Mycobacterium tuberculosis subverts negative regulatory pathways in human macrophages to drive immunopathology.

Tuberculosis remains a global pandemic and drives lung matrix destruction to transmit. Whilst pathways driving inflammatory responses in macrophages have been relatively well described, negative regulatory pathways are less well defined. We hypothesised that Mycobacterium tuberculosis (Mtb) specifically targets negative regulatory pathways to augment immunopathology. Inhibition of signalling through the PI3K/AKT/mTORC1 pathway increased matrix metalloproteinase-1 (MMP-1) gene expression and secretion, a collagenase central to TB pathogenesis, and multiple pro-inflammatory cytokines. In patients with confirmed pulmonary TB, PI3Kδ expression was absent within granulomas. Furthermore, Mtb infection suppressed PI3Kδ gene expression in macrophages. Interestingly, inhibition of the MNK pathway, downstream of pro-inflammatory p38 and ERK MAPKs, also increased MMP-1 secretion, whilst suppressing secretion of TH1 cytokines. Cross-talk between the PI3K and MNK pathways was demonstrated at the level of eIF4E phosphorylation. Mtb globally suppressed the MMP-inhibitory pathways in macrophages, reducing levels of mRNAs encoding PI3Kδ, mTORC-1 and MNK-1 via upregulation of miRNAs. Therefore, Mtb disrupts negative regulatory pathways at multiple levels in macrophages to drive a tissue-destructive phenotype that facilitates transmission

The Influence of Personality Traits on Reported Adherence to Medication in Individuals with Chronic Disease: An Epidemiological Study in West Sweden

BACKGROUND: Limited research exists exploring the influence of personality on adherence behaviour. Since non-adherence is a major obstacle in treating prevalent chronic diseases the aim was to determine whether personality traits are related to reported adherence to medication in individuals with chronic disease. METHODOLOGY/PRINCIPAL FINDINGS: Individuals with chronic disease (n = 749) were identified in a random population sample of 5000 inhabitants aged 30-70 in two municipalities in West Sweden. Data on five personality traits, Neuroticism, Extraversion, Openness to experiences, Agreeableness, and Conscientiousness, and medication adherence behaviour was collected by questionnaires. Statistical analyses resulted in a negative relationship between Neuroticism and medication adherence (P < 0.001), while both Agreeableness (P < 0.001) and Conscientiousness (P < 0.001) were positively related to adherence. At high levels of Conscientiousness, low adherence was related to higher scores in Neuroticism. At high levels of Agreeableness, low adherence was related to low scores in Conscientiousness and high scores in Openness to experiences. CONCLUSIONS: This study demonstrated that multiple personality traits are of significant importance for adherence behaviour in individuals with chronic disease. The findings suggest that several personality traits may interact in influencing adherence behaviour. Personality traits could putatively be used to focus efforts to educate and support patients with high risk of low medical adherence

New perspectives on evolutionary medicine: the relevance of microevolution for human health and disease

Evolutionary medicine (EM) is a growing field focusing on the evolutionary basis of human diseases and their changes through time. To date, the majority of EM studies have used pure theories of hominin macroevolution to explain the present-day state of human health. Here, we propose a different approach by addressing more empirical and health-oriented research concerning past, current and future microevolutionary changes of human structure, functions and pathologies. Studying generation-to-generation changes of human morphology that occurred in historical times, and still occur in present-day populations under the forces of evolution, helps to explain medical conditions and warns clinicians that their current practices may influence future humans. Also, analyzing historic tissue specimens such as mummies is crucial in order to address the molecular evolution of pathogens, of the human genome, and their coadaptations.Frank Jakobus Rühli and Maciej Henneber

Benzothienyloxy phenylpropanamines, novel dual inhibitors of serotonin and norepinephrine reuptake

A series of benzothienyloxy propylamines have been prepared and are demonstrated to be inhibitors of both serotonin and norepinephrine reuptake. (C) 2004 Published by Elsevier Ltd

Mycobacterium tuberculosis Exploits a Molecular Off Switch of the Immune System for Intracellular Survival

Mycobacterium tuberculosis (M. tuberculosis) survives and multiplies inside human macrophages by subversion of immune mechanisms. Although these immune evasion strategies are well characterised functionally, the underlying molecular mechanisms are poorly understood. Here we show that during infection of human whole blood with M. tuberculosis, host gene transcriptional suppression, rather than activation, is the predominant response. Spatial, temporal and functional characterisation of repressed genes revealed their involvement in pathogen sensing and phagocytosis, degradation within the phagolysosome and antigen processing and presentation. To identify mechanisms underlying suppression of multiple immune genes we undertook epigenetic analyses. We identified significantly differentially expressed microRNAs with known targets in suppressed genes. In addition, after searching regions upstream of the start of transcription of suppressed genes for common sequence motifs, we discovered novel enriched composite sequence patterns, which corresponded to Alu repeat elements, transposable elements known to have wide ranging influences on gene expression. Our findings suggest that to survive within infected cells, mycobacteria exploit a complex immune “molecular off switch” controlled by both microRNAs and Alu regulatory elements