Land use management in mountainous areas: combining ground-based and EO (Earth Observation) data to investigate the shallow landsliding susceptibility in the Duron valley (Trento, Italy).

Throughout the alpine domain, shallow landslides represent a serious geologic hazard, often causing severe damages to infrastructures, private properties, natural resources and in the most catastrophic events, threatening human lives. Landslides are a major factor of landscape evolution in mountainous and hilly regions and represent a critical issue for mountainous land management, since they cause loss of pastoral lands. In several alpine contexts, shallow landsliding distribution is strictly connected to the presence and condition of vegetation on the slopes. With the aid of high-resolution satellite images, it's possible to divide automatically the mountainous territory in land cover classes, which contribute with different magnitude to the stability of the slopes. The aim of this research is to combine EO (Earth Observation) land cover maps with ground-based measurements of the land cover properties. In order to achieve this goal, a new procedure has been developed to automatically detect grass mantle degradation patterns from satellite images. Moreover, innovative surveying techniques and instruments are tested to measure in situ the shear strength of grass mantle and the geomechanical and geotechnical properties of these alpine soils. Shallow landsliding distribution is assessed with the aid of physically based models, which use the EO-based map to distribute the resistance parameters across the landscape.

Biokinetics of nanoparticles and susceptibility to particulate exposure in a murine model of cystic fibrosis.

BACKGROUND Persons with cystic fibrosis (CF) are at-risk for health effects from ambient air pollution but little is known about the interaction of nanoparticles (NP) with CF lungs. Here we study the distribution of inhaled NP in a murine CF model and aim to reveal mechanisms contributing to adverse effects of inhaled particles in susceptible populations. METHODS Chloride channel defective CftrTgH (neoim) Hgu mice were used to analyze lung function, lung distribution and whole body biokinetics of inhaled NP, and inflammatory responses after intratracheal administration of NP. Distribution of 20-nm titanium dioxide NP in lungs was assessed on ultrathin sections immediately and 24 h after a one-hour NP inhalation. NP biokinetics was deduced from total and regional lung deposition and from whole body translocation of inhaled 30-nm iridium NP within 24 h after aerosol inhalation. Inflammatory responses were assessed within 7 days after carbon NP instillation. RESULTS Cftr mutant females had moderately reduced lung compliance and slightly increased airway resistance compared to wild type mice. We found no genotype dependent differences in total, regional and head deposition or in secondary-organ translocation of inhaled iridium NP. Titanium dioxide inhalation resulted in higher NP uptake by alveolar epithelial cells in Cftr mutants. Instillation of carbon NP induced a comparable acute and transient inflammatory response in both genotypes. The twofold increase of bronchoalveolar lavage (BAL) neutrophils in Cftr mutant compared to wild type mice at day 3 but not at days 1 and 7, indicated an impaired capacity in inflammation resolution in Cftr mutants. Concomitant to the delayed decline of neutrophils, BAL granulocyte-colony stimulating factor was augmented in Cftr mutant mice. Anti-inflammatory 15-hydroxyeicosatetraenoic acid was generally significantly lower in BAL of Cftr mutant than in wild type mice. CONCLUSIONS Despite lacking alterations in lung deposition and biokinetics of inhaled NP, and absence of significant differences in lung function, higher uptake of NP by alveolar epithelial cells and prolonged, acute inflammatory responses to NP exposure indicate a moderately increased susceptibility of lungs to adverse effects of inhaled NP in Cftr mutant mice and provides potential mechanisms for the increased susceptibility of CF patients to air pollution.

Comparative genetic analyses point to HCP5 as susceptibility locus for HCV-associated hepatocellular carcinoma

BACKGROUND & AIMS: Recently, genetic variations in MICA (lead single nucleotide polymorphism [SNP] rs2596542) were identified by a genome-wide association study (GWAS) to be associated with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) in Japanese patients. In the present study, we sought to determine whether this SNP is predictive of HCC development in the Caucasian population as well. METHODS: An extended region around rs2596542 was genotyped in 1924 HCV-infected patients from the Swiss Hepatitis C Cohort Study (SCCS). Pair-wise correlation between key SNPs was calculated both in the Japanese and European populations (HapMap3: CEU and JPT). RESULTS: To our surprise, the minor allele A of rs2596542 in proximity of MICA appeared to have a protective impact on HCC development in Caucasians, which represents an inverse association as compared to the one observed in the Japanese population. Detailed fine-mapping analyses revealed a new SNP in HCP5 (rs2244546) upstream of MICA as strong predictor of HCV-related HCC in the SCCS (univariable p=0.027; multivariable p=0.0002, odds ratio=3.96, 95% confidence interval=1.90-8.27). This newly identified SNP had a similarly directed effect on HCC in both Caucasian and Japanese populations, suggesting that rs2244546 may better tag a putative true variant than the originally identified SNPs. CONCLUSIONS: Our data confirms the MICA/HCP5 region as susceptibility locus for HCV-related HCC and identifies rs2244546 in HCP5 as a novel tagging SNP. In addition, our data exemplify the need for conducting meta-analyses of cohorts of different ethnicities in order to fine map GWAS signals.

Caracterización funcional de los genes sgb (suppressors of agb1-2 susceptibility to pathogens): Nuevos reguladores de la respuesta de inmunidad innata de Arabidopsis thaliana

Un porcentaje importante de las pérdidas de la producción agrícola se deben a las enfermedades que causan en los cultivos los hongos necrótrofos y vasculares. Para mejorar la productividad agrícola es necesario tener un conocimiento detallado de las bases genéticas y moleculares que regulan la resistencia de las plantas a este tipo de patógenos. En Arabidopsis thaliana la resistencia frente a patógenos necrótrofos, como el hongo Plectosphaerella cucumerina BMM (PcBMM), es genéticamente compleja y depende de la activación coordinada de distintas rutas de señalización, como las reguladas por las hormonas ácido salicílico (SA), ácido jasmónico (JA), etileno (ET) y ácido abscísico (ABA), así como de la síntesis de compuestos antimicrobianos derivados del Triptófano y de la integridad de la pared celular (Llorente et al., 2005, Hernández-Blanco et al., 2007; Delgado-Cerezo et al., 2012). Uno de los componentes claves en la regulación de la resistencia de las plantas a patógenos (incluidos hongos necrótrofos y biótrofos) es la proteína G heterotrimérica, un complejo proteico formado por tres subunidades (Gα, Gβ y Gγ), que también regula distintos procesos del desarrollo vegetal. En Arabidopsis hay un gen que codifica para la subunidad α (GPA1), otro para la β (AGB1), y tres genes para la subunidad γ (AGG1, AGG2 y AGG3). El complejo GPA1-AGB1-AGG (1-3) se activa y disocia tras la percepción de una señal específica, actuando el dímero AGB1-AGG1/2 como un monómero funcional que regula las respuestas de defensa (Delgado-Cerezo et al., 2012). Estudios transcriptómicos y análisis bioquímicos de la pared celular en los que se comparaban los mutantes agb1-2 y agg1 agg2, y plantas silvestres (Col-0) revelaron que la resistencia mediada por Gβ-Gγ1/2 no es dependiente de rutas de defensa previamente caracterizadas, y sugieren que la proteína G podría modular la composición/estructura (integridad) de la pared celular (Delgado-Cerezo et al., 2012). Recientemente, se ha demostrado que AGB1 es un componente fundamental de la respuesta inmune mediada por Pathogen- Associated Molecular Patterns (PTI), ya que los mutantes agb1-2 son incapaces de activar tras el tratamiento con PAMPs respuestas de inmunidad, como la producción de especies reactivas de oxígeno (ROS; Liu et al., 2013). Dada la importancia de la proteína G heterotrimérica en la regulación de la respuestas de defensa (incluida la PTI) realizamos un escrutinio de mutantes supresores de la susceptibilidad de agb1-2 al hongo necrótrofo, PcBMM, para identificar componentes adicionales de las rutas de señalización reguladas por AGB1. En este escrutinio se aislaron cuatro mutantes sgb (suppressors of agb1-2 susceptibility to pathogens), dos de los cuales, sgb10 y sgb11, se han caracterizado en la presente Tesis Doctoral. El mutante sgb10 es un segundo alelo nulo del gen MKP1 (At3g55270) que codifica la MAP quinasa-fosfatasa 1 (Bartels et al., 2009). Este mutante presenta lesiones espontáneas en plantas adultas y una activación constitutiva de las principales rutas de defensa (SA, JA y ET, y de metabolitos secundarios, como la camalexina), que explicaría su elevada resistencia a PcBMM y Pseudomonas syringae. Estudios epistáticos sugieren que la resistencia mediada por SGB10 no es dependiente, si no complementaria a la regulada por AGB1. El mutante sgb10 es capaz de restablecer en agb1-2 la producción de ROS y otras respuestas PTI (fosforilación de las MAPK6/3/4/11) tras el tratamiento con PAMPs tan diversos como flg22, elf18 y quitina, lo que demuestra el papel relevante de SGB10/MKP1 y de AGB1 en PTI. El mutante sgb11 se caracteriza por presentar un fenotipo similar a los mutantes irregular xylem (e.g. irx1) afectado en pared celular secundaria: irregularidades en las células xilemáticas, reducción en el tamaño de la roseta y altura de planta, y hojas con un mayor contenido de clorofila. La resistencia de sgb11 a PcBMM es independiente de agb1-2, ya que la susceptibilidad del doble mutante sgb11 agb1-2 es intermedia entre la de agb1-2 y sgb11. El mutante sgb11 no revierte la deficiente PTI de agb1-2 tras el tratamiento con flg22, lo que indica que está alterado en una ruta distinta de la regulada por SGB10. sgb11 presenta una sobreactivación de la ruta del ácido abscísico (ABA), lo que podría explicar su resistencia a PcBMM. La mutación sgb11 ha sido cartografiada en el cromosoma III de Arabidopsis entre los marcadores AthFUS6 (81,64cM) y nga6 (86,41cM) en un intervalo de aproximadamente 200 kb, que comprende genes, entre los que no se encuentra ninguno previamente descrito como IRX. El aislamiento y caracterización de SGB11 apoya la relevancia de la proteína G heterotrimérica en la regulación de la interconexión entre integridad de la pared celular e inmunidad. ABSTRACT A significant percentage of agricultural losses are due to diseases caused by necrotrophic and vascular fungi. To enhance crop yields is necessary to have a detailed knowledge of the genetic and molecular bases regulating plant resistance to these pathogens. Arabidopsis thaliana resistance to necrotrophic pathogens, such as Plectosphaerella cucumerina BMM (PcBMM) fungus, is genetically complex and depends on the coordinated activation of various signaling pathways. These include those regulated by salicylic acid (SA), jasmonic acid (JA), ethylene (ET) and abscisic acid (ABA) hormones and the synthesis of tryptophan-derived antimicrobial compounds and cell wall integrity (Llorente et al., 2005, Hernández-Blanco et al., 2007; Delgado-Cerezo et al., 2012). One key component in the regulation of plant resistance to pathogens (including biotrophic and necrotrophic fungi) is the heterotrimeric G-protein. This protein complex is formed by three subunits (Gα, Gβ and Gγ), which also regulates various plant developmental processes. In Arabidopsis only one gene encodes for subunits α (GPA1) and β (AGB1), and three genes for subunit γ (AGG1, AGG2 y AGG3). The complex GPA1- AGB1-AGG(1-3) is activated and dissociates after perception of an specific signal, AGB1- AGG1/2 acts as a functional monomer regulating defense responses (Delgado-Cerezo et al., 2012). Comparative transcriptomic studies and biochemical analyses of the cell wall of agb1-2 and agg1agg2 mutant and wild plants (Col-0), showed that Gβ-Gγ1/2-mediated resistance is not dependent on previously characterized defense pathways. In addition, it suggests that G protein may modulate the composition/structure (integrity) of the plant cell wall (Delgado-Cerezo et al., 2012). Recently, it has been shown that AGB1 is a critical component of the immune response mediated by Pathogen-Associated Molecular Patterns (PTI), as agb1-2 mutants are unable to activate immune responses such as oxygen reactive species (ROS) production after PAMPs treatment (Liu et al., 2013). Considering the importance of the heterotrimeric G protein in regulation of defense responses (including PTI), we performed a screening for suppressors of agb1-2 susceptibility to the necrotrophic fungus PcBMM. This would allow the identification of additional components of the signaling pathways regulated by AGB1. In this search four sgb mutants (suppressors of agb1-2 susceptibility to pathogens) were isolated, two of which, sgb10 and sgb11, have been characterized in this PhD thesis. sgb10 mutant is a second null allele of MKP1 gene (At3g55270), which encodes the MAP kinase-phosphatase 1 (Bartels et al., 2009). This mutant exhibits spontaneous lesions in adult plants and a constitutive activation of the main defense pathways (SA, JA and ET, and secondary metabolites, such as camalexin), which explains its high resistance to Pseudomonas syringae and PcBMM. Epistatic studies suggest that SGB10- mediated resistance is not dependent, but complementary to the regulated by AGB1. The sgb10 mutant is able to restore agb1-2 ROS production and other PTI responses (MAPK6/3/4/11 phosphorylation) upon treatment with PAMPs as diverse as, flg22, elf18 and chitin, demonstrating the relevant role of SGB10/MKP1 and AGB1 in PTI. sgb11 mutant is characterized by showing a similar phenotype to irregular xylem mutants (e.g. irx1), affected in secondary cell wall: irregular xylems cells, rosette size reduction and plant height, and higher chlorophyll content on leaves. The resistance of sgb11 to PcBMM is independent of agb1-2, as susceptibility of the double mutant agb1-2sgb11 is intermediate between agb1-2 and sgb11. The sgb11 mutant does not revert the deficient PTI response in agb1-2 after flg22 treatment, indicating that is altered in a pathway different to the one regulated by SGB10. sgb11 presents an over-activation of the abscisic acid pathway (ABA), which could explain its resistance to PcBMM. The sgb11 mutation has been mapped on chromosome III of Arabidopsis, between AthFUS6 (81.64 cM) and nga6 (86.41 cM) markers, in 200 kb interval, which does not include previously known IRX genes. The isolation and characterization of SGB11 supports the importance of heterotrimeric G protein in the regulation of the interconnection between the cell wall integrity and immunity.

Localization of atherosclerosis susceptibility loci to chromosomes 4 and 6 using the Ldlr knockout mouse model

Atherosclerosis is a complex disease resulting from the interaction of multiple genes. We have used the Ldlr knockout mouse model in an interspecific genetic cross to map atherosclerosis susceptibility loci. A total of 174 (MOLF/Ei × B6.129S7-Ldlrtm1Her) × C57BL/6J-Ldlrtm1Her backcross mice, homozygous for the Ldlr null allele, were fed a Western-type diet for 3 months and then killed for quantification of aortic lesions. A genome scan was carried out by using DNA pools and microsatellite markers spaced at ≈18-centimorgan intervals. Quantitative trait locus analysis of individual backcross mice confirmed linkages to chromosomes 4 (Athsq1, logarithm of odds = 6.2) and 6 (Athsq2, logarithm of odds = 6.7). Athsq1 affected lesions in females only whereas Athsq2 affected both sexes. Among females, the loci accounted for ≈50% of the total variance of lesion area. The susceptible allele at Athsq1 was derived from the MOLF/Ei genome whereas the susceptible allele at Athsq2 was derived from C57BL/6J. Inheritance of susceptible alleles at both loci conferred a 2-fold difference in lesion area, suggesting an additive effect of Athsq1 and Athsq2. No associations were observed between the quantitative trait loci and levels of plasma total cholesterol, high density lipoprotein cholesterol, non-high density lipoprotein cholesterol, insulin, or body weight. We provide strong evidence for complex inheritance of atherosclerosis in mice with elevated plasma low density lipoprotein cholesterol and show a major influence of nonlipoprotein-related factors on disease susceptibility. Athsq1 and Athsq2 represent candidate susceptibility loci for human atherosclerosis, most likely residing on chromosomes 1p36–32 and 12p13–12, respectively.

Fine mapping of colon tumor susceptibility (Scc) genes in the mouse, different from the genes known to be somatically mutated in colon cancer.

The predisposition to colon cancer is multigenetically controlled in animals and probably also in humans. We have analyzed the multigenic control of susceptibility to 1,2-dimethylhydrazine-induced colon tumors in mice by using a set of 20 homozygous CcS/Dem recombinant congenic strains, each of which contains a different random subset of approximately 12.5% of genes from the susceptible strain STS/A and 87.5% of genes from the relatively resistant strain BALB/cHeA. Some CcS/Dem strains received the alleles from the susceptible strain STS/A at one or more of the multiple colon tumor susceptibility loci and are susceptible, whereas others are resistant. Linkage analysis shows that these susceptibility genes are different from the mouse homologs of the genes known to be somatically mutated in human colon cancer (KRAS2, TP53, DCC, MCC, APC, MSH2, and probably also MLH1). Different subsets of genes control tumor numbers and size. Two colon cancer susceptibility genes, Scc1 and Scc2, map to mouse chromosome 2. The Scc1 locus has been mapped to a narrow region of 2.4 centimorgans (90% confidence interval).

Terrain Controls and Landscape-Scale Susceptibility Modelling of Active-Layer Detachments, Sabine Peninsula, Melville Island, Nunavut

Modelling the susceptibility of permafrost slopes to disturbance can identify areas at risk to future disturbance and result in safer infrastructure and resource development in the Arctic. In this study, we use terrain attributes derived from a digital elevation model, an inventory of permafrost slope disturbances known as active-layer detachments (ALDs) and generalised additive modelling to produce a map of permafrost slope disturbance susceptibility for an area on northern Melville Island, in the Canadian High Arctic. By examining terrain variables and their relative importance, we identified factors important for initiating slope disturbance. The model was calibrated and validated using 70 and 30 per cent of a data-set of 760 mapped ALDs, including disturbed and randomised undisturbed samples. The generalised additive model calibrated and validated very well, with areas under the receiver operating characteristic curve of 0.89 and 0.81, respectively, demonstrating its effectiveness at predicting disturbed and undisturbed samples. ALDs were most likely to occur below the marine limit on slope angles between 3 and 10° and in areas with low values of potential incoming solar radiation (north-facing slopes).

Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation.

We conducted a genome-wide association study (GWAS) on multiple sclerosis (MS) susceptibility in German cohorts with 4888 cases and 10,395 controls. In addition to associations within the major histocompatibility complex (MHC) region, 15 non-MHC loci reached genome-wide significance. Four of these loci are novel MS susceptibility loci. They map to the genes L3MBTL3, MAZ, ERG, and SHMT1. The lead variant at SHMT1 was replicated in an independent Sardinian cohort. Products of the genes L3MBTL3, MAZ, and ERG play important roles in immune cell regulation. SHMT1 encodes a serine hydroxymethyltransferase catalyzing the transfer of a carbon unit to the folate cycle. This reaction is required for regulation of methylation homeostasis, which is important for establishment and maintenance of epigenetic signatures. Our GWAS approach in a defined population with limited genetic substructure detected associations not found in larger, more heterogeneous cohorts, thus providing new clues regarding MS pathogenesis.

Polymorphisms in the trace amine receptor 4 (TRAR4) gene on chromosome 6q23.2 are associated with susceptibility to schizophrenia

Several linkage studies across multiple population groups provide convergent support for a susceptibility locus for schizophrenia - and, more recently, for bipolar disorder - on chromosome 6q13-q26. We genotyped 192 European-ancestry and African American (AA) pedigrees with schizophrenia from samples that previously showed linkage evidence to 6q13-q26, focusing on the MOXD1-STX7-TRARs gene cluster at 6q23.2, which contains a number of prime candidate genes for schizophrenia. Thirty-one screening single-nucleotide polymorphisms (SNPs) were selected, providing a minimum coverage of at least 1 SNP/20 kb. The association observed with rs4305745 (P = .0014) within the TRAR4 (trace amine receptor 4) gene remained significant after correction for multiple testing. Evidence for association was proportionally stronger in the smaller AA sample. We performed database searches and sequenced genomic DNA in a 30-proband subsample to obtain a high-density map of 23 SNPs spanning 21.6 kb of this gene. Single-SNP analyses and also haplotype analyses revealed that rs4305745 and/or two other polymorphisms in perfect linkage disequilibrium (LD) with rs4305745 appear to be the most likely variants underlying the association of the TRAR4 region with schizophrenia. Comparative genomic analyses further revealed that rs4305745 and/or the associated polymorphisms in complete LD with rs4305745 could potentially affect gene expression. Moreover, RT-PCR studies of various human tissues, including brain, confirm that TRAR4 is preferentially expressed in those brain regions that have been implicated in the pathophysiology of schizophrenia. These data provide strong preliminary evidence that TRAR4 is a candidate gene for schizophrenia; replication is currently being attempted in additional clinical samples.

Terrain Controls and Landscape-Scale Susceptibility Modelling of Active-Layer Detachments, Sabine Peninsula, Melville Island, Nunavut

Modelling the susceptibility of permafrost slopes to disturbance can identify areas at risk to future disturbance and result in safer infrastructure and resource development in the Arctic. In this study, we use terrain attributes derived from a digital elevation model, an inventory of permafrost slope disturbances known as active-layer detachments (ALDs) and generalised additive modelling to produce a map of permafrost slope disturbance susceptibility for an area on northern Melville Island, in the Canadian High Arctic. By examining terrain variables and their relative importance, we identified factors important for initiating slope disturbance. The model was calibrated and validated using 70 and 30 per cent of a data-set of 760 mapped ALDs, including disturbed and randomised undisturbed samples. The generalised additive model calibrated and validated very well, with areas under the receiver operating characteristic curve of 0.89 and 0.81, respectively, demonstrating its effectiveness at predicting disturbed and undisturbed samples. ALDs were most likely to occur below the marine limit on slope angles between 3 and 10° and in areas with low values of potential incoming solar radiation (north-facing slopes).

Disruptive Ambient Music: Mobile Phone Music Listening as Portable Urbanism

This article explores the use of mobile phones as portable remediated sound devices for mobile listening — from boom boxes to personal stereos and mp3 players. This mode of engaging the city through music playing and listening reveals a particular urban strategy and acoustic urban politics. It increases the sonic presence of mobile owners and plays a role in territorialisation dynamics, as well as in eliciting territorial controversies in public. These digital practices play a key role in the enactment of the urban mood and ambience, as well as in the modulation of people’s presence — producing forms of what Spanish architect Roberto González calls portable urbanism: an entanglement of the digital, the urban and the online that activates a map of a reality over the fabric of the city, apparently not so present, visible and audible