Laura M. Fiori

Antidepressants (ADs) are the most common treatment for major depressive disorder (MDD). However, only ∼30% of patients experience adequate response after a single AD trial, and this variability remains poorly understood. Here, we investigated microRNAs (miRNAs) as biomarkers of AD response using small RNA-sequencing in paired samples from MDD patients enrolled in a large, randomized placebo-controlled trial of duloxetine collected before and 8 weeks after treatment. Our results revealed differential expression of miR-146a-5p, miR-146b-5p, miR-425-3p and miR-24-3p according to treatment response. These results were replicated in two independent clinical trials of MDD, a well-characterized animal model of depression, and post-mortem human brains. Furthermore, using a combination of bioinformatics, mRNA studies and functional in vitro experiments, we showed significant dysregulation of genes involved in MAPK/Wnt signalling pathways. Together, our results indicate that these miRNAs are consistent markers of treatment response and regulators of the MAPK/Wnt systems.

Major depressive disorder (MDD) is a common, heterogenous, and potentially serious psychiatric illness. Diverse brain cell types have been implicated in MDD etiology. Significant sexual differences exist in MDD clinical presentation and outcome, and recent evidence suggests different molecular bases for male and female MDD. We evaluated over 160,000 nuclei from 71 female and male donors, leveraging new and pre-existing single-nucleus RNA-sequencing data from the dorsolateral prefrontal cortex. Cell type specific transcriptome-wide threshold-free MDD-associated gene expression patterns were similar between the sexes, but significant differentially expressed genes (DEGs) diverged. Among 7 broad cell types and 41 clusters evaluated, microglia and parvalbumin interneurons contributed the most DEGs in females, while deep layer excitatory neurons, astrocytes, and oligodendrocyte precursors were the major contributors in males. Further, the Mic1 cluster with 38% of female DEGs and the ExN10_L46 cluster with 53% of male DEGs, stood out in the meta-analysis of both sexes.

In eukaryotes, N-linked protein glycosylation is a universal modification involving addition of preformed oligosaccharides to select Asn-Xaa-Ser/Thr motifs and influencing multiple biological events. We recently demonstrated that Campylobacter jejuni is the first member of the Bacteria to possess an N-linked glycan pathway. In this study, high-resolution magic angle spinning nuclear magnetic resonance (HR-MAS NMR) was applied to probe and quantitate C. jejuni N-glycan biosynthesis in vivo. To confirm HR-MAS NMR findings, glycosylation mutants were screened for chicken colonization potential, and glycoproteins were examined by mass spectrometry and lectin blotting. Consistent with the mechanism in eukaryotes, the combined data indicate that bacterial glycans are assembled en bloc, emphasizing the evolutionary conservation of protein N glycosylation. We also show that under the conditions examined, PglG plays no role in glycan biosynthesis, PglI is the glucosyltransferase and the putative ABC transporter, and WlaB (renamed PglK) is required for glycan assembly. These studies underpin the mechanism of N-linked protein glycosylation in Bacteria and provide a simple model system for investigating protein glycosylation and for exploitation in glycoengineering.

The polyamine pathway has an essential role in many cellular functions and has been implicated in several pathological conditions. Accumulating evidence suggests that the polyamine system also plays a role in the etiology and pathology of mental disorders. Alterations in the expression and activity of polyamine metabolic enzymes, as well as changes in the levels of the individual polyamines, have been observed in multiple conditions, including schizophrenia, mood disorders, anxiety and suicidal behaviour. Additionally, these components have been found to be altered by various psychiatric treatments. Further, the polyamines and their precursors have demonstrated both antidepressant and anxiolytic effects. Overall, findings to date suggest that the polyamine pathway represents an important frontier for the development of neuropharmacological treatments.

BACKGROUND AND PURPOSE: The ultrasonic image can offer unique information on the composition of atherosclerotic plaque, ie, the relative content of lipids, fibrous tissue, and calcific deposits. To date, however, the echographic assessment of plaque structure is based on a subjective, qualitative evaluation of the bidimensional images. We evaluated the feasibility and accuracy of assessing, in vivo, the acoustic properties of arterial carotid plaques by means of a suitably modified echographic apparatus allowing direct access to the radiofrequency signal. METHODS: In 15 patients undergoing carotid thromboendarterectomy, the ultrasonic findings in 70 discrete sites (within the plaque, n = 54; normal sites, n = 11; or intraluminal thrombi, n = 5) were correlated with the histological analysis (hematoxylin-eosin and Mallory trichrome stains) independently performed on the arterial samples. The pathological examination was carried out at a similar level of the insonation; the sites analyzed within the plaque were chosen because of their uniform echoic characteristics. In each ultrasonic region of interest selected from the echographic image, the integrated amplitude of the rectified radiofrequency signal was measured as the integrated backscatter index. RESULTS: The intimal-medial layer of normal carotid wall (n = 11) exhibited values of -32.5 +/- 9.4 dB. The integrated backscatter index in fatty sites (n = 11, -40.3 +/- 5.4 dB) differed from that of fibrous (n = 12, -23.8 +/- 5.0 dB) and calcified (n = 26, -11.5 +/- 5.2 dB, P < .01 for all intergroup differences) sites. Intraluminal thrombotic sites (n = 5, -42 +/- 5.1 dB, P < .01) differed from fibrous and calcified subsets (P < .01) but overlapped (P = NS) with fatty sites. Histological sampling also showed two sites of intraplaque hemorrhage that exhibited very low backscatter values (-53 and -58 dB) and three fibrofatty sites showing backscatter values (-28, -28, and -32 dB) intermediate between the fibrous and the fatty subsets. CONCLUSIONS: Quantitative analysis of integrated backscatter of the arterial wall is feasible in humans and provides an operator-independent assessment of plaque echoic structure. In particular, integrated backscatter is effective in distinguishing lipidic, fibrotic, and calcific components in human atherosclerotic plaques.