Automatiser la construction de règles de corrélation : prérequis et processus

National audienceLes systèmes d'entreprise sont aujourd'hui composés de plusieurs dizaines, centaines ou milliers d'entités communiquant potentiellement avec des machines externes inconnues. Dans ces systèmes de nombreux détecteurs, sondes et IDS sont déployés et inondent les systèmes de supervision de messages et d'alertes. La problématique d'un administrateur en charge de la supervision est alors de détecter des motifs d'attaques contre le système au sein de ce flot de notifications. Pour cela, il dispose d'outils de corrélation permettant d'identifier des scénarios complexes à partir de ces notifications de bas niveau. Cependant, la spécification de ces scénarios demande d'avoir au préalable construit les règles de corrélation adéquates. Ce papier se focalise sur une méthode de génération de règles de corrélation et des prérequis nécessaires à cette opération. Il évalue ensuite le travail requis pour obtenir de telles règles dans le cas d'un processus de génération automatisé

Total hemoglobin mass, aerobic capacity, and hbb gene in polish road cyclists

The relationship between genes, amount of hemoglobin, and physical performance are still not clearly defined. The aim of this study was to examine the association between-551C/T and intron 2, +16 C/G polymorphisms in the beta hemoglobin (HBB) gene and total hemoglobin mass (tHbmass) and aerobic capacity in endurance athletes. Total hemoglobin mass and aerobic capacity indices, i. e.,VO2max, oxygen uptake at anaerobic threshold (VO2AT), maximal power output (Pmax), and power at anaerobic threshold (PAT) were determined in 89 young road cyclists, female (n = 39) and male (n = 50), who were genotyped for 2 polymorphisms in the HBB gene. The relative values of aerobic capacity indices differed significantly among intron 2, +16 C/G polymorphisms of the HBB gene only in female cyclists; athletes with GG genotype had significantly higher values of V O2max (p = 0.003), VO2AT (p = 0.007), PAT (p = 0.015), and Pmax (p = 0.004) than C carriers. No relationships were found between the C-carrier model (CC + CG vs. GG in the case of intron 2, +16 C/G and CC + CT vs. TT for -551 C/T polymorphisms of the HBB gene) and relative values of tHbmass. Our results demonstrated that the HBB gene could be related to aerobic capacity, but it seems that it does not result from an increase in the amount of hemoglobin in the blood

Human Gb3/CD77 synthase produces P1 glycotope-capped N-glycans, which mediate Shiga toxin 1 but not Shiga toxin 2 cell entry

The humanGb3/CD77 synthase, encoded by theA4GALT gene, is an unusually promiscuous glycosyltransferase. It synthesizes the Gala1 -> 4Gal linkage on two different glycosphingolipids (GSLs), producing globotriaosylceramide (Gb3, CD77, P-k) and the P1 antigen. Gb3 is themajor receptor for Shiga toxins (Stxs) produced by enterohemorrhagic Escherichia coli. A single amino acid sub-stitution (p.Q211E) ramps up the enzyme's promiscuity, rendering it able to attach Gal both to another Gal residue and to GalNAc, giving rise toNOR1 andNOR2GSLs. HumanGb3/CD77 synthase was long believed to transfer Gal only to GSL acceptors, therefore its GSL products were, by default, considered the only human Stx receptors. Here, using soluble, recombinant human Gb3/CD77 synthase and p.Q211E mutein, we demonstrate that both enzymes can synthesize the P1 glycotope (terminal Gal-alpha 1 -> 4Gal beta 1 -> 4GlcNAc-R) on a complex type N-glycan and a syntheticN-glycoprotein (saposinD). Moreover, by transfection of CHO-Lec2 cells with vectors encoding human Gb3/CD77 synthase and its p.Q211E mutein, we demonstrate that both enzymes produce P1 glycotopes on N-glycoproteins, with the mutein exhibiting elevated activity. These P1-terminatedN-glycoproteins are recognized by Stx1 but not Stx2 B subunits. Finally, cytotoxicity assays showthat Stx1 can useP1N-glycoproteins produced in CHO-Lec2 cells as functional receptors. We conclude that Stx1 can recognize and use P1 N-glycoproteins in addition to its canonicalGSL receptors to enter and kill the cells, while Stx2 can use GSLs only. Collectively, these results may have important implications for our understanding of the Shiga toxin pathology.Proteomic

Killer immunoglobulin-like receptor and human leukocyte antigen-C genotypes in rheumatoid arthritis primary responders and non-responders to anti-TNF-α therapy

The identification of patients who will respond to anti-tumor necrosis factor alpha (anti-TNF-α) therapy will improve the efficacy, safety, and economic impact of these agents. We investigated whether killer cell immunoglobulin-like receptor (KIR) genes are related to response to anti-TNF-α therapy in patients with rheumatoid arthritis (RA). Sixty-four RA patients and 100 healthy controls were genotyped for 16 KIR genes and human leukocyte antigen-C (HLA-C) group 1/2 using polymerase chain reaction sequence-specific oligonucleotide probes (PCR-SSOP). Each patient received anti-TNF-α therapy (adalimumab, etanercept, or infliximab), and clinical responses were evaluated after 3 months using the disease activity score in 28 joints (DAS28). We investigated the correlations between the carriership of KIR genes, HLA-C group 1/2 genes, and clinical data with response to therapy. Patients responding to therapy showed a significantly higher frequency of KIR2DS2/KIR2DL2 (67.7% R vs. 33.3% NR; P = 0.012). A positive clinical outcome was associated with an activating KIR–HLA genotype; KIR2DS2(+)HLA-C group 1/2 homozygous. Inversely, non-response was associated with the relatively inhibitory KIR2DS2(–)HLA-C group 1/2 heterozygous genotype. The KIR and HLA-C genotype of an RA patient may provide predictive information for response to anti-TNF-α therapy

Killer immunoglobulin-like Receptors (KIR) haplogroups A and B track with Natural Killer Cells and Cytokine Profile in Aged Subjects: Observations from Octo/Nonagenarians in the Belfast Elderly Longitudinal Free-living Aging STudy (BELFAST)

BACKGROUND: Natural Killer Cells (NK) play an important role in detection and elimination of virus-infected, damaged or cancer cells. NK cell function is guided by expression of Killer Immunoglobulin-like Receptors (KIRs) and contributed to by the cytokine milieu. KIR molecules are grouped on NK cells into stimulatory and inhibitory KIR haplotypes A and B, through which NKs sense and tolerate HLA self-antigens or up-regulate the NK-cytotoxic response to cells with altered HLA self-antigens, damaged by viruses or tumours. We have previously described increased numbers of NK and NK-related subsets in association with sIL-2R cytokine serum levels in BELFAST octo/nonagenarians. We hypothesised that changes in KIR A and B haplotype gene frequencies could explain the increased cytokine profiles and NK compartments previously described in Belfast Elderly Longitudinal Free-living Aging STudy (BELFAST) octo/nonagenarians, who show evidence of ageing well. RESULTS: In the BELFAST study, 24% of octo/nonagenarians carried the KIR A haplotype and 76% KIR B haplotype with no differences for KIR A haplogroup frequency between male or female subjects (23% v 24%; p=0.88) or for KIR B haplogroup (77% v 76%; p=0.99). Octo/nonagenarian KIR A haplotype carriers showed increased NK numbers and percentage compared to Group B KIR subjects (p=0.003; p=0.016 respectively). There were no KIR A/ B haplogroup-associated changes for related CD57+CD8 ((high or low)) subsets. Using logistic regression, KIR B carriers were predicted to have higher IL-12 cytokine levels compared to KIR A carriers by about 3% (OR 1.03, confidence limits CI 0.99–1.09; p=0.027) and 14% higher levels for TGF-β (active), a cytokine with an anti-inflammatory role, (OR 1.14, confidence limits CI 0.99–1.09; p=0.002). CONCLUSION: In this observational study, BELFAST octo/nonagenarians carrying KIR A haplotype showed higher NK cell numbers and percentage compared to KIR B carriers. Conversely, KIR B haplotype carriers, with genes encoding for activating KIRs, showed a tendency for higher serum pro-inflammatory cytokines compared to KIR A carriers. While the findings in this study should be considered exploratory they may serve to stimulate debate about the immune signatures of those who appear to age slowly and who represent a model for good quality survivor-hood

Automatiser la construction de règles de corrélation : prérequis et processus

National audienceLes systèmes d'entreprise sont aujourd'hui composés de plusieurs dizaines, centaines ou milliers d'entités communiquant potentiellement avec des machines externes inconnues. Dans ces systèmes de nombreux détecteurs, sondes et IDS sont déployés et inondent les systèmes de supervision de messages et d'alertes. La problématique d'un administrateur en charge de la supervision est alors de détecter des motifs d'attaques contre le système au sein de ce flot de notifications. Pour cela, il dispose d'outils de corrélation permettant d'identifier des scénarios complexes à partir de ces notifications de bas niveau. Cependant, la spécification de ces scénarios demande d'avoir au préalable construit les règles de corrélation adéquates. Ce papier se focalise sur une méthode de génération de règles de corrélation et des prérequis nécessaires à cette opération. Il évalue ensuite le travail requis pour obtenir de telles règles dans le cas d'un processus de génération automatisé

NO ASSOCIATION BETWEEN tHbmass AND POLYMORPHISMS IN THE HBB GENE IN ENDURANCE ATHLETES

The aim of this study was to examine the association between tHbmass and HBB gene polymorphisms in athletes of endurance disciplines. Eighty-two well-trained athletes (female n=36, male n=46), aged 19.3 ± 2.7 years, representing cross country skiing (n=37) and middle- and long-distance running (n=45), participated in the study. Genotyping for 2 polymorphisms in the HBB gene (- 551C/T and intron 2, +16 C/G) was performed using restriction fragment length polymorphism analysis. Total haemoglobin mass (tHbmass) was determined by the optimized carbon monoxide rebreathing method. Blood morphology, indices of iron status (ferritin, transferrin receptor and total iron binding capacity) and C reactive protein were also determined. No differences were found in the HBB genotype and allele frequencies between male and female athletes. Regardless of the polymorphisms, no relationships were found between HBB genotypes as well as alleles and relative values of tHbmass, expressed per body mass (g · kg-1 BM), both in female and male athletes. Our results demonstrated that -551 C/T and intron 2, +16 C/G polymorphisms of the HBB gene have no association with total haemoglobin mass in endurance athletes. It cannot be ruled out that several polymorphisms, each with a small but significant contribution, may be responsible for the amount of haemoglobin

KIR2DL2/2DL3-E35 alleles are functionally stronger than -Q35 alleles

KIR2DL2 and KIR2DL3 segregate as alleles of a single locus in the centromeric motif of the killer cell immunoglobulin-like receptor (KIR) gene family. Although KIR2DL2/L3 polymorphism is known to be associated with many human diseases and is an important factor for donor selection in allogeneic hematopoietic stem cell transplantation, the molecular determinant of functional diversity among various alleles is unclear. In this study we found that KIR2DL2/L3 with glutamic acid at position 35 (E(35)) are functionally stronger than those with glutamine at the same position (Q(35)). Cytotoxicity assay showed that NK cells from HLA-C1 positive donors with KIR2DL2/L3-E(35) could kill more target cells lacking their ligands than NK cells with the weaker -Q(35) alleles, indicating better licensing of KIR2DL2/L3(+) NK cells with the stronger alleles. Molecular modeling analysis reveals that the glutamic acid, which is negatively charged, interacts with positively charged histidine located at position 55, thereby stabilizing KIR2DL2/L3 dimer and reducing entropy loss when KIR2DL2/3 binds to HLA-C ligand. The results of this study will be important for future studies of KIR2DL2/L3-associated diseases as well as for donor selection in allogeneic stem cell transplantation