Age-dependent visual exploration during simulated day- and night driving on a motorway: a cross-sectional study

BACKGROUND: Central and peripheral vision is needed for object detection. Previous research has shown that visual target detection is affected by age. In addition, light conditions also influence visual exploration. The aim of the study was to investigate the effects of age and different light conditions on visual exploration behavior and on driving performance during simulated driving. METHODS: A fixed-base simulator with 180 degree field of view was used to simulate a motorway route under daylight and night conditions to test 29 young subjects (25-40 years) and 27 older subjects (65-78 years). Drivers' eye fixations were analyzed and assigned to regions of interests (ROI) such as street, road signs, car ahead, environment, rear view mirror, side mirror left, side mirror right, incoming car, parked car, road repair. In addition, lane-keeping and driving speed were analyzed as a measure of driving performance. RESULTS: Older drivers had longer fixations on the task relevant ROI, but had a lower frequency of checking mirrors when compared to younger drivers. In both age groups, night driving led to a less fixations on the mirror. At the performance level, older drivers showed more variation in driving speed and lane-keeping behavior, which was especially prominent at night. In younger drivers, night driving had no impact on driving speed or lane-keeping behavior. CONCLUSIONS: Older drivers' visual exploration behavior are more fixed on the task relevant ROI, especially at night, when driving performance becomes more heterogeneous than in younger drivers.

Magnitude-frequency aspects of alpine debris flows

Based on historic documents the event history for 17 mountain torrents in the Swiss Alps was evaluated. Four classes could be determined for the recurrence interval of the debris flow events. The magnitude is not necessarily dependent on the recurrence interval. The characteristics of the catchment basin (disposition) are mainly controlling the magnitude. In order to evaluate the effects of climatic change on the debris flow activity, knowledge about the magnitude and the frequency are necessary.

Duration-dependent influence of dynamic torsion on the intervertebral disc: an intact disc organ culture study.

PURPOSE Mechanical loading is an important parameter that alters the homeostasis of the intervertebral disc (IVD). Studies have demonstrated the role of compression in altering the cellular metabolism, anabolic and catabolic events of the disc, but little is known how complex loading such as torsion-compression affects the IVD cell metabolism and matrix homeostasis. Studying how the duration of torsion affects disc matrix turnover could provide guidelines to prevent overuse injury to the disc and suggest possible beneficial effect of torsion. The aim of the study was to evaluate the biological response of the IVD to different durations of torsional loading. METHODS Intact bovine caudal IVD were isolated for organ culture in a bioreactor. Different daily durations of torsion were applied over 7 days at a physiological magnitude (±2°) in combination with 0.2 MPa compression, at a frequency of 1 Hz. RESULTS Nucleus pulpous (NP) cell viability and total disc volume decreased with 8 h of torsion-compression per day. Gene expression analysis suggested a down-regulated MMP13 with increased time of torsion. 1 and 4 h per day torsion-compression tended to increase the glycosaminoglycans/hydroxyproline ratio in the NP tissue group. CONCLUSIONS Our result suggests that load duration thresholds exist in both torsion and compression with an optimal load duration capable of promoting matrix synthesis and overloading can be harmful to disc cells. Future research is required to evaluate the specific mechanisms for these observed effects.

Global diversity, population stratification and selection of human copy number variation

In order to explore the diversity and selective signatures of duplication and deletion human copy number variants (CNVs), we sequenced 236 individuals from 125 distinct human populations. We observed that duplications exhibit fundamentally different population genetic and selective signatures than deletions and are more likely to be stratified between human populations. Through reconstruction of the ancestral human genome, we identify megabases of DNA lost in different human lineages and pinpoint large duplications that introgressed from the extinct Denisova lineage now found at high frequency exclusively in Oceanic populations. We find that the proportion of CNV base pairs to single nucleotide variant base pairs is greater among non-Africans than it is among African populations, but we conclude that this difference is likely due to unique aspects of non-African population history as opposed to differences in CNV load.

IL-33 promotes an innate immune pathway of intestinal tissue protection dependent on amphiregulin-EGFR interactions

The barrier surfaces of the skin, lung, and intestine are constantly exposed to environmental stimuli that can result in inflammation and tissue damage. Interleukin (IL)-33-dependent group 2 innate lymphoid cells (ILC2s) are enriched at barrier surfaces and have been implicated in promoting inflammation; however, the mechanisms underlying the tissue-protective roles of IL-33 or ILC2s at surfaces such as the intestine remain poorly defined. Here we demonstrate that, following activation with IL-33, expression of the growth factor amphiregulin (AREG) is a dominant functional signature of gut-associated ILC2s. In the context of a murine model of intestinal damage and inflammation, the frequency and number of AREG-expressing ILC2s increases following intestinal injury and genetic disruption of the endogenous AREG-epidermal growth factor receptor (EGFR) pathway exacerbated disease. Administration of exogenous AREG limited intestinal inflammation and decreased disease severity in both lymphocyte-sufficient and lymphocyte-deficient mice, revealing a previously unrecognized innate immune mechanism of intestinal tissue protection. Furthermore, treatment with IL-33 or transfer of ILC2s ameliorated intestinal disease severity in an AREG-dependent manner. Collectively, these data reveal a critical feedback loop in which cytokine cues from damaged epithelia activate innate immune cells to express growth factors essential for ILC-dependent restoration of epithelial barrier function and maintenance of tissue homeostasis.

7000-year human legacy of elevation-dependent European fire regimes

Variability in fire regime at the continental scale has primarily been attributed to climate change, often overshadowing the widely potential impact of human activities. However, human ignition modifies the rhythm of fire episodes occurrence (fire frequency), whereas land use alters vegetation composition and fuel load, and thus the amount of biomass burned. It is unclear, however, whether and how humans have exercised a significant influence over fire regimes at continental and millennial scales. Based on sedimentary charcoal records, we use new alternative estimate of fire frequency and biomass burned for the last 16000 years (here after 16 ky) that we evaluate with outputs from climate, vegetation, land use and population models. We find that pronounced regional-scale land use changes in southern Europe at the beginning of the Neolithic (8–6 ky), during the Bronze Age (5–4 ky) and the medieval period (1 ky) caused a doubling of fire frequency compared to the Holocene average (the last 11.5 ky). Despite anthropogenic influences, southern European biomass burned decreased from 7 ky, which is in line both with changes in orbital parameters leading climate cooling and also reductions in biomass availability because of land use. Our study underscores the role of elevation-dependent parameters, and particularly biomass and land management, as major drivers of fire regime variability. Results attest a determinant anthropogenic driving-force on fire regime and a decrease in fire-carbon emissions since 7 ky in Southern Europe.

Measurements of velocity-dependent and slip-dependent frictional strength in laboratory friction experiments on natural samples from IODP Expedition 316 and ODP Hole 190-1174B

Slowslip forms part of the spectrum of fault behaviour between stable creep and destructive earthquakes. Slow slip occurs near the boundaries of large earthquake rupture zones and may sometimes trigger fast earthquakes. It is thought to occur in faults comprised of rocks that strengthen under fast slip rates, preventing rupture as a normal earthquake, or on faults that have elevated pore-fluid pressures. However, the processes that control slow rupture and the relationship between slow and normal earthquakes are enigmatic. Here we use laboratory experiments to simulate faulting in natural rock samples taken from shallow parts of the Nankai subduction zone, Japan, where very low-frequency earthquakes - a form of slow slip - have been observed.We find that the fault rocks exhibit decreasing strength over millimetre-scale slip distances rather than weakening due to increasing velocity. However, the sizes of the slip nucleation patches in our laboratory simulations are similar to those expected for the very lowfrequency earthquakes observed in Nankai. We therefore suggest that this type of fault-weakening behaviour may generate slow earthquakes. Owing to the similarity between the expected behaviour of slow earthquakes based on our data, and that of normal earthquakes during nucleation, we suggest that some types of slow slip may represent prematurely arrested earthquakes.

Haemolymph inorganic ion composition, physiology and behaviour dependent on temperature and ambient magnesium concentration in early life history stages of Paralomis granulosa (Decapoda, Anomura, Lithodidae)

Marine brachyuran and anomuran crustaceans are completely absent from the extremely cold (-1.8 °C) Antarctic continental shelf, but caridean shrimps are abundant. This has at least partly been attributed to low capacities for magnesium excretion in brachyuran and anomuran lithodid crabs ([Mg2+]HL = 20-50 mmol/L) compared to caridean shrimp species ([Mg2+]HL = 5-12 mmol/L). Magnesium has an anaesthetizing effect and reduces cold tolerance and activity of adult brachyuran crabs. We investigated whether the capacity for magnesium regulation is a factor that influences temperature-dependent activity of early ontogenetic stages of the Sub-Antarctic lithodid crab Paralomis granulosa. Ion composition (Na+, Mg2+, Ca2+, Cl-, [SO4]2-) was measured in haemolymph withdrawn from larval stages, the first and second juvenile instars (crabs I and II) and adult males and females. Magnesium excretion improved during ontogeny, but haemolymph sulphate concentration was lowest in the zoeal stages. Neither haemolymph magnesium concentrations nor Ca2+:Mg2+ ratios paralleled activity levels of the life stages. Long-term (3 week) cold exposure of crab I to 1 °C caused a significant rise of haemolymph sulphate concentration and a decrease in magnesium and calcium concentrations compared to control temperature (9 °C). Spontaneous swimming activity of the zoeal stages was determined at 1, 4 and 9 °C in natural sea water (NSW, [Mg2+] = 51 mmol/L) and in sea water enriched with magnesium (NSW + Mg2+, [Mg2+] = 97 mmol/L). It declined significantly with temperature but only insignificantly with increased magnesium concentration. Spontaneous velocities were low, reflecting the demersal life style of the zoeae. Heart rate, scaphognathite beat rate and forced swimming activity (maxilliped beat rate, zoea I) or antennule beat rate (crab I) were investigated in response to acute temperature change (9, 6, 3, 1, -1 °C) in NSW or NSW + Mg2+. High magnesium concentration reduced heart rates in both stages. The temperature-frequency curve of the maxilliped beat (maximum: 9.6 beats/s at 6.6 °C in NSW) of zoea I was depressed and shifted towards warmer temperatures by 2 °C in NSW + Mg2+, but antennule beat rate of crab I was not affected. Magnesium may therefore influence cold tolerance of highly active larvae, but it remains questionable whether the slow-moving lithodid crabs with demersal larvae would benefit from an enhanced magnesium excretion in nature.

Haemolymph inorganic ion composition, physiology and behaviour dependent on temperature and magnesium in adult Paralomis granulosa (Decapoda, Anomura, Lithodidae)

A low capacity for regulation of extracellular Mg2+ has been proposed to exclude reptant marine decapod crustaceans from temperatures below 0°C and thus to exclude them from the high Antarctic. To test this hypothesis and to elaborate the underlying mechanisms in the most cold-tolerant reptant decapod family of the sub-Antarctic, the Lithodidae, thermal tolerance was determined in the crab Paralomis granulosa (Decapoda, Anomura, Lithodidae) using an acute stepwise temperature protocol (-1°, 1°, 4°, 7°, 10°, and 13°C). Arterial and venous oxygen partial pressures (Po2) in hemolymph, heartbeat and ventilation beat frequencies, and hemolymph cation composition were measured at rest and after a forced activity (righting) trial. Scopes for heartbeat and ventilation beat frequencies and intermittent heartbeat and scaphognathite beat rates at rest were evaluated. Hemolymph [Mg2+] was experimentally reduced from 30 mmol/L to a level naturally observed in Antarctic caridean shrimps (12 mmol/L) to investigate whether the animals remain more active and tolerant to cold (-1°, 1°, and 4°C). In natural seawater, righting speed was significantly slower at -1° and 13°C, compared with acclimation temperature (4°C). Arterial and venous hemolymph Po2 increased in response to cooling even though heartbeat and ventilation beat frequencies as well as scopes decreased. At rest, ionic composition of the hemolymph was not affected by temperature. Activity induced a significant increase in hemolymph [K+] at -1° and 1°C. Reduction of hemolymph [Mg2+] did not result in an increase in activity, an increase in heartbeat and ventilation beat frequencies, or a shift in thermal tolerance to lower temperatures. In conclusion, oxygen delivery in this cold-water crustacean was not acutely limiting cold tolerance, and animals may have been constrained more by their functional capacity and motility. In contrast to earlier findings in temperate and subpolar brachyuran crabs, these constraints remained insensitive to changing Mg2+ levels.

Moonlight and shelter cause differential seed selection and removal by rodents

Various environmental factors may influence the foraging behaviour of seed dispersers which could ultimately affect the seed dispersal process. We examined whether moonlight levels and the presence or absence of rodentshelter affect rodentseedremoval (rate, handling time and time of removal) and seedselection (size and species) among seven oak species. The presence or absence of safe microhabitats was found to be more important than moonlight levels in the removal of seeds. Bright moonlight caused a different temporal distribution of seedremoval throughout the night but only affected the overall removal rates in open microhabitats. Seeds were removed more rapidly in open microhabitat (regardless of the moon phase), decreasing the time allocated to seed discrimination and translocation. Only in open microhabitats did increasing levels of moonlight decrease the time allocated to selection and removal of seeds. As a result, a more precise seedselection was made under shelter, owing to lower levels of predation risk. Rodent ranking preference for species was identical between full/new moon in shelter but not in open microhabitats. For all treatments, species selection by rodents was much stronger than size selection. Nevertheless, heavy seeds, which require more energy and time to be transported, were preferentially removed under shelter, where there is no time restriction to move the seeds. Our findings reveal that seedselection is safety dependent and, therefore, microhabitats in which seeds are located (sheltered versus exposed) and moonlight levels in open areas should be taken into account in rodent food selection studies.

Fertilization Management: Assessing New Techniques and Key Interactions to Increase Crop Yields With Less N2O Emissions

El óxido nitroso (N2O) es un potente gas de efecto invernadero (GHG) proveniente mayoritariamente de la fertilización nitrogenada de los suelos agrícolas. Identificar estrategias de manejo de la fertilización que reduzcan estas emisiones sin suponer un descenso de los rendimientos es vital tanto a nivel económico como medioambiental. Con ese propósito, en esta Tesis se han evaluado: (i) estrategias de manejo directo de la fertilización (inhibidores de la nitrificación/ureasa); y (ii) interacciones de los fertilizantes con (1) el manejo del agua, (2) residuos de cosecha y (3) diferentes especies de plantas. Para conseguirlo se llevaron a cabo meta-análisis, incubaciones de laboratorio, ensayos en invernadero y experimentos de campo. Los inhibidores de la nitrificación y de la actividad ureasa se proponen habitualmente como medidas para reducir las pérdidas de nitrógeno (N), por lo que su aplicación estaría asociada al uso eficiente del N por parte de los cultivos (NUE). Sin embargo, su efecto sobre los rendimientos es variable. Con el objetivo de evaluar en una primera fase su efectividad para incrementar el NUE y la productividad de los cultivos, se llevó a cabo un meta-análisis. Los inhibidores de la nitrificación dicyandiamide (DCD) y 3,4-dimetilepyrazol phosphate (DMPP) y el inhibidor de la ureasa N-(n-butyl) thiophosphoric triamide (NBPT) fueron seleccionados para el análisis ya que generalmente son considerados las mejores opciones disponibles comercialmente. Nuestros resultados mostraron que su uso puede ser recomendado con el fin de incrementar tanto el rendimiento del cultivo como el NUE (incremento medio del 7.5% y 12.9%, respectivamente). Sin embargo, se observó que su efectividad depende en gran medida de los factores medioambientales y de manejo de los estudios evaluados. Una mayor respuesta fue encontrada en suelos de textura gruesa, sistemas irrigados y/o en cultivos que reciben altas tasas de fertilizante nitrogenado. En suelos alcalinos (pH ≥ 8), el inhibidor de la ureasa NBPT produjo el mayor efecto. Dado que su uso representa un coste adicional para los agricultores, entender las mejores prácticas que permitan maximizar su efectividad es necesario para posteriormente realizar comparaciones efectivas con otras prácticas que incrementen la productividad de los cultivos y el NUE. En base a los resultados del meta-análisis, se seleccionó el NBPT como un inhibidor con gran potencial. Inicialmente desarrollado para reducir la volatilización de amoniaco (NH3), en los últimos años algunos investigadores han demostrado en estudios de campo un efecto mitigador de este inhibidor sobre las pérdidas de N2O provenientes de suelos fertilizados bajo condiciones de baja humedad del suelo. Dada la alta variabilidad de los experimentos de campo, donde la humedad del suelo cambia rápidamente, ha sido imposible entender mecanísticamente el potencial de los inhibidores de la ureasa (UIs) para reducir emisiones de N2O y su dependencia con respecto al porcentaje de poros llenos de agua del suelo (WFPS). Por lo tanto se realizó una incubación en laboratorio con el propósito de evaluar cuál es el principal mecanismo biótico tras las emisiones de N2O cuando se aplican UIs bajo diferentes condiciones de humedad del suelo (40, 60 y 80% WFPS), y para analizar hasta qué punto el WFPS regula el efecto del inhibidor sobre las emisiones de N2O. Un segundo UI (i.e. PPDA) fue utilizado para comparar el efecto del NBPT con el de otro inhibidor de la ureasa disponible comercialmente; esto nos permitió comprobar si el efecto de NBPT es específico de ese inhibidor o no. Las emisiones de N2O al 40% WFPS fueron despreciables, siendo significativamente más bajas que las de todos los tratamientos fertilizantes al 60 y 80% WFPS. Comparado con la urea sin inhibidor, NBPT+U redujo las emisiones de N2O al 60% WFPS pero no tuvo efecto al 80% WFPS. La aplicación de PPDA incrementó significativamente las emisiones con respecto a la urea al 80% WFPS mientras que no se encontró un efecto significativo al 60% WFPS. Al 80% WFPS la desnitrificación fue la principal fuente de las emisiones de N2O en todos los tratamientos mientras que al 60% tanto la nitrificación como la desnitrificación tuvieron un papel relevante. Estos resultados muestran que un correcto manejo del NBPT puede suponer una estrategia efectiva para mitigar las emisiones de N2O. Con el objetivo de trasladar nuestros resultados de los estudios previos a condiciones de campo reales, se desarrolló un experimento en el que se evaluó la efectividad del NBPT para reducir pérdidas de N y aumentar la productividad durante un cultivo de cebada (Hordeum vulgare L.) en secano Mediterráneo. Se determinó el rendimiento del cultivo, las concentraciones de N mineral del suelo, el carbono orgánico disuelto (DOC), el potencial de desnitrificación, y los flujos de NH3, N2O y óxido nítrico (NO). La adición del inhibidor redujo las emisiones de NH3 durante los 30 días posteriores a la aplicación de urea en un 58% y las emisiones netas de N2O y NO durante los 95 días posteriores a la aplicación de urea en un 86 y 88%, respectivamente. El uso de NBPT también incrementó el rendimiento en grano en un 5% y el consumo de N en un 6%, aunque ninguno de estos incrementos fue estadísticamente significativo. Bajo las condiciones experimentales dadas, estos resultados demuestran el potencial del inhibidor de la ureasa NBPT para mitigar las emisiones de NH3, N2O y NO provenientes de suelos arables fertilizados con urea, mediante la ralentización de la hidrólisis de la urea y posterior liberación de menores concentraciones de NH4 + a la capa superior del suelo. El riego por goteo combinado con la aplicación dividida de fertilizante nitrogenado disuelto en el agua de riego (i.e. fertirriego por goteo) se considera normalmente una práctica eficiente para el uso del agua y de los nutrientes. Algunos de los principales factores (WFPS, NH4 + y NO3 -) que regulan las emisiones de GHGs (i.e. N2O, CO2 y CH4) y NO pueden ser fácilmente manipulados por medio del fertirriego por goteo sin que se generen disminuciones del rendimiento. Con ese propósito se evaluaron opciones de manejo para reducir estas emisiones en un experimento de campo durante un cultivo de melón (Cucumis melo L.). Los tratamientos incluyeron distintas frecuencias de riego (semanal/diario) y tipos de fertilizantes nitrogenados (urea/nitrato cálcico) aplicados por fertirriego. Fertirrigar con urea en lugar de nitrato cálcico aumentó las emisiones de N2O y NO por un factor de 2.4 y 2.9, respectivamente (P < 0.005). El riego diario redujo las emisiones de NO un 42% (P < 0.005) pero aumentó las emisiones de CO2 un 21% (P < 0.05) comparado con el riego semanal. Analizando el Poder de Calentamiento global en base al rendimiento así como los factores de emisión del NO, concluimos que el fertirriego semanal con un fertilizante de tipo nítrico es la mejor opción para combinar productividad agronómica con sostenibilidad medioambiental en este tipo de agroecosistemas. Los suelos agrícolas en las áreas semiáridas Mediterráneas se caracterizan por su bajo contenido en materia orgánica y bajos niveles de fertilidad. La aplicación de residuos de cosecha y/o abonos es una alternativa sostenible y eficiente desde el punto de vista económico para superar este problema. Sin embargo, estas prácticas podrían inducir cambios importantes en las emisiones de N2O de estos agroecosistemas, con impactos adicionales en las emisiones de CO2. En este contexto se llevó a cabo un experimento de campo durante un cultivo de cebada (Hordeum vulgare L.) bajo condiciones Mediterráneas para evaluar el efecto de combinar residuos de cosecha de maíz con distintos inputs de fertilizantes nitrogenados (purín de cerdo y/o urea) en estas emisiones. La incorporación de rastrojo de maíz incrementó las emisiones de N2O durante el periodo experimental un 105%. Sin embargo, las emisiones de NO se redujeron significativamente en las parcelas enmendadas con rastrojo. La sustitución parcial de urea por purín de cerdo redujo las emisiones netas de N2O un 46 y 39%, con y sin incorporación de residuo de cosecha respectivamente. Las emisiones netas de NO se redujeron un 38 y un 17% para estos mismos tratamientos. El ratio molar DOC:NO3 - demostró predecir consistentemente las emisiones de N2O y NO. El efecto principal de la interacción entre el fertilizante nitrogenado y el rastrojo de maíz se dio a los 4-6 meses de su aplicación, generando un aumento del N2O y una disminución del NO. La sustitución de urea por purín de cerdo puede considerarse una buena estrategia de manejo dado que el uso de este residuo orgánico redujo las emisiones de óxidos de N. Los pastos de todo el mundo proveen numerosos servicios ecosistémicos pero también suponen una importante fuente de emisión de N2O, especialmente en respuesta a la deposición de N proveniente del ganado mientras pasta. Para explorar el papel de las plantas como mediadoras de estas emisiones, se analizó si las emisiones de N2O dependen de la riqueza en especies herbáceas y/o de la composición específica de especies, en ausencia y presencia de una deposición de orina. Las hipótesis fueron: 1) las emisiones de N2O tienen una relación negativa con la productividad de las plantas; 2) mezclas de cuatro especies generan menores emisiones que monocultivos (dado que su productividad será mayor); 3) las emisiones son menores en combinaciones de especies con distinta morfología radicular y alta biomasa de raíz; y 4) la identidad de las especies clave para reducir el N2O depende de si hay orina o no. Se establecieron monocultivos y mezclas de dos y cuatro especies comunes en pastos con rasgos funcionales divergentes: Lolium perenne L. (Lp), Festuca arundinacea Schreb. (Fa), Phleum pratense L. (Php) y Poa trivialis L. (Pt), y se cuantificaron las emisiones de N2O durante 42 días. No se encontró relación entre la riqueza en especies y las emisiones de N2O. Sin embargo, estas emisiones fueron significativamente menores en ciertas combinaciones de especies. En ausencia de orina, las comunidades de plantas Fa+Php actuaron como un sumidero de N2O, mientras que los monocultivos de estas especies constituyeron una fuente de N2O. Con aplicación de orina la comunidad Lp+Pt redujo (P < 0.001) las emisiones de N2O un 44% comparado con los monocultivos de Lp. Las reducciones de N2O encontradas en ciertas combinaciones de especies pudieron explicarse por una productividad total mayor y por una complementariedad en la morfología radicular. Este estudio muestra que la composición de especies herbáceas es un componente clave que define las emisiones de N2O de los ecosistemas de pasto. La selección de combinaciones de plantas específicas en base a la deposición de N esperada puede, por lo tanto, ser clave para la mitigación de las emisiones de N2O. ABSTRACT Nitrous oxide (N2O) is a potent greenhouse gas (GHG) directly linked to applications of nitrogen (N) fertilizers to agricultural soils. Identifying mitigation strategies for these emissions based on fertilizer management without incurring in yield penalties is of economic and environmental concern. With that aim, this Thesis evaluated: (i) the use of nitrification and urease inhibitors; and (ii) interactions of N fertilizers with (1) water management, (2) crop residues and (3) plant species richness/identity. Meta-analysis, laboratory incubations, greenhouse mesocosm and field experiments were carried out in order to understand and develop effective mitigation strategies. Nitrification and urease inhibitors are proposed as means to reduce N losses, thereby increasing crop nitrogen use efficiency (NUE). However, their effect on crop yield is variable. A meta-analysis was initially conducted to evaluate their effectiveness at increasing NUE and crop productivity. Commonly used nitrification inhibitors (dicyandiamide (DCD) and 3,4-dimethylepyrazole phosphate (DMPP)) and the urease inhibitor N-(n-butyl) thiophosphoric triamide (NBPT) were selected for analysis as they are generally considered the best available options. Our results show that their use can be recommended in order to increase both crop yields and NUE (grand mean increase of 7.5% and 12.9%, respectively). However, their effectiveness was dependent on the environmental and management factors of the studies evaluated. Larger responses were found in coarse-textured soils, irrigated systems and/or crops receiving high nitrogen fertilizer rates. In alkaline soils (pH ≥ 8), the urease inhibitor NBPT produced the largest effect size. Given that their use represents an additional cost for farmers, understanding the best management practices to maximize their effectiveness is paramount to allow effective comparison with other practices that increase crop productivity and NUE. Based on the meta-analysis results, NBPT was identified as a mitigation option with large potential. Urease inhibitors (UIs) have shown to promote high N use efficiency by reducing ammonia (NH3) volatilization. In the last few years, however, some field researches have shown an effective mitigation of UIs over N2O losses from fertilized soils under conditions of low soil moisture. Given the inherent high variability of field experiments where soil moisture content changes rapidly, it has been impossible to mechanistically understand the potential of UIs to reduce N2O emissions and its dependency on the soil water-filled pore space (WFPS). An incubation experiment was carried out aiming to assess what is the main biotic mechanism behind N2O emission when UIs are applied under different soil moisture conditions (40, 60 and 80% WFPS), and to analyze to what extent the soil WFPS regulates the effect of the inhibitor over N2O emissions. A second UI (i.e. PPDA) was also used aiming to compare the effect of NBPT with that of another commercially available urease inhibitor; this allowed us to see if the effect of NBPT was inhibitor-specific or not. The N2O emissions at 40% WFPS were almost negligible, being significantly lower from all fertilized treatments than that produced at 60 and 80% WFPS. Compared to urea alone, NBPT+U reduced the N2O emissions at 60% WFPS but had no effect at 80% WFPS. The application of PPDA significantly increased the emissions with respect to U at 80% WFPS whereas no significant effect was found at 60% WFPS. At 80% WFPS denitrification was the main source of N2O emissions for all treatments. Both nitrification and denitrification had a determinant role on these emissions at 60% WFPS. These results suggest that adequate management of the UI NBPT can provide, under certain soil conditions, an opportunity for N2O mitigation. We translated our previous results to realistic field conditions by means of a field experiment with a barley crop (Hordeum vulgare L.) under rainfed Mediterranean conditions in which we evaluated the effectiveness of NBPT to reduce N losses and increase crop yields. Crop yield, soil mineral N concentrations, dissolved organic carbon (DOC), denitrification potential, NH3, N2O and nitric oxide (NO) fluxes were measured during the growing season. The inclusion of the inhibitor reduced NH3 emissions in the 30 d following urea application by 58% and net N2O and NO emissions in the 95 d following urea application by 86 and 88%, respectively. NBPT addition also increased grain yield by 5% and N uptake by 6%, although neither increase was statistically significant. Under the experimental conditions presented here, these results demonstrate the potential of the urease inhibitor NBPT in abating NH3, N2O and NO emissions from arable soils fertilized with urea, slowing urea hydrolysis and releasing lower concentrations of NH4 + to the upper soil layer. Drip irrigation combined with split application of N fertilizer dissolved in the irrigation water (i.e. drip fertigation) is commonly considered best management practice for water and nutrient efficiency. Some of the main factors (WFPS, NH4 + and NO3 -) regulating the emissions of GHGs (i.e. N2O, carbon dioxide (CO2) and methane (CH4)) and NO can easily be manipulated by drip fertigation without yield penalties. In this study, we tested management options to reduce these emissions in a field experiment with a melon (Cucumis melo L.) crop. Treatments included drip irrigation frequency (weekly/daily) and type of N fertilizer (urea/calcium nitrate) applied by fertigation. Crop yield, environmental parameters, soil mineral N concentrations, N2O, NO, CH4, and CO2 fluxes were measured during the growing season. Fertigation with urea instead of calcium nitrate increased N2O and NO emissions by a factor of 2.4 and 2.9, respectively (P < 0.005). Daily irrigation reduced NO emissions by 42% (P < 0.005) but increased CO2 emissions by 21% (P < 0.05) compared with weekly irrigation. Based on yield-scaled Global Warming Potential as well as NO emission factors, we conclude that weekly fertigation with a NO3 --based fertilizer is the best option to combine agronomic productivity with environmental sustainability. Agricultural soils in semiarid Mediterranean areas are characterized by low organic matter contents and low fertility levels. Application of crop residues and/or manures as amendments is a cost-effective and sustainable alternative to overcome this problem. However, these management practices may induce important changes in the nitrogen oxide emissions from these agroecosystems, with additional impacts on CO2 emissions. In this context, a field experiment was carried out with a barley (Hordeum vulgare L.) crop under Mediterranean conditions to evaluate the effect of combining maize (Zea mays L.) residues and N fertilizer inputs (organic and/or mineral) on these emissions. Crop yield and N uptake, soil mineral N concentrations, dissolved organic carbon (DOC), denitrification capacity, N2O, NO and CO2 fluxes were measured during the growing season. The incorporation of maize stover increased N2O emissions during the experimental period by c. 105 %. Conversely, NO emissions were significantly reduced in the plots amended with crop residues. The partial substitution of urea by pig slurry reduced net N2O emissions by 46 and 39 %, with and without the incorporation of crop residues respectively. Net emissions of NO were reduced 38 and 17 % for the same treatments. Molar DOC:NO3 - ratio was found to be a robust predictor of N2O and NO fluxes. The main effect of the interaction between crop residue and N fertilizer application occurred in the medium term (4-6 month after application), enhancing N2O emissions and decreasing NO emissions as consequence of residue incorporation. The substitution of urea by pig slurry can be considered a good management strategy since N2O and NO emissions were reduced by the use of the organic residue. Grassland ecosystems worldwide provide many important ecosystem services but they also function as a major source of N2O, especially in response to N deposition by grazing animals. In order to explore the role of plants as mediators of these emissions, we tested whether and how N2O emissions are dependent on grass species richness and/or specific grass species composition in the absence and presence of urine deposition. We hypothesized that: 1) N2O emissions relate negatively to plant productivity; 2) four-species mixtures have lower emissions than monocultures (as they are expected to be more productive); 3) emissions are lowest in combinations of species with diverging root morphology and high root biomass; and 4) the identity of the key species that reduce N2O emissions is dependent on urine deposition. We established monocultures and two- and four-species mixtures of common grass species with diverging functional traits: Lolium perenne L. (Lp), Festuca arundinacea Schreb. (Fa), Phleum pratense L. (Php) and Poa trivialis L. (Pt), and quantified N2O emissions for 42 days. We found no relation between plant species richness and N2O emissions. However, N2O emissions were significantly reduced in specific plant species combinations. In the absence of urine, plant communities of Fa+Php acted as a sink for N2O, whereas the monocultures of these species constituted a N2O source. With urine application Lp+Pt plant communities reduced (P < 0.001) N2O emissions by 44% compared to monocultures of Lp. Reductions in N2O emissions by species mixtures could be explained by total biomass productivity and by complementarity in root morphology. Our study shows that plant species composition is a key component underlying N2O emissions from grassland ecosystems. Selection of specific grass species combinations in the context of the expected nitrogen deposition regimes may therefore provide a key management practice for mitigation of N2O emissions.

Análisis de los factores de adopción de comercio electrónico en segmentos de consumidores finales. Aplicación al caso español

El comercio electrónico ha experimentado un fuerte crecimiento en los últimos años, favorecido especialmente por el aumento de las tasas de penetración de Internet en todo el mundo. Sin embargo, no todos los países están evolucionando de la misma manera, con un espectro que va desde las naciones pioneras en desarrollo de tecnologías de la información y comunicaciones, que cuentan con una elevado porcentaje de internautas y de compradores online, hasta las rezagadas de rápida adopción en las que, pese a contar con una menor penetración de acceso, presentan una alta tasa de internautas compradores. Entre ambos extremos se encuentran países como España que, aunque alcanzó hace años una tasa considerable de penetración de usuarios de Internet, no ha conseguido una buena tasa de transformación de internautas en compradores. Pese a que el comercio electrónico ha experimentado importantes aumentos en los últimos años, sus tasas de crecimiento siguen estando por debajo de países con características socio-económicas similares. Para intentar conocer las razones que afectan a la adopción del comercio por parte de los compradores, la investigación científica del fenómeno ha empleado diferentes enfoques teóricos. De entre todos ellos ha destacado el uso de los modelos de adopción, proveniente de la literatura de adopción de sistemas de información en entornos organizativos. Estos modelos se basan en las percepciones de los compradores para determinar qué factores pueden predecir mejor la intención de compra y, en consecuencia, la conducta real de compra de los usuarios. Pese a que en los últimos años han proliferado los trabajos de investigación que aplican los modelos de adopción al comercio electrónico, casi todos tratan de validar sus hipótesis mediante el análisis de muestras de consumidores tratadas como un único conjunto, y del que se obtienen conclusiones generales. Sin embargo, desde el origen del marketing, y en especial a partir de la segunda mitad del siglo XIX, se considera que existen diferencias en el comportamiento de los consumidores, que pueden ser debidas a características demográficas, sociológicas o psicológicas. Estas diferencias se traducen en necesidades distintas, que sólo podrán ser satisfechas con una oferta adaptada por parte de los vendedores. Además, por contar el comercio electrónico con unas características particulares que lo diferencian del comercio tradicional –especialmente por la falta de contacto físico entre el comprador y el producto– a las diferencias en la adopción para cada consumidor se le añaden las diferencias derivadas del tipo de producto adquirido, que si bien habían sido consideradas en el canal físico, en el comercio electrónico cobran especial relevancia. A la vista de todo ello, el presente trabajo pretende abordar el estudio de los factores determinantes de la intención de compra y la conducta real de compra en comercio electrónico por parte del consumidor final español, teniendo en cuenta el tipo de segmento al que pertenezca dicho comprador y el tipo de producto considerado. Para ello, el trabajo contiene ocho apartados entre los que se encuentran cuatro bloques teóricos y tres bloques empíricos, además de las conclusiones. Estos bloques dan lugar a los siguientes ocho capítulos por orden de aparición en el trabajo: introducción, situación del comercio electrónico, modelos de adopción de tecnología, segmentación en comercio electrónico, diseño previo del trabajo empírico, diseño de la investigación, análisis de los resultados y conclusiones. El capítulo introductorio justifica la relevancia de la investigación, además de fijar los objetivos, la metodología y las fases seguidas para el desarrollo del trabajo. La justificación se complementa con el segundo capítulo, que cuenta con dos elementos principales: en primer lugar se define el concepto de comercio electrónico y se hace una breve retrospectiva desde sus orígenes hasta la situación actual en un contexto global; en segundo lugar, el análisis estudia la evolución del comercio electrónico en España, mostrando su desarrollo y situación presente a partir de sus principales indicadores. Este apartado no sólo permite conocer el contexto de la investigación, sino que además permite contrastar la relevancia de la muestra utilizada en el presente estudio con el perfil español respecto al comercio electrónico. Los capítulos tercero –modelos de adopción de tecnologías– y cuarto –segmentación en comercio electrónico– sientan las bases teóricas necesarias para abordar el estudio. En el capítulo tres se hace una revisión general de la literatura de modelos de adopción de tecnología y, en particular, de los modelos de adopción empleados en el ámbito del comercio electrónico. El resultado de dicha revisión deriva en la construcción de un modelo adaptado basado en los modelos UTAUT (Unified Theory of Acceptance and Use of Technology, Teoría unificada de la aceptación y el uso de la tecnología) y UTAUT2, combinado con dos factores específicos de adopción del comercio electrónico: el riesgo percibido y la confianza percibida. Por su parte, en el capítulo cuatro se revisan las metodologías de segmentación de clientes y productos empleadas en la literatura. De dicha revisión se obtienen un amplio conjunto de variables de las que finalmente se escogen nueve variables de clasificación que se consideran adecuadas tanto por su adaptación al contexto del comercio electrónico como por su adecuación a las características de la muestra empleada para validar el modelo. Las nueve variables se agrupan en tres conjuntos: variables de tipo socio-demográfico –género, edad, nivel de estudios, nivel de ingresos, tamaño de la unidad familiar y estado civil–, de comportamiento de compra – experiencia de compra por Internet y frecuencia de compra por Internet– y de tipo psicográfico –motivaciones de compra por Internet. La segunda parte del capítulo cuatro se dedica a la revisión de los criterios empleados en la literatura para la clasificación de los productos en el contexto del comercio electrónico. De dicha revisión se obtienen quince grupos de variables que pueden tomar un total de treinta y cuatro valores, lo que deriva en un elevado número de combinaciones posibles. Sin embargo, pese a haber sido utilizados en el contexto del comercio electrónico, no en todos los casos se ha comprobado la influencia de dichas variables respecto a la intención de compra o la conducta real de compra por Internet; por este motivo, y con el objetivo de definir una clasificación robusta y abordable de tipos de productos, en el capitulo cinco se lleva a cabo una validación de las variables de clasificación de productos mediante un experimento previo con 207 muestras. Seleccionando sólo aquellas variables objetivas que no dependan de la interpretación personal del consumidores y que determinen grupos significativamente distintos respecto a la intención y conducta de compra de los consumidores, se obtiene un modelo de dos variables que combinadas dan lugar a cuatro tipos de productos: bien digital, bien no digital, servicio digital y servicio no digital. Definidos el modelo de adopción y los criterios de segmentación de consumidores y productos, en el sexto capítulo se desarrolla el modelo completo de investigación formado por un conjunto de hipótesis obtenidas de la revisión de la literatura de los capítulos anteriores, en las que se definen las hipótesis de investigación con respecto a las influencias esperadas de las variables de segmentación sobre las relaciones del modelo de adopción. Este modelo confiere a la investigación un carácter social y de tipo fundamentalmente exploratorio, en el que en muchos casos ni siquiera se han encontrado evidencias empíricas previas que permitan el enunciado de hipótesis sobre la influencia de determinadas variables de segmentación. El capítulo seis contiene además la descripción del instrumento de medida empleado en la investigación, conformado por un total de 125 preguntas y sus correspondientes escalas de medida, así como la descripción de la muestra representativa empleada en la validación del modelo, compuesta por un grupo de 817 personas españolas o residentes en España. El capítulo siete constituye el núcleo del análisis empírico del trabajo de investigación, que se compone de dos elementos fundamentales. Primeramente se describen las técnicas estadísticas aplicadas para el estudio de los datos que, dada la complejidad del análisis, se dividen en tres grupos fundamentales: Método de mínimos cuadrados parciales (PLS, Partial Least Squares): herramienta estadística de análisis multivariante con capacidad de análisis predictivo que se emplea en la determinación de las relaciones estructurales de los modelos propuestos. Análisis multigrupo: conjunto de técnicas que permiten comparar los resultados obtenidos con el método PLS entre dos o más grupos derivados del uso de una o más variables de segmentación. En este caso se emplean cinco métodos de comparación, lo que permite asimismo comparar los rendimientos de cada uno de los métodos. Determinación de segmentos no identificados a priori: en el caso de algunas de las variables de segmentación no existe un criterio de clasificación definido a priori, sino que se obtiene a partir de la aplicación de técnicas estadísticas de clasificación. En este caso se emplean dos técnicas fundamentales: análisis de componentes principales –dado el elevado número de variables empleadas para la clasificación– y análisis clúster –del que se combina una técnica jerárquica que calcula el número óptimo de segmentos, con una técnica por etapas que es más eficiente en la clasificación, pero exige conocer el número de clústeres a priori. La aplicación de dichas técnicas estadísticas sobre los modelos resultantes de considerar los distintos criterios de segmentación, tanto de clientes como de productos, da lugar al análisis de un total de 128 modelos de adopción de comercio electrónico y 65 comparaciones multigrupo, cuyos resultados y principales consideraciones son elaboradas a lo largo del capítulo. Para concluir, el capítulo ocho recoge las conclusiones del trabajo divididas en cuatro partes diferenciadas. En primer lugar se examina el grado de alcance de los objetivos planteados al inicio de la investigación; después se desarrollan las principales contribuciones que este trabajo aporta tanto desde el punto de vista metodológico, como desde los punto de vista teórico y práctico; en tercer lugar, se profundiza en las conclusiones derivadas del estudio empírico, que se clasifican según los criterios de segmentación empleados, y que combinan resultados confirmatorios y exploratorios; por último, el trabajo recopila las principales limitaciones de la investigación, tanto de carácter teórico como empírico, así como aquellos aspectos que no habiendo podido plantearse dentro del contexto de este estudio, o como consecuencia de los resultados alcanzados, se presentan como líneas futuras de investigación. ABSTRACT Favoured by an increase of Internet penetration rates across the globe, electronic commerce has experienced a rapid growth over the last few years. Nevertheless, adoption of electronic commerce has differed from one country to another. On one hand, it has been observed that countries leading e-commerce adoption have a large percentage of Internet users as well as of online purchasers; on the other hand, other markets, despite having a low percentage of Internet users, show a high percentage of online buyers. Halfway between those two ends of the spectrum, we find countries such as Spain which, despite having moderately high Internet penetration rates and similar socio-economic characteristics as some of the leading countries, have failed to turn Internet users into active online buyers. Several theoretical approaches have been taken in an attempt to define the factors that influence the use of electronic commerce systems by customers. One of the betterknown frameworks to characterize adoption factors is the acceptance modelling theory, which is derived from the information systems adoption in organizational environments. These models are based on individual perceptions on which factors determine purchase intention, as a mean to explain users’ actual purchasing behaviour. Even though research on electronic commerce adoption models has increased in terms of volume and scope over the last years, the majority of studies validate their hypothesis by using a single sample of consumers from which they obtain general conclusions. Nevertheless, since the birth of marketing, and more specifically from the second half of the 19th century, differences in consumer behaviour owing to demographic, sociologic and psychological characteristics have also been taken into account. And such differences are generally translated into different needs that can only be satisfied when sellers adapt their offer to their target market. Electronic commerce has a number of features that makes it different when compared to traditional commerce; the best example of this is the lack of physical contact between customers and products, and between customers and vendors. Other than that, some differences that depend on the type of product may also play an important role in electronic commerce. From all the above, the present research aims to address the study of the main factors influencing purchase intention and actual purchase behaviour in electronic commerce by Spanish end-consumers, taking into consideration both the customer group to which they belong and the type of product being purchased. In order to achieve this goal, this Thesis is structured in eight chapters: four theoretical sections, three empirical blocks and a final section summarizing the conclusions derived from the research. The chapters are arranged in sequence as follows: introduction, current state of electronic commerce, technology adoption models, electronic commerce segmentation, preliminary design of the empirical work, research design, data analysis and results, and conclusions. The introductory chapter offers a detailed justification of the relevance of this study in the context of e-commerce adoption research; it also sets out the objectives, methodology and research stages. The second chapter further expands and complements the introductory chapter, focusing on two elements: the concept of electronic commerce and its evolution from a general point of view, and the evolution of electronic commerce in Spain and main indicators of adoption. This section is intended to allow the reader to understand the research context, and also to serve as a basis to justify the relevance and representativeness of the sample used in this study. Chapters three (technology acceptance models) and four (segmentation in electronic commerce) set the theoretical foundations for the study. Chapter 3 presents a thorough literature review of technology adoption modelling, focusing on previous studies on electronic commerce acceptance. As a result of the literature review, the research framework is built upon a model based on UTAUT (Unified Theory of Acceptance and Use of Technology) and its evolution, UTAUT2, including two specific electronic commerce adoption factors: perceived risk and perceived trust. Chapter 4 deals with client and product segmentation methodologies used by experts. From the literature review, a wide range of classification variables is studied, and a shortlist of nine classification variables has been selected for inclusion in the research. The criteria for variable selection were their adequacy to electronic commerce characteristics, as well as adequacy to the sample characteristics. The nine variables have been classified in three groups: socio-demographic (gender, age, education level, income, family size and relationship status), behavioural (experience in electronic commerce and frequency of purchase) and psychographic (online purchase motivations) variables. The second half of chapter 4 is devoted to a review of the product classification criteria in electronic commerce. The review has led to the identification of a final set of fifteen groups of variables, whose combination offered a total of thirty-four possible outputs. However, due to the lack of empirical evidence in the context of electronic commerce, further investigation on the validity of this set of product classifications was deemed necessary. For this reason, chapter 5 proposes an empirical study to test the different product classification variables with 207 samples. A selection of product classifications including only those variables that are objective, able to identify distinct groups and not dependent on consumers’ point of view, led to a final classification of products which consisted on two groups of variables for the final empirical study. The combination of these two groups gave rise to four types of products: digital and non-digital goods, and digital and non-digital services. Chapter six characterizes the research –social, exploratory research– and presents the final research model and research hypotheses. The exploratory nature of the research becomes patent in instances where no prior empirical evidence on the influence of certain segmentation variables was found. Chapter six also includes the description of the measurement instrument used in the research, consisting of a total of 125 questions –and the measurement scales associated to each of them– as well as the description of the sample used for model validation (consisting of 817 Spanish residents). Chapter 7 is the core of the empirical analysis performed to validate the research model, and it is divided into two separate parts: description of the statistical techniques used for data analysis, and actual data analysis and results. The first part is structured in three different blocks: Partial Least Squares Method (PLS): the multi-variable analysis is a statistical method used to determine structural relationships of models and their predictive validity; Multi-group analysis: a set of techniques that allow comparing the outcomes of PLS analysis between two or more groups, by using one or more segmentation variables. More specifically, five comparison methods were used, which additionally gives the opportunity to assess the efficiency of each method. Determination of a priori undefined segments: in some cases, classification criteria did not necessarily exist for some segmentation variables, such as customer motivations. In these cases, the application of statistical classification techniques is required. For this study, two main classification techniques were used sequentially: principal component factor analysis –in order to reduce the number of variables– and cluster analysis. The application of the statistical methods to the models derived from the inclusion of the various segmentation criteria –for both clients and products–, led to the analysis of 128 different electronic commerce adoption models and 65 multi group comparisons. Finally, chapter 8 summarizes the conclusions from the research, divided into four parts: first, an assessment of the degree of achievement of the different research objectives is offered; then, methodological, theoretical and practical implications of the research are drawn; this is followed by a discussion on the results from the empirical study –based on the segmentation criteria for the research–; fourth, and last, the main limitations of the research –both empirical and theoretical– as well as future avenues of research are detailed.

Axisymmetric long liquid bridges in a time-dependent microgravity field

This paper deals with the dynamics of liquid bridges when subjected to an oscillatory microgravity field. The analysis has been performed by using a one-dimensional slice model, already used in liquid bridge problems, which allows to calculate not only the resonance frequencies of a wide range of such fluid configurations but also the dependence of the dynamic response of the liquid bridge on the frequency on the imposed perturbations. Theoretical results are compared with experimental ones obtained aboard Spacelab-Dl, the agreement between theoretical and experimental results being satisfactory

Msh2 status modulates both apoptosis and mutation frequency in the murine small intestine

Deficiency in genes involved in DNA mismatch repair increases susceptibility to cancer, particularly of the colorectal epithelium. Using Msh2 null mice, we demonstrate that this genetic defect renders normal intestinal epithelial cells susceptible to mutation in vivo at the Dlb-1 locus. Compared with wild-type mice, Msh2-deficient animals had higher basal levels of mutation and were more sensitive to the mutagenic effects of temozolomide. Experiments using Msh2-deficient cells in vitro suggest that an element of this effect is attributable to increased clonogenicity. Indeed, we show that Msh2 plays a role in the in vivo initiation of apoptosis after treatment with temozolomide, N-methyl-N′-nitro-N-nitrosoguanidine, and cisplatin. This was not influenced by the in vivo depletion of O6-alkylguanine-DNA-alkyltransferase after administration of O6-benzylguanine . By analyzing mice mutant for both Msh2 and p53, we found that the Msh2-dependent apoptotic response was primarily mediated through a p53-dependent pathway. Msh2 also was required to signal delayed p53-independent death. Taken together, these studies characterize an in vivo Msh2-dependent apoptotic response to methylating agents and raise the possibility that Msh2 deficiency may predispose to malignancy not only through failed repair of mismatch DNA lesions but also through the failure to engage apoptosis.

Demonstration of an interferon γ-dependent tumor surveillance system in immunocompetent mice

This study demonstrates that endogenously produced interferon γ (IFN-γ) forms the basis of a tumor surveillance system that controls development of both chemically induced and spontaneously arising tumors in mice. Compared with wild-type mice, mice lacking sensitivity to either IFN-γ (i.e., IFN-γ receptor-deficient mice) or all IFN family members (i.e., Stat1-deficient mice) developed tumors more rapidly and with greater frequency when challenged with different doses of the chemical carcinogen methylcholanthrene. In addition, IFN-γ-insensitive mice developed tumors more rapidly than wild-type mice when bred onto a background deficient in the p53 tumor-suppressor gene. IFN-γ-insensitive p53−/− mice also developed a broader spectrum of tumors compared with mice lacking p53 alone. Using tumor cells derived from methylcholanthrene-treated IFN-γ-insensitive mice, we found IFN-γ’s actions to be mediated at least partly through its direct effects on the tumor cell leading to enhanced tumor cell immunogenicity. The importance and generality of this system is evidenced by the finding that certain types of human tumors become selectively unresponsive to IFN-γ. Thus, IFN-γ forms the basis of an extrinsic tumor-suppressor mechanism in immunocompetent hosts.