The interleukin-6 gene −572C/G promoter polymorphism modifies Alzheimer's risk in APOE ɛ4 carriers

Inflammatory response is involved in the etiopathology of Alzheimer's disease (AD). Interleukin-6 (IL-6), a pleiotropic inflammatory cytokine, was reported to be associated with both increased Aβ aggregation and the appearance of hyperphosphorylated tau in AD brain. To explore the association of genetic variants in the promoter of IL-6 gene with sporadic AD (SAD), a case–control study was conducted in a North Chinese Han population. A systematic screening of IL-6 promoter was performed using direct sequencing and two polymorphisms were obtained including −572C/G (rs1800796) and −384A/T (rs7802308). Definitive genotyping of these markers and apolipoprotein E (APOE) polymorphism were surveyed in 341 SAD patients and 421 controls. The results revealed no significant differences in the distributions of alleles or genotypes between SAD and control groups. However, there was an interaction between −572C/G and APOE genotypes (P = 0.016) using logistic analysis. In the subjects with APOE ?4, there were significant differences in the allele (P = 0.004) and genotype (P = 0.004) distributions of −572C/G polymorphism between SAD and control groups. The −572CC genotype increased risk for AD by 3.301-fold (Wald = 11.093, adjust OR = 3.301, 95% CI = 1.635–6.665, P = 0.001) compared to CG + GG genotype. The present results suggest the −572 polymorphism could modify the risk for SAD in APOE ?4 carriers.     

Amplification of the RARA gene in acute myeloid leukemia: significant finding or coincidental observation?

Oncogene amplification resulting in aberrant expression, although common in solid tumors, is rare in acute myeloid leukemia (AML) and is mostly associated with amplification of MYC, RUNX1, and MLL genes. Retinoic acid receptor α (RARA) and other target sequences at 17p11.2 often represent the amplicons expressed in breast cancer, not in AML. We present a unique case of a 59-year-old female with a history of breast cancer, now presenting with pancytopenia and bilateral infiltration with effusion in nodules of the right upper lobe of the lung. She was diagnosed with AML-M5. Chromosome analysis demonstrated a hypodiploid clone with complex numerical/structural abnormalities including 5q deletion, monosomy 7, as well as structurally rearranged chromosome 11 and several marker chromosomes. Fluorescence in situ hybridization (FISH) analysis showed amplification of RARA, loss of 7q, monosomy 7, loss of DEK (6p23), and additional copies of NUP214 (9q34) and MLL (11q23). Additional FISH studies showed both ERBB2 and TOP2A genes, which were co-amplified on one of the marker chromosomes. The follow-up bone marrow did not yield any metaphases, but FISH was normal for all probes, including RARA. After a short remission, the patient relapsed and showed clonal evolution. Additional case reports are necessary to assess whether RARA amplification in hematologic malignancies serves as an independent prognostic factor.     

Association of cerebrospinal fluid Aβ42 with A2M gene in cognitively normal subjects

Low cerebrospinal fluid (CSF) Aβ₄₂ levels correlate with increased brain Aβ deposition in Alzheimer's disease (AD), which suggests a disruption in the degradation and clearance of Aβ from the brain. In addition, APOE ε4 carriers have lower CSF Aβ₄₂ levels than non-carriers. The hypothesis of this investigation was that CSF Aβ₄₂ levels would correlate with regulatory region variation in genes that are biologically associated with degradation or clearance of Aβ from the brain. CSF Aβ₄₂ levels were tested for associations with Aβ degradation and clearance genes and APOE ε4. Twenty-four SNPs located within the 5′ and 3′ regions of 12 genes were analyzed. The study sample consisted of 99 AD patients and 168 cognitively normal control subjects. CSF Aβ₄₂ levels were associated with APOE ε4 status in controls but not in AD patients; A2M regulatory region SNPs were also associated with CSF Aβ₄₂ levels in controls but not in AD patients, even after adjusting for APOE ε4. These results suggest that genetic variation within the A2M gene influences CSF Aβ₄₂ levels.     

Involvement of germline DDX1–MYCN duplication in inherited nephroblastoma

This report concerns a 3-year-old girl with prenatal bilateral nephroblastomatosis and a family history of nephroblastoma. This girl had a chromosome 8 pericentric inversion inherited from her father. This inversion was observed in healthy individuals of the family and was absent in other individuals suffering from embryonic kidney tumor. We then supposed that another genetic anomaly predisposed her to tumorogenesis. Additional cryptic imbalances are reported in cases of apparently balanced chromosomal rearrangements with an abnormal phenotype. Array-CGH analysis showed a 569 kb duplication at 2p24.3 including the DDX1 and MYCN genes. This duplication was inherited from the patient's father who also had a nephroblastoma. A link between germline MYCN duplication and the occurrence of other embryonic cancers such as neuroblastoma has already been described. We supposed that germline DDX1–MYCN duplication could also be involved in the apparition of nephroblastomas.     

Plasmodium falciparum origin recognition complex subunit 1 (PfOrc1) functionally complements Δsir3 mutant of Saccharomyces cerevisiae

Telomere position effect efficiently controls silencing of subtelomeric var genes, which are involved in antigenic variation in human malaria parasite Plasmodium falciparum. Although, PfOrc1 has been found to be associated with PfSir2 in the silencing complex, its function in telomere silencing remained uncertain especially due to an apparent lack of BAH domain at its amino-terminal region. Here we report that PfOrc1 possesses a Sir3/Orc1 like silencing activity. Using yeast as a surrogate organism we have shown that PfOrc1 could complement yeast Sir3 activity during telomere silencing in a Sir2 dependent manner. By constructing a series of chimera between PfOrc1 and ScSir3 we have observed that the amino-terminal domain of PfOrc1 harbors silencing activity similar to that present in the amino-terminal domain of ScSir3. We further generated several amino-terminal deletion mutants to dissect out such silencing activity and found that the first seventy amino acids at the amino-terminal domain are dispensable for its activity. Thus our results strongly supports that PfOrc1 may have a role in telomere silencing in this parasite. This finding will help to decipher the mechanism of telomere position effect in P. falciparum.     

Deletion of Braun lipoprotein gene (lpp) attenuates Yersinia pestis KIM/D27 strain: Role of Lpp in modulating host immune response,NF-κB activation and cell death

The pathogenic species of yersiniae potently blocks immune responses in host cells by using the type III secretion apparatus and its effector proteins. In this study, we characterized potential mechanisms associated with the Braun lipoprotein (Lpp) that contributed to a further attenuation of a pigmentation locus-minus Yersinia pestis KIM/D27 mutant strain and its ability to generate immune responses in mice. The lpp gene encodes one of the major outer membrane lipoproteins that is involved in inflammatory responses and septic shock. We found that sera and splenocytes from Δlpp mutant-immunized mice, when transferred to naïve animals, provided protection to the latter against challenge with a lethal dose of the Y. pestis parental strain. Further, the Δlpp mutant promoted ex vivo a significantly higher interleukin (IL)-2 and interferon-gamma production from T cells of immunized mice, when compared to those from animals infected with the sub-lethal dose of the parental Y. pestis KIM/D27 strain. Likewise, murine primary macrophages infected with the mutant, when compared to those infected with the parental strain in vitro, produced significantly higher IL-12 levels. Importantly, increased nuclear factor-kappa B activation and decreased apoptosis were noted in splenocytes and primary macrophages of mice challenged with the Δlpp mutant, when compared to those in animals infected with the parental Y. pestis KIM/D27 strain. Finally, significantly higher levels of antibodies specific for the parental Y. pestis antigens were developed in mice first immunized with the Δlpp mutant and then challenged with the parental strain, compared to the antibody levels in animals that were immunized and then infected with the parental KIM/D27 strain. To our knowledge, this is the first report of a mechanistic basis for attenuation and immunological responses associated with deletion of the lpp gene from the Y. pestis KIM/D27 strain.     

Yersinia enterocolitica and Photorhabdus asymbiotica β-lactamases BlaA are exported by the twin-arginine translocation pathway

In general, β-lactamases of medically important Gram-negative bacteria are Sec-dependently translocated into the periplasm. In contrast, β-lactamases of Mycobacteria spp. (BlaC, BlaS) and the Gram-negative environmental bacteria Stenotrophomonas maltophilia (L2) and Xanthomonas campestris (Bla_XCC-1) have been reported to be secreted by the twin-arginine translocation (Tat) system. Yersinia enterocolitica carries 2 distinct β-lactamase genes (blaA and blaB) encoding BlaA_Ye and the AmpC-like β-lactamase BlaB, respectively. By using the software PRED-TAT for prediction and discrimination of Sec from Tat signal peptides, we identified a functional Tat signal sequence for Yersinia BlaA_Ye. The Tat-dependent translocation of BlaA_Ye could be clearly demonstrated by using a Y. enterocolitica tatC-mutant and cell fractionation. Moreover, we could demonstrate a unique unusual temperature-dependent activity profile of BlaA_Ye ranging from 15 to 60 °C and a high ‘melting temperature’ (T_M = 44.3°) in comparison to the related Sec-dependent β-lactamase TEM-1 (20–50 °C, T_M = 34.9 °C). Strikingly, the blaA gene of Y. enterocolitica is present in diverse environmental Yersinia spp. and a blaA homolog gene could be identified in the closely related Photorhabdus asymbiotica (BlaA_Pa; 69% identity to BlaA_Ye). For BlaA_Pa of P. asymbiotica, we could also demonstrate Tat-dependent secretion. These results suggest that Yersinia BlaA-related β-lactamases may be the prototype of a large Tat-dependent β-lactamase family, which originated from environmental bacteria.     

Role for the fibrinogen-binding proteins Coagulase and Efb in the Staphylococcus aureus–Candida interaction

Staphylococcus aureus and Candida species are increasingly coisolated from implant-associated polymicrobial infections creating an incremental health care problem. Synergistic effects between both genera seem to facilitate the formation of mixed S. aureus–Candida biofilms, which is thought to play a critical role in coinfections with these microorganisms. To identify and characterize S. aureus factors involved in the interaction with Candida species, we affinity-panned an S. aureus phage display library against Candida biofilms in the presence or absence of fibrinogen. Repeatedly isolated clones contained DNA fragments encoding portions of the S. aureus fibrinogen-binding proteins coagulase or Efb. The coagulase binds to prothrombin in a 1:1 ratio thereby inducing a conformational change and non-proteolytic activation of prothrombin, which in turn cleaves fibrinogen to fibrin. Efb has been known to inhibit opsonization. To study the role of coagulase and Efb in the S. aureus–Candida cross-kingdom interaction, we performed flow-cytometric phagocytosis assays. Preincubation with coagulase reduced the phagocytosis of Candida yeasts by granulocytes significantly and dose-dependently. By using confocal laser scanning microscopy, we demonstrated that the coagulase mediated the formation of fibrin surrounding the candidal cells. Furthermore, the addition of Efb significantly protected the yeasts against phagocytosis by granulocytes in a dose-dependent and saturable fashion. In conclusion, the inhibition of phagocytosis of Candida cells by coagulase and Efb via two distinct mechanisms suggests that S. aureus might be beneficial for Candida to persist as it helps Candida to circumvent the host immune system.     

Botulinum toxin, Quo Vadis?

Botulinum toxin (BTX), derived from the exotoxin of Clostridium botulinum, cleaves Soluble N-ethylmaleimide-sensitive factor-Attachment protein REceptor (SNARE) proteins, causing chemodenervation of cholinergic neurons. BTX also inhibits exocytosis of vesicles containing norepinephrine, glutamate, substance P and calcitonin gene-related peptide (CGRP) and inhibits expression of the vanilloid receptor. Clinical applications of BTX, which include the treatment of overactive skeletal and smooth muscles, hypersecretory and painful disorders, have increased exponentially since it was first used clinically to treat strabismus more than two decades ago. In this editorial, we discuss reports of new therapeutic indications of BTX, and propose new areas for research.     

An association study between the genetic polymorphisms within GnRHI, LHβ and FSHβ genes and central precocious puberty in Chinese girls

Objectives: Gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH) and follicle-stimulating hormone (FSH) are three hypothalamic–pituitary–gonadal axis expressing hormones. They play critical roles in the onset of puberty. Here we report the relationship between the three hormones and Central Precocious Puberty (CPP) in Chinese Han girls. Methods: We analyzed the single nucleotide polymorphisms (SNPs) of 5′-flanking regions of these genes by DNA sequencing in 27 CPP samples. Then the SNPs sites were genotyped by ligase detection reaction in a total of 283 Chinese Han CPP cases and 284 matched controls. Distributions of the polymorphisms and haplotypes were calculated for statistical evaluation. Results: Nine SNPs (One in GnRHI gene: −2003 C/T; Five in LHβ gene: −1456 C/G, −1424 C/G, −238 G/A, −164 G/A and −34 T/A; Three in FSHβ gene: −1825 T/C, −261 G/T and −132 T/A.) were found. A quantitative genetic association study was made. −1825 T/C in FSHβ gene was related with CPP with a weak effect (P = 0.025). A haplotype in the 5′-flanking region of LHβ gene was significantly associated with CPP in Chinese Han girls (P = 8.25 × 10⁻⁰⁹). However, analysis software showed that none of SNP was found in the regulating control element of these genes. Conclusions: Our finding implies that the polymorphisms in the 5′-flanking regions of FSHβ gene and LHβ gene probably were related to the puberty onset time of these girls. Further studies on the polymorphisms are needed for the exact mechanism.     

Finegoldia magna (formerly Peptostreptococcus magnus): An overlooked etiology for toxic shock syndrome?

Finegoldia magna is an anaerobic Gram positive coccus, previously classified as Peptostreoptococcus magnus. It is normal flora of the gastrointestinal and genitourinary tract, and can be isolated from skin and the oral cavity and is often regarded as a contaminant in cultures. As the most frequently isolated anaerobic coccus, it is implicated in a range of mono- and polymicrobial infections, including skin and skin structure, bone and joint (native and prosthetic joints), infective endocarditis (native and prosthetic valves), necrotizing pneumonia, mediastinitis and meningitis. Recently, whole genome sequencing furthered the understanding of the pathogenicity of this organism by elucidating both chromosomally encoded and mobile plasmid mediated virulence factors. Although no cases of toxic shock syndrome have been attributed to F. magna, we present a case of a fatal monomicrobial F. magna bacteremia and hypothesize that superantigen activity, mediated via Protein L binding the variable domain of the κ light chains of IgG, resulted in the syndrome observed in our patient. Additionally, we suspect the overall significance of this pathogen is underestimated and with more sensitive detection methods, this organism will be identified more frequently in clinical cultures and associated with true infection.