The JNK binding domain of islet-brain 1 inhibits IL-1 induced JNK activity and apoptosis but not the transcription of key proapoptotic or protective genes in insulin-secreting cell lines.

The stress-activated protein kinase c-Jun NH2-terminal kinase (JNK) is a central signal for interleukin-1beta (IL-1beta)-induced apoptosis in insulin-producing beta-cells. The cell-permeable peptide inhibitor of JNK (JNKI1), that introduces the JNK binding domain (JBD) of the scaffold protein islet-brain 1 (IB1) inside cells, effectively prevents beta-cell death caused by this cytokine. To define the molecular targets of JNK involved in cytokine-induced beta-cell apoptosis we investigated whether JNKI1 or stable expression of JBD affected the expression of selected pro- and anti-apoptotic genes induced in rat (RIN-5AH-T2B) and mouse (betaTC3) insulinoma cells exposed to IL-1beta. Inhibition of JNK significantly reduced phosphorylation of the specific JNK substrate c-Jun (p<0.05), IL-1beta-induced apoptosis (p<0.001), and IL-1beta-mediated c-fos gene expression. However, neither JNKI1 nor JBD did influence IL-1beta-induced NO synthesis or iNOS expression or the transcription of the genes encoding mitochondrial manganese superoxide dismutase (MnSOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase rho (GSTrho), heat shock protein (HSP) 70, IL-1beta-converting enzyme (ICE), caspase-3, apoptosis-inducing factor (AIF), Bcl-2 or Bcl-xL. We suggest that the anti-apoptotic effect of JNK inhibition by JBD is independent of the transcription of major pro- and anti-apoptotic genes, but may be exerted at the translational or posttranslational level.

The cuticle: Not only a barrier for plant defence: A novel defence syndrome in plants with cuticular defects.

The cuticle is a physical barrier that prevents water loss and protects against irradiation, xenobiotics and pathogens. This classic textbook statement has recently been revisited and several observations were made showing that this dogma falls short of being universally true. Both transgenic Arabidopsis thaliana lines expressing cell wall-targeted fungal cutinase (so-called CUTE plants) or lipase as well as several A. thaliana mutants with altered cuticular structure remained free of symptoms after an inoculation with Botrytis cinerea. The alterations in cuticular structure lead to the release of fungitoxic substances and changes in gene expression that form a multifactorial defence response. Several models to explain this syndrome are discussed.

Simultaneous co-expression of memory- and effector-related genes by individual human CD8 T cells depends on antigen specificity and differentiation

Purpose/Objective: Phenotypic and functional T cell properties are usually analyzed at the level of defined cell populations. However, large differences between individual T cells may have important functional consequences. To answer this issue, we performed highly sensitive single-cell gene expression profiling, which allows the direct ex vivo characterization of individual virus- and tumor-specific T cells from healthy donors and melanoma patients. Materials and methods: HLA-A*0201-positive patients with stage III/ IV metastatic melanoma were included in a phase I clinical trial (LUD- 00-018). Patients received monthly low-dose of the Melan-AMART- 1 26_35 unmodified natural (EAAGIGILTV) or the analog A27L (ELAGIGILTV) peptides, mixed CPG and IFA. Individual effector memory CD28+ (EM28+) and EM28- tetramer-specific CD8pos T cells were sorted by flow cytometer. Following direct cell lysis and reverse transcription, the resulting cDNA was precipitated and globally amplified. Semi-quantitative PCR was used for gene expression and TCR BV repertoire analyses. Results: We have previously shown that vaccination with the natural Melan-A peptide induced T cells with superior effector functions as compared to the analog peptide optimized for enhanced HLA binding. Here we found that natural peptide vaccination induced EM28+ T cells with frequent co-expression of both memory/homing-associated genes (CD27, IL7R, EOMES, CXCR3 and CCR5) and effector-related genes (IFNG, KLRD1, PRF1 and GZMB), comparable to protective EBV- and CMV-specific T cells. In contrast, memory/homing- and effectorassociated genes were less frequently co-expressed after vaccination with the analog peptide. Conclusions: These findings reveal a previously unknown level of gene expression diversity among vaccine- and virus-specific T cells with the simultaneous co-expression of multiple memory/homing- and effector- related genes by the same cell. Such broad functional gene expression signatures within antigen-specific T cells may be critical for mounting efficient responses to pathogens or tumors. In summary, direct ex vivo high-resolution molecular characterization of individual T cells provides key insights into the processes shaping the functional properties of tumor- and virus-specific T cells.

Circadian clock genes and sleep homeostasis.

Circadian and sleep-homeostatic processes both contribute to sleep timing and sleep structure. Elimination of circadian rhythms through lesions of the suprachiasmatic nuclei (SCN), the master circadian pacemaker, leads to fragmentation of wakefulness and sleep but does not eliminate the homeostatic response to sleep loss as indexed by the increase in EEG delta power. In humans, EEG delta power declines during sleep episodes nearly independently of circadian phase. Such observations have contributed to the prevailing notion that circadian and homeostatic processes are separate but recent data imply that this segregation may not extend to the molecular level. Here we summarize the criteria and evidence for a role for clock genes in sleep homeostasis. Studies in mice with targeted disruption for core circadian clock genes have revealed alterations in circadian rhythmicity as well as changes in sleep duration, sleep structure and EEG delta power. Clock-gene expression in brain areas outside the SCN, in particular the cerebral cortex, depends to a large extent on prior sleep-wake history. Evidence for effects of clock genes on sleep homeostasis has also been obtained in Drosophila and humans, pointing to a phylogenetically preserved pathway. These findings suggest that, while within the SCN clock genes are utilized to set internal time-of-day, in the forebrain the same feedback circuitry may be utilized to track time spent awake and asleep. The mechanisms by which clock-gene expression is coupled to the sleep-wake distribution could be through cellular energy charge whereby clock genes act as energy sensors. The data underscore the interrelationships between energy metabolism, circadian rhythmicity, and sleep regulation.

Genetics for clinicians: from candidate genes to whole genome scans (technological advances).

Human genetics has progressed at an unprecedented pace during the past 10 years. DNA microarrays currently allow screening of the entire human genome with high level of coverage and we are now entering the era of high-throughput sequencing. These remarkable technical advances are influencing the way medical research is conducted and have boosted our understanding of the structure of the human genome as well as of disease biology. In this context, it is crucial for clinicians to understand the main concepts and limitations of modern genetics. This review will describe key concepts in genetics, including the different types of genetic markers in the human genome, review current methods to detect DNA variation, describe major online public databases in genetics, explain key concepts in statistical genetics and finally present commonly used study designs in clinical and epidemiological research. This review will therefore concentrate on human genetic variation analysis.

Long-distance wound signalling in arabidopsis

The leaves of all plants use elaborate and inducible defence systems to protect themselves. A wide variety of such defences are known and they include defence chemicals such as alkaloids, phenolics and terpenes, physical structures ranging from fibre cells to silica deposits, and a wide variety of defence proteins many of which target digestive processes in herbivores. It has long been known that the defence responses of plants under attack by insects are not restricted to the site of attack. Instead, if a leaf is damaged, defence can be triggered in other parts of the plant body, for example in distal leaves or even in roots and flowers. This raises the question of what are the organ-to-organ signals that coordinate this process. Several hypotheses have been proposed. These include the long-distance transfer of chemical signals through the plant vasculature, hydraulic signals that may transit through the xylem, and electrical signals that would move through living tissues such as the phloem. Much evidence for each of these scenarios has been published. In this thesis we took advantage of the fact that many plant defence responses are regulated by a signal transduction pathway based on a molecule called jasmonic acid. We used this molecule, one of its derivatives (jasmonoyl-isoleucine), and some of the genes it regulates as markers. Using these we investigated the possible role of the electrical signals in the leaf- to-leaf activation of the jasmonate pathway. We found that feeding insects stimulate easily detected electrical activity in the leaves of Arabidopsis thaliana and we used non-invasive surface electrodes to record this activity. This approach showed that jasmonate pathway activity and the electrical activity provoked by mechanical wounding occurred within identical spatial boundaries. Measurements of the apparent speed of surface potentials agreed well with previous velocity estimates for the speed of leaf-to-leaf signals that activate the jasmonate pathway. Using this knowledge we were able to investigate the effects of current injection into Arabidopsis leaves. This resulted in the strong expression of many jasmonate-regulated genes. All these results showed that electrical activity and the activation of jasmonate signalling were highly correlated. In order to test for possible causal links between the two processes, we conducted a small-scale reverse genetic screen on a series of T-DNA insertion mutants in ion channel genes and in other genes encoding proteins such as proton pumps. This screen, which was based on surface potential measurements, revealed that mutations in genes related to ionotropic glutamate receptors in animals had impaired electrical activity after wounding. Combining mutation of two of these glutamate-receptor-like genes in a double mutant reduced the response of leaves to current injection. When a leaf of this double mutant was wounded it failed to transmit a long-distance signal to a distal leaf. This result distinguished the double mutant from the wild-type plant and provides the first genetic evidence that electrical signalling is necessary to coordinate defence responses between organs in plants. - Les feuilles des plantes disposent de systèmes de défense inductibles très élaborés. Un grand nombre de ces systèmes de défenses sont connus et sont basés sur des composés chimiques comme les alcaloïdes, les composés phénoliques ou les terpènes, des systèmes physiques allant de la production de cellules fibreuses aux cristaux de silice ainsi qu'un grand nombre de protéines de défense ciblant le processus digestif des herbivores. Il est connu dépuis longtemps que la réponse défensive de la plante face à l'attaque pas un insecte n'est pas seulement localisée au niveau de la zone d'attaque. A la place, si une feuille est attaquée, les systèmes de défense peuvent être activés ailleurs dans la plante, comme par exemple dans d'autres feuilles, les racines ou même les fleurs. Ces observations soulèvent la question de la nature des signaux d'organes à organes qui régulent ces systèmes. Plusieurs hypothèses ont été formulées; une ou plusieures molécules pourraient être véhiculées dans la plante grâce au système vasculaire, un signal hydraulique transmis au travers du xylème ou encore des signaux électriques transmis par les cellules comme dans le phloème par exemple. De nombreuses études ont été publiées sur ces différentes hypothèses. Dans ce travail de thèse, nous avons choisi d'utiliser à notre avantage le fait que de nombreuses réponses de défense de la plante sont régulées par une même voie de signalisation utilisant l'acide jasmonique. Nous avons utilisé comme marqueurs cette molécule, un de ses dérivés (le jasmonoyl-isoleucine) ainsi que certains des gènes que l'acide jasmonique régule. Nous avons alors testé l'implication de la transmission de signaux électriques dans l'activation de la voie du jasmonate de feuille à feuille. Nous avons découvert que les insectes qui se nourrissent de feuilles d'Arabidopsis thaliana activent un signal électrique que nous avons pu mesurer grâce à une technique non invasive d'électrodes de surface. Les enregistrements ont montré que la génération de signaux électriques et l'activation de la voie du jasmonate avaient lieu aux mêmes endroits. La mesure de la vitesse de déplacement des impulsions électriques correspond aux estimations faites concernant l'activation de la voie du jasmonate. Grâce à cela, nous avons pu tester l'effet d'injection de courant électrique dans les feuilles d'Arabidopsis. La conséquence a été une forte expression de nombreux gènes de la voie du jasmonate, suggérant une forte corrélation entre l'activité électrique et l'activation de la voie du jasmonate. Afin de tester le lien de cause entre ces deux phénomènes, nous avons entrepris un criblage génétique sur une série de mutants d'insertion à l'ADN-T dans des gènes de canaux ioniques et d'autres gènes d'intérêt comme les gènes des pompes à protons. Ce criblage, basé sur la mesure de potentiels de surface, a permis de montrer que plusieurs mutations de gènes liés aux récepteurs au glutamate ionotropique présentent une baisse drastique de leurs activités électriques après une blessure mécanique des feuilles par rapport au type sauvage. Par la combinaison de deux mutations de ces récepteurs au glutamate en un double mutant, on obtient une réponse à la stimulation électrique encore plus faible. Quand une feuille du double mutant est blessée, elle est incapable de transmettre un signal à longue distance vers une feuille éloignée. Ce résultat permet de distinguer le double mutant de la plante sauvage et amène la première preuve génétique que l'activité électrique est nécessaire pour coordonner les réponses de défense entre les organes chez les plantes.

Genometric analyses of the organization of circular chromosomes: a universal pressure determines the direction of ribosomal RNA genes transcription relative to chromosome replication.

Selective pressures related to gene function and chromosomal architecture are acting on genome sequences and can be revealed, for instance, by appropriate genometric methods. Cumulative nucleotide skew analyses, i.e., GC, TA, and ORF orientation skews, predict the location of the origin of DNA replication for 88 out of 100 completely sequenced bacterial chromosomes. These methods appear fully reliable for proteobacteria, Gram-positives, and spirochetes as well as for euryarchaeotes. Based on this genome architecture information, coorientation analyses reveal that in prokaryotes, ribosomal RNA (rRNA) genes encoding the small and large ribosomal subunits are all transcribed in the same direction as DNA replication; that is, they are located along the leading strand. This result offers a simple and reliable method for circumscribing the region containing the origin of the DNA replication and reveals a strong selective pressure acting on the orientation of rRNA genes similar to the weaker one acting on the orientation of ORFs. Rate of coorientation of transfer RNA (tRNA) genes with DNA replication appears to be taxon-specific. Analyzing nucleotide biases such as GC and TA skews of genes and plotting one against the other reveals a taxonomic clusterization of species. All ribosomal RNA genes are enriched in Gs and depleted in Cs, the only so far known exception being the rRNA genes of deuterostomian mitochondria. However, this exception can be explained by the fact that in the chromosome of the human mitochondrion, the model of the deuterostomian organelle genome, DNA replication, and rRNA transcription proceed in opposite directions. A general rule is deduced from prokaryotic and mitochondrial genomes: ribosomal RNA genes that are transcribed in the same direction as the DNA replication are enriched in Gs, and those transcribed in the opposite direction are depleted in Gs.

Evaluation de la sarcopénie de la personne agée par la bio-impédance spectroscopique [Multispectral bioimpedance and sarcopenia in the elderly].

The definition of sarcopenia includes both a loss of muscle strength and a decline in functional quality in addition to the loss of muscle protein mass. Multispectral bioimpendance allows bedside assessment of muscle mass. Using this new tool, we performed a pilot study to look for a possible correlation between muscle mass and various tests of muscle strength (grip strength, key-pitch, tip-pinch) and with functional tests (walk speed on 10 meters and Tinetti test). Our study demonstrates a good correlation between muscle mass determined by spectroscopic bioimpendance and muscle strength assessment, but no correlation with functional tests.

Repression of flagellar genes in exponential phase by CsgD and CpxR, two crucial modulators of Escherichia coli biofilm formation.

Escherichia coli adapts its lifestyle to the variations of environmental growth conditions, swapping between swimming motility or biofilm formation. The stationary-phase sigma factor RpoS is an important regulator of this switch, since it stimulates adhesion and represses flagellar biosynthesis. By measuring the dynamics of gene expression, we show that RpoS inhibits the transcription of the flagellar sigma factor, FliA, in exponential growth phase. RpoS also partially controls the expression of CsgD and CpxR, two transcription factors important for bacterial adhesion. We demonstrate that these two regulators repress the transcription of fliA, flgM, and tar and that this regulation is dependent on the growth medium. CsgD binds to the flgM and fliA promoters around their -10 promoter element, strongly suggesting direct repression. We show that CsgD and CpxR also affect the expression of other known modulators of cell motility. We propose an updated structure of the regulatory network controlling the choice between adhesion and motility.

Biogeochemical evolution of a marine shore tailings deposit during bioremediation

Summary : Mining activities produce enormous amounts of waste material known as tailings which are composed of fine to medium size particles. These tailings often contain sulfides, which oxidation can lead to acid and metal contamination of water; therefore they need to be remediated. In this work a tailings bioremediation approach was investigated by an interdisciplinary study including geochemistry, mineralogy and microbiology. The aim of the work was to study the effect of the implementation of wetland above oxidizing tailings on the hydrogeology and the biogeochemical element cycles, and to assess the system evolution over time. To reach these goals, biogeochemical processes occurring in a marine shore tailings deposit were investigated. The studied tailings deposit is located at the Bahìa de Ite, Pacific Ocean, southern Peru, where between 1940 and 1996 the tailings were discharged from the two porphyry copper mines Cuajone and Toquepala. After the end of deposition, a remediation approach was initiated in 1997 with a wetland implementation above the oxidizing tailings. Around 90% of the tailings deposits (total 16 km2) were thus remediated, except the central delta area and some areas close to the shoreline. The multi-stable isotope study showed that the tailings were saturated with fresh water in spite of the marine setting, due to the high hydraulic gradient resulting from the wetland implementation. Submarine groundwater discharge (SGD) was the major source of SO4 2-, C1-, Na+, Fe2+, and Mn2+ input into the tailings at the original shelf-seawater interface. The geochemical study (aquatic geochemistry and X-Ray diffraction (XRD) and sequential extractions from the solid fraction) showed that iron and sulfur oxidation were the main processes in the non-remediated tailings, which showed a top a low-pH oxidation zone with strong accumulation of efflorescent salts at the surface due to capillary upward transport of heavy metals (Fe, Cu, Zn, Mn, Cd, Co, and Ni) in the arid climate. The study showed also that the implementation of the wetland resulted in very low concentrations of heavy metals in solution (mainly under the detection limit) due to the near neutral pH and more reducing conditions (100-150 mV). The heavy metals, which were taken from solution, precipitated as hydroxides and sulfides or were bound to organic matter. The bacterial community composition analysis by Terminal Restriction Fragment Length Polymorphism (T-RFLP) and cloning and sequencing of 16S rRNA genes combined with a detailed statistical analysis revealed a high correlation between the bacterial distribution and the geochemical variables. Acidophilic autotrophic oxidizing bacteria were dominating the oxidizing tailings, whereas neutrophilic and heterotrophic reducing bacteria were driving the biogeochemical processes in the remediated tailings below the wetland. At the subsurface of the remediated tailings, an iron cycling was highlighted with oxidation and reduction processes due to micro-aerophilic niches provided by the plant rhizosphere in this overall reducing environment. The in situ bioremediation experiment showed that the main parameter to take into account for the effectiveness was the water table and chemistry which controls the system. The constructed remediation cells were more efficient and rapid in metal removal when saturation conditions were available. This study showed that the bioremediation by wetland implementation could be an effective and rapid treatment for some sulfidic mine tailings deposits. However, the water saturation of the tailings has to be managed on a long-term basis in order to guarantee stability. Résumé : L'activité minière produit d'énormes quantités de déchets géologiques connus sous le nom de « tailings » composées de particules de taille fine à moyenne. Ces déchets contiennent souvent des sulfures dont l'oxydation conduit à la formation d'effluents acides contaminés en métaux, d'où la nécessité d'effectuer une remédiation des sites de stockage concernés. Le but de ce travail est dans un premier temps d'étudier l'effet de la bio-remédiation d'un dépôt de tailings oxydés sur l'hydrogéologie du système et les cycles biogéochimiques des éléments et en second lieu, d'évaluer l'évolution du processus de remédiation dans le temps. Le site étudié dans ce travail est situé dans la Bahía de Ite, au sud du Pérou, au bord de l'Océan Pacifique. Les déchets miniers en question sont déposés dans un environnement marin. De 1940 à 1996, les déchets de deux mines de porphyre cuprifère - Cuajone et Toquepala - ont été acheminés sur le site via la rivière Locumba. En 1997, une première remédiation a été initiée avec la construction d'une zone humide sur les tailings. Depuis, environ 90% de la surface du dépôt (16 km2) a été traité, les parties restantes étant la zone centrale du delta du Locumba et certaines zones proches de la plage. Malgré la proximité de l'océan, les études isotopiques menées dans le cadre de ce travail ont montré que les tailings étaient saturés en eau douce. Cette saturation est due à la pression hydraulique résultant de la mise en place des zones humides. Un écoulement d'eau souterrain sous-marin a été à détecté à l'interface entre les résidus et l'ancien fond marin. En raison de la géologie locale, il constitue une source d'entrée de SO4 2-, Cl-, Na+, FeZ+, et Mn2+ dans le système. L'analyse de la géochimie aquatique, la Diffraction aux Rayons X (XRD) et l'extraction séquentielle ont montré que l'oxydation du fer et .des sulfures est le principal processus se produisant dans les déchets non remédiés. Ceci a entraîné le développement d'une zone d'oxydation à pH bas induisant une forte accumulation des sels efflorescents, conséquence de la migration capillaire des métaux lourds (Fe, Cu, Zn, Mn, Cd, Co et Ni) de la solution vers la surface dans ce climat aride. Cette étude a montré également que la construction de la zone humide a eu comme résultats une précipitation des métaux dans des phases minérales en raison du pH neutre et des conditions réductrices (100-150mV). Les métaux lourds ont précipité sous la forme d'hydroxydes et de sulfures ou sont adsorbés à la matière organique. L'analyse de la composition de la communauté bactérienne à l'aide la technique T-RFLP (Terminal Restriction Fragment Length Polymorphism) et par le clonage/séquençage des gènes de l'ARNr 16S a été combinée à une statistique détaillée. Cette dernière a révélé une forte corrélation entre la distribution de bactéries spécifiques et la géochimie : Les bactéries autotrophes acidophiles dominent dans les déchets oxydés non remédiés, tandis que des bactéries hétérotrophes neutrophiles ont mené les processus microbiens dans les déchets remédiés sous la zone humide. Sous la surface de la zone humide, nos analyses ont également mis en évidence un cycle du fer par des processus d'oxydoréduction rendus possibles par la présence de niches micro-aérées par la rhizosphère dans cet environnement réducteur. L'expérience de bio-remédiation in situ a montré que les paramètres clés qui contrôlent l'efficacité du traitement sont le niveau de la nappe aquifère et la chimie de l'eau. Les cellules de remédiation se sont montrées plus efficaces et plus rapides lorsque le système a pu être saturé en eau. Finalement, cette étude a montré que la bio-remédiation de déchets miniers par la construction de zones humides est un moyen de traitement efficace, rapide et peu coûteux. Cependant, la saturation en eau du système doit être gérée sur le long terme afin de garantir la stabilité de l'ensemble du système.

The CNGCb and CNGCd genes from Physcomitrella patens moss encode for thermosensory calcium channels responding to fluidity changes in the plasma membrane.

Land plants need precise thermosensors to timely establish molecular defenses in anticipation of upcoming noxious heat waves. The plasma membrane-embedded cyclic nucleotide-gated Ca(2+) channels (CNGCs) can translate mild variations of membrane fluidity into an effective heat shock response, leading to the accumulation of heat shock proteins (HSP) that prevent heat damages in labile proteins and membranes. Here, we deleted by targeted mutagenesis the CNGCd gene in two Physcomitrella patens transgenic moss lines containing either the heat-inducible HSP-GUS reporter cassette or the constitutive UBI-Aequorin cassette. The stable CNGCd knockout mutation caused a hyper-thermosensitive moss phenotype, in which the heat-induced entry of apoplastic Ca(2+) and the cytosolic accumulation of GUS were triggered at lower temperatures than in wild type. The combined effects of an artificial membrane fluidizer and elevated temperatures suggested that the gene products of CNGCd and CNGCb are paralogous subunits of Ca(2+)channels acting as a sensitive proteolipid thermocouple. Depending on the rate of temperature increase, the duration and intensity of the heat priming preconditions, terrestrial plants may thus acquire an array of HSP-based thermotolerance mechanisms against upcoming, otherwise lethal, extreme heat waves.

Network-guided analysis of genes with altered somatic copy number and gene expression reveals pathways commonly perturbed in metastatic melanoma.

Cancer genomes frequently contain somatic copy number alterations (SCNA) that can significantly perturb the expression level of affected genes and thus disrupt pathways controlling normal growth. In melanoma, many studies have focussed on the copy number and gene expression levels of the BRAF, PTEN and MITF genes, but little has been done to identify new genes using these parameters at the genome-wide scale. Using karyotyping, SNP and CGH arrays, and RNA-seq, we have identified SCNA affecting gene expression ('SCNA-genes') in seven human metastatic melanoma cell lines. We showed that the combination of these techniques is useful to identify candidate genes potentially involved in tumorigenesis. Since few of these alterations were recurrent across our samples, we used a protein network-guided approach to determine whether any pathways were enriched in SCNA-genes in one or more samples. From this unbiased genome-wide analysis, we identified 28 significantly enriched pathway modules. Comparison with two large, independent melanoma SCNA datasets showed less than 10% overlap at the individual gene level, but network-guided analysis revealed 66% shared pathways, including all but three of the pathways identified in our data. Frequently altered pathways included WNT, cadherin signalling, angiogenesis and melanogenesis. Additionally, our results emphasize the potential of the EPHA3 and FRS2 gene products, involved in angiogenesis and migration, as possible therapeutic targets in melanoma. Our study demonstrates the utility of network-guided approaches, for both large and small datasets, to identify pathways recurrently perturbed in cancer.

Early maternal investment in mice: no evidence for compatible-genes sexual selection despite hybrid vigor.

Confronting a recently mated female with a strange male can induce a pregnancy block ('Bruce effect'). The physiology of this effect is well studied, but its functional significance is still not fully understood. The 'anticipated infanticide hypothesis' suggests that the pregnancy block serves to avoid the cost of embryogenesis and giving birth to offspring that are likely to be killed by a new territory holder. Some 'compatible-genes sexual selection hypotheses' suggest that the likelihood of a pregnancy block is also dependent on the female's perception of the stud's and the stimulus male's genetic quality. We used two inbred strains of mice (C57BL/6 and BALB/c) to test all possible combinations of female strain, stud strain, and stimulus strain under experimental conditions (N(total) = 241 mated females). As predicted from previous studies, we found increased rates of pregnancy blocks if stud and stimulus strains differed, and we found evidence for hybrid vigour in offspring of between-strain mating. Despite the observed heterosis, pregnancies of within-strain matings were not more likely to be blocked than pregnancies of between-strain matings. A power analysis revealed that if we missed an existing effect (type-II error), the effect must be very small. If a female gave birth, the number and weight of newborns were not significantly influenced by the stimulus males. In conclusion, we found no support for the 'compatible-genes sexual selection hypotheses'.