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Infect Immun. 2009 October; 77(10): 4480–4486.
Published online 2009 July 20. doi:  10.1128/IAI.00519-09
PMCID: PMC2747964

Role of Nod1 in Mucosal Dendritic Cells during Salmonella Pathogenicity Island 1-Independent Salmonella enterica Serovar Typhimurium Infection [down-pointing small open triangle]


Recent advances in immunology have highlighted the critical function of pattern-recognition molecules (PRMs) in generating the innate immune response to effectively target pathogens. Nod1 and Nod2 are intracellular PRMs that detect peptidoglycan motifs from the cell walls of bacteria once they gain access to the cytosol. Salmonella enterica serovar Typhimurium is an enteric intracellular pathogen that causes a severe disease in the mouse model. This pathogen resides within vacuoles inside the cell, but the question of whether cytosolic PRMs such as Nod1 and Nod2 could have an impact on the course of S. Typhimurium infection in vivo has not been addressed. Here, we show that deficiency in the PRM Nod1, but not Nod2, resulted in increased susceptibility toward a mutant strain of S. Typhimurium that targets directly lamina propria dendritic cells (DCs) for its entry into the host. Using this bacterium and bone marrow chimeras, we uncovered a surprising role for Nod1 in myeloid cells controlling bacterial infection at the level of the intestinal lamina propria. Indeed, DCs deficient for Nod1 exhibited impaired clearance of the bacteria, both in vitro and in vivo, leading to increased organ colonization and decreased host survival after oral infection. Taken together, these findings demonstrate a key role for Nod1 in the host response to an enteric bacterial pathogen through the modulation of intestinal lamina propria DCs.

Recognition of microbes is a critical step in the initiation of the host immune response against infection. Indeed, detection of microbe-associated molecular patterns by germ line-encoded receptors such as Toll-like receptors (18) and Nod-like receptors (NLRs) (8) is an early event that leads to inflammatory responses through the production of cytokines and chemokines. Nod1 and Nod2 are cytosolic proteins of the NLR family that detect distinct substructures from bacterial peptidoglycan (8). Whereas Nod2 detects muramyl dipeptide (12, 16), a motif common to gram-negative and gram-positive bacteria, Nod1 senses meso-diaminopimelic acid-containing peptidoglycan (3, 11), which is more commonly found in gram-negative bacteria. In macrophages and dendritic cells (DC), triggering of Nod1 and Nod2 induces proinflammatory cytokines and costimulatory molecules (21). In addition, synergistic effects of Nod ligands with Toll-like receptor ligands in myeloid cells have been reported (9, 29). Nod1 has been shown to regulate the colonization of mice by Helicobacter pylori (31), and Nod2 affects the pathogenicity of Listeria monocytogenes (19) and Mycobacterium tuberculosis (6) in mice models. However, no studies have been conducted on the impact of Nod1 and Nod2 on the in vivo infection process of the specific enteric pathogen, Salmonella enterica serovar Typhimurium.

Salmonella enterica is a gram-negative bacterium of the Enterobacteriaceae family. S. enterica serovar Typhimurium is a mouse pathogen that provokes a typhoid-like syndrome in orally infected mice, with colonization of the deeper organs, including the liver and spleen (5). S. Typhimurium is capable of entering intestinal epithelial cells using a unique mechanism involving a type 3 secretion system, Salmonella pathogenicity island 1 (Spi1) (10), and resides in a vacuole within infected cells via a mechanism dependent on a second type 3 secretion system, Spi2 (27). Hence, the bacteria are able to avoid killing and spread throughout the infected host by invading immune cells. The intracellular lifestyle of Salmonella is in line with a possible implication of Nod proteins during the course of the infection. However, to date, no study has been conducted in vivo to determine the role of Nod1 and Nod2 after oral infection with S. Typhimurium.

Spi1 is critical for the invasiveness of the bacteria in epithelial cells and is thought to be responsible for the main route of entry of the bacteria through Peyer's patches (13, 30). Strikingly, bacteria deficient for Spi2 are completely avirulent whereas Spi1 mutants are still capable of inducing the disease (26). Recently, myeloid cells from the intestinal lamina propria have been shown to sample the luminal contents of the gut, including intact bacteria. This mechanism is crucial for gut homeostasis but provides a portal of entry for S. Typhimurium and explains the persistent virulence of Spi1-deficient bacteria (4, 24, 30).

In the present study we show that Nod1 deficiency leads to increased susceptibility to Spi1 deficient-S. Typhimurium but not the wild-type (WT) strain, suggesting a critical role for Nod1 in myeloid cells from the intestinal lamina propria for defense against S. Typhimurium infection in vivo. Accordingly, using bone marrow-chimeric mice, we have been able to locate the defect in in vivo hematopoietic cells. Indeed, Nod1 deficient animals show increased S. Typhimurium in the lamina propria DC subpopulation and an impaired cellular response after infection with Spi1-deficient bacteria. Additionally, we observed an impaired response of Nod1-deficient DCs toward the bacteria. Taken together, our findings uncover a surprising role of Nod1 in lamina propria DCs in the control of S. Typhimurium infection in vivo.



All animal experiments were approved by the Animal Ethics Review Committee of the University of Toronto. C57BL/6 mice were purchased from Charles River Laboratories (Wilmington, MA) and bred in our facility. Nod1-deficient mice, originally from Millenium Pharmaceuticals, and Nod2-deficient mice, obtained from Jean-Pierre Hugot (Hôpital Robert Debré, Université Paris Diderot, Paris, France), have been backcrossed eight times into the C57BL/6 background and have been selected to be Nramp sensitive. The animals were subjected to sanitary control tests and used at the age of 6 to 10 weeks. All animal experiments were performed according to local guidelines.

For the generation of chimeras, recipient mice (WT or Nod1−/−) were gamma irradiated with 8 Gy and were reconstituted with 108 T-cell-depleted bone marrow cells from donor mice (6 to 8 weeks of age). Donor marrow was depleted of T lymphocytes using CD4 and CD8 microbeads (Miltenyi Biotech, Bergisch-Gladbach, Germany) according to the manufacturer's protocol. At 6 to 8 weeks after reconstitution, mice were tested for chimerism by examining CD45.1 (WT) or CD45.2 (Nod1-deficient) expression on the donor cells. Typical chimerism reached 95 to 98%.

Bacterial strains.

Salmonella enterica serovar Typhimurium strain SL1344 was used as the WT strain and for background for mutant strains. Spi1- and HilA-deficient bacteria have been previously described (1, 10).


Bacterial cultures for mouse infections were grown in Luria broth to early stationary phase (optical density at 600 nm of 2 to 3), harvested by centrifugation, and diluted to the appropriate CFU ml−1 in sterile phosphate-buffered saline (PBS) for infections. Appropriate dilutions were used for in vitro gentamicin protection infection assay. Briefly, cells were infected at a multiplicity of infection of 1 to 100 and bacteria spun down to synchronize the infection. After 30 min of infection, cells were washed and fresh medium containing 100 μg/ml of gentamicin was added to kill extracellular bacteria.

For oral infections, bacteria were resuspended at 106 CFU ml−1, and 0.1 ml of the suspension (105 bacteria) was used to infect groups of WT and knockout mice. The total infective dose was determined in parallel by plating dilutions on agar plates. Afterwards, mice were sacrificed by cervical dislocation, and spleens, mesenteric lymph nodes (MLN), and livers were removed for determination of organ bacterial loads. Isolated organs were washed once in PBS and homogenized in 1 ml of PBS. Dilutions of the cell lysates were plated on agar plates for enumeration of total intracellular bacteria. Intraperitoneal infections were performed by injection of 0.1 ml of a solution of 102 CFU ml−1 into the peritoneal space, yielding a final infective dose of 10 CFU per animal.

DC preparations.

Bone marrow-derived DCs (BMDCs) were obtained from WT and Nod1−/− mice as previously described. In brief, total bone marrow cells depleted of red blood cells were seeded at 1.5 × 106 cells/well in six-well plates (3 ml/well) in complete culture medium (Dulbecco modified Eagle medium supplemented with 2 mM l-glutamine, 1 mM sodium pyruvate, 1× nonessential amino acids, 50 mM 2-β-mercaptoethanol [all purchased from Invitrogen], and 10% fetal calf serum [FCS] [HyClone]) supplemented with 100 ng/ml of granulocyte-macrophage colony-stimulating factor for BMDCs. Cells were incubated for 6 days at 37°C. On day 6, cells were harvested and seeded in complete culture medium in 24-well plates at 105 cells/well.

BMDCs were then used for in vitro infection assay. Cells were lysed for CFU counts and stained for fluorescence-activated cell sorter (FACS) analysis, and/or supernatant was harvested for cytokine and nitric oxide dosage. NO was quantified with the modified Griess reagent (Sigma) following the manufacturer's information.

Analysis of immune cells from lamina propria.

To determine the ratio of lymphocyte populations in WT and Nod1−/− mice, single-cell suspensions of spleen, MLN, and Peyer's patches from mice were prepared by grinding on a 70-μm cell strainer and analyzed by flow cytometry.

For analysis of lamina propria immune cells, small intestines were aseptically removed and washed once in PBS. The luminal content was then removed by repeated PBS flushing, the Peyer's patches were excised, and the organ was sliced open. The intestine was then cut in four pieces and washed in PBS twice and then in Hanks balanced salt solution-5% FCS-5 mM EDTA three times to remove epithelial and epithelium-associated lymphocytes. After several washes in large volumes of PBS, the intestine was cut in 2-millimeter pieces and digested in Hanks balanced salt solution-5% FCS-0.5 mg collagenase (Sigma) for 1 hour. A cell suspension was obtained by filtering on a 70-μm strainer.

Cells were resuspended in FACS buffer (1× PBS containing 0.05% of sodium azide) and incubated with CD16/32 (eBioscience) antibody for 15 min on ice to block unspecific staining. Subsequently, cells were incubated with the following antibodies: biotin-labeled antibodies specific for major histocompatibility complex class II (BD); phycoerythrin-labeled antibodies specific for CD3epsilon (BD), B220 (eBioscience), and CD11b (eBioscience); and allophycocyanin-labeled antibodies specific for CD8 (eBioscience), Gr-1 (eBioscience), and CD11c (eBioscience). After staining, cells were washed twice with FACS buffer and analyzed by FACS (FACSCaliburflow cytometer; Becton Dickinson). FlowJo software was used for the analysis of the results.

Statistical analysis.

The results are given as means ± standard deviations. Statistical analysis was performed with Graphpad Prism 5 software using a Mann-Whitney U test. Kaplan-Meier plots and log rank tests were used to assess the survival differences between control and mutant mice after bacterial infection. A P value of <0.05 was considered significant.


Nod1 or Nod2 deficiency does not increase susceptibility of C57BL/6 mice to WT S. Typhimurium.

We orally infected WT C57BL6 mice and Nod1−/− mice with a virulent strain of S. Typhimurium, SL1344. Similar to results of previous studies, mice were susceptible to the infection and succumbed starting at day 7 postinfection. No differences were seen in Nod1−/− mice compared to WT mice in both survival and organ colonization (Fig. 1A and B). The same could be observed in Nod2-deficient animals (Fig. (Fig.1C)1C) as well as in the Nod1/Nod2 double-knockout mice (Fig. (Fig.1D1D).

FIG. 1.
Nod1 and Nod2 deficiency does not increase susceptibility of mice to WT S. Typhimurium. (A and B) C57BL6 (WT) (n = 15) and Nod1-deficient (n = 13) mice were infected orally with 105 S. Typhimurium organisms. (A) Survival was monitored ...

Nod1 plays a role in Spi1-independent S. Typhimurium infection.

Recently, myeloid cells of the lamina propria have been shown to be able to sample the luminal contents of the intestine through formation of protrusions between epithelial cells. Indeed, lamina propria DCs are able to “pick up” luminal bacteria, which is likely an important process to sample luminal antigens. To test the implication of Nod1 in this pickup process, we infected WT and Nod1−/− mice with mutant strains of S. Typhimurium defective for invasiveness of epithelial cells: a ΔHilA mutant (Fig. (Fig.2A),2A), which has a deletion of a regulator of the Spi1 locus, and a ΔSpi1 mutant, which harbors a total deletion of the pathogenicity island (data not shown). Surprisingly, Nod1-deficient animals were more susceptible to these bacteria than their WT counterparts. Levels of bacteria were higher in Nod1 knockout mice at day 5 postinfection (Fig. (Fig.2B).2B). However, similar levels of colonization of the intestinal tract were observed, suggesting a defect after the entry process rather than increased bacterial growth in the host gut (Fig. (Fig.2C).2C). Surprisingly, no difference was observed in Nod2−/− mice (Fig. (Fig.2D),2D), and no greater difference than for the single Nod1 knockout was observed in the Nod1−/− Nod2−/− double-knockout mice (Fig. (Fig.2E),2E), indicating nonredundant roles of these two closely related molecules in response to S. Typhimurium. Overall, these findings indicate that Nod1 but not Nod2 is critical in S. Typhimurium Spi1-independent infection.

FIG. 2.
Nod1- but not Nod2-deficient mice are more susceptible to Spi1-deficient S. Typhimurium. (A) C57BL6 (WT) (n = 20) and Nod1-deficient (n = 21) mice were infected orally with 105 WT S. Typhimurium ΔHilA organisms. Survival was monitored ...

Nod1 deficiency in the hematopoietic compartment is responsible for increased susceptibility to S. Typhimurium infection.

Our results suggest that the defect seen in the Nod1−/− mice with respect to S. Typhimurium infection can be attributed to cells within the hematopoietic compartment. To test this hypothesis, we conducted bone marrow chimera experiments. We reconstituted lethally irradiated WT and Nod1−/− mice with bone marrow obtained from control WT mice (WT<-WT and WT<-Nod1−/−, respectively). We also examined the reverse chimera where WT bone marrow was injected into Nod1−/− mice (Nod1−/−<-WT). Interestingly, after infection with S. Typhimurium ΔHilA, the survival curve for Nod1−/−<-WT mice was comparable to that for the WT<-WT mice (Fig. (Fig.3A),3A), suggesting that the presence of Nod1 in the hematopoietic cells was sufficient to rescue the phenotype observed in Nod1−/− mice. Surprisingly, WT<-Nod1−/− mice had the same survival rate as the WT<-WT mice, suggesting that factors derived from nonhematopoietic cells are also implicated in the survival of infected mice. Despite the lack of difference in survival, however, colonization of the spleen by the bacteria was higher in WT<-Nod1−/− mice than in WT<-WT and Nod1−/−<-WT mice (Fig. (Fig.3B).3B). Of note, no difference was observed when mice were injected intraperitoneally with S. Typhimurium WT or ΔHilA bacteria (data not shown), suggesting that the defect in Nod1-deficient myeloid cells in vivo does not become manifest during systemic infection. On the contrary, since increased susceptibility in Nod1-deficient mice is observed during oral infection with the Spi1 mutant of Salmonella, this likely indicates that impaired early responses in myeloid cells occur specifically at the intestinal mucosal surface. Therefore, Nod1 in the hematopoietic compartment at the level of the mucosa appeared to restrict bacterial translocation to the deeper organs, affecting the survival of the animal.

FIG. 3.
Nod1 in the hematopoietic compartment is important for the response to Spi1-deficient bacteria. WT or Nod1−/− irradiated mice reconstituted with the indicated bone marrow (WT<-WT, n = 8; WT<-Nod1, n = 7; ...

Nod1-deficient DCs from the lamina propria are more highly infected by S. Typhimurium.

We next aimed to investigate whether Nod1 deficiency translated to increased numbers of bacteria at the level of the intestinal lamina propria. To begin with, we examined the different immune cell populations from the intestinal lamina propria. We saw no difference between Nod1−/− and WT mice in the proportions of the different cell types populating the lamina propria (see Fig. Fig.5A).5A). Similar to the results described in previous reports, we could also isolate four different subpopulations of macrophages and DCs characterized by the expression of the surface integrins CD11c and CD11b. We analyzed CD11b+ macrophages (R1), CD11b+ CD11c+ DCs (R2), and CD11c+ DCs (R3) for surface marker expression, and no significant differences were observed between WT and Nod1−/− mice (Fig. (Fig.4A4A and data not shown). We then conducted the same phenotyping after 1 day of infection with S. Typhimurium ΔHilA expressing green fluorescent protein (GFP). Although the three myeloid populations characterized previously within the lamina propria were altered after infection, there were no differences when comparing WT versus Nod1−/− mice (Fig. (Fig.4A)4A) (P = 0.246). Surprisingly, macrophages were not infected by the bacteria (Fig. (Fig.4B).4B). However, and in line with previous reports, CD11b+ CD11c+ DCs were preferentially infected by S. Typhimurium ΔHilA (Fig. (Fig.4C).4C). Interestingly, the percentage of these cells infected was higher in Nod1-deficient mice than in their WT counterparts (Fig. (Fig.4C),4C), while the CD11 CD11c+ DC population was equally infected by the bacteria in both WT and Nod1-deficient mice (Fig. (Fig.4D).4D). These findings underscore the importance of Nod1 expression in restricting S. Typhimurium ΔHilA infection in the CD11b+ CD11c+ DC population of the lamina propria. Interestingly, we also identified the CD11b CD11c+ DC population as a potential carrier of Salmonella bacteria, although the targeting to this cell type was not different in WT and Nod1-deficient mice.

FIG. 4.
Myeloid populations of WT and Nod1−/− intestinal lamina propria. Small intestines from WT and Nod1−/− mice were removed and lamina propria cell suspensions prepared. Cells were stained for CD11b and CD11c. Populations of ...
FIG. 5.
Defect of Nod1-deficient DCs in S. Typhimurium ΔHilA infection. BMDCs were infected at a multiplicity of infection of 1 with SL1344 or the ΔHilA mutant. After 30 min, cells were treated with gentamicin. After another 2 h, cells were lysed ...

An intrinsic defect in Nod1-deficient DCs infected by S. Typhimurium ΔHilA.

We have shown above that Nod1-deficient mice were more susceptible to bacteria that are mostly picked up directly by immune cells of the lamina propria, more specifically DCs. We confirm that this increased susceptibility is due to Nod1 deficiency in the hematopoietic compartment at the level of the mucosa. Hence, we wanted to test whether DCs have an intrinsic defect after Salmonella infection. BMDCs were prepared from WT and Nod1−/− mice and infected with S. Typhimurium ΔHilA. After 2 hours of infection, the number of viable bacteria recovered from the cell lysate was significantly higher in Nod1-deficient cells infected with S. Typhimurium ΔHilA (Fig. 5 A), and the levels of intracellular inducible nitric oxide synthase (iNOS) were reduced in Nod1−/− compared to WT mice (Fig. (Fig.5B).5B). Accordingly, after overnight culture, the levels of nitric oxide (Fig. (Fig.5C)5C) were reduced in the supernatants of cultures of Nod1−/− cells. These findings suggest that Nod1-deficient DCs are intrinsically impaired in the early response to S. Typhimurium ΔHilA.


Our study shows, for the first time, the implication of Nod1 in S. Typhimurium infection in vivo. Nod1-deficient animals exhibited an increased susceptibility to Spi1-deficient bacteria, with higher colonization of deep organs and a decreased survival rate. Interestingly, these mutant bacteria enter the organism through the active pickup of the pathogen by lamina propria resident myeloid cells. Accordingly, we could localize the defect to the myeloid compartment at the intestinal mucosal surface, as we observed increased bacterial infection of lamina propria DCs in Nod1-deficient mice. Moreover, BMDCs deficient in Nod1 were impaired in their response to infection, with reduced production of the antimicrobial compound NO.

Ex vivo evidence suggests that other members of the NLR family (NLRC4/IPAF, NLRB1/NAIP, and NLRP3/NALP3) are implicated in the cellular response to S. Typhimurium (7, 20, 22, 23). In particular, macrophages deficient in these NLRs are resistant to bacterially induced caspase 1-dependent cell death (2). Nod1-deficient cells, on the other hand, were killed normally by the infection (data not shown) and, more strikingly, were less able to control multiplying bacteria. Taken together, these finding underscore the distinct roles for these NLRs in host cell survival during S. Typhimurium infection. Interestingly, in our experimental model, Nod2 does not play a role in the response against S. Typhimurium in vivo despite the fact that, as S. Typhimurium is a gram-negative bacterium, its peptidoglycan contains both Nod1 and Nod2 ligands. However, Nod1 and Nod2 detect similar yet distinct peptidoglycan motifs (3, 11, 12, 17). An interesting report showed that S. Typhimurium alters the composition of its peptidoglycan during intracellular growth (25), which could skew the host response to the intracellular bacteria toward a Nod1- rather than a Nod2-dependent mechanism of detection.

In this model, little inflammation is generated at the level of the intestinal mucosa when the bacteria cross the epithelial layer. Indeed, our observations identified a lack of innate cell recruitment, specifically neutrophils, in the intestinal lamina propria at early times of infection (data not shown), which is in line with the mechanism of Salmonella enterica serovar Typhi infection in humans (14). This stealth process of Salmonella entry through the mucosal barrier is a key event in the pathology. Indeed, the infection by the oral route requires an inoculum at least 104 times higher than that by intraperitoneal injection (reference 15 and this study). This suggests that the rate-limiting step to S. Typhimurium pathogenicity lies at the mucosal surface and that once this barrier is crossed, the bacteria have a strong advantage over the host's immune system. Using an S. Typhimurium mutant (ΔHilA) that enters exclusively through the lamina propria DCs, we uncovered a critical role for Nod1 in these cells, which thereby had an impact on host survival.

We then characterized the functional consequence of Nod1 deficiency in lamina propria myeloid cells following infection with S. Typhimurium ΔHilA. In particular, our results established that CD11b+ CD11c+ (R2) DCs are the primary target of S. Typhimurium ΔHilA after oral infection, as previously shown. This mechanism depends on the production of fractalkine/CX3CL1 by the epithelial cells and the expression of the receptor CX3CR1 on myeloid cells. CX3CR1-positive myeloid cells, mainly DCs, follow the chemotactic gradient of CX3CR1, which enables them to push between epithelial cells and sample the lumen content of the intestine. We observed that Nod1 deficiency resulted in increased numbers of bacteria in these cells, which likely contributes to the enhanced spreading of the pathogen in Nod1−/− mice following oral infection. This might be explained either by an increase in bacterial uptake from the intestinal lumen, by a defective immune response induced by these DCs, or by an intrinsic defect of these cells in controlling intracellular growth of the bacteria. The last hypothesis is supported by our ex vivo results with BMDCs that exhibit reduced iNOS expression and altered NO synthesis, which correlates with an increased bacterial burden in infected Nod1−/− cells compared to WT cells. This intrinsic defect of the Nod1-deficient DCs might in part explain the decrease survival rates observed after oral infection with S. Typhimurium ΔHilA. Our results are in line with previous studies where the Nod1 ligand has been shown to induce NO (21) and, more recently, in another infectious model using Chlamydophila pneumoniae (28) and Listeria monocytogenes (23a).

After infection with S. Typhimurium ΔHilA, we detected bacteria in CD11b CD11c+ DCs (R3), which are normally unable to sample through the epithelial layer because of their lack of expression of CX3CR1. Interestingly, similar results have been previously described using a model of S. Typhimurium-induced colitis (13). Several possibilities could explain this observation. First, infection of these cells could occur as a bystander effect after the death of other infected cells. Second, Salmonella-containing DCs might downregulate their surface markers, such as CD11b and CX3CR1, prior to their migration to MLN. Further studies are required to track down the modulation of expression of cell surface markers in lamina propira DCs infected with S. Typhimurium ΔHilA, both within the lamina propria and during the migration to MLN and deeper tissues.

Our study uncovers a critical role for Nod1 in intestinal lamina propria DCs following infection with S. Typhimurium. The expression of Nod1 in these myeloid cells might therefore contribute to regulate the balance between tolerance toward the intestinal microbiota and pathogen-driven inflammation. Furthermore, polymorphisms in Nod1 have been linked to inflammatory bowel disease (32), and thus our findings may contribute to the development of new therapeutic approaches to treat or prevent inflammatory disorders, as well as enteric infections, by modulating Nod1 function.


L.L.B. received funding from the Fondation Recherche Médicale and Association François Aupetit. J.G.M. received funding from The Fundaçaõ pana a Ciência e a Tecnologia. T.S. received funding from the Allergy/Asthma Information Association. L.H.T. received support from the Canadian Institutes of Health Research (CIHR 174658). J.H.F. is a recipient of an APART fellowship of the Austrian Academy of Sciences at the University of Toronto. D.J.P. is a Howard Hughes International Scholar. This work was supported by the following grants: CIHR: MOP480142 (to D.J.P.), CIHR: MOP81360 (to S.E.G.), American Asthma Foundation (to D.J.P.), and Crohn's and Colitis Foundation of Canada (to S.E.G.).


Editor: A. J. Bäumler


[down-pointing small open triangle]Published ahead of print on 20 July 2009.


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