Symptoms of depression and cardiovascular reactions to acute psychological stress: Evidence from a population study

Depression and exaggerated cardiovascular reactivity are considered risk factors for cardiovascular disease, possibly as a result of common antecedents, such as altered autonomic nervous system function. We examined the association between depressive symptomatology and cardiovascular reactions to psychological stress in 1608 adults (875 women) comprising three distinct age cohorts: 24-, 44-, and 63-year olds. Depression was assessed using the Hospital Anxiety and Depression Scale. Blood pressure and heart rate were measured at baseline and during the paced auditory serial arithmetic test. Depression scores were negatively associated with systolic blood pressure and heart rate reactions, after adjustment for likely confounders such as sex, cohort, occupational status, body mass index, stress task performance score, baseline cardiovascular activity, antidepressant and antihypertensive medication. The direction of association was opposite to that which would be expected if excessive reactivity were to mediate the association between depression and cardiovascular disease outcomes or if they shared common antecedents

Escherichia coli genome-wide promoter analysis: Identification of additional AtoC binding target elements

<p>Abstract</p> <p>Background</p> <p>Studies on bacterial signal transduction systems have revealed complex networks of functional interactions, where the response regulators play a pivotal role. The AtoSC system of <it>E. coli </it>activates the expression of <it>atoDAEB </it>operon genes, and the subsequent catabolism of short-chain fatty acids, upon acetoacetate induction. Transcriptome and phenotypic analyses suggested that <it>atoSC </it>is also involved in several other cellular activities, although we have recently reported a palindromic repeat within the <it>atoDAEB </it>promoter as the single, <it>cis</it>-regulatory binding site of the AtoC response regulator. In this work, we used a computational approach to explore the presence of yet unidentified AtoC binding sites within other parts of the <it>E. coli </it>genome.</p> <p>Results</p> <p>Through the implementation of a computational <it>de novo </it>motif detection workflow, a set of candidate motifs was generated, representing putative AtoC binding targets within the <it>E. coli </it>genome. In order to assess the biological relevance of the motifs and to select for experimental validation of those sequences related robustly with distinct cellular functions, we implemented a novel approach that applies Gene Ontology Term Analysis to the motif hits and selected those that were qualified through this procedure. The computational results were validated using Chromatin Immunoprecipitation assays to assess the <it>in vivo </it>binding of AtoC to the predicted sites. This process verified twenty-two additional AtoC binding sites, located not only within intergenic regions, but also within gene-encoding sequences.</p> <p>Conclusions</p> <p>This study, by tracing a number of putative AtoC binding sites, has indicated an AtoC-related cross-regulatory function. This highlights the significance of computational genome-wide approaches in elucidating complex patterns of bacterial cell regulation.</p

Target protection as a key antibiotic resistance mechanism

Antibiotic resistance is mediated through several distinct mechanisms, most of which are relatively well understood and the clinical importance of which has long been recognized. Until very recently, neither of these statements was readily applicable to the class of resistance mechanism known as target protection, a phenomenon whereby a resistance protein physically associates with an antibiotic target to rescue it from antibiotic-mediated inhibition. In this Review, we summarize recent progress in understanding the nature and importance of target protection. In particular, we describe the molecular basis of the known target protection systems, emphasizing that target protection does not involve a single, uniform mechanism but is instead brought about in several mechanistically distinct ways

Embo J.

Tet(O) is an elongation factor-like protein which confers resistance to the protein synthesis inhibitor tetracycline by promoting the release of the drug from its inhibitory site on the ribosome. Here we investigated the interaction of Tet(O) with the elongating ribosome and show, using dimethyl sulfate (DMS) probing and binding assays, that it interacts preferentially with the post-translocational ribosome. Furthermore, using an XTP-dependent mutant of Tet(O), we demonstrated that Tet(O) induces conformational rearrangements within the ribosome which can be detected by EF-Tu, and manifested as a stimulation in the GTPase activity of this elongation factor. As such, these conformational changes probably involve the ribosomal GTPase-associated center and, accordingly, Tet(O) alters the DMS modification pattern of the L11 region. Additionally, tetracycline binding is associated with an Ea of 58 kJ/mol. These results suggest a model where both Tet(O) and tetracycline induce a conformational change in functionally opposite directions and the Tet(O)-induced conformation persists after it has left the ribosome; this prevents rebinding of the drug while allowing productive A-site occupation by a ternary complex in the presence of tetracycline

The tetracycline resistance protein Tet() perturbs the conformation of the ribosomal decoding centre

Tet() is an elongation factor-like protein found in clinical isolates of Campylobacter jejuni that confers resistance to the protein-synthesis inhibitor tetracycline. Tet() interacts with the 70S ribosome and promotes the release of bound tetracycline, however, as shown here, it does not form the same functional interaction with the 30S subunit. Chemical probing demonstrates that Tet() changes the reactivity of the 16S rRNA to dimethyl sulphate (DMS). These changes cluster within the decoding site, where C1214 is protected and A1408 is enhanced to DMS reactivity. C1214 is close to, but does not overlap, the primary tetracycline-binding site, whereas A1408 is in a region distinct from the Tet() binding site visualized by cryo-EM, indicating that Tet() induces long-range rearrangements that may mediate tetracycline resistance. Tetracycline enhances C1054 to DMS modification but this enhancement is inhibited in the presence of Tet() unlike the tetracycline-dependent protection of A892 which is unaffected by Tet(). C1054 is part of the primary binding site of tetracycline and A892 is part of the secondary binding site. Therefore, the results for the first time demonstrate that the primary tetracycline binding site is correlated with tetracycline's inhibitory effect on protein synthesis