Impaired aldehyde dehydrogenase 1 subfamily member 2A-dependent retinoic acid signaling is related with a mesenchymal-like phenotype and an unfavorable prognosis of head and neck squamous cell carcinoma.

BACKGROUND: An inverse correlation between expression of the aldehyde dehydrogenase 1 subfamily A2 (ALDH1A2) and gene promoter methylation has been identified as a common feature of oropharyngeal squamous cell carcinoma (OPSCC). Moreover, low ALDH1A2 expression was associated with an unfavorable prognosis of OPSCC patients, however the causal link between reduced ALDH1A2 function and treatment failure has not been addressed so far. METHODS: Serial sections from tissue microarrays of patients with primary OPSCC (n = 101) were stained by immunohistochemistry for key regulators of retinoic acid (RA) signaling, including ALDH1A2. Survival with respect to these regulators was investigated by univariate Kaplan-Meier analysis and multivariate Cox regression proportional hazard models. The impact of ALDH1A2-RAR signaling on tumor-relevant processes was addressed in established tumor cell lines and in an orthotopic mouse xenograft model. RESULTS: Immunohistochemical analysis showed an improved prognosis of ALDH1A2(high) OPSCC only in the presence of CRABP2, an intracellular RA transporter. Moreover, an ALDH1A2(high)CRABP2(high) staining pattern served as an independent predictor for progression-free (HR: 0.395, p = 0.007) and overall survival (HR: 0.303, p = 0.002), suggesting a critical impact of RA metabolism and signaling on clinical outcome. Functionally, ALDH1A2 expression and activity in tumor cell lines were related to RA levels. While administration of retinoids inhibited clonogenic growth and proliferation, the pharmacological inhibition of ALDH1A2-RAR signaling resulted in loss of cell-cell adhesion and a mesenchymal-like phenotype. Xenograft tumors derived from FaDu cells with stable silencing of ALDH1A2 and primary tumors from OPSCC patients with low ALDH1A2 expression exhibited a mesenchymal-like phenotype characterized by vimentin expression. CONCLUSIONS: This study has unraveled a critical role of ALDH1A2-RAR signaling in the pathogenesis of head and neck cancer and our data implicate that patients with ALDH1A2(low) tumors might benefit from adjuvant treatment with retinoids.

Are alcohol outlet densities strongly associated with alcohol-related outcomes? A critical review of recent evidence.

ISSUES: There have been reviews on the association between density of alcohol outlets and harm including studies published up to December 2008. Since then the number of publications has increased dramatically. The study reviews the more recent studies with regard to their utility to inform policy. APPROACH: A systematic review found more than 160 relevant studies (published between January 2009 and October 2014). The review focused on: (i) outlet density and assaultive or intimate partner violence; (ii) studies including individual level data; or (iii) 'natural experiments'. KEY FINDINGS: Despite overall evidence for an association between density and harm, there is little evidence on causal direction (i.e. whether demand leads to more supply or increased availability increases alcohol use and harm). When outlet types (e.g. bars, supermarkets) are analysed separately, studies are too methodologically diverse and partly contradictory to permit firm conclusions besides those pertaining to high outlet densities in areas such as entertainment districts. Outlet density commonly had little effect on individual-level alcohol use, and the few 'natural experiments' on restricting densities showed little or no effects. IMPLICATIONS AND CONCLUSIONS: Although outlet densities are likely to be positively related to alcohol use and harm, few policy recommendations can be given as effects vary across study areas, outlet types and outlet cluster size. Future studies should examine in detail outlet types, compare different outcomes associated with different strengths of association with alcohol, analyse non-linear effects and compare different methodologies. Purely aggregate-level studies examining total outlet density only should be abandoned. [Gmel G, Holmes J, Studer J. Are alcohol outlet densities strongly associated with alcohol-related outcomes? A critical review of recent evidence. Drug Alcohol Rev 2015].

Effect of Cumulating Exposure to Abacavir on the Risk of Cardiovascular Disease Events in Patients From the Swiss HIV Cohort Study.

BACKGROUND: Patients with HIV exposed to the antiretroviral drug abacavir may have an increased risk of cardiovascular disease (CVD). There is concern that this association arises because of a channeling bias. Even if exposure is a risk, it is not clear how that risk changes as exposure cumulates. METHODS: We assess the effect of exposure to abacavir on the risk of CVD events in the Swiss HIV Cohort Study. We use a new marginal structural Cox model to estimate the effect of abacavir as a flexible function of past exposures while accounting for risk factors that potentially lie on a causal pathway between exposure to abacavir and CVD. RESULTS: A total of 11,856 patients were followed for a median of 6.6 years; 365 patients had a CVD event (4.6 events per 1000 patient-years). In a conventional Cox model, recent--but not cumulative--exposure to abacavir increased the risk of a CVD event. In the new marginal structural Cox model, continued exposure to abacavir during the past 4 years increased the risk of a CVD event (hazard ratio = 2.06; 95% confidence interval: 1.43 to 2.98). The estimated function for the effect of past exposures suggests that exposure during the past 6-36 months caused the greatest increase in risk. CONCLUSIONS: Abacavir increases the risk of a CVD event: the effect of exposure is not immediate, rather the risk increases as exposure cumulates over the past few years. This gradual increase in risk is not consistent with a rapidly acting mechanism, such as acute inflammation.

Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels.

Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.

Impact of T cell receptor affinity on the molecular mechanisms modulating CD8 T cell signalling and function against NY-ESO-1 tumour antigen

It is well established that cytotoxic T lymphocytes play a pivotal role in the protection against intracellular pathogens and tumour cells. Such protective immune responses rely on the specific T cell receptor (TCR)-mediated recognition by CD8 T cells of small antigenic peptides presented in the context of class-I Major Histocompatibility Complex molecules (pMHCs) on the surface of infected or malignant cells. The strength (affinity/avidity) of this interaction is a major correlate of protection. Although tumour-reactive CD8 T cells can be observed in cancer patients, anti-tumour immune responses are often ineffective in controlling or eradicating the disease due to the relative low TCR affinity of these cells. To overcome this limitation, tumour-specific CD8 T cells can be genetically modified to express TCRs of improved binding strength against a defined tumour antigen before adoptive cell transfer into cancer patients. We previously generated a panel of TCRs specific for the cancer-testis antigen NY-ESO-l,57.165 with progressively increased affinities for the pMHC complex, thus providing us with a unique tool to investigate the causal link between the surface expression of such TCRs and T cell activation and function. We recently demonstrated that anti-tumour CD8 T cell reactivity could only be improved within physiological affinity limits, beyond which drastic functional declines were observed, suggesting the presence of multiple regulatory mechanisms limiting T cell activation and function in a TCR affinity-dependent manner. The overarching goal of this thesis was (i) to assess the precise impact of TCR affinity on T cell activation and signalling at the molecular level and (ii) to gain further insights on the mechanisms that regulate and delimitate maximal/optimized CD8 T cell activation and signalling. Specifically, by combining several technical approaches we characterized the activation status of proximal (i.e. CD3Ç, Lek, and ZAP-70) and distal (i.e. ERK1/2) signalling molecules along the TCR affinity gradient. Moreover, we assessed the extent of TCR downmodulation, a critical step for initial T cell activation. CD8 T cells engineered with the optimal TCR affinity variants showed increased activation levels of both proximal and distal signalling molecules when compared to the wild-type T cells. Our analyses also highlighted the "paradoxical" status of tumour-reactive CD8 T cells bearing very high TCR affinities, which retained strong proximal signalling capacity and TCR downmodulation, but were unable to propagate signalling distally (i.e. pERKl/2), resulting in impaired cell-mediated functions. Importantly, these very high affinity T cells displayed maximal levels of SHP-1 and SHP-2 phosphatases, two negative regulatory molecules, and this correlated with a partial pERKl/2 signalling recovery upon pharmacological SHP-l/SHP-2 inhibition. These findings revealed the putative presence of inhibitory regulators of the TCR signalling cascade acting very rapidly following tumour-specific stimulation. Moreover, the very high affinity T cells were only able to transiently express enhanced proximal signalling molecules, suggesting the presence of an additional level of regulation that operates through the activation of negative feedback loops over time, limiting the duration of the TCR-mediated signalling. Overall, the determination of TCR-pMHC binding parameters eliciting optimal CD8 T cell activation, signalling, and effector function while guaranteeing high antigen specificity, together with the identification of critical regulatory mechanisms acting proximally in the TCR signalling cascade, will directly contribute to optimize and support the development of future TCR-based adoptive T cell strategies for the treatment of malignant diseases. -- Les lymphocytes T CD8 cytotoxiques jouent un rôle prédominant dans la protection contre les pathogènes intracellulaires et les cellules tumorales. Ces réponses immunitaires dépendent de la spécificité avec laquelle les récepteurs T (TCR) des lymphocytes CD8 reconnaissent les peptides antigéniques présentés par les molécules du complexe Majeur de Histocompatibilité de classe I (pCMH) à la surface des cellules infectées ou malignes. La force (ou affinité/avidité) de l'interaction du TCR-pCMH est un corrélat majeur de protection. Les réponses immunitaires sont cependant souvent inefficaces et ne permettent pas de contrôler ou d'éliminer les cellules tumorales chez les patients atteint du cancer, et ce à cause de la relative faible reconnaissance des TCRs exprimés par les lymphocytes T CD8 envers les antigènes tumoraux. Afin de surmonter cette limitation, les cellules T anti-tumorales peuvent être génétiquement modifiées en les dotant de TCRs préalablement optimisés afin d'augmenter leur reconnaissance ou affinité contre les antigènes tumoraux, avant leur ré¬infusion dans le patient. Nous avons récemment généré des cellules T CD8 exprimant un panel de TCRs spécifiques pour l'antigène tumoral NY-ESO-l157.16J avec des affinités croissantes, permettant ainsi d'investiguer la causalité directe entre l'affinité du TCR-pCMH et la fonction des cellules T CD8. Nous avons démontré que la réactivité anti-tumorale pouvait être améliorée en augmentant l'affinité du TCR dans une intervalle physiologique, mais au delà duquel nous observons un important déclin fonctionnel. Ces résultats suggèrent la présence de mécanismes de régulation limitant l'activation des cellules T de manière dépendante de l'affinité du TCR. Le but de cette thèse a été (i) de définir l'impact précis de l'affinité du TCR sur l'activation et la signalisation des cellules T CD8 au niveau moléculaire et (ii) d'acquérir de nouvelles connaissances sur les mécanismes qui régulent et délimitent l'activation et la signalisation maximale des cellules T CD8 optimisées. Spécifiquement, en combinant plusieurs approches technologiques, nous avons caractérisé l'état d'activation de différentes protéines de la voie de signalisation proximale (CD3Ç, Lek et ZAP-70) et distale (ERK1/2) le long du gradient d'affinité du TCR, ainsi que l'internalisation du TCR, une étape clef dans l'activation initiale des cellules T. Les lymphocytes T CD8 exprimant des TCRs d'affinité optimale ont montré des niveaux d'activation augmentés des molécules proximales et distales par rapport aux cellules de type sauvage (wild-type). Nos analyses ont également mis en évidence un paradoxe chez les cellules T CD8 équipées avec des TCRs de très haute affinité. En effet, ces cellules anti-tumorales sont capables d'activer leurs circuits biochimiques au niveau proximal et d'internaliser efficacement leur TCR, mais ne parviennent pas à propager les signaux biochimiques dépendants du TCR jusqu'au niveau distal (via phospho-ERKl/2), avec pour conséquence une limitation de leur capacité fonctionnelle. Finalement, nous avons démontré que SHP-1 et SHP-2, deux phosphatases avec des propriétés régulatrices négatives, étaient majoritairement exprimées dans les cellules T CD8 de très hautes affinités. Une récupération partielle des niveaux d'activation de ERK1/2 a pu être observée après l'inhibition pharmacologique de ces phosphatases. Ces découvertes révèlent la présence de régulateurs moléculaires qui inhibent le complexe de signalisation du TCR très rapidement après la stimulation anti-tumorale. De plus, les cellules T de très hautes affinités ne sont capables d'activer les molécules de la cascade de signalisation proximale que de manière transitoire, suggérant ainsi un second niveau de régulation via l'activation de mécanismes de rétroaction prenant place progressivement au cours du temps et limitant la durée de la signalisation dépendante du TCR. En résumé, la détermination des paramètres impliqués dans l'interaction du TCR-pCMH permettant l'activation de voies de signalisation et des fonctions effectrices optimales ainsi que l'identification des mécanismes de régulation au niveau proximal de la cascade de signalisation du TCR contribuent directement à l'optimisation et au développement de stratégies anti-tumorales basées sur l'ingénierie des TCRs pour le traitement des maladies malignes.

Multidetector-row computed tomography in the preoperative diagnosis of intestinal complications caused by clinically unsuspected ingested dietary foreign bodies: a case series emphasizing the use of volume rendering techniques

Objective The present study was aimed at describing a case series where a preoperative diagnosis of intestinal complications secondary to accidentally ingested dietary foreign bodies was made by multidetector-row computed tomography (MDCT), with emphasis on complementary findings yielded by volume rendering techniques (VRT) and curved multiplanar reconstructions (MPR). Materials and Methods The authors retrospectively assessed five patients with surgically confirmed intestinal complications (perforation and /or obstruction) secondary to unsuspected ingested dietary foreign bodies, consecutively assisted in their institution between 2010 and 2012. Demographic, clinical, laboratory and radiological data were analyzed. VRT and curved MPR were subsequently performed. Results Preoperative diagnosis of intestinal complications was originally performed in all cases. In one case the presence of a foreign body was not initially identified as the causal factor, and the use of complementary techniques facilitated its retrospective identification. In all cases these tools allowed a better depiction of the entire foreign bodies on a single image section, contributing to the assessment of their morphology. Conclusion Although the use of complementary techniques has not had a direct impact on diagnostic performance in most cases of this series, they may provide a better depiction of foreign bodies' morphology on a single image section.

The seasonal evolution of high vertical–mode internal waves in a deep reservoir

The causal mechanism and seasonal evolution of the internal wave field in a deep, warm, monomictic reservoirare examined through the analysis of field observations and numerical techniques. The study period extends fromthe onset of thermal stratification in the spring until midsummer in 2005. During this time, wind forcing wasperiodic, with a period of 24 h (typical of land–sea breezes), and the thermal structure in the lake wascharacterized by the presence of a shallow surface layer overlying a thick metalimnion, typical of small to mediumsized reservoirs with deep outtakes. Basin-scale internal seiches of high vertical mode (ranging from mode V3 toV5) were observed in the metalimnion. The structure of the dominant modes of oscillation changed asstratification evolved on seasonal timescales, but in all cases, their periods were close to that of the local windforcing (i.e., 24 h), suggesting a resonant response. Nonresonant oscillatory modes of type V1 and V2 becamedominant after large frontal events, which disrupted the diurnal periodicity of the wind forcing

Surfing the Net: A Pathway to Participation for the Politically Uninterested?

This article explores whether use of the Internetchanges the role that political motivation hastraditionally played in classic explanations ofparticipation. We ask if, by reducing so dramatically the costs of political participation,the Internet causes interest in politics to loseimportance as a causal factor of participation.We examine this issue analysing a representativesurvey of the Spanish population which deals withpolitical participation and Internet use. Theresults show that use of Internet has a directeffect on participation independently of motivation, and that, in order to participate online, skilled Internet users do not need to be motivated or interested in politics.

Sovereigns and banks in the euro area : a tale of two crises

This study attempts to identify and trace inter-linkages between sovereign and banking risk in the euro area. To this end, we use an indicator of banking risk in each country based on the Contingent Claim Analysis literature, and 10-year government yield spreads over Germany as a measure of sovereign risk. We apply a dynamic approach to testing for Granger causality between the two measures of risk in 10 euro area countries, allowing us to check for contagion in the form of a significant and abrupt increase in short-run causal linkages. The empirical results indicate that episodes of contagion vary considerably in both directions over time and within the different EMU countries. Significantly, we find that causal linkages tend to strengthen particularly at the time of major financial crises. The empirical evidence suggests the presence of contagion, mainly from banks to sovereigns.

Erwinia amylovora Novel Plasmid pEI70: Complete Sequence, Biogeography, and Role in Aggressiveness in the Fire Blight Phytopathogen

Comparative genomics of several strains of Erwinia amylovora, a plant pathogenic bacterium causal agent of fire blight disease, revealed that its diversity is primarily attributable to the flexible genome comprised of plasmids. We recently identified and sequenced in full a novel 65.8 kb plasmid, called pEI70. Annotation revealed a lack of known virulence-related genes, but found evidence for a unique integrative conjugative element related to that of other plant and human pathogens. Comparative analyses using BLASTN showed that pEI70 is almost entirely included in plasmid pEB102 from E. billingiae, an epiphytic Erwinia of pome fruits, with sequence identities superior to 98%. A duplex PCR assay was developed to survey the prevalence of plasmid pEI70 and also that of pEA29, which had previously been described in several E. amylovora strains. Plasmid pEI70 was found widely dispersed across Europe with frequencies of 5–92%, but it was absent in E. amylovora analyzed populations from outside of Europe. Restriction analysis and hybridization demonstrated that this plasmid was identical in at least 13 strains. Curing E. amylovora strains of pEI70 reduced their aggressiveness on pear, and introducing pEI70 into low-aggressiveness strains lacking this plasmid increased symptoms development in this host. Discovery of this novel plasmid offers new insights into the biogeography, evolution and virulence determinants in E. amylovora

Concepts and Reference. Defending a Dual Theory of Natural Kind Concepts

In this thesis I argue that the psychological study of concepts and categorisation, and the philosophical study of reference are deeply intertwined. I propose that semantic intuitions are a variety of categorisation judgements, determined by concepts, and that because of this, concepts determine reference. I defend a dual theory of natural kind concepts, according to which natural kind concepts have distinct semantic cores and non-semantic identification procedures. Drawing on psychological essentialism, I suggest that the cores consist of externalistic placeholder essence beliefs. The identification procedures, in turn, consist of prototypes, sets of exemplars, or possibly also theory-structured beliefs. I argue that the dual theory is motivated both by experimental data and theoretical considerations. The thesis consists of three interrelated articles. Article I examines philosophical causal and description theories of natural kind term reference, and argues that they involve, or need to involve, certain psychological elements. I propose a unified theory of natural kind term reference, built on the psychology of concepts. Article II presents two semantic adaptations of psychological essentialism, one of which is a strict externalistic Kripkean-Putnamian theory, while the other is a hybrid account, according to which natural kind terms are ambiguous between internalistic and externalistic senses. We present two experiments, the results of which support the strict externalistic theory. Article III examines Fodor’s influential atomistic theory of concepts, according to which no psychological capacities associated with concepts constitute them, or are necessary for reference. I argue, contra Fodor, that the psychological mechanisms are necessary for reference.

Older consumers adopting information and communication technology: Evaluating opportunities for health care applications

The purpose of this dissertation is to analyse older consumers' adoption of information and communication technology innovations, assess the effect of aging related characteristic, and evaluate older consumers' willingness to apply these technologies in health care services. This topic is considered important, because the population in Finland (as in other welfare states) is aging and thus offers a possibility for marketers, but on the other hand threatens society with increasing costs for healthcare. Innovation adoption has been under research from several aspects in both organizational and consumer research. In the consumer behaviour, several theories have been developed to predict consumer responses to innovation. The present dissertation carefully reviews previous research and takes a closer look at the theory of planned behaviour, technology acceptance model and diffusion of innovations perspective. It is here suggested that there is a possibility that these theories can be combined and complemented to predict the adoption of ICT innovations among aging consumers, taking the aging related personal characteristics into account. In fact, there are very few studies that have concentrated on aging consumers in the innovation research, and thus there was a clear indent for the present research. ICT in the health care context has been studied mainly from the organizational point of view. If the technology is thus applied for the communication between the individual end-user and service provider, the end-user cannot be shrugged off. The present dissertation uses empirical evidence from a survey targeted to 55-79 year old people from one city in Southern-Carelia. The empirical analysis of the research model was mainly based on structural equation modelling that has been found very useful on estimating causal relationships. The tested models were targeted to predict the adoption stage of personal computers and mobile phones, and the adoption intention of future health services that apply these devices for communication. The present dissertation succeeded in modelling the adoption behaviour of mobile phones and PCs as well as adoption intentions of future services. Perceived health status and three components behind it (depression, functional ability, and cognitive ability) were found to influence perception of technology anxiety. Better health leads to less anxiety. The effect of age was assessed as a control variable, in order to evaluate its effect compared to health characteristics. Age influenced technology perceptions, but to lesser extent compared to health. The analyses suggest that the major determinant for current technology adoption is perceived behavioural control, and additionally technology anxiety that indirectly inhibit adoption through perceived control. When focusing on future service intentions, the key issue is perceived usefulness that needs to be highlighted when new services are launched. Besides usefulness, the perception of online service reliability is important and affects the intentions indirectly. To conclude older consumers' adoption behaviour is influenced by health status and age, but also by the perceptions of anxiety and behavioural control. On the other hand, launching new types of health services for aging consumers is possible after the service is perceived reliable and useful.

Molluscan radiations and landscape evolution in Miocene Amazonia

This PhD study aims to exploit the rich archive provided by the Miocene mollusc fauna of the Pebas Formation and other inland Miocene Amazonian formations to reconstruct landscape evolution and biotic development in lowland Amazonia during the Neogene. Over 160 samples from more than 70 Pebas Formation outcrops mostly collected by the author were processed for this study. Additional samples were collected in Andean areas of Colombia and Venezuela and further material from other northwestern South American basins was studied in museums. Pebas Formation samples and well log data made available by Occidental Peru from three wells in the Marañon Basin in Peru were also investigated. During this study four genera and 74 species from the Pebas Formation have been described and a further 13 species have been introduced in open nomenclature, and several species were reported for the first time. The number of mollusc species attributed to the Pebas fauna has increased from around 50 to 156. The Pebas fauna is characterised as aquatic, endemic and extinct, and is a typical representative of a long-lived lake fauna. Fluvial taxa are not common, (marginal) marine taxa are rare. An additional molluscan fauna from the Miocene Solimões Formation of Brazil, containing 13 fresh water species was also described. The newly documented fauna was used to improve biostratigraphic framework of Miocene Amazonian deposits. Twelve mollusc zones were introduced, the upper eleven of which cover a time interval of approximately seven million years covered previously by only three pollen zones. An age model calculated for the borehole data indicates that the Pebas Formation was deposited between c. 24 and 11 Ma. The areal distribution of the outcropping mollusc zones uncovered a broad dome structure, termed here the Iquitos-Araracuara anteclise in the study area. The structure appears to have influenced river courses and also contributed to edaphic heterogeneity that may have been in part responsible for the current high biodiversity in the study area. The Pebas system was a huge system (> one million km2) dominated by relatively shallow lakes, but also containing swamps and rivers. The system was fed by rivers draining the emergent Andes in the west and lowlands and cratons to the east. The Pebas system was located at sea level and was open to marine settings through a northern portal running through the Llanos Basin and East Venezuela Basin towards the Caribbean. Cyclical baselevel changes possibly related to Mylankhovitch cycles, have been documented in depositional sequences of the Pebas Formation. The composition of the Pebasian mollusc fauna implies that the system was mostly a fresh water system. Such an interpretation is matched by strontium isotope ratios as well as very negative δ18O ratios found in the shells, but is at odds with oligohaline and mesohaline ichnofacies found in the same strata. The mollusc fauna of the Pebas Formation diversified through most of the existence of the lake system. The diversification was mostly the result of in-situ cladogenesis. The success of some of the Pebasian endemic clades is explained by adaptation to fresh water, low oxygen, common unconsolidated lake bottoms (soup grounds) as well as high predation intensity. Maximum diversity was reached at the base of the late Middle to early Late Miocene Grimsdalea pollen zone, some 13 Ma. At the time some 85 species co-occurred, 67 of which are considered as Pebasian endemics. A subsequent drop in species richness coincides with indications of elevated salinities, although a causal relation still needs to be established. Apparently the Pebas fauna went (almost) entirely extinct with the replacement of the lake system into a fluvio-tidal system during the Early Late Miocene, some 11 Ma.

Kiinteistönvälittäjän vastuu vanhan asunnon kaupassa

Tutkielman tarkoituksena oli selvittää kiinteistönvälittäjän vastuuta vanhan asunnon kaupassa, kun toisena osapuolena on kuluttajan asemassa oleva yksityishenkilö. Työn perustana on kiinteistönvälittäjän toimintaa ohjaava voimassa oleva lainsäädäntö. Tutkimusaineistona käytettiin lisäksi kirjallisuutta ja viime vuosien oikeuskäytäntöä. Kiinteistönvälittäjän vastuu kaupan osapuolille perustuu joko sopimus- tai vahingonkorvausvastuuseen riippuen siitä, onko vahinkoa kärsinyt toimeksiantaja vai tämän vastapuoli. Vastuu edellyttää virhettä välittäjän toiminnassa, joka on tuottamuksen lisäksi syy-yhteydessä aiheutuneeseen vahinkoon. Välittäjän toimissa on virhe, jos se ei vastaa sovittua tai laissa säädettyä.

Proposta de model per mesurar el valor percebut, la satisfacció i la lleialtat a les destinacions turístiques transfrontereres

L’objectiu d’aquesta treball és proposar un model de relacions causals i unes hipòtesis de treball sobre la lleialtat dels turistes a les destinacions transfrontereres en el context de la Unió Europea