A Label space reduction algorithm for P2MP LSPs using asymmetric tunnels

The aim of traffic engineering is to optimise network resource utilization. Although several works on minimizing network resource utilization have been published, few works have focused on LSR label space. This paper proposes an algorithm that uses MPLS label stack features in order to reduce the number of labels used in LSPs forwarding. Some tunnelling methods and their MPLS implementation drawbacks are also discussed. The algorithm described sets up the NHLFE tables in each LSR, creating asymmetric tunnels when possible. Experimental results show that the algorithm achieves a large reduction factor in the label space. The work presented here applies for both types of connections: P2MP and P2P

Specific duplication and dorsoventrally asymmetric expression patterns of Cycloidea-like genes in zygomorphic species of Ranunculaceae.

Floral bilateral symmetry (zygomorphy) has evolved several times independently in angiosperms from radially symmetrical (actinomorphic) ancestral states. Homologs of the Antirrhinum majus Cycloidea gene (Cyc) have been shown to control floral symmetry in diverse groups in core eudicots. In the basal eudicot family Ranunculaceae, there is a single evolutionary transition from actinomorphy to zygomorphy in the stem lineage of the tribe Delphinieae. We characterized Cyc homologs in 18 genera of Ranunculaceae, including the four genera of Delphinieae, in a sampling that represents the floral morphological diversity of this tribe, and reconstructed the evolutionary history of this gene family in Ranunculaceae. Within each of the two RanaCyL (Ranunculaceae Cycloidea-like) lineages previously identified, an additional duplication possibly predating the emergence of the Delphinieae was found, resulting in up to four gene copies in zygomorphic species. Expression analyses indicate that the RanaCyL paralogs are expressed early in floral buds and that the duration of their expression varies between species and paralog class. At most one RanaCyL paralog was expressed during the late stages of floral development in the actinomorphic species studied whereas all paralogs from the zygomorphic species were expressed, composing a species-specific identity code for perianth organs. The contrasted asymmetric patterns of expression observed in the two zygomorphic species is discussed in relation to their distinct perianth architecture.

Tetrasomy 8 in a patient with acute nonlymphocytic leukemia: a metaphase and interphase study with fluorescence in situ hybridization.

Tetrasomy 8 constitutes a relatively rare recurring chromosome defect in myeloid disorders. The patient reported here, a 71-year-old man, presented with tetrasomy 8 as the sole chromosome abnormality associated with an acute nonlymphocytic leukemia of the M2 type. He failed to respond to chemotherapy and died one year after diagnosis. Following conventional cytogenetics and fluorescence in situ hybridization (FISH) with a centromeric probe specific for chromosome 8, tetrasomy 8 was detected in 61% of the metaphases analyzed and trisomy 8 in 39%. FISH analysis of interphase nuclei confirmed the existence of tetrasomic (35%) and trisomic cells (56%) and revealed a number of cells with two chromosomes 8 (8%). This normal population may represent lymphocytes or myeloid cells that escaped conventional analysis due to their inability to divide or to the small number of metaphases available. The relatively higher proportion of tetrasomic cells in metaphase compared with interphase may be attributed to a proliferative advantage of tetrasomic cells in vitro or to the longer duration of their cell cycle. The simultaneous presence of trisomic and tetrasomic cells confirms the hypothesis of a clonal relationship between trisomy 8 and tetrasomy 8. Our case brings further evidence to the specificity of tetrasomy 8 to myeloid disorders and to the association of this chromosome abnormality with a relatively poor prognosis. However, new patients must be studied to further delineate this cytogenetic entity.

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.

Delta9-tetrahydrocannabinol decreases somatic and motivational manifestations of nicotine withdrawal in mice

The possible interactions between Delta9-tetrahydrocannabinol (THC) and nicotine remain unclear in spite of the current association of cannabis and tobacco in humans. The aim of the present study was to explore the interactions between these two drugs of abuse by evaluating the consequences of THC administration on the somatic manifestations and the aversive motivational state associated to nicotine withdrawal in mice. Acute THC administration significantly decreased the incidence of several nicotine withdrawal signs precipitated by mecamylamine or naloxone, such as wet-dog-shakes, paw tremor and scratches. In both experimental conditions, the global withdrawal score was also significantly attenuated by acute THC administration. THC also reversed conditioned place aversion associated to naloxone precipitated nicotine withdrawal. We have then evaluated whether this effect of THC was due to possible adaptive changes induced by chronic nicotine on CB1 cannabinoid receptors. The stimulation of GTPS-binding proteins by the cannabinoid agonist WIN 55,212-2 and the density of CB1 cannabinoid receptor binding labelled with [3H] CP-55,940 were not modified by chronic nicotine treatment in the different brain structures investigated. Finally, we evaluated the consequences of THC administration on c-Fos expression in several brain structures after chronic nicotine administration and withdrawal. c-Fos was decreased in the caudate putamen and the dentate gyrus after mecamylamine precipitated nicotine withdrawal. However, acute THC administration did not modify c-Fos expression under these experimental conditions. Taken together, these results indicate that THC administration attenuated somatic signs of nicotine withdrawal and this effect was not associated to compensatory changes on CB1 cannabinoid receptors during chronic nicotine administration. In addition, THC also ameliorated the aversive motivational consequences of nicotine withdrawal.

A protocol describing the genetic correction of somatic human cells and subsequent generation of IPS cell

The generation of patient-specific induced pluripotent stem cells (iPSCPSCPSCs) offers unprecedented opportunities for modeling and treating human disease. In combination with gene therapy, the iPSCPSCPSC technology can be used to generate disease-free progenitor cells of potential interest for autologous cell therapy. We explain a protocol for the reproducible generation of genetically corrected iPSCPSCPSCs starting from the skin biopsies of Fanconi anemia patients using retroviral transduction with OCT4, SOX2 and KLF4. Before reprogramming, the fibroblasts and/or keratinocytes of the patients are genetically corrected with lentiviruses expressing FANCA. The same approach may be used for other diseases susceptible to gene therapy correction. Genetically corrected, characterized lines of patient-specific iPSCPSCPSCs can be obtained in 4–5 months.

The truncated mean of an asymmetric distribution

This paper investigates a simple procedure to estimate robustly the mean of an asymmetric distribution. The procedure removes the observations which are larger or smaller than certain limits and takes the arithmetic mean of the remaining observations, the limits being determined with the help of a parametric model, e.g., the Gamma, the Weibull or the Lognormal distribution. The breakdown point, the influence function, the (asymptotic) variance, and the contamination bias of this estimator are explored and compared numerically with those of competing estimates.

An integrated genomic and expression analysis of 7q deletion in splenic marginal zone lymphoma.

Splenic marginal zone lymphoma (SMZL) is an indolent B-cell lymphoproliferative disorder characterised by 7q32 deletion, but the target genes of this deletion remain unknown. In order to elucidate the genetic target of this deletion, we performed an integrative analysis of the genetic, epigenetic, transcriptomic and miRNomic data. High resolution array comparative genomic hybridization of 56 cases of SMZL delineated a minimally deleted region (2.8 Mb) at 7q32, but showed no evidence of any cryptic homozygous deletion or recurrent breakpoint in this region. Integrated transcriptomic analysis confirmed significant under-expression of a number of genes in this region in cases of SMZL with deletion, several of which showed hypermethylation. In addition, a cluster of 8 miRNA in this region showed under-expression in cases with the deletion, and three (miR-182/96/183) were also significantly under-expressed (P<0.05) in SMZL relative to other lymphomas. Genomic sequencing of these miRNA and IRF5, a strong candidate gene, did not show any evidence of somatic mutation in SMZL. These observations provide valuable guidance for further characterisation of 7q deletion.

Inferring the degree of incipient speciation in secondary contact zones of closely related lineages of Palearctic green toads (Bufo viridis subgroup).

Reproductive isolation between lineages is expected to accumulate with divergence time, but the time taken to speciate may strongly vary between different groups of organisms. In anuran amphibians, laboratory crosses can still produce viable hybrid offspring >20 My after separation, but the speed of speciation in closely related anuran lineages under natural conditions is poorly studied. Palearctic green toads (Bufo viridis subgroup) offer an excellent system to address this question, comprising several lineages that arose at different times and form secondary contact zones. Using mitochondrial and nuclear markers, we previously demonstrated that in Sicily, B. siculus and B. balearicus developed advanced reproductive isolation after Plio-Pleistocene divergence (2.6 My, 3.3-1.9), with limited historic mtDNA introgression, scarce nuclear admixture, but low, if any, current gene flow. Here, we study genetic interactions between younger lineages of early Pleistocene divergence (1.9 My, 2.5-1.3) in northeastern Italy (B. balearicus, B. viridis). We find significantly more, asymmetric nuclear and wider, differential mtDNA introgression. The population structure seems to be molded by geographic distance and barriers (rivers), much more than by intrinsic genomic incompatibilities. These differences of hybridization between zones may be partly explained by differences in the duration of previous isolation. Scattered research on other anurans suggests that wide hybrid zones with strong introgression may develop when secondary contacts occur <2 My after divergence, whereas narrower zones with restricted gene flow form when divergence exceeds 3 My. Our study strengthens support for this rule of thumb by comparing lineages with different divergence times within the same radiation.

A hybrid zone with coincident clines for autosomal and sex-specific markers in the Sorex araneus group.

In hybrid zones, endogenous counter-selection of hybrids is usually first expressed as reduced fertility or viability in hybrids of the heterogametic sex, a mechanism known as Haldane's rule. This phenomenon often leads to a differential of gene flow between sex-linked markers. Here, we address the possibility of a differential gene flow for Y chromosome, mtDNA and autosomal markers across the hybrid zone between the genetically and chromosomally well-differentiated species Sorex antinorii and Sorex araneus race Vaud. Intermarker comparison clearly revealed coincidental centre and very abrupt clines for all three types of markers. The overall level of genetic differentiation between the two species must be strong enough to hinder asymmetric introgression. Cyto-nuclear mismatches were also observed in the centre of hybrid zone. The significantly lower number of mismatches observed in males than in females possibly results from Y chromosome-mtDNA interactions. Results are compared with those previously reported in another hybrid zone between S. antinori and S. araneus race Cordon.

Asymmetric information and trade policy

Economists understand protectionism as a costly mechanism to redistribute from the average citizen to special-interest groups; yet political platforms that deviate from free trade have surprising popular appeal. I present an explanation based on heterogeneous information across citizens whose voting decision has an intensive margin. For each politician and each sector, the optimal trade-policy choice caters to the preferences of those voters who are more likely to be informed of that proposal. An overall protectionist bias emerges because in every industry producers are better informed than consumers. This asymmetry emerges in equilibrium because co-workers share industry-specific knwoledge, and because producers have greater incentives to engage in costly learning about their sector. My model implies that more widespread information about trade policy for an industry is associated with lower protection. Cross-sectoral evidence on U.S. non-tariff barriers and newspaper coverage is consistent with this prediction.

Hybridization and speciation.

Hybridization has many and varied impacts on the process of speciation. Hybridization may slow or reverse differentiation by allowing gene flow and recombination. It may accelerate speciation via adaptive introgression or cause near-instantaneous speciation by allopolyploidization. It may have multiple effects at different stages and in different spatial contexts within a single speciation event. We offer a perspective on the context and evolutionary significance of hybridization during speciation, highlighting issues of current interest and debate. In secondary contact zones, it is uncertain if barriers to gene flow will be strengthened or broken down due to recombination and gene flow. Theory and empirical evidence suggest the latter is more likely, except within and around strongly selected genomic regions. Hybridization may contribute to speciation through the formation of new hybrid taxa, whereas introgression of a few loci may promote adaptive divergence and so facilitate speciation. Gene regulatory networks, epigenetic effects and the evolution of selfish genetic material in the genome suggest that the Dobzhansky-Muller model of hybrid incompatibilities requires a broader interpretation. Finally, although the incidence of reinforcement remains uncertain, this and other interactions in areas of sympatry may have knock-on effects on speciation both within and outside regions of hybridization.

Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma.

We performed exome sequencing to detect somatic mutations in protein-coding regions in seven melanoma cell lines and donor-matched germline cells. All melanoma samples had high numbers of somatic mutations, which showed the hallmark of UV-induced DNA repair. Such a hallmark was absent in tumor sample-specific mutations in two metastases derived from the same individual. Two melanomas with non-canonical BRAF mutations harbored gain-of-function MAP2K1 and MAP2K2 (MEK1 and MEK2, respectively) mutations, resulting in constitutive ERK phosphorylation and higher resistance to MEK inhibitors. Screening a larger cohort of individuals with melanoma revealed the presence of recurring somatic MAP2K1 and MAP2K2 mutations, which occurred at an overall frequency of 8%. Furthermore, missense and nonsense somatic mutations were frequently found in three candidate melanoma genes, FAT4, LRP1B and DSC1.

Hybridization and Population Structure of the Culex Pipiens Complex in the Islands of Macaronesia

The Culex pipiens complex includes two widespread mosquito vector species, Cx. pipiens and Cx. quinquefasciatus. The distribution of these species varies in latitude, with the former being present in temperate regions and the latter in tropical and subtropical regions. However, their distribution range overlaps in certain areas and interspecific hybridization has been documented. Genetic introgression between these species may have epidemiological repercussions for West Nile virus (WNV) transmission. Bayesian clustering analysis based on multilocus genotypes of 12 microsatellites was used to determine levels of hybridization between these two species in Macaronesian islands, the only contact zone described in West Africa. The distribution of the two species reflects both the islands’ biogeography and historical aspects of human colonization. Madeira Island displayed a homogenous population of Cx. pipiens, whereas Cape Verde showed a more intriguing scenario with extensive hybridization. In the islands of Brava and Santiago, only Cx. quinquefasciatus was found, while in Fogo and Maio high hybrid rates (~40%) between the two species were detected. Within the admixed populations, second-generation hybrids (~50%) were identified suggesting a lack of isolation mechanisms. The observed levels of hybridization may locally potentiate the transmission to humans of zoonotic arboviruses such as WNV.