Eliette Touati
email: etouati@pasteur.fr

When bacteria become mutagenic and carcinogenic: lessons from H. pylori

Keywords: Infection, nucleotide modification, DNA repair, inflammation, cancer

More and more convincing data link bacteria to the development of cancers. How bacteria act as mutagens by altering host genomes, what are the different strategies they develop and what consequences do they have on infection-associated pathogenesis are the main questions addressed in this review, which focuses in particular on Helicobacter pylori infection. H. pylori is a major risk factor for gastric cancer development. Its oncogenic role is mediated by the chronic active inflammation it elicits in the gastric mucosa, associated with its capacity to persistently colonize the human stomach.

However, direct genotoxicity of H. pylori through the action of bacterial cytotoxin or resulting from a DNA damaging effect of its metabolic derivatives as nitroso compounds cannot be excluded. Numerous studies have investigated inflammation-associated DNA damaging activity and mutagenic response due to H. pylori infection in both human and animal models. Recent findings on its mutagenic effects at the nuclear and mitochondrial genome and related DNA damage are reviewed. This genotoxic activity associated with oxidative species produced during inflammation is linked to the decreased efficiency of DNA repair systems. DNA methylation, which plays an important role in the regulation of the host response to H. pylori infection, is also documented. Furthermore, H. pylori affects genome integrity by increasing activation-induced cytidine deaminase (AID), a DNA/RNA editing cytidine deaminase linking mutagenesis and tumorigenesis. These different strategies occurring during bacteria-host cell interaction, lead to nucleotide modifications and genome instabilities recognized as early events in the carcinogenesis process and contribute to the oncogenic properties of H. pylori infection.

Introduction

Sixteen percent of cancer incidence throughout the world can be attributed to infectious agents. Although the viral origin of human cancers is well established, convincing data also link bacteria to cancer development [START_REF] Mager | Bacteria and cancer: cause, coincidence or cure? A review[END_REF]. Helicobacter pylori is associated with the majority of gastric cancers classified as intestinal-type adenocarcinoma and recognized as a type 1 carcinogenic agent [START_REF] Mbulaiteye | Helicobacter pylori associated global gastric cancer burden[END_REF] [START_REF]IARC Working Group on the Evaluation of Carcinogenic Risks to Humans Infection with Helicobacter pylori[END_REF]. The associated gastric lesions are initiated by chronic superficial gastritis, atrophic gastritis, and intestinal metaplasia that evolve into to dysplasia and adenocarcinoma [START_REF] Peek | Helicobacter pylori and gastrointestinal tract adenocarcinomas[END_REF] [START_REF] Correa | Helicobacter pylori and gastric cancer: state of the art[END_REF]. Chronic gastritis is the hallmark of H. pylori infection. Several H. pylori virulence factors such as variants of vacA encoding a vacuolating cytotoxin [START_REF] Isomoto | Pleiotropic actions of Helicobacter pylori vacuolating cytotoxin, VacA[END_REF], and the presence of the cag pathogenicity island (Cag-PAI) are associated with the most severe gastric pathologies [START_REF] Handa | CagA protein of Helicobacter pylori: a hijacker of gastric epithelial cell signaling[END_REF]. Recently, the CagA protein, a member of Cag-PAI has been shown to induce chromosomal instability by causing mitotic impairment [START_REF] Umeda | Helicobacter pylori CagA causes mitotic impairment and induces chromosomal instability[END_REF]. However, H. pylori can also be considered as an indirect carcinogenic agent due to the chronic active inflammation it elicits in the gastric mucosa associated with its ability to escape immune response [START_REF] D'elios | Inflammation, Immunity and vaccines for Helicobacter pylori[END_REF] and thus colonize the human stomach for decades. A combination of indirect and direct mechanisms make it likely that H. pylori contributes to gastric cancer development via complex interplay between chronic inflammation, bacterial effects on host cell physiology, probably changes in tissue stem cell homeostasis and the consequences of environmental triggering factors [START_REF] Costa | Touati Pathogenesis of Helicobacter pylori infection[END_REF] [START_REF] Correia | Basic aspects of gastric cancer[END_REF]. The scope of this review is to report recent findings on the different strategies developed by H. pylori either directly or indirectly to induce DNA damage and host genome instability and the biological consequences of the latter on pathogenesis.

Mutagenic response induced by H pylori infection

1.a DNA damage and mutation at the nuclear genome

Several reports have described a wide range of genetic instabilities in intestinal type gastric cancer and its precursor lesions, specially focusing on the tumor suppressor gene p53 [START_REF] Hamilton | A review of the genomics of gastric cancer[END_REF] [START_REF] Fenoglio-Preiser | TP53 and gastric carcinoma: a review[END_REF]. Most common mutational events are GC->AT transitions occurring at CpG dinucleotides and resulting from cytosine deamination. GC->AT transitions caused by carcinogenic N-nitrosamines from dietary amine and nitrates present in the acid gastric environment have been suggested [START_REF] Fenoglio-Preiser | TP53 and gastric carcinoma: a review[END_REF]. Increased formation of nitrosamines has also been reported during acute and chronic inflammation. It can lead to deamination of 5methylcytosine at CpG dinucleotides resulting in C to T transition [START_REF] Sawa | Nitrative DNA damage in inflammation and its possible role in carcinogenesis[END_REF]. GC->AT is the most common transition event found in european compared to AT->GC that is mainly found in asian population. More p53 mutations were found in H. pylori positive gastric cancer patients than in H. pylori negative ones [START_REF] Kubicka | P53 mutation pattren and expresion of c-erbB2 and cmet in gastric cancer[END_REF]. CagA+ H. pylori strains are associated with severe gastric inflammation in the gastric mucosa. Gastric tumors from CagA + H. pylori patients were found 3.7 times more likely to harbor p53 mutations than tumors from CagA -subjects [START_REF] Shibata | CagA status of Helicobacter pylori infection and p53 gene mutations in gastric adenocarcinoma[END_REF]. Also in that case, mutations were predominantly insertions/deletions and GC->AT transitions that were found associated with precancerous gastric lesions in H. pylori positive patients [START_REF] Morgan | Detection of p53 mutations in precancerous gastric tissue[END_REF]. In K-ras, GC->CG transversions occurred more frequently in H. pylori-associated chronic gastritis in patients with gastric cancer than those without it [START_REF] Hiyama | K-ras mutation in Helicobacter pyloriassociated chronic gastritis in patients with and without gastric cancer[END_REF].

The development of gastric cancer lesions directly associated with the presence of H. pylori infection was demonstrated in mongolian gerbil model [START_REF] Watanabe | Helicobacter pylori infection induces gastric cancer in mongolian gerbils[END_REF] [START_REF] Franco | Activation of β-catenin by carcinogenic Helicobacter pylori[END_REF]. Using the Big Blue mice assay [START_REF] Lambert | Detailed review of transgenic rodent mutation assays[END_REF] [22], we showed a direct gastric mutagenic effect induced by a chronic H. pylori infection [START_REF] Touati | Chronic Helicobacter pylori infections induce gastric mutations in mice[END_REF]. A 5-fold increase in gastric mutation frequency after 6 months in comparison to non-infected mice was found with the presence of an active gastritis. It is associated with high expression of the inducible nitric oxide synthase (iNOS) responsible for the production of NO that can react with superoxide to form peroxinitrite, leading to 8-nitroguanine (8-NG). The induced mutation spectra is mainly composed of transversions of GC to TA, AT to CG and AT to TA, suggesting the involvement of oxidative DNA damage [START_REF] Touati | Chronic Helicobacter pylori infections induce gastric mutations in mice[END_REF]. Also, in p53 +/-Big Blue mice chronically infected with H. felis, a cat isolate, an increase of mutations in the gastric mucosa associated with a higher risk of gastric neoplastic lesions has been confirmed [START_REF] Jenks | Long-term infection with Helicobacter felis and inactivation of the tumour suppressor gene p53 cumulatively enhance the gastric mutation frequency in Big Blue® transgenic mice[END_REF].

During chronic inflammation, reactive oxygen and nitrogen species (ROS and RNS) are generated from inflammatory cells recruted in the gastric mucosa following H. pylori interaction with gastric epithelial cells, inducing mainly 8-oxo-7, 8-dihydro-2'deoxyguanosine (8-oxodG) and 8-nitroguanine, known to elicit GC -> TA transversions [START_REF] Ohshima | 8-nitroguanine, a product of nitrative DNA damage caused by reactive nitrogen species: Formation, occurrence, and implications in inflammation and carcinogenesis[END_REF]. An immunohistochemistry analysis of gastric samples from patients with H. pylori positive gastritis and from patients in which it had been eradicated, correlated the increase of 8-oxodG and 8-NG in the framework of H. pylori infection [START_REF] Katsurahara | Reactive nitrogen species mediate DNA damage in Helicobacter pylori-infected gastric mucosa[END_REF]. Several teams presented data to claim that H. pylori infection is apparently the single most important factor in determining the levels of DNA oxidative damage as 8-oxodG in the gastric mucosa [START_REF] Wang | Oxidative stress defense mechanisms in counter iron-promoter DNA damage in Helicobacter pylori[END_REF] [START_REF] Siomek | Helicobacter pylori infection is associated with oxidatively damaged DNA in human leukocytes and decreased level of urinary 8oxo-7,8-dihydroguanine[END_REF][START_REF] Farinati | Helicobacter pylori, inflammation, oxidative damage and gastric cancer: a morphological, biological and molecular pathway[END_REF]. The association between the presence of these DNA adducts and gastric mucosal atrophy and intestinal metaplasia was clearly established. Another pathway leading to oxidative DNA damage during H. pylori infection is the induction of polyamine oxidation resulting from spermine oxidase activity generating H 2 O 2 [START_REF] Xu | Spermine oxidation induced by Helicobacter pylori results in apoptosis and DNA damage: implication fro gastric carcinogenesis[END_REF].

Like DNA, deoxyribonucleoside triphosphates (dNTP) pools are also targets for oxidative species. Mutations can also be generated by the incorporation of oxidized-dNTP into DNA by DNA polymerases [START_REF] Pavlov | DNA replication fidelity with 8oxodeoxyguanosine triphosphate[END_REF], despite them being poor substrates [START_REF] Nohmi | Modulation of oxidative mutagenesis and carcinogenesis by polymorphic forms of human DNA repair enzymes[END_REF].

Idaka et al reported the incorporation of 2-hydroxy-2'-deoxyadenosine 5'-triphosphate (2-OH-dATP) and 8-hydroxy-2'-deoxyguanosine 5'-triphosphate (8-OH-dGTP) by human DNA polymerase η (hpolη), leading to G to T and A to C transversions respectively [START_REF] Hidaka | Specificity of mutations induced by incorporation of oxidized dNTPs into DNA by human DNA polymerase η[END_REF]. ROS and RNS produced by inflammatory cells can also induce base alkylation via lipid peroxidation (LPO). Etheno-modified (ε-modified) bases are generated by the reaction of DNA with a major LPO product (trans-4-hydroxy-2nonenal). Increased levels of etheno adducts are found in chronically inflamed human tissues and have been suggested as potential markers for assessing the progression of inflammatory cancer-prone diseases [START_REF] Bartsch | Oxidative stress and lipid peroxidation-derived DNA lesions in inflammation driven carcinogenesis[END_REF]. The role of etheno DNA adducts in the genotoxicity of H. pylori must be considered. As suggested by the multistep model of gastric carcinogenesis and despite the important role of inflammation due to oxidative and nitrative DNA damage, a direct genotoxic activity of H. pylori bacteria on the gastric mucosa cannot be excluded. H. pylori produces different substances able to promote DNA damage including cytotoxins and metabolic derivatives such as nitroso compounds.

Moreover, ammonium derived from H. pylori urease activity, which allows bacteria to resist gastric acidity [START_REF] Bury-Moné | The Helicobacter pylori UreI protein: role in adaptation to acidity and identification of residues essential for its activity and for acid activation[END_REF], can form mutagenic derivatives such as HNO 2 by oxidation. A direct genotoxic effect of bacteria is in agreement with in vitro studies on H. pyloriinfected gastric epithelial cells which reported a release of free radicals, the induction of DNA damage and frameshifts and point mutations [START_REF] Obst | Helicobacter pylori causes DNA damage in gastric epithelial cells[END_REF] [START_REF] Yao | Demonstration and characterization of mutations induced by Helicobacter organims in gastric epithelial cells[END_REF].

1b. H. pylori is also a mutagen for mitochondrial DNA

MtDNA mutations have been detected in all types of tumors [START_REF] Modica-Napolitano | Mitochondria and human cancer[END_REF]. In gastric cancer, mtDNA instabilities occur at the early stage of tumorigenesis [START_REF] Kamalidehghan | Tumoral cell mtDNA approximately 8.9kb deletion is more common than other deletions in gastric cancer[END_REF] [START_REF] Maximo | Microsatellite instability, mitochondrial DNA large deletions and mitochondrial DNA mutations in gastric carcinoma[END_REF]. They are more frequently found in H. pylori-positive patients with gastric cancer [START_REF] Hiyama | Somatic mutation in mitochondrial DNA and nuclear microsatellite instability in gastric cancer[END_REF] [START_REF] Rigoli | Histological heterogeneity and somatic mtDNA mutations in gastric intraepithelial neoplasia[END_REF]. An association between H. pylori-related peptic ulcers and mtDNA mutations has also been suggested [START_REF] Lee | Association between Helicobacter pylori-Related Peptic Ulcer Tissue and Somatic Mitochondrial DNA Mutations[END_REF]. In most of these studies, mtDNA mutations concerned deletion/insertion events in the mtDNA D-loop region. Recently, we have demonstrated the induction of mtDNA mutations in gastric epithelial cells chronically infected with H. pylori in both the mitochondrial D-loop region and genes encoding subunits of the electron transport chain [START_REF] Machado | Helicobacter pylori infection downregulates nuclear and mitochondrial DNA repair in gastric cells[END_REF]. The mutation spectra consisted mainly in AT->GC and GC->AT transitions and single insertion. These data were also validated in vivo on gastric biopsies from H. pylori-infected patients with chronic gastritis [START_REF] Machado | Helicobacter pylori infection downregulates nuclear and mitochondrial DNA repair in gastric cells[END_REF]. We confirmed the induction of mtDNA mutation in the gastric mucosa of H. pylori infected mice after 12 and 18 months, including mainly AT->GC, AT->CG and single (G ;C) insertion [unpublished results]. By inducing mutation in the mitochondrial genome, H. pylori may impair oxidative phosphorylation metabolism, leading to an increase of ROS production and mtDNA damage. The close proximity of mtDNA to the respiratory chain and sources of reactive oxygen species may promote oxidative DNA damage. Oxidative stress has been recently demonstrated to lead to the degradation of mtDNA, as strand breaks and abasic sites prevail over mutagenic base lesions in ROS damaged mtDNA [START_REF] Shokolenko | Oxidative stress induces degradation of mitochondrial DNA[END_REF]. Another factor to be considered that can influence the mutation specificity at mtDNA is the reduced DNA repair availability in mitochondria that need to import DNA repair components.

In recent years, a major role of stem cells in gastric carcinogenesis has been proposed. Using mtDNA mutations as a marker of clonal expansion, McDonald et al, [START_REF] Mcdonald | Mechanism of field cancerization in the human stomach: the expansion and spread of mutated gastric stem cells[END_REF] reported that mutation originally occurs in the stem cell that colonizes a unit or crypt and spreads by fission until a mutated field of epithelial cells develops, subsequently leading via further mutational events to tumor development. A role of mtDNA mutation in the acquisition of metastatic properties of tumor cells has been demonstrated [START_REF] Ishikawa | ROS-Generating Mitochondrial DNA Mutations Can Regulate Tumor Cell Metastasis[END_REF].

Using cytoplasmic hybrid technology, the endogenous mtDNA in a mouse tumor cell line with low metastatic properties was replaced by mtDNA from a highly metastatic cell line, mutated in the gene coding for NADH (reduced form of nicotinamide adenine dinucleotide) dehydrogenase subunit 6 (ND6). This mutation resulted in a deficiency of respiratory complex I activity and was associated with an overproduction of ROS. These authors demonstrated that the presence of mutated mtDNA is associated with the acquisition of high metastatic ability for the receptor cells.

The H. pylori-induced mutator phenotype is associated with DNA repair impairment

In 6 month H. pylori-infected mice, the expression of mismatch repair (MMR) components is down-regulated [START_REF] Machado | Helicobacter pylori infection downregulates nuclear and mitochondrial DNA repair in gastric cells[END_REF]. We also observed an induction of microsatellite instabilities (MSI) at gastric mucosa level. MSI is a hallmark of MMR deficiency frequently associated with colorectal and gastric adenocarcinoma [START_REF] Seruca | Sporadic gastric carcinomas with microsatellite instabiity display a particular clinicopathologic profile[END_REF] [START_REF] Wheeler | DNA mismatch repair genes and colorectal cancer[END_REF]. Deficiency in mismatch repair has also been confirmed in gastric biopsies from H. pylori-infected patients [START_REF] Park | Effect of Helicobacter pylori Infection on the Expression of DNA Mismatch Repair Protein[END_REF] [START_REF] Mirzaee | Helicobacter pylori infection and expression of DNA mismatch repair proteins[END_REF]. During Base-Excision Repair (BER) abasic sites are repaired by apurinic/apyrimidinic (AP) endonuclease (APE1). The expression of APE1 was also observed to be downregulated in H. pylori-infected gastric epithelial cells (AGS) [START_REF] Machado | Helicobacter pylori infection downregulates nuclear and mitochondrial DNA repair in gastric cells[END_REF]. It should lead to the accumulation of abasic sites that can be converted by mutation during DNA replication or DNA repair. DNA damage induced by ROS and RNS are recognized by alkyladenine DNA glycosylase (Aag) involved in BER. Recently, Meira et al reported that a deficiency in BER alkyladenine DNA glycosylase (Aag) in mice triggers the development of a preneoplastic stage [START_REF] Meira | DNA damage induced by chronic inflammation contributes to colon carcinogenesis in mice[END_REF]. The expression of O6-Methylguanine DNA methyltransferase (MGMT) involved in the repair of O6-Methylguanine (O6-mG) preventing GC to AT transitions is also decreased by H. pylori infection [START_REF] Sepulveda | CpG methylation and reduced expression of O6methylguanine DNA methyltransferase is associated with H. pylori infection[END_REF]. This is due to CpG methylation at the MGMT gene promoter region and associated with chronic active gastritis. Thus the induction of genome instability and mutations during H. pylori infection is direcly related to a decrease of the DNA repair efficiency of host cells, thereby influencing the associated mutation spectra and promoting malignant transformation.

DNA methylation and relation with inflammation

Epigenetic alterations have been suggested as key initiating events in tumorigenesis occurring very early in cancer development [START_REF] Feinberg | The epigenetic progenitor origin of human cancer[END_REF]. As recently reviewed, the cancer epigenome is marked by genome-wide hypomethylation and site specific CpG island promoter hypermethylation [START_REF] Sharma | Epigenetics in cancer[END_REF]. The resulting 5-methylcytosine is relatively unstable and prone to spontaneous deamination changing it to thymine, a source of endogenous mutagenesis. In several studies, aberrant DNA methylation in gastric biopsies from H. pylori-positive patients has been correlated with higher risks of gastric cancer [START_REF] Maekita | High levels of aberrant DNA methylation in Helicobacter pylori-infected gastric mucosae and its possible association with gastric cancer risk[END_REF] [START_REF] Nakajima | Higher methylation levels in gastric mucosa significantly correlate with higher risk of gastric cancers[END_REF] [58] [START_REF] Nardone | Helicobacter and epigenetic mechanisms underlying gastric carcinogenesis[END_REF]. The role of H. pylori in the induction of DNA hypermethylation is confirmed by a low incidence of DNA methylation in patients after eradication of the infection [START_REF] Perri | Aberrant DNA methylation in non-neoplastic gastric mucosa of H. pylori infected patients and effect of eradication[END_REF] [61] [START_REF] Leung | Effects of Helicobacter pylori eradication on methylation status of E-cadherin gene in noncancerous stomach[END_REF]. DNA hypermethylation contributes to tumorigenesis by silencing tumor suppressor genes. It can also indirectly modulate gene expression, by downregulating transcription factors and DNA repair gene expression [START_REF] Baylin | Epigenetic gene silencing in cancer-a mechanism for early oncogenic pathway addiction?[END_REF]. We have recently demonstrated that H. pylori downregulates the gene expression of upstream stimulatory factors USF1 and USF2 by DNA hypermethylation of their promoter region [START_REF] Bussière | pylori-induced promoter hypermethylation downregulates USF1 and USF2 transcription factor gene expression[END_REF]. USF1 and USF2 are pleiotropic transcription factors that regulate the expression of genes related to immune response, cell proliferation and chromosome stability. Thus, by modulating the levels of such pleitotropic regulators, DNA methylation plays an important role in host response to H. pylori infection. As mentioned above, H. pylori promotes genetic instability through the decrease of DNA repair gene expression. In agreement with this, CpG hypermethylation has been described in the presence of infection in the promoter region of MLHI, a component of MMR and in the promoter region of MGMT involved in BER DNA repair [START_REF] Bartchewsky | Influence of Helicobacter pylori infection on the expression of MLHI and MGMT in patients with chronic gastritis and gastric cancer[END_REF] [START_REF] Sepulveda | CpG methylation and reduced expression of O6methylguanine DNA methyltransferase is associated with H. pylori infection[END_REF].

Aberrant DNA hypermethylation is frequently associated with chronic inflammation, as observed in non-cancerous tissues of patients with inflammation-associated cancers. In the case of gastric cancer, a link between polymorphoneutrophil infiltration and hypermethylation of CpG islands has been reported by Kaise et al [START_REF] Kaise | CpG island hypermethylation of tumor-suppressor genes in H. pylori-infected non-neoplastic gastric mucosa is linked with gastric cancer risk[END_REF].

Using the Mongolian gerbil model, Niwa et al demonstrated that H. pylori-associated DNA methylation is composed of transient components that disappeared after eradication of the infection and permanent components, mainly associated with chronic inflammation [START_REF] Niwa | Inflammatory processes triggered by Helicobacter pylori infection cause aberrant DNA methylation in gastric epithelial cells[END_REF]. These data were also confirmed in humans [START_REF] Nakajima | Persistence of a component of DNA methylation in gastric mucosae after Helicobacter pylori eradication[END_REF]. In line with this, we showed that DNA hypermethylation induced by H. pylori in the gastric mucosa of mice chronically infected for 18 months occurred in the context of dysplastic lesions [START_REF] Bussière | pylori-induced promoter hypermethylation downregulates USF1 and USF2 transcription factor gene expression[END_REF]. Recently, Sepulveda et al suggested that permanent DNA methylation after H. pylori eradication should occur in stem cells, thus promoting tumorigenesis [START_REF] Sepulveda | CpG methylation and reduced expression of O6methylguanine DNA methyltransferase is associated with H. pylori infection[END_REF]. How inflammation triggers DNA methylation has not been completely elucidated. Several years ago, Henderson et al reported the presence of HOCl from activated neutrophils and HOBr from activated eosinophils in the area of tissue inflammation [START_REF] Henderson | Production of brominating intermediates by myeloperoxidases. A transhalogenation pathway for generating mutagenic nucleobases during inflammation[END_REF]. HOCl and HOBr are known to react with DNA to form, among other products, 5-chlorocytosine and 5bromocytosine, which are mutagenic [START_REF] Suzuki | DNA damage and mutation caused by vital biomolecules, water, nitric oxide, and hypochlorous acid[END_REF].Valinluck et al have established a potential role for these halogenated cytosine damage products in methylation changes [START_REF] Valinluck | 5-halogenated pyrimidine lesions within a CpG sequence context mimic 5-methylcytosine by enhancing the binding of the methyl CpG binding domain of methyl-CpG-binding protein 2 (MeCP2)[END_REF].

Halocytosines were revealed to be as efficient as 5-methylcytosine in enhancing the binding of the methyl-CpG-binding protein 2 in directing DNA methylation at CpG. These studies provide further insights into inflammation-related tumorigenesis mechanisms and DNA methylation [START_REF] Valinluck | Inflammation-mediated cytosine damage: a mechanistic link between inflammation and the epigenetic alterations in human cancers[END_REF], that must be investigated in the context of H. pylori infection.

Activation-induced cytidine deaminase (AID), a link between inflammation and tumorigenesis

Activation-induced cytidine deaminase (AID) is a DNA/RNA editing cytidine deaminase which converts cytosine into uracil. It plays an essential role in the diversity of immunoglobulins in activated B cells, by somatic hypermutation (SHM) and class switch recombination (CSR) [START_REF] Muramatsu | Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme[END_REF]. AID is mutagenic due to its cytidine deaminase activity, leading GC->AT transitions. Its mutagenic properties have been recently analysed in non-B cells, using a system based on the reversion of a nonsense mutation in an EGFP gene [START_REF] Jovanic | Ectopic Expression of AID in a Non-B Cell Line Triggers A:T and G:C Point Mutations in NonReplicating Episomal Vectors[END_REF]. Under these conditions, transiently transfected DNA can be mutated in an AID-dependent manner with the induction of mutation both at G:C and A:T. The constitutive expression of AID in transgenic mice is correlated with tumor development in various organs associated with high mutation frequencies [START_REF] Okazaki | Constitutive expression of AID leads to tumorigenesis[END_REF]. The role of AID in tumorigenesis via its mutagenic activity has been recently demonstrated in inflammation related-human cholangiocarcinoma [START_REF] Komori | Activation-Induced Cytidine Deaminase Links Bile Duct Inflammation to Human Cholangiocarcinoma[END_REF]. In this study, a pro-inflammatory cytokinesdependent aberrant expression of AID in biliary cells resulted in somatic mutations in tumor related-genes such as p53, c-myc and the promoter region of INK4A/p16 sequences. This induction of AID depends on the activation of the proinflammatory transcription nuclear factor κB (NF-κB). An upregulation of AID with an accumulation of nucleotide alterations in the p53 tumor suppressor gene in H. pylori-infected gastric cells has been reported [START_REF] Matsumoto | Helicobacter pylori infection triggers aberrant expression of activation-induced cytidine deaminase in gastric epithelium[END_REF]. In this case, AID upregulation is dependent on the NF-κB activation pathway, known to play an important role in inflammation-associated carcinogenesis [START_REF] Pikarsky | NF-kappaB functions as a tumour promoter in inflammation-associated cancer[END_REF] [START_REF] Greten | IKKBeta links inflammation and tumorigenesis in a mouse model of colitis associated cancer[END_REF]. High levels of AID were also observed in H. pylori positive gastritis and gastric cancer tissues from human biopies [START_REF] Matsumoto | Helicobacter pylori infection triggers aberrant expression of activation-induced cytidine deaminase in gastric epithelium[END_REF]. Recent data from our group confirmed the direct effect of H. pylori infection on the induction of AID expression associated with active chronic gastritis in mice [unpublished results]. These results illustrate the ability of H. pylori to affect genome integrity indirectly by inducing a DNA mutator enzyme usually active in normal B-cells.

Conclusion

In conclusion, the recent findings reported in this review confirm the capacity of H. pylori infection to induce genetic instabilities and DNA repair deficiency in host cells. Its mutagenic effect can also result from the induction of high levels of a DNA mutator like AID. These genotoxic properties are directly linked with the chronicity of the infection.

Current knowledge and in vitro data lead to the assumption that the oncogenic properties of H. pylori infection result from two mechanisms: i) a direct H. pylori genotoxic effect resulting from the action of its virulent factors and products stemming from bacterial metabolism ; ii) the major role played by gastric inflammation, mainly attributed to ROS and RNS-mediated DNA and cell damage, that is well documented. Thus, H. pylori related gastric cancer lesions are the results of this complex interplay. H. pylori is also a source of epigenetic alterations, and up to now DNA methylation is the best characterized associated epigenetic modification. However the study of other epigenetic events such as histone modification and the involvement of microRNAs are promising fields for a better understanding of the relation between H. pylori infection and cancer. Other bacteria are suspected to be associated with tumor development such as Salmonella typhi and gallbladder cancer, Chlamydophila pneumoniae and lung cancer, Streptococcus bovis and Escherichia coli in colorectal cancer [START_REF] Mager | Bacteria and cancer: cause, coincidence or cure? A review[END_REF]. Better knowledge of the mechanisms involved in the relation between H. pylori and gastric cancer will lead to further insights in the genotoxicity associated with these different bacterial pathogens and their consequences on the development of malignancies.

Conflict of interest

There is no conflicting interest.


Pascal Bruel

Wake vortices Horseshoe vortex 12

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Low Mach flows: a better insight about the major players with an asymptotic expansion of the governing equations Pascal Bruel -Universidad Nacional de Córdoba -30 March 2017 (0)

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Low Mach flows: a better insight about the major players with an asymptotic expansion of the governing equations Pascal Bruel -Universidad Nacional de Córdoba -31 March 2017

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divergence of the first order momentum equation yields:

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with ( , ) This is a wave equation and its source is the change

p q p t c p c t              over acoustic time    x of
the leading order of the heat release rate.

Low Mach flows: a better insight about the major players with an asymptotic expansion of the governing equations Short term objective:

-Providing an experimental database with forcing and relevant conditions: non circular hole geometry and non conformal jet exit section with an acoustic forcing of the crossflow. This experimental database is meant to be first for RANS/DNS/LES assessment.

Long term objective :

improving the understanding of the effect of the presence of the forcing may have on the unsteadiness of adiabatic cooling efficiency. Identifying optimal hole shapes (if any) compatible with the existing manufacturing process.

13

Low Mach flow simulations : AUSM-IT, a discrete flux scheme for a low order FV colocated method

Together with proper initial and boundary conditions

The continuous system of PDE's: Euler equations

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1 e i V 1 1 2 i   n e 1 1 2 i    n e        -3 / 2 i 1 i  1/ 2 i  i 1/ 2 i  3 / 2 i  1 i  x O Primal mesh cell



Expression of the fluxes at the interfaces: momentum equation

              1 1 1 1 1 1 1/ 2 1/ 2 1/ 2 1/ 2 1/ 2 1/ 2
Consider a first order Euler implicit time discretization. Thus, the discrete system at time ( 1) reads as:

n n n n n n n i i i i i i i i t n t t u u uu uu p p x x                             
So, expressions for the transporting velocities and the face pressure have to be derived. To handle this for the transporting velocity, there is broadly speaking two different alternatives:

Expression of the fluxes at the interfaces 1. Either you assume that the transporting velocity is given a dynamical meaning and so consider that it satisfies an evolution equation obtained by discretizing the continuous momentum equation on the dual mesh  this is the starting point of the momentum interpolation method, 2. Or you solve a Riemann problem derived from the charateristics system written at the interface between two adjacent control volumes (Godunov type schemes) .

          1 1 1 1 1 1 1/2 1/2 1/2 1/2 1/2 1/2 1 1/2 n n n n n n i i i i i i n i uu u u uu u u u                      transported
For the flux of momentum, let's re-write it formally as : and conversely

Then, consider that is the sought quantity

1 1/2 1 1/2 n i n i u u    
transporting and that is the velocity. On the ground of the sole discretization on the primal cell, can be thought of as an interpolated quantity based on the cell based values .

 

, 1 1 1 1 1/2 , n n n i i i u Interp u u        We shall denote it by . , 1 , 1/ 2 1/ 2 2) n n i i u u      
Then we make the following approximations:

1) The transporting velocity is treated explicitly in time so

An upwind first order expression in space is retained for the transport

          1 1 , 1/ 2 1/ 2 1 1 1 1 , 1 1/ 2 1/ 2 notation n n n i i i i notation n n n n i i i i i i uu u u B uu u u u A B                       
ed quantity.

So one gets the following expressions (positive velocities):

27

Momentum interpolation method

Pascal Bruel -Universidad Nacional de Códoba -March 2017 '

' i i B s A s
So, the stand for the momentum flux at the interfaces of the primal mesh and the stand for the transporting velocities therein, so with these notations, the discretized momentum equation on a

                            1 1 1 1 1/ 2 1/ 2 1 1 1 1 1/ 2 1/ 2 1 1 1 1 1/ 2 1/ 2 n n n n n i i i i i i i n n n n n i i i i i i i n n n n i i i i i i t u u u A B p p x x B u A p p u u t x B B p p u u t                                                         
primal mesh cell reads now as:

or equivalently: or   Momentum interpolation method i V        -3 / 2 i 1 i  1/ 2 i  i 1/ 2 i  3 / 2 i  1 i  x O Primal mesh cell  i B   1 i i i B A u    
Momentum interpolation method: primal mesh view

1/2 i V         -3 / 2 i 1 i  1/ 2 i  i 1/ 2 i  3 / 2 i  1 i  x O Dual mesh cell
Momentum interpolation method: dual mesh equation

  3/ 2 1/ 2 1/ 2 i i i B A u        1/ 2 i B            1 1 1 1 1/2 1/2 1/2 1 1/2 1/2
The same type of discretized momentum equation is postulated on the dual mesh, namely:

n n n n n i i i i i i i x B u A p p u u t                        
Momentum interpolation method: relating primal and dual cells quantities

      1/ 2 1/ 2 1 1/ 2 1 1/ 2 1 1/ 2 1 1 1 , , 1 1/ 2 1/ 2 1 , 1/ 2 1/ 2
Where and are supposed to be such that (Rhie and Chow, 1993): 2 1 which leads to: 2

1 2 i i i i i i i i i i i i i n n n n i i i i n i i A B A A A A A B B B A A A u u u u u u                                            1 1 , 1 3/ 2 1/ 2 1 1/ 2 1/ 2 1/ 2 1 1 n n n n i i i i n n i i i p p u A t u u A x                                  
Momentum interpolation method: the final expression of the primal cell face velocity

    1 1 1 1 1 1 1/ 2 1/ 2 1 1/ 2 1/ 2 1 1 /
where 2 and the are calculated through the continuity equation discretized as the momentum on the primal mesh.

We are done with the inte

n n n n n n i i i i i i n i u u                                  1 1/ 2 1 2
rface velocity on the primal mesh but not with the pressure interface ! To calculate the latter, an AUSM expression is used (Liou, 1996), :

( ) ( ) with:

1 3 ( ) ( 1) 2 4 1 n n n p i p i i i i p p f M p f M p f M M M              
( ) 0 '( ) ( ) 0 '( ) 1 (1 ) 2 t s u t u u t v t v t w t w t T T M           
The combinations are numerous, see Poinsot and Lele (JCP, 1992) for more details about well posedness vs implementation feedback Incoprorating a STG approach into a compressible Euler solver: the ATCBC method at a subsonic inlet (Moguen et

(

  If one proceeds similarly as before, the zeroth, first and second order equations yields:

"

  Examples of experiments: -Frick and Roshko (1994), Kelso et al. (1996), Smith and Mungal (1998), Gustafsson (2001), M'Closkey et al. (2001), Most (2007), Michel (2010), Ali (2010),…. Flow structure: Effusion cooling: The related canonical flow is the jet in cross flow (JICF) Four coherent structures  Shear-layer (Kelvin-Helmoltz vortices)  Horseshoe vortices  Wake vortices  Counter rotating vortex pair (CVP)

From a real combustor.

  to a baseline lab configuration: the test bench MAVERIC Pascal Bruel -Universidad Nacional de Córdoba -30 March 2017 " With the acoustic forcing system  Setting-up of automatic displacement system for optic measurement tools. combustor to a baseline lab configuration: the test bench MAVERIC Pascal Bruel -Universidad Nacional de Córdoba -30 March 2017 " Pressure drop between lower and upper channel [10 -140] Pa " Main stream Reynolds number [2000 -35000] " Jet Reynolds number [1200 -9000] Streamwise velocity component spectra (right) and the ir related histograms (left) in the inlet upper channel Acoustic forcing: Experimental evidence of the flow response. Acoustic forcing: Experimental evidence of the flow response. Pascal Bruel -Universidad Nacional de Córdoba -30 March 2017 KIAI database -AF-CV-12R-60-146-24 , central jet of rows 3 and 5: phase average time variation incorporating four phase locked averages (0°, 90 °, 180° and 270°, (statistics over 600 images per phase angle). Examples of extraction of the jets' coherent motion: 19 Acoustic forcing: Experimental evidence of the flow response. KIAI database -AF-CV-12R-15-146-24 , central jet of rows 3 and 5: examples of extraction of the jet coherent motion: phase average time variation incorporating four phase locked averages (0°, 90 °, 180° and 270°, (statistics over 600 images per phase angle). If the relative intensity of the forcing is inscreased by reducing the mean pressure drop from 60 Pa to 15 Pa Acoustic forcing: Experimental evidence of the flow response.

  Pascal Bruel -Universidad Nacional de Córdoba -30 March 2017Context and simplifying assumptionsCell centered finite volume method with variables' colocation on the domain

  Momentum interpolation method: example of results for a 2D pulse simulations (second order discretization, from Moguen et al., 2012) Evolution of the momentum interpolation method for low Mach number Riemann problem (from Moguen et al., JCP, 2015a) Centering the velocity in the face velocity expression Using the momentum interpolation as a guide to improve a Godunov type scheme (from Moguen et al., JCP, 2015b) for low Mach number Mimicking the form obtained when using the momentum interpolation method Focus 2 -Low Mach flux scheme: from AUSM+up to AUSM-IT (Liou, 2006) (Moguen et al., 2015a) Low Mach turbulent flow unsteady simulation: ATCBC, a proposal for the boundary condition prescription.

  : example of connection to develop unsteady inlet BC for DNS with the SEM (inlet of MAVERIC rig)Measurements: provide some of the targeted values for the SEM Consider a one-dimensional flow governed by the Euler equation for simplicity, thus the temporal rates of change of the wave amplitudes are given by:

  al., 2014) Recent Cagire references related to low/all Mach number flow simulation issues 6. Moguen, Y., Bruel, P., Perrier, V., Dick, E. (2014) "Non-reflective inlet conditions for the calculation of unsteady turbulent compressible flows at low Mach number", Mechanics and Industry, Vol. 15, No 3, pp. 179-189. 7. Moguen, Y., Bruel, P., Dick, E. (2013) "Semi-implicit characteristic-based boundary treatment for acoustics in low Mach number flows", Journal of Computational Physics, Vol. 255, pp. 339-361. 8. Moguen, Y., Dick, E., Vierendeels, J., Bruel, P. (2013) "Pressure-velocity coupling for unsteady low Mach number flow simulations: an improvement of the AUSM+-up scheme", Journal of Computational and Applied Mathematics, Vol. 246, pp. 136-143. 9. Moguen, Y., Kousksou, T., Bruel, P., Vierendeels, J. and Dick, E. (2012) "Pressure-velocity coupling allowing acoustic calculation in low Mach number flow", Journal of Computational Physics, Vol. 231, pp. 5522-5541.

Pascal Bruel -Universidad Nacional de Córdoba -30 March 2017

Pascal Bruel -Universidad Nacional de Córdoba -30 March 2017 VISUALIZATION TO GET A FLAVOUR OF THE JICF (1-HOLE PLATE WITH FORCING @146 HZ)

 Option A (continued):

Finite differences, finite volumes, finite elements, high performance computing strategy (LES), method of solution (explicit, implicit), mesh generation (structured vs unstructured) management issues (related to HPC) .

Prescribing boundary conditions for low Mach flow simulations

To determine the number of physical boundary conditions to be imposed, the guide is the wave pattern system analysis at the considered boundary. The sign of the eigenvalues of the Euler flux jacobian matrix and their multiplicity order is the guide (Poinsot and Lele, 1992) (assuming that 0)

At the inlet, how to generate ' '( , ), ( , ), '( , ) ? u x t v x t w x t Precursor simulation: perform a separate simulation and store the results in a plane that will be used to feed the current simulation (computationaly expansive, simple geometries only) Recycling on the fly: select a plane at some downstream section in the current simulation and regularly reinject the (scaled) values at the inlet (Simple geometries, absence of strong pressure gradients, pb with recycling frequency for aeroacoustics). Synthetic turbulence generation (STG): white noise, stochastic differential equations, digital filtering, synthetic eddy method (the artificial nature of turbulence leads to long adaptation length, but can be improved). Example of choice of STG: the synthetic eddy method Eddy method (SEM): direct injection at the inlet plane of analytically defined structures that reproduce to some extent the coherent structures of the turbulent flow.

Incoprorating a STG approach into a compressible Euler solver: the ATCBC method at a subsonic inlet These Li's satisfy the following LODI system at the inlet:

Subsonic inlet (1D): Two Li's have to be imposed. Main hypothesis (H1) behind the ATCBC method to avoid reflection: at the inlet, the gap (if any) between the targeted velocity v † coming from the STG process and the current one v is solely attributed to the upstream travelling acoustic wave. Methodology to check the proposal coherence at low Mach: two-scale asymptotic analysis of the LODI system.

Incoprorating a STG approach into a compressible solver: the ATCBC method at a subsonic inlet From (1b), H1 is enforced by assuming that: †

which is achieved by imposing that: † 3

The remaining boundary condition is derived by 1) assuming a frozen turbulence hypothesis (H2) and 2) asymptotically expanding L 2 which finally yields L 2 =0 (at order -1 and 0).


Ramon Marti Solano

Ramón Martí Solano

Introduction

A loan translation is a means that natural languages have to increase their lexicon by borrowing, translating and adapting a foreign word into the recipient language. In this sense, loan translations are considered as neology. This can be done in various ways resulting in a number of adaptations known as loan translations proper, loan renditions and loan creations (Weinreich 1953: 51;Görlach 2003: 62).

Multi-word loan translations or phraseological calques have been widely studied in the areas of languages in contact and bilingualism. Two wellknown examples are represented by the influence of English on French for speakers of Canadian French and the influence of English on Spanish in Latin-American communities in the United States. 1 (1) Vous êtes drôle... Dommage que Greene soit mort, je vous aurais présenté... Ce n'est pas votre tasse de thé ? Ah bon... Remarquez, je n'y connais pas grand-chose. Cela dit, y a-t-il une vie plus passionnante que la nôtre ? Sincèrement ? (Sollers Ph., Le Secret, 1993, p. 53) 1 For the influence of English on Canadian French, see Jean-Louis Darbelnet, Le français en contact avec l'anglais en Amérique du Nord. As for the influence of English on U.S. Spanish, see Ricardo Otheguy, A reconsideration of the notion of loan translation in the analysis of U.S. Spanish.

Ce n'est pas ma tasse de thè (< 'it's not my cup of tea') is a stereotypical example of the influence of English phraseology on French as illustrated in

(1). The phrase is highly institutionalised and therefore quite familiar among French speakers. However, it is rarely found in written corpora as it is more frequently used in speech than in written form-only three occurrences of this phrase have been found in the French general corpus Frantext.

On the other hand, multi-word semantic borrowings or phraseological semantic loans constitute another way of enriching the recipient language by means of borrowing a new figurative sense or developing a semantic extension for an existing lexicalised string in the recipient language as is the case with trou noir (< 'black hole'):

(2) Les militaires français, qui s'y sont déployés en 2008, décrivent souvent cette région comme un « trou noir » qui avait selon eux été négligée auparavant car située à cheval sur deux zones du commandement militaire des forces internationales, celui de Kaboul et de l'est afghan. (Le Nouvel Observateur, 28 December 2010)

The use of inverted commas in (2) signals the phraseologial awareness on the part of the journalist of the new sense of the existing French multi-word unit. The present study is therefore concerned with the influence of English multi-word units on journalistic discourse in France.

Influence of English phraseology on French: a historic outline

Loan translations and semantic calques can be at times difficult to identify if we compare them to loanwords. The latter are either direct borrowings from the donor language or have been adapted to conform to the orthographical or morphosyntactic structure of the recipient language but in any case their foreignness is evident. Loan translations or calques represent cases of lexical or phraseological interference which are definitely less conspicuous (Pergnier 1989: 89).

The long, lively and, at times, turbulent linguistic relation between English and French goes back to the Norman Conquest in 1066 and has been more often than not a subject of controversy, above all on the continental side of the English Channel. We shall not look into the enormous and significant influence of English syntax and phraseology on Canadian French and the extent and pervasiveness of multi-word loan translations and semantic borrowings in this language variety: this influence is mainly the product of languages in contact and of bilingualism and these matters fall outside the scope of the present study. We will focus on the French language of France and especially on these two types of Anglicism in journalistic discourse. 2

2 We concur with the idea that loan translations and semantic loans from English are Anglicisms at the same level as loanwords (Picone 1996: 3).

Former studies on the influence of English on French have dealt nearly exclusively with direct borrowings or renderings of English single words or compounds such as vers blanc, a calque from 'blank verse' (Mackenzie 1939: 44) or presse jaune, from 'yellow press' (Mackenzie 1939: 252).

L'homme de la rue (< 'the man in the street') is one of the few instances of a full idiomatic phrase analysed as an emprunt déguisé ('disguised loan'),

having been used for the first time by a French politician back from a trip to England in 1911 (Mackenzie 1939: 259). This same string has also been classified as a case of a translation from English into French and into Italian even though "chronological evidence would be difficult to establish" [START_REF] Rey-Debove | Anglicisms in French-Notes on Their Chronology, Range and Reception[END_REF](Ullmann : 1175)).

It is the Dictionnaire des Expressions et Locutions (DEL) by Alain Rey and

Sophie Chantreau that supplies some information concerning the origin of French idiomatic expressions and the date on which phrases were first attested in French. Other French general dictionaries such as the Le Petit Robert (LPR) also label a certain number of the strings under investigation as calques from English. Some multi-word units were calqued from English during the 19 th century but there were, nevertheless, not very many: the idiomatic compound noun 'pea-souper' or 'pea-soup' was rendered as purée de pois in French and was first attested in 1896, according to the DEL.

The 20 th century brought with it a large swathe of multi-word units, among which marché aux puces (< 'flea market') and jeter l'éponge (< 'throw in the sponge'), the former attested at the very beginning of the last century and the latter first attested in 1918.

Both purée de pois and marché aux puces confirm the preponderance of idiomatic compound nouns as potential candidates for phraseological calquing. We will be dealing further down with a synchronic state-of-the-art investigation of the presence of phraseological calques in French journalistic discourse focused on the incidence of this type of multi-word loan translations mainly in the first decade of the 21 st century.

Research methodology, corpora and dictionaries

We have searched in the nomenclature of the DEL for French idioms

showing the same or nearly the same syntactic and lexical structure as their English counterparts. Then these items have been classified according to whether they are labelled or not as Anglicisms.

We We have used the Oxford English Dictionary (OED) to verify the date when the English phrase was first attested and the 2000 and 2009 editions of the Le Petit Robert (LPR00, LPR09) in order to corroborate the presence of loan translations or semantic loans and be able to account for the lexicographical evolution of the items under scrutiny. others, is recorded as a stereotypical example of a phraseological calque rendered into Spanish from English with the phrase estar en el mismo barco (Lorenzo 1996: 633). This same example is also given as an Anglicism in the case of the German phrase im selben Boot sitzen (Görlach 2003: 62).

Internationalisms or common loan translations

Only if we take into consideration the fact that even though much of the common phraseology shared by many European and non-European languages may have its roots in the distant past, it is certain that the contrastive use of synchronic and diachronic corpora can clearly show the emergence of new items or a break in their semantic continuity (Gardiner 1983: 514). At any rate, a fundamental distinction should be made between the metaphorical source and the phraseological source of a given expression.

The metaphorical source conjures up the original image rendered in whatever lexico-grammatical form whereas the phraseological source constitutes the exact or quasi-exact rendering of the phrase as found in the donor language.

Typologies of multi-word loan translations and semantic borrowings in French

Several attempts have been made to classify loan translations and semantic borrowings in French. We will refer here to the taxonomies concerning exclusively multi-word loan translations and semantic borrowings or calques phraséologiques (Deroy 1956: 217;Humbley 1974: 63;Meney 1994: 938).

Humbley considers loan translations and semantic borrowings as two entirely different entities since a semantic borrowing "ne produit pas de lexie différente" (Humbley 1974: 62). 3 He subdivides loan translations into three distinct groups putting together compounds and idioms. The first one includes compounds such as air conditionné (< 'air conditioned') which do not conform to the standard rules of word-formation in French. To the second group belong idiosyncratic collocations in English which have been 3 According to Humbley a semantic borrowing "does not produce a new lexical item".

rendered verbatim into French such as grève sauvage (< 'wild strike') and finally a third group where he includes the so-called emprunts phraséologiques ('phraseological borrowings') such as un cadavre dans le placard (< 'a skeleton in the cupboard') (Humbley 1974: 63).

But the most comprehensive taxonomy of Anglicisms in French is the one developed by Meney. This scholar restricts it to Canadian French and divides loan translations into calques lexicaux ('lexical loan translations'), calques locutionnels ('phrasal loan translations'), calques idiomatiques ou phraséologiques ('idiomatic or phraseological loan translations') and calques au niveau de la phrase ('sentence-like loan translations') (Meney 1994: 936-938). Except for the first type, we are here concerned by the other three which will be conflated under the heading 'multi-word loan translations'.

The first typology below includes the grammatical types found in multiword loan translations and semantic borrowings. They comprise all different types of combinations. Contrary to general phraseology in which predicates-a verb and its arguments-are the commonest type followed by adverbial phrases (Moon 1998: 88), noun groups-idiomatic lexical compounds and noun phrases-tend to be here the commonest type, corroborating the idea that "nouns are most easily borrowed" (Haugen 1950: 224):

1. Complex prepositions: en terme(s) de. 4 2. Prepositional phrases: en temps réel, au-dessous de la ceinture.

3. Idiomatic lexical compounds: patate chaude, cercle vertueux, zone grise.

4. Noun phrases: plafond de verre, effet domino, des papillons dans le ventre, un éléphant dans la chambre, la conquête des coeurs et des esprits.

5. Collocations: faire du sens, faire la difference.

6. Collocational frameworks: être en charge de.5

7. Predicate idioms: croiser les doigts, jeter l'éponge, jeter le bébé avec l'eau du bain.

8. Sayings and proverbs: Le temps c'est de l'argent.

9. Allusions and quotations: Le lait de la tendresse humaine.

Être en charge de is analysed as an example of loan translation from English and is representative of the type of interference whose use is increasing exponentially in French and substituting extremely similar existing structures such as avoir la charge de or être chargé de (Pergnier 1989: 150). The loan translation of English collocations and collocational frameworks is clearly fostered by the resemblance of cognate forms and syntactic structures.

A second typology, dealing with the semantic, pragmatic and discursive proprieties, breaks down as follows:

1. The idiomatic reading does not exist in the recipient language: plafond de verre.

2. Synonymous multi-word units exist in the recipient language and are still in good health: effet domino. 6

3. The semantic extension to a certain number of pragmatic contexts is calqued resulting in idiomatic polysemy in the recipient language: trou noir.

4. Calquing of discursive functions: en terme(s) de. 7

5. An uncommon collocation is literally rendered into the recipient language substituting an analogous collocation, avoir du sens, or a different structure altogether such as être logique: faire du sens.

The case of trou noir is representative of the phenomenon of calquing of a semantic extension. The compound noun is either used as a specialised term in astronomy meaning "a region in space where gravity is so strong that nothing, not even light, can escape" or figuratively in the phrase C'est le trou noir to indicate a situation of deep unhappiness or depression. The 2009 edition of the LPR only registers these two senses. The sense that the 6 Onde de choc and réaction en chaîne have 27 and 55 occurrences respectively in Frantext. 7 The Trésor de la Langue Française informatisé (TLFi) registers only one sense of the complex preposition, i.e. "in the terminology or in the language of a certain art or profession". All the senses and pragmatic uses that we know today are not attested in this updated state-of-the-art dictionary. For the use of in terms of as a focaliser and a topicaliser, see Martí Solano (forthcoming).

compound has acquired in English as "an imaginary place in which things are lost" has been calqued in French as illustrated in the following example:

(3) Sur un million de personnes qui devraient arriver en fin de

Presence and impact of multi-word loan translations and semantic borrowings in French journalistic discourse and dictionaries

We have selected a number of items labelled as Anglicisms in the DEL and we have checked their presence in the printed press in order to account for pervasiveness and institutionalisation. We have manually selected a number of French multi-word units-for the most part predicate idioms and figurative lexical compounds-currently used in the printed press, the radio or television. The reason for working with the French weekly Le Nouvel

Observateur lies in the fact that it is one of the very few French news publications that allow exact multi-word searches and free access to the articles. Frequencies are obviously to be considered as relative if they were to be benchmarked against the results in much bigger archives. However, the figures supplied in tables 1 and 2 are definitely pivotal and significant for the degree of integration and institutionalisation of each of the units under analysis. The results correspond to the number of articles where the exact phrase is used between 2000 and 2010.

Multi-word units, if compared to single-word units, are usually not easy to classify as calques. We have only found two instances of phraseological calques labelled as Anglicisms by the LPR and the DEL. These are adopter un profil bas (< 'keep a low profile') and faire la différence (< 'make the difference'). 8 The former does not exactly conform to the original phrase in the donor language in the sense that the order of adjective + noun in English has been reversed in French and that the French verbal constituent is not the exact equivalent of 'keep' although some verb variants such as maintenir or garder (both meaning 'keep') show the influence of the English verb. But the phrase is much more frequently found under the form faire profil bas which lexico-grammatically further distances itself from its English counterpart and whose only occurrence in Frantext goes back to 2008. As to the collocation faire la différence, the calque is exact and it works satisfactorily in the written press although some speakers can still wrinkle their nose in disapproval when heard in conversation. This calque is very well established and is the second most widespread item on the frequency 8 Adopter un profil bas is mentioned as a phraseological neologism in [START_REF] Merle | Néologie lexicale n° 2[END_REF]. It is classified as a loan translation applying "to units above word rank" by Görlach (2003: 62).

list with a total of 728 hits. It is referred to as a calque from English in the LPR09.

It is interesting to notice the cases of en terme(s) de and adopter un profil bas, progressively mounting since the year 2000 and exploding in the last three or four years. This steady and unbroken evolution goes hand in hand with the extremely high frequency of use of both phrases. _______________________________________________________ Some loan translations have been benchmarked against other Romance languages, especially Spanish, in which the phrase el palo y la zanahoria (lit. 'the stick and the carrot') has been given as an example of a phraseological calque from English (Lorenzo 1996: 486). All the occurrences in the Frantext corpus of croiser les doigts are attested between 1887 and 1975 and they make reference to the physical sense of the phrase, proving the importation of the figurative sense into French. The high 9 For predicate idioms we have used both the infinitive and the past participle for our searches as these two forms put together account for most of the tokens amid all the conjugated forms. It goes without saying that the total number of tokens of predicate idioms is therefore a little higher.

number of tokens of l'homme de la rue corresponds to the free syntactic combination in most cases: the first token found in Frantext of its idiomatic sense was used in a book by Paul Morand entitled New York in 1930.

We have carried out another frequency study concerning French expressions which are not attested either in French general dictionaries or in dictionaries of idioms but that crop up in the French press and other media: voulu lui refiler tout de suite sa patate chaude" takes on the figurative sense. 10 Only the 2009 edition of the LPR has a sub-entry for the figurative sense of this phrase which is classified as a calque from English. All things considered, the results in tables 1 and 2 are but tentative frequency scores that can definitely be improved by subsequent quantitative analysis in larger text databases.

Degrees and strategies of integration

It is widely accepted that journalists are regularly and systematically in contact with international news coming to them most of the time in English (Pergnier 1989: 131) and that the majority of the examples of loan translations and semantic borrowings come from the written press or other 10 The same calque from English has been rendered into Spanish with the phrase patata caliente (Lorenzo 1996: 599).

types of mass media, which makes journalists, TV conductors and radio presenters responsible for not only extending their use but also for legitimising it (Pergnier 1989: 155).

A common practice in journalism consists in inserting words, phrases, sentences and even whole paragraphs in articles between inverted commas.

These quotations, when uttered by English-speaking people, are usually rendered in the recipient language respecting formulae, phraseology and other stylistic traits from the donor language as illustrated in the following example:

(4) Le CIO a annoncé fin novembre qu'il allait examiner l'implication possible de l'un de ses membres au lendemain de la diffusion d'un documentaire diffusé par la BBC, concernant des affaires présumées de corruption au sein de la Concerning their degree of integration, loan translations and semantic borrowings must be observed under the light of restricted or unrestricted cultural contexts (Chesley 2010: 236). High-frequency units tend to appear in unrestricted cultural contexts and are never or rarely between inverted commas. On the other hand, some of the low-frequency units are clearly recognisable because they appear either between inverted commas or in restricted cultural contexts-in pieces of news from or about Englishspeaking countries.

To compensate for the introduction of an idiomatic calque, some metalinguistic strategies can be put into action. Their degree of novelty is signalled by the use of inverted commas, by an explicit reference to its context of use or by the use of all sorts of explanations or other linguistic formulae.

(5) L'arrivée sur le marché du travail d'un nombre croissant de femmes diplômées n'a pas suffi à briser le plafond de verre qui empêche leur ascension au sommet de la hiérarchie des entreprises. (Le Monde, 1 June 2010)

In (5) the defining relative clause which follows the underlined idiomatic expression is used as an explanation of its meaning for the potential French readers-the corresponding information for an English-speaking audience would probably not have been needed.

( The expression in (6) collocates with the word campagne ('campaign') and represents a step further in the general process of adaptation and institutionalisation: the whole phrase, which could be rendered as a 'belowthe-belt campaign' is a clear example of an attributive use of a multi-word unit. We have not found a figurative use of the phrase in the LPR09, which obviously only registers the unit in its literal sense. The idiomatic noun phrase éléphants blancs in ( 7) is both between inverted commas and expanded by a long explanation in the form of an apposition.

This example illustrates the lowest degree of the continuum or cline of The case of zone grise in ( 8) is revealing of the fact that, due to the difficulty of pinpointing this phenomenon, the frequency of semantic borrowings in French has been clearly underestimated (Picone 1996: 101).

We know that new meanings are not always the product of a semantic borrowing and that languages can and do actually develop the same new senses, semantic extensions or semantic shifts regardless of the influence that a given foreign language might eventually exert. However, we subscribe, for the cases we have considered so far, to the principles outlined in the following quotation:

The other general type of semantic analogy, namely that due to extraneous influence, has to do with the borrowing of meanings.

[…]

And yet the possibility of loan-meanings cannot be overlooked in any thorough semantic investigation. Furthermore, while a loanword is traceable by its form, which usually is easily identified with the parent stem, the loan-meaning has no distinct earmarks except in the few cases where a singularly idiomatic turn stamps it as exotic.

[…] But even where proof is lacking, it is more reasonable, from what we know of the readiness of the mind to take up new ideas, to suppose that where we have an idea carried by a number of unrelated words in many dialects, there has been semantic transference rather than independent origin. (Kroesch 1926: 43-44)

Lexicographical treatment

We A special case among this group is éléphant blanc which is recorded in the LPR09 with the geographic label region Canada.

Finally, other expressions are not recorded at all with their idiomatic sense in any of the dictionaries consulted such as trou noir or zone grise, bearing out the fact that semantic borrowings are harder and take longer to be naturalised and therefore recorded in lexicographical works, serving as a way of measuring integration into French.

We consider that the inclusion of the idiomatic loan translation or the semantic borrowing in a French general dictionary accounts for their level of institutionalisation and acknowledgment among language users.

Conclusions

Multi-word loan translations and semantic borrowings in French are not only a product of languages in contact or bilingualism. Mass media in general and the French press in particular abound with these multi-word units which tend to pass unnoticed as Anglicisms for the general reader.

Idiomatic noun phrases, followed closely by predicate idioms, are definitely the type most usually found although all different types of lexical and syntactic combinations are more or less pervasive. Even though the French language has been influenced by English for centuries, this phenomenon is principally a result of the new globalised era of communication and information. Some strings have already been used as a fixed, more or less lexicalised combination, as for instance zone grise, but it is the new sense that the pre-existing phrase develops in certain contexts that is considered innovative and unprecedented. Multi-word loan translations represent not only a phraseological borrowing but also a cultural one as a new image or metaphor is imported into the recipient language. Two different stages of integration (high and low level) should be considered depending on frequency rates, typographical markers and lexicographical treatment.

Obviously, a much bigger corpus would be needed to obtain more finegrained results even though clear tendencies and patterns can be observed, above all in the use of newly imported idiomatic noun phrases.

  from biblical, classical or literary sourcesAccording to Bologne, a saying such as Loin des yeux, loin du coeur (< 'Out of sight, out of mind.') has its origin in the work De Imitatio Christi by Thomas à Kempis published in 1441(Bologne 1999: 299) and Le temps c'est de l'argent (< 'Time is money.') would go back to the ancient Greeks, in particular to the work of Theophrastus(Bologne 1999: 305). However, according to the DEL the latter is a calque from the American adage Time is money, attributed to Benjamin Franklin and appearing in the book Advice to a Young Tradesman published in 1748 (DEL: 750). It should be pointed out that Bologne cites the metaphorical source of the loan translation, the original Greek phrase-translated into English as 'Time is a luxurious expense'-whose lexico-grammar does not correspond exactly to either the English or the French expression whereas the DEL strictly accounts for the actual word-by-word phraseological source.The Bible, said to be the most influential book in the history of humankind, represents a major source of paremiological and phraseological loan translations in myriads of languages. The same applies to classical languages, such as Latin and Greek, which stand for the second source of inspiration. The English expression 'to be in seventh heaven' is a clear example of what has been termed an Europeanism or internationalism(Piirainen 2005: 45). The phrase is found in numerous languages such as German im siebten Himmel sein, French être au septième ciel, Spanish estar en el séptimo cielo, Portuguese estar no sétimo céu, Italian essere al settimo cielo, etc. and its origins can be traced back to ancient sources such as the Apocrypha, the Koran and the Cabbalists(Piirainen, forthcoming). Other examples of internationalisms include phrases belonging to the great classics of world literature as is the case with tilt at windmills, a multi-word loan translation from the novel Don Quixote by the Spanish writer Cervantes. Piirainen also mentions the tip of the iceberg as an internationalism and classifies it in the group of 22 Widespread Idioms (WIs) coming under the subheading "Natural environment, plants, and animals". This scholar gives plenty of examples in her book such as the already mentioned the tip of the iceberg or to throw the baby out with the bath (water), both of which are sources of equivalent translations in French that are classified as Anglicisms in the DEL. To be in the same boat, also mentioned by Piirainen as an internationalism and attested in Cicero and

  droits à une indemnisation chômage en 2010, « une partie bénéficie de la solidarité nationale (RSA, ASS, autres aides) et d'autres […] sont un peu dans un trou noir de notre système de solidarité nationale », a observé Laurent Wauquiez. (Libération, 25 February 2010)

Fifa. «

 « Aux fans de sports, je suis désolé et je regrette qu'ils soient déçus par la mauvaise gestion […] mais en même temps, j'ai envie de leur dire qu'il ne faut pas jeter le bébé avec l'eau du bain », a-t-il ajouté. (Le Nouvel Observateur, 29 September 2010) This practice represents the most straightforward instance of multi-word loan translations and semantic borrowings that find their way into the recipient language and get subsequently established and eventually institutionalised. Other reasons that have been suggested for the introduction of calques in the press have to do with journalists being more proficient at English and with the fact of English being a lingua franca, actually spoken in different professional circles in Europe (Lenoble-Pinson 1991: 7).

  adaptation and institutionalisation of phraseological calques. The use of a general corpus such as Frantext can shed light on the presence of certain word combinations or phrases and the fact of having extended or taken on a new meaning. Zone grise (< 'grey area') has only three occurrences in this corpus, all of them from the same work La fin des asiles by Hervé Bazin from 1959. The combination is used in the field of psychiatry and mental health and is not related at all to the figurative sense of the English idiom meaning 'a subject or problem that people do not know how to deal with because there are no clear rules'. Moreover, the phrase is not attested in any of the French dictionaries consulted, even though the new sense can be found in the written press as illustrated in the following example: (8) « Il faut prendre de façon apaisée le traitement de la question tout en rappelant le cadre de la non-discrimination », a conseillé le Halde. Son président Eric Molinié a estimé la semaine dernière dans La Croix qu'« entre la vie privée et les services publics, il existe une zone grise, tout un secteur d'activités où l'on sert l'intérêt général ». (Le Nouvel Observateur, 8 February 11)

  have used both the 2000 and 2009 editions of the LPR in order to observe entries and sub-entries and their evolution in a span of time roughly corresponding to our frequency research in the online archives of the Le Nouvel Observateur. Long-established phraseological calques such as avoir un cadavre/squelette dans le placard, l'homme de la rue, se refiler la patate chaude or adopter un profil bas are recorded by both general dictionaries as well as by French dictionaries of idioms.Some of the expressions we have investigated that are not recorded in the DEL or in the LPR00 have been recorded in the LPR09, which is indicative of their degree of integration into the language. Cercle vertueux (< 'virtuous circle', in its turn an institutionalised variation on the canonical form 'vicious circle', not yet recorded in English dictionaries of idioms), plafond de verre and effet domino clearly exemplify this lexicographical practice despite the fact that these strings have been in use for several decades as illustrated by the following example: L'expression « cercle vertueux » est à la mode. Les politiques, dans leurs discours, les journalistes, dans leurs articles, l'utilisent alors qu'ils n'y a guère ils l'ignoraient. Peut-être son emploi manifeste-t-il l'espoir de voir notre pays, enfin, sortir de la crise, grâce, à partir des premiers…(Le Monde, 30 December 1989)

  Equallynoteworthy are the cases of strings such as plafond de verre, effet domino,

			1
	jeter l'éponge	501	7
	un profil bas	301	7
	la cerise sur le gâteau	216	7
	croiser les doigts	75	6
	ce n'est pas ma tasse de thé	66	3
	la politique de/faire l'autruche	64	6
	l'homme de la rue	63	58
	la partie visible de l'iceberg	43	2
	jeter le bébé avec l'eau du bain	42	1
	la carotte et le bâton	29	4
	_______________________________________________________
	MWUs	LNO	Frantext
	_______________________________________________________
	le feu vert	1497	33

cercle vertueux, jeter le bébé avec l'eau du bain et jeter l'éponge, among others, whose occurrences are found nearly exclusively from 2007 to date. These data clearly demonstrate how these phraseological calques are gaining ground in French and prove their significance as a recent phenomenon.

Table 1. Multi-word loan translations and semantic borrowings classified as Anglicisms in the DEL and number of occurrences in the Le Nouvel Observateur (LNO) and the Frantext corpus

Table 2 .

 2 Multi-word loan translations and semantic borrowings not recorded in the DEL and number of occurrences in the Le Nouvel Frantext is comparatively lower in table 2 than in table 1, which reflects the coherence between frequency range in texts and lexicographical treatment. There are 37 examples of éléphant blanc in the Frantext corpus but none of these correspond to the figurative sense of the phrase as used in Canadian French. The two examples of patate chaude (< 'hot potato') are from 2001 and 2006 but only the latter "J'aurais

	Observateur (LNO) and the Frantext corpus
	_______________________________________________________
	MWUs	LNO	Frantext
	_______________________________________________________
	cercle vertueux	149	1
	effet domino	121	0
	patate chaude	81	2
	plafond de verre	49	0
	conquête des coeurs et des esprits	7	1
	quinze minutes de gloire	6	0
	éléphant blanc	5	0
	sous le(s) feu(x) des projecteurs	1	0
	avoir des papillons dans le ventre	1	0

En termes de has already been classified as a loan translation from English(Meney 1994: 937).

See Renouf A. & Sinclair J. M., "Collocational Frameworks in English".