Comparative analysis of mycobacterium and related actinomycetes yields insight into the evolution of mycobacterium tuberculosis pathogenesis

<p>Abstract</p> <p>Background</p> <p>The sequence of the pathogen <it>Mycobacterium tuberculosis </it>(<it>Mtb</it>) strain <it>H37Rv </it>has been available for over a decade, but the biology of the pathogen remains poorly understood. Genome sequences from other <it>Mtb </it>strains and closely related bacteria present an opportunity to apply the power of comparative genomics to understand the evolution of <it>Mtb </it>pathogenesis. We conducted a comparative analysis using 31 genomes from the Tuberculosis Database (TBDB.org), including 8 strains of <it>Mtb </it>and <it>M. bovis</it>, 11 additional Mycobacteria, 4 Corynebacteria, 2 Streptomyces, <it>Rhodococcus jostii RHA1, Nocardia farcinia, Acidothermus cellulolyticus, Rhodobacter sphaeroides, Propionibacterium acnes</it>, and <it>Bifidobacterium longum</it>.</p> <p>Results</p> <p>Our results highlight the functional importance of lipid metabolism and its regulation, and reveal variation between the evolutionary profiles of genes implicated in saturated and unsaturated fatty acid metabolism. It also suggests that DNA repair and molybdopterin cofactors are important in pathogenic Mycobacteria. By analyzing sequence conservation and gene expression data, we identify nearly 400 conserved noncoding regions. These include 37 predicted promoter regulatory motifs, of which 14 correspond to previously validated motifs, as well as 50 potential noncoding RNAs, of which we experimentally confirm the expression of four.</p> <p>Conclusions</p> <p>Our analysis of protein evolution highlights gene families that are associated with the adaptation of environmental Mycobacteria to obligate pathogenesis. These families include fatty acid metabolism, DNA repair, and molybdopterin biosynthesis. Our analysis reinforces recent findings suggesting that small noncoding RNAs are more common in Mycobacteria than previously expected. Our data provide a foundation for understanding the genome and biology of <it>Mtb </it>in a comparative context, and are available online and through TBDB.org.</p

Metabolically Favorable Remodeling of Human Adipose Tissue by Human Adenovirus Type 36

OBJECTIVE—Experimental infection of rats with human adenovirus type 36 (Ad-36) promotes adipogenesis and improves insulin sensitivity in a manner reminiscent of the pharmacologic effect of thiozolinediones. To exploit the potential of the viral proteins as a therapeutic target for treating insulin resistance, this study investigated the ability of Ad-36 to induce metabolically favorable changes in human adipose tissue

Viral Capsid Is a Pathogen-Associated Molecular Pattern in Adenovirus Keratitis

Human adenovirus (HAdV) infection of the human eye, in particular serotypes 8, 19 and 37, induces the formation of corneal subepithelial leukocytic infiltrates. Using a unique mouse model of adenovirus keratitis, we studied the role of various virus-associated molecular patterns in subsequent innate immune responses of resident corneal cells to HAdV-37 infection. We found that neither viral DNA, viral gene expression, or viral replication was necessary for the development of keratitis. In contrast, empty viral capsid induced keratitis and a chemokine profile similar to intact virus. Transfected viral DNA did not induce leukocyte infiltration despite CCL2 expression similar to levels in virus infected corneas. Mice without toll-like receptor 9 (Tlr9) signaling developed clinical keratitis upon HAdV-37 infection similar to wild type mice, although the absolute numbers of activated monocytes in the cornea were less in Tlr9−/− mice. Virus induced leukocytic infiltrates and chemokine expression in mouse cornea could be blocked by treatment with a peptide containing arginine glycine aspartic acid (RGD). These results demonstrate that adenovirus infection of the cornea induces chemokine expression and subsequent infiltration by leukocytes principally through RGD contact between viral capsid and the host cell, possibly through direct interaction between the viral capsid penton base and host cell integrins

Implantation in patients over 40 and raising FSH levels--a review

There is an evident decline of female fertility with age. This decline is mainly due to increased risk of pregnancy termination either after conception or after embryo implantation. Very likely the major cause of this embryo and pregnancy loss is chromosomal aneuploidies caused mostly by increasing rates of ‘poor quality’ oocytes. This phenomenon can be explained either by an age dependent accumulation of damage and/or by the hypothesis that the defective oocytes are there in the ovaries from the fetal life. ‘Good quality’ oocytes are ovulated first, leaving ‘poor quality’ oocytes to be ovulated later in life. Besides the quality of the oocytes which is mainly responsible of the embryo quality (we have not to forget a paternal effect) the process of implantation is dependent upon two variables: the probability of a viable embryo and that of a receptive uterine environment. From the oocyte donation model it seems that the endometrium also plays a minor role in human reproductive ageing as it does in some laboratory animals. However, besides some macroscopic possible causes which may play a role in the reduction of the age-related endometrial receptivity, there are so many endometrial factors possibly related to its receptivity which need to be further studied especially in older women

CUMULATIVE PREGNANCY RATES AFTER TRANSFER OF FRESH AND THAWED EMBRYOS

Frozen-thawed embryo transfer is an effective procedure that allows further possibilities of pregnancy in addition to those obtained after the fresh in vitro fertilization (IVF). In our follow-up study we analysed all fresh embryo transfer procedures and every frozen-thawed embryo transfer performed from January 2000 to December 2001 evaluating the cumulative pregnancy rates. The study population was divided into two groups according to the female age: 38 years (group II). All the best embryos were chosen for transfer and all the supernumerary good quality embryos were cryopreserved on the day of transfer. The embryos were then thawed and manipulated using a new technique. In group I, 527 patients (619 cycles) underwent fresh embryo transfer and in 232 of them (238 cycles) the embryos were frozen (44% per patients and 38.4% per cycle). In group II, 156 patients (193 cycles) underwent fresh embryo transfer and in 14 of them (15 cycles) the embryos were frozen (9% per patient and 7.8% per cycle). The pregnancy rate of group I patients that had their supernumerary embryos frozen (232 patients and 238 cycles) was 47.4% per cycle and 48.7% per patient whereas in the same population of group II patients (14 patients and 15 cycles) the clinical pregnancy rate was 35.7% per cycle and 38.5% per patients. The cumulative clinical pregnancy rate after transfer of fresh and thawed embryos was: group I, 74% per cycle and 76% per patients; group II, 42.8% per cycle and 46.1% per patient. Frozen-thawed embryo transfer is a cost-effective practice

GP96 Interacts with HHV-6 during Viral Entry and Directs It for Cellular Degradation

CD46 and CD134 mediate attachment of Human Herpesvirus 6A (HHV-6A) and HHV-6B to host cell, respectively. But many cell types interfere with viral infection through rapid degradation of viral DNA. Hence, not all cells expressing these receptors are permissive to HHV-6 DNA replication and production of infective virions suggesting the involvement of additional factors that influence HHV-6 propagation. Here, we used a proteomics approach to identify other host cell proteins necessary for HHV-6 binding and entry. We found host cell chaperone protein GP96 to interact with HHV-6A and HHV-6B and to interfere with virus propagation within the host cell. In human peripheral blood mononuclear cells (PBMCs), GP96 is transported to the cell surface upon infection with HHV-6 and interacts with HHV-6A and -6B through its C-terminal end. Suppression of GP96 expression decreased initial viral binding but increased viral DNA replication. Transient expression of human GP96 allowed HHV-6 entry into CHO-K1 cells even in the absence of CD46. Thus, our results suggest an important role for GP96 during HHV-6 infection, which possibly supports the cellular degradation of the virus