Is there a Function for a Sex Pheromone Precursor?:A Predicted Link between Bacterial Redox Metabolism and Propagation of Antibiotic Resistance

Functional coupling and comparative genomics analysis have been applied to study functional associations of orthologs of enterococcal cAD1 sex pheromone (P13268) known to be responsible for biofilm formation, conjugative plasmid transfer and spreading of bacterial antibiotics resistance. cAD1 peptide pheromone is released from the membrane lipoprotein with the peptide precursor encoded by a gene cad (tr|C2JQE7). Our analysis of genomic neighbourhood of cad and motifs of the encoded polypeptide and its orthologs suggests a close functional association between cAD1 and ApbE protein (Q82Z24), a FMN insertion and trafficking facilitator. The cad and apbE orthologs were coupled in the genomes and ApbE-specific motifs for FMN covalent attachment were identified in cad-encoded protein sequence and its orthologs. These findings suggest a potential role of FMN-based reductase function of the cAD1 lipoprotein precursor in its processing and release of the active sex pheromone peptide. They may lead to a new approach in prevention of antibiotic resistance spread via targeting sex pheromone processing chaperones or by suppression of the FMN availability and covalent binding. This methods can be also applied to a controlled evolution of bacterial pathogenicity in microbial fuel cells, as the findings suggest the crosstalk between bacterial pathogenicity and bacterial electro-activity

A systems biology approach to defining regulatory mechanisms for cartilage and tendon cell phenotypes

Phenotypic plasticity of adult somatic cells has provided emerging avenues for the development of regenerative therapeutics. In musculoskeletal biology the mechanistic regulatory networks of genes governing the phenotypic plasticity of cartilage and tendon cells has not been considered systematically. Additionally, a lack of strategies to effectively reproduce in vitro functional models of cartilage and tendon is retarding progress in this field. De- and redifferentiation represent phenotypic transitions that may contribute to loss of function in ageing musculoskeletal tissues. Applying a systems biology network analysis approach to global gene expression profiles derived from common in vitro culture systems (monolayer and three-dimensional cultures) this study demonstrates common regulatory mechanisms governing de- and redifferentiation transitions in cartilage and tendon cells. Furthermore, evidence of convergence of gene expression profiles during monolayer expansion of cartilage and tendon cells, and the expression of key developmental markers, challenges the physiological relevance of this culture system. The study also suggests that oxidative stress and PI3K signalling pathways are key modulators of in vitro phenotypes for cells of musculoskeletal origin

Library of Apicomplexan Metabolic Pathways: a manually curated database for metabolic pathways of apicomplexan parasites.

The Library of Apicomplexan Metabolic Pathways (LAMP, http://www.llamp.net) is a web database that provides near complete mapping from genes to the central metabolic functions for some of the prominent intracellular parasites of the phylum Apicomplexa. This phylum includes the causative agents of malaria, toxoplasmosis and theileriosis-diseases with a huge economic and social impact. A number of apicomplexan genomes have been sequenced, but the accurate annotation of gene function remains challenging. We have adopted an approach called metabolic reconstruction, in which genes are systematically assigned to functions within pathways/networks for Toxoplasma gondii, Neospora caninum, Cryptosporidium and Theileria species, and Babesia bovis. Several functions missing from pathways have been identified, where the corresponding gene for an essential process appears to be absent from the current genome annotation. For each species, LAMP contains interactive diagrams of each pathway, hyperlinked to external resources and annotated with detailed information, including the sources of evidence used. We have also developed a section to highlight the overall metabolic capabilities of each species, such as the ability to synthesize or the dependence on the host for a particular metabolite. We expect this new database will become a valuable resource for fundamental and applied research on the Apicomplexa

Potential impact of primate‐specific SVA retrotransposons during the evolution of human cognitive function.

The SVA family of hominid-specific non-LTR retrotransposon comprises the youngest group of transposable elements in the human genome. The propagation of the most ancient SVA subfamily took place about 13.5 million years ago, and the youngest SVA subfamily appeared in the human genome after the human/chimpanzee divergence. Functional analysis of genes associated with SVA insertions demonstrated their link to multiple ontological categories, with one of the major categories being attributed to brain function. Further analysis of this subset demonstrated that SVA elements expanded their presence in the human genome at different stages of hominoid evolution and were associated with progressively evolving behavioral features that indicate a potential impact of SVA propagation on the cognitive ability of a modern human. Our analysis suggests a potential role of SVAs in the evolution of human central nervous system and especially in the emergence of functional trends relevant to social and parental behavior. Coevolution of behavioral features and reproductive functions are suggested by our analysis and discussed

On the heterogeneity of human populations as reflected by mortality dynamics

The heterogeneity of human populations is a common consideration in describing and validating their various age-related features. Heterogeneity, in particular, amongst other factors, is used to explain the variability of mortality rates across the lifespan and deviations from an exponential growth at young and very old ages. A mathematical model that combines the population heterogeneity with the assumption that the mortality of each constituent subpopulation increases exponentially with age, has recently been shown to successfully reproduce the entire mortality pattern across the lifespan as well as its evolution over time. Furthermore, the analysis of time-evolution of the mortality pattern, performed by fitting the model to actual data of consecutive periods, confirms the applicability of the compensation law of mortality to each subpopulation and concludes on the evolution of the population towards homogenisation. In this work we aim to show that the heterogeneity of human populations is not only a convenient consideration for fitting mortality data but is indeed the actual structure of the population as reflected by the dynamics of its mortality over age and time. In particular, we demonstrate that the model of heterogeneous populations fits mortality data better than most of the other models if the data are taken for the entire lifespan and better than all other models if we consider only old ages. Also, we show that the model can reproduce seemingly contradicting observations in late-life mortality dynamics namely deceleration, levelling-off and mortality decline. Assuming that heterogeneity is reflected in genetic variations within the population, using Swedish mortality data for 20th century we show that the homogenisation of the population, observed in the model fits, can be associated with the evolution of allele frequencies

Post-transcriptional gene regulation following exposure of osteoarthritic human articular chondrocytes to hyperosmotic conditions

SummaryObjectiveOsmolarity is a major biophysical regulator of chondrocyte function. Modulation of chondrocytic marker gene expression occurs at the post-transcriptional level following exposure of human articular chondrocytes (HAC) to hyperosmotic conditions. This study aims to further characterise the post-transcriptional response of HAC to hyperosmolarity.MethodsGene expression and microRNA (miRNA) levels in freshly isolated HAC after 5h under control or hyperosmotic conditions were measured using microarrays. Regulated genes were checked for the presence of AU rich elements (AREs) in their 3′ untranslated regions (3′UTR), whilst gene ontology was examined using Ingenuity Pathway Analysis (IPA). RNA decay rates of candidate ARE-containing genes were determined in HAC using actinomycin D chase experiments and the involvement of the p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinases 1 and 2 (ERK1/2) pathways were investigated using pharmacological inhibitors.ResultsHyperosmolarity led to the regulation of a wide variety of genes. IPA identified enrichment of genes involved with cell stress responses, cell signalling and transforming growth factor β (TGFβ) signalling. Importantly, upregulated genes were over-represented with those containing AREs, and RNA decay analysis demonstrated that many of these were regulated post-transcriptionally by hyperosmolarity in HAC. Analysis of miRNA levels in HAC indicated that they are only modestly regulated by hyperosmotic conditions, whilst inhibitor studies showed that p38 MAPK and ERK1/2 were able to block hyperosmotic induction of many of these genes.ConclusionThrough microarray and bioinformatics analysis we have identified genes which are post-transcriptionally regulated in HAC following exposure to hyperosmotic conditions. These genes have a range of functions, and their regulation involves transduction through the p38 MAPK and ERK1/2 pathways. Interestingly, our results suggest that miRNA regulation is not key to the process. Overall, this work illustrates the range of processes regulated in chondrocytes by changes in their osmotic environment, and underlines the importance of post-transcriptional mRNA regulation to chondrocyte function

On predicting regulatory genes by analysis of functional networks in C. elegans

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