Pharmacogenomics of Interferon-ß Therapy in Multiple Sclerosis: Baseline IFN Signature Determines Pharmacological Differences between Patients

Multiple sclerosis (MS) is a heterogeneous disease. In order to understand the partial responsiveness to IFNbeta in Relapsing Remitting MS (RRMS) we studied the pharmacological effects of IFNbeta therapy. Large scale gene expression profiling was performed on peripheral blood of 16 RRMS patients at baseline and one month after the start of IFNbeta therapy. Differential gene expression was analyzed by Significance Analysis of Microarrays. Subsequent expression analyses on specific genes were performed after three and six months of treatment. Peripheral blood mononuclear cells (PBMC) were isolated and stimulated in vitro with IFNbeta. Genes of interest were measured and validated by quantitative realtime PCR. An independent group of 30 RRMS patients was used for validation. Pharmacogenomics revealed a marked variation in the pharmacological response to IFNbeta between patients. A total of 126 genes were upregulated in a subset of patients whereas in other patients these genes were downregulated or unchanged after one month of IFNbeta therapy. Most interestingly, we observed that the extent of the pharmacological response correlates negatively with the baseline expression of a specific set of 15 IFN response genes (R = -0.7208; p = 0.0016). The negative correlation was maintained after three (R = -0.7363; p = 0.0027) and six (R = -0.8154; p = 0.0004) months of treatment, as determined by gene expression levels of the most significant correlating gene. Similar results were obtained in an independent group of patients (n = 30; R = -0.4719; p = 0.0085). Moreover, the ex vivo results could be confirmed by in vitro stimulation of purified PBMCs at baseline with IFNbeta indicating that differential responsiveness to IFNbeta is an intrinsic feature of peripheral blood cells at baseline. These data imply that the expression levels of IFN response genes in the peripheral blood of MS patients prior to treatment could serve a role as biomarker for the differential clinical response to IFNbet

Prophage Spontaneous Activation Promotes DNA Release Enhancing Biofilm Formation in Streptococcus pneumoniae

Streptococcus pneumoniae (pneumococcus) is able to form biofilms in vivo and previous studies propose that pneumococcal biofilms play a relevant role both in colonization and infection. Additionally, pneumococci recovered from human infections are characterized by a high prevalence of lysogenic bacteriophages (phages) residing quiescently in their host chromosome. We investigated a possible link between lysogeny and biofilm formation. Considering that extracellular DNA (eDNA) is a key factor in the biofilm matrix, we reasoned that prophage spontaneous activation with the consequent bacterial host lysis could provide a source of eDNA, enhancing pneumococcal biofilm development. Monitoring biofilm growth of lysogenic and non-lysogenic pneumococcal strains indicated that phage-infected bacteria are more proficient at forming biofilms, that is their biofilms are characterized by a higher biomass and cell viability. The presence of phage particles throughout the lysogenic strains biofilm development implicated prophage spontaneous induction in this effect. Analysis of lysogens deficient for phage lysin and the bacterial major autolysin revealed that the absence of either lytic activity impaired biofilm development and the addition of DNA restored the ability of mutant strains to form robust biofilms. These findings establish that limited phage-mediated host lysis of a fraction of the bacterial population, due to spontaneous phage induction, constitutes an important source of eDNA for the S. pneumoniae biofilm matrix and that this localized release of eDNA favors biofilm formation by the remaining bacterial population

DNA glycosylases: in DNA repair and beyond

The base excision repair machinery protects DNA in cells from the damaging effects of oxidation, alkylation, and deamination; it is specialized to fix single-base damage in the form of small chemical modifications. Base modifications can be mutagenic and/or cytotoxic, depending on how they interfere with the template function of the DNA during replication and transcription. DNA glycosylases play a key role in the elimination of such DNA lesions; they recognize and excise damaged bases, thereby initiating a repair process that restores the regular DNA structure with high accuracy. All glycosylases share a common mode of action for damage recognition; they flip bases out of the DNA helix into a selective active site pocket, the architecture of which permits a sensitive detection of even minor base irregularities. Within the past few years, it has become clear that nature has exploited this ability to read the chemical structure of DNA bases for purposes other than canonical DNA repair. DNA glycosylases have been brought into context with molecular processes relating to innate and adaptive immunity as well as to the control of DNA methylation and epigenetic stability. Here, we summarize the key structural and mechanistic features of DNA glycosylases with a special focus on the mammalian enzymes, and then review the evidence for the newly emerging biological functions beyond the protection of genome integrity

嗜盐嗜碱多能硫碱弧菌SOB306代谢工程及脱硫工艺研究

Abstract Background Infant feeding practices are known to influence the child’s long-term health. Studies have associated obesity and other diseases with reduced breastfeeding and early introduction of high calorie beverages (HCBs). The rising prevalence of obesity is already a problem in most developed countries, especially Australia, but cultural differences are influential. Our aim is to examine and compare infant feeding practices and educational levels of respondents through questionnaires in three culturally different sites: Campbelltown (South Western Sydney), Australia, Singapore and Ho Chi Minh City, Vietnam (HCMC). Methods Consenting parents and carers (aged ≥18 years old) of at least one child (≤6 years old) were recruited from paediatric clinics in Campbelltown, Singapore and HCMC. Participants completed an infant feeding practices questionnaire regarding breastfeeding, beverage and solid initiation in addition to the parent’s ethnicity, age, and educational level. Data was analysed quantitatively using SPSS. Results Two hundred eighty-three participants were recruited across the three sites, HCMC (n = 84), Campbelltown (n = 108), and Singapore (n = 91). 237 (82.6%) children were breastfed but in all only 100 (60.2%) were exclusively breastfed for five months or more. There was a statistical difference in rates of breast feeding between each region. HCMC (n = 18, 21.4%) had the lowest, followed by Campbelltown (n = 35, 32.4%), and then Singapore (n = 47, 51.7%). There was also a difference in rates of introduction of HCBs by 3 years of age, with those in HCMC (n = 71, 84.5%) were higher than Campbelltown (n = 71, 65.8%) and Singapore (n = 48, 52.8%). The educational level of respondents was lower in Vietnam where only 46.4% (n = 39) had completed post-secondary education, compared to 75.0% (n = 81) in Campbelltown and 75.8% (n = 69) in Singapore. Conclusions Rates of breast feeding were inversely correlated with rates of introduction of HCB and positively related to educational achievement. Vietnam had lowest rates of breast feeding, higher rates of introduction of HCBs, and lower rates of education. Given rising rates of obesity, there is a need for more effective programmes to promote breast feeding and restrict false advertising of HCBs