonio-238. La NASA, por medio de un informe de la National Academy of Science (5 de Mayo del 2009), expresó una profunda preocupación por la baja cantidad de plutonio almacenado, insuficiente para desarrollar todas las misiones de exploración planetaria planeadas en el futuro [81, 91]. Esta circustancia ha llevado a dicha Agencia tomar la decisión de limitar el uso de estos sistemas RPS en algunas misiones de especial interés científico y una recomendación de alta prioridad para que el Congreso de los EEUU apruebe el reestablecimiento de la producción de plutonio-238, -son necesarios cerca de 5 kg de este material radiactivo al año-, para salvaguardar las misiones que requieran dichos sistemas de potencia a partir del año 2018. Por otro lado, la Agencia estadounidense ha estado considerando el uso de fuentes de energía alternativa; como la fisión nuclear a través del ambicioso proyecto Prometheus, para llevar a cabo una misión de exploración en el sistema jovial (JIMO). Finalmente, dicha misión fue desestimada por su elevado coste. Recientemente se han estado desarrollando sistemas que consigan energía a través de los recursos naturales que nos aporta el Sol, mediante paneles solares -poco eficientes para misiones a planetas alejados de la luz solar-. En este contexto, la misión JUNO del programa Nuevas Fronteras de la NASA, cuyo lanzamiento fue realizado con éxito en Agosto de 2011, va a ser la primera misión equipada con paneles solares que sobrevolará Júpiter en el 2015 siguiendo una órbita polar. Anteriormente se habían empleado los antes mencionados RPS para las misiones Pioneer 10,11, Voyager 1,2, Ulysses, Cassini-Huygens y Galileo (todas sobrevuelos excepto Galileo). Dicha misión seguirá una órbita elíptica de alta excentricidad con un periápside muy cercano a Júpiter, y apoápside lejano, evitando que los intensos cinturones de radiación puedan dañar los instrumentos de navegación y científicos. Un tether o amarra electrodinámica es capaz de operar como sistema propulsivo o generador de potencia, pero también puede ser considerado como solución científicotecnológica en misiones espaciales tanto en LEO (Órbita Baja Terrestre) como en planetas exteriores. Siguiendo una perspectiva histórica, durante las misiones terrestres TSS-1 (1992) y TSS-1R (1996) se emplearon amarras estandard con recubrimiento aislante en toda su longitud, aplicando como terminal anódico pasivo un colector esférico para captar electrones. En una geometría alternativa, propuesta por J. R. Sanmartín et al. (1993) [93], se consideró dejar la amarra sin recubrimiento aislante (“bare tether”), y sin colector anódico esférico, de forma que recogiera electrones a lo largo del segmento que resulta polarizado positivo, como si se tratara de una sonda de Langmuir de gran longitud. A diferencia de la amarra estandard, el “bare tether” es capaz de recoger electrones a lo largo de una superficie grande ya que este segmento es de varios kilómetros de longitud. Como el radio de la amarra es del orden de la longitud de Debye y pequeño comparado con el radio de Larmor de los electrones, permite una recolección eficiente de electrones en el régimen OML (Orbital Motion Limited) de sondas de Langmuir. La corriente dada por la teoría OML varía en función del perímetro y la longitud. En el caso de una cinta delgada, el perímetro depende de la anchura, que debe ser suficientemente grande para evitar cortes producidos por debris y micrometeoritos, y suficientemente pequeño para que la amarra funcione en dicho régimen [95]. En el experimento espacial TSS-1R mencionado anteriormente, se identificó una recolección de corriente más elevada que la que predecía el modelo teórico de Parker- Murphy, debido posiblemente a que se utilizaba un colector esférico de radio bastante mayor que la longitud de Debye [79]. En el caso de una amarra “bare”, que recoge electrones a lo largo de gran parte de su longitud, se puede producir un fenómeno conocido como atrapamiento adiabático de electrones (adiabatic electron trapping) [25, 40, 60, 73, 74, 97]. En el caso terrestre (LEO) se da la condición mesotérmica en la que la amarra se mueve con una velocidad muy superior a la velocidad térmica de los iones del ambiente y muy inferior a la velocidad térmica de los electrones. J. Laframboise y L. Parker [57] mostraron que, para una función de distribución quasi-isotrópica, la densidad de electrones debe entonces ser necesariamente inferior a la densidad ambiente. Por otra parte, debido a su flujo hipersónico y a la alta polarización positiva de la amarra, la densidad de los iones es mayor que la densidad ambiente en una vasta región de la parte “ram” del flujo, violando la condición de cuasi-neutralidad,-en una región de dimensión mayor que la longitud de Debye-. La solución a esta paradoja podría basarse en el atrapamiento adiabático de electrones ambiente en órbitas acotadas entorno al tether. ABSTRACT New technological and scientific applications by electrodynamic tethers for planetary missions are analyzed: i) A set of cylindrical, parallel tethers (electric solar sail or e-sail) is considered for an interplanetary mission; ions from the solar wind are repelled by the high potential of the tether, providing momentum to the e-sail. An approximated model of a stationary potential for a high solar wind flow is considered. With the force provided by a negative biased tether, an indirect method for the optimization trajectory of an Earth-to-Jupiter orbit transfer is analyzed. ii) The deployment of a tether from the e-sail allows several scientific applications in Jupiter. iia) It might be used as a source of radiative waves for plasma diagnostics and artificial aurora generator. A conductive tether orbiting in the Jovian magnetosphere produces waves. Wave radiation by a conductor carrying a steady current in both a polar, highly eccentric, low perijove orbit, as in NASA’s Juno mission, and an equatorial low Jovian orbit (LJO) mission below the intense radiation belts, is considered. Both missions will need electric power generation for scientific instruments and communication systems. Tethers generate power more efficiently than solar panels or radioisotope power systems (RPS). The radiation impedance is required to determine the current in the overall tether circuit. In a cold plasma model, radiation occurs mainly in the Alfven and fast magnetosonic modes, exhibiting a large refraction index. The radiation impedance of insulated tethers is determined for both modes and either mission. Unlike the Earth ionospheric case, the low-density, highly magnetized Jovian plasma makes the electron gyrofrequency much larger than the plasma frequency; this substantially modifies the power spectrum for either mode by increasing the Alfven velocity. An estimation of the radiation impedance of bare tethers is also considered. iib) In LJO, a spacecraft orbiting in a slow downward spiral under the radiation belts would allow determining magnetic field structure and atmospheric composition for understanding the formation, evolution, and structure of Jupiter. Additionally, if the cathodic contactor is switched off, a tether floats electrically, allowing e-beam emission that generate auroras. On/off switching produces bias/current pulses and signal emission, which might be used for Jovian plasma diagnostics. In LJO, the ions impacting against the negative-biased tether do produce secondary electrons, which racing down Jupiter’s magnetic field lines, reach the upper atmosphere. The energetic electrons there generate auroral effects. Regions where the tether efficiently should produce secondary electrons are analyzed. iic) Other scientific application suggested in LJO is the in-situ detection of charged grains. Charged grains naturally orbit near Jupiter. High-energy electrons in the Jovian ambient may be modeled by the kappa distribution function. In complex plasma scenarios, where the Jovian high electric field may accelerate charges up superthermal velocities, the use of non-Maxwellian distributions should be considered. In these cases, the distribution tails fit well to a power-law dependence for electrons. Fluctuations of the charged grains for non-Mawellian distribution function are here studied. iii) The present thesis is concluded with the analysis for de-orbiting satellites at end of mission by electrodynamic tethers. A de-orbit tether system must present very small tether-to-satellite mass ratio and small probability of a tether cut by small debris too. The present work shows how to select tape dimensions so as to minimize the product of those two magnitudes. Preliminary results of tape-tether design are here discussed to minimize that function. Results for de-orbiting Cryosat and Envisat are also presented.

Negative density dependence and environmental heterogeneity effects on tree ferns across succession in a tropical montane forest.

Although tree ferns are an important component of temperate and tropical forests, very little is known about their ecology. Their peculiar biology (e.g., dispersal by spores and two-phase life cycle) makes it difficult to extrapolate current knowledge on the ecology of other tree species to tree ferns. In this paper, we studied the effects of negative density dependence (NDD) and environmental heterogeneity on populations of two abundant tree fern species, Cyathea caracasana and Alsophila engelii, and how these effects change across a successional gradient. Species patterns harbor information on processes such as competition that can be easily revealed using point pattern analysis techniques. However, its detection may be difficult due to the confounded effects of habitat heterogeneity. Here, we mapped three forest plots along a successional gradient in the montane forests of Southern Ecuador. We employed homogeneous and inhomogeneous K and pair correlation functions to quantify the change in the spatial pattern of different size classes and a case-control design to study associations between juvenile and adult tree ferns. Using spatial estimates of the biomass of four functional tree types (short- and long-lived pioneer, shade- and partial shade-tolerant) as covariates, we fitted heterogeneous Poisson models to the point pattern of juvenile and adult tree ferns and explored the existence of habitat dependencies on these patterns. Our study revealed NDD effects for C. caracasana and strong environmental filtering underlying the pattern of A. engelii. We found that adult and juvenile populations of both species responded differently to habitat heterogeneity and in most cases this heterogeneity was associated with the spatial distribution of biomass of the four functional tree types. These findings show the effectiveness of factoring out environmental heterogeneity to avoid confounding factors when studying NDD and demonstrate the usefulness of covariate maps derived from mapped communities.

Low density lipoprotein receptor-negative mice expressing human apolipoprotein B-100 develop complex atherosclerotic lesions on a chow diet: No accentuation by apolipoprotein(a)

We have generated mice with markedly elevated plasma levels of human low density lipoprotein (LDL) and reduced plasma levels of high density lipoprotein. These mice have no functional LDL receptors [LDLR−/−] and express a human apolipoprotein B-100 (apoB) transgene [Tg(apoB+/+)] with or without an apo(a) transgene [Tg(apoa+/−)]. Twenty animals (10 males and 10 females) of each of the following four genotypes were maintained on a chow diet: (i) LDLR−/−, (ii) LDLR−/−;Tg(apoa+/−), (iii) LDLR−/−;Tg(apoB+/+), and (iv)LDLR−/−;Tg(apoB+/+);Tg(apo+/−). The mice were killed at 6 mo, and the percent area of the aortic intimal surface that stained positive for neutral lipid was quantified. Mean percent areas of lipid staining were not significantly different between the LDLR−/− and LDLR−/−;Tg(apoa+/−) mice (1.0 ± 0.2% vs. 1.4 ± 0.3%). However, the LDLR−/−;Tg(apoB+/+) mice had ≈15-fold greater mean lesion area than the LDLR−/− mice. No significant difference was found in percent lesion area in the LDLR−/−;Tg(apoB+/+) mice whether or not they expressed apo(a) [18.5 ± 2.5%, without lipoprotein(a), Lp(a), vs. 16.0 ± 1.7%, with Lp(a)]. Histochemical analyses of the sections from the proximal aorta of LDLR−/−;Tg(apoB+/+) mice revealed large, complex, lipid-laden atherosclerotic lesions that stained intensely with human apoB-100 antibodies. In mice expressing Lp(a), large amounts of apo(a) protein colocalized with apoB-100 in the lesions. We conclude that LDLR−/−; Tg(apoB+/+) mice exhibit accelerated atherosclerosis on a chow diet and thus provide an excellent animal model in which to study atherosclerosis. We found no evidence that apo(a) increased atherosclerosis in this animal model.

Cross-lineage expression of Ig-β (B29) in thymocytes: Positive and negative gene regulation to establish T cell identity

Developmental commitment involves activation of lineage-specific genes, stabilization of a lineage-specific gene expression program, and permanent inhibition of inappropriate characteristics. To determine how these processes are coordinated in early T cell development, the expression of T and B lineage-specific genes was assessed in staged subsets of immature thymocytes. T lineage characteristics are acquired sequentially, with germ-line T cell antigen receptor-β transcripts detected very early, followed by CD3ɛ and terminal deoxynucleotidyl transferase, then pTα, and finally RAG1. Only RAG1 expression coincides with commitment. Thus, much T lineage gene expression precedes commitment and does not depend on it. Early in the course of commitment to the T lineage, thymocytes lose the ability to develop into B cells. To understand how this occurs, we also examined expression of well defined B lineage-specific genes. Although λ5 and Ig-α are not expressed, the μ0 and Iμ transcripts from the unrearranged IgH locus are expressed early, in distinct patterns, then repressed just before RAG1 expression. By contrast, RNA encoding the B cell receptor component Ig-β was found to be transcribed in all immature thymocyte subpopulations and throughout most thymocyte differentiation. Ig-β expression is down-regulated only during positive selection of CD4+CD8– cells. Thus several key participants in the B cell developmental program are expressed in non-B lineage-committed cells, and one is maintained even through commitment to an alternative lineage, and repressed only after extensive T lineage differentiation. The results show that transcriptional activation of “lymphocyte-specific” genes can occur in uncommitted precursors, and that T lineage commitment is a composite of distinct positive and negative regulatory events.

Retardation of skeletal development and cervical abnormalities in transgenic mice expressing a dominant-negative retinoic acid receptor in chondrogenic cells

Skeletal formation is a fundamental element of body patterning and is strictly regulated both temporally and spatially by a variety of molecules. Among these, retinoic acid (RA) has been shown to be involved in normal skeletal development. However, its pleiotropic effects have caused difficulty in identifying its crucial target cells and molecular mechanisms for each effect. Development of cartilage primordia is an important process in defining the skeletal structures. To address the role of RA in skeletal formation, we have generated mice expressing a dominant-negative retinoic acid receptor (RAR) in chondrogenic cells by using the type II collagen α1 promoter, and we have analyzed their phenotypes. These mice exhibited small cartilage primordia during development and retarded skeletal formation in both embryonic and postnatal periods. They also showed selective degeneration in their cervical vertebrae combined with homeotic transformations, but not in their extremities. The cervical phenotypes are reminiscent of phenotypes involving homeobox genes. We found that the expression of Hoxa-4 was indeed reduced in the cartilage primordia of cervical vertebrae of embryonic day 12.5 embryos. These observations demonstrate that endogenous RA acts directly on chondrogenic cells to promote skeletal growth in both embryonic and growing periods, and it regulates the proper formation of cervical vertebrae. Furthermore, RA apparently specifies the identities of the cervical vertebrae through the regulation of homeobox genes in the chondrogenic cells. Great similarities of the phenotypes between our mice and reported RAR knockout mice revealed that chondrogenic cells are a principal RA target during complex cascades of skeletal development.

NF-κB activation and interleukin 6 production in fibroblasts by estrogen receptor-negative breast cancer cell-derived interleukin 1α

Several angiogenic factors and extracellular matrix-degrading enzymes that promote invasion and metastasis of cancer are produced by stromal fibroblasts that surround cancer cells. The expression of genes that code for some of these proteins is regulated by the transcription factor NF-κB. In this report, we demonstrate that conditioned medium (CM) from estrogen receptor (ER)-negative but not ER-positive breast cancer cells induces NF-κB in fibroblasts. In contrast, CM from both ER-positive and ER-negative breast cancer cells induces NF-κB in macrophages and endothelial cells. NF-κB activation in fibroblasts was accompanied by induction of interleukin 6 (IL-6) and urokinase plasminogen activator (uPA), both of which promote angiogenesis and metastasis. A survey of cytokines known for their ability to induce NF-κB identified IL-1α as the factor responsible for NF-κB activation in fibroblasts. Analysis of primary breast carcinomas revealed the presence of IL-1α transcripts in majority of lymph node-positive breast cancers. These results along with the known role of IL-1α and IL-6 in osteoclast formation provide insight into the mechanism of metastasis and hypercalcemia in advanced breast cancers.

A negative regulator mediates quorum-sensing control of exopolysaccharide production in Pantoea stewartii subsp. stewartii

Classical quorum-sensing (autoinduction) regulation, as exemplified by the lux system of Vibrio fischeri, requires N-acyl homoserine lactone (AHL) signals to stimulate cognate transcriptional activators for the cell density-dependent expression of specific target gene systems. For Pantoea stewartii subsp. stewartii, a bacterial pathogen of sweet corn and maize, the extracellular polysaccharide (EPS) stewartan is a major virulence factor, and its production is controlled by quorum sensing in a population density-dependent manner. Two genes, esaI and esaR, encode essential regulatory proteins for quorum sensing. EsaI is the AHL signal synthase, and EsaR is the cognate gene regulator. esaI, ΔesaR, and ΔesaI-esaR mutations were constructed to establish the regulatory role of EsaR. We report here that strains containing an esaR mutation produce high levels of EPS independently of cell density and in the absence of the AHL signal. Our data indicate that quorum-sensing regulation in P. s. subsp. stewartii, in contrast to most other described systems, uses EsaR to repress EPS synthesis at low cell density, and that derepression requires micromolar amounts of AHL. In addition, derepressed esaR strains, which synthesize EPS constitutively at low cell densities, were significantly less virulent than the wild-type parent. This finding suggests that quorum sensing in P. s. subsp. stewartii may be a mechanism to delay the expression of EPS during the early stages of infection so that it does not interfere with other mechanisms of pathogenesis.