Mechanisms of ring chromosome formation, ring instability and clinical consequences

<p>Abstract</p> <p>Background</p> <p>The breakpoints and mechanisms of ring chromosome formation were studied and mapped in 14 patients.</p> <p>Methods</p> <p>Several techniques were performed such as genome-wide array, MLPA (Multiplex Ligation-Dependent Probe Amplification) and FISH (Fluorescent <it>in situ </it>Hybridization).</p> <p>Results</p> <p>The ring chromosomes of patients I to XIV were determined to be, respectively: r(3)(p26.1q29), r(4)(p16.3q35.2), r(10)(p15.3q26.2), r(10)(p15.3q26.13), r(13)(p13q31.1), r(13)(p13q34), r(14)(p13q32.33), r(15)(p13q26.2), r(18)(p11.32q22.2), r(18)(p11.32q21.33), r(18)(p11.21q23), r(22)(p13q13.33), r(22)(p13q13.2), and r(22)(p13q13.2). These rings were found to have been formed by different mechanisms, such as: breaks in both chromosome arms followed by end-to-end reunion (patients IV, VIII, IX, XI, XIII and XIV); a break in one chromosome arm followed by fusion with the subtelomeric region of the other (patients I and II); a break in one chromosome arm followed by fusion with the opposite telomeric region (patients III and X); fusion of two subtelomeric regions (patient VII); and telomere-telomere fusion (patient XII). Thus, the r(14) and one r(22) can be considered complete rings, since there was no loss of relevant genetic material. Two patients (V and VI) with r(13) showed duplication along with terminal deletion of 13q, one of them proved to be inverted, a mechanism known as inv-dup-del. Ring instability was detected by ring loss and secondary aberrations in all but three patients, who presented stable ring chromosomes (II, XIII and XIV).</p> <p>Conclusions</p> <p>We concluded that the clinical phenotype of patients with ring chromosomes may be related with different factors, including gene haploinsufficiency, gene duplications and ring instability. Epigenetic factors due to the circular architecture of ring chromosomes must also be considered, since even complete ring chromosomes can result in phenotypic alterations, as observed in our patients with complete r(14) and r(22).</p

A single administration of the antibiotic, minocycline, reduces fear processing and improves implicit learning in healthy volunteers: analysis of the serum metabolome

Minocycline has shown therapeutic promise in pre-clinical animal models and early phase clinical trials for a variety of psychiatric disorders. Previous studies on minocycline have shown its ability to suppress microglia activity and reduce inflammatory cytokine levels, and its amelioration of depressive-like behaviour in animals and humans. However, the underlying mechanisms that lead to minocycline’s psychotropic effects are not clear. In this study, we investigated the psychological and biochemical effects of an acute dose of minocycline or placebo in 40 healthy adult volunteers. Psychological changes in emotional processing, implicit learning, and working memory were assessed. Plasma inflammatory markers, measured with enzyme-linked immunosorbent assays, and serum metabolites, measured with proton nuclear magnetic resonance combined with multi-variate analysis techniques, were also studied. Results showed that minocycline administration decreased fear misclassification and increased contextual learning, which suggested that reducing negative biases and improving cognition, respectively, may underlie the antidepressant actions of this agent. An examination of serum metabolites revealed higher levels of lipoproteins, particularly cholesterol, in the minocycline group. Minocycline also decreased circulating concentrations of the inflammatory marker C-Reactive Peptide, which is consistent with previous research. These effects highlight two important psychological mechanisms that may be relevant to the efficacy of minocycline reported in clinical trials, and also suggest a possible largely unexplored lipid-related biochemical pathway for the action of this drug