Cilia were one of the characteristic traits of the last eukaryotic common ancestor and are highly conserved among eukaryotes. Their proteomic makeup is remarkably similar throughout all eukaryotic lin Show more
Cilia were one of the characteristic traits of the last eukaryotic common ancestor and are highly conserved among eukaryotes. Their proteomic makeup is remarkably similar throughout all eukaryotic lineages. Recently, several ciliary transport proteins, namely the Bardet-Biedl Syndrome (BBS) proteins, were shown to traverse the nuclear envelope, and to modulate gene expression. Insects have been critically understudied in cilia biology since they only exhibit cilia on a subset of cells. We present evidence that the BBSome is largely conserved in multiple insect lineages. To examine BBS protein expression within insects, we profiled tissues, castes, and sexes of the honeybee Apis mellifera, a species where the genome encodes for multiple behavioural and morphological phenotypes. We find variation in expression profiles of putative BBSome-associated genes across different tissues, including those lacking cilia, indicating possible non-ciliary functions. We also demonstrate that expression of individual BBS proteins varies significantly between queens' and males' tissues, especially in neuronal tissue. Particularly high overexpression of BBS4 in glandular tissue indicates a cilia-independent role. Our findings provide evolutionary insight into the conservation of BBSome components across insects, suggesting potential additional roles for cilia proteins in non-ciliated tissues, providing candidate genes from diverse insect orders for future experimental work. Show less
Although phosphodiesterase-4 (PDE4) inhibitors have been shown to reduce COPD exacerbation rate, their biological mechanism of action is not completely elucidated at the molecular level. We aimed to c Show more
Although phosphodiesterase-4 (PDE4) inhibitors have been shown to reduce COPD exacerbation rate, their biological mechanism of action is not completely elucidated at the molecular level. We aimed to characterise the whole genome gene expression profile of the inhaled PDE4-inhibitor CHF6001 on top of triple therapy in sputum cells and whole blood of patients with COPD and chronic bronchitis. Whole genome gene expression analysis was carried out by microarray in 54 patients before and after 32 days treatment with CHF6001 800 and 1600 μg and placebo twice daily (BID) in a randomised crossover study. CHF6001 had a strong effect in sputum, with 1471 and 2598 significantly differentially-expressed probe-sets relative to placebo (p-adjusted for False Discovery Rate < 0.05) with 800 and 1600 μg BID, respectively. Functional enrichment analysis showed significant modulation of key inflammatory pathways involved in cytokine activity, pathogen-associated-pattern-recognition activity, oxidative stress and vitamin D with associated inhibition of downstream inflammatory effectors. A large number of pro-inflammatory genes coding for cytokines and matrix-metalloproteinases were significantly differentially expressed for both doses; the majority (> 87%) were downregulated, including macrophage inflammatory protein-1-alpha and 1-beta, interleukin-27-beta, interleukin-12-beta, interleukin-32, tumour necrosis factor-alpha-induced-protein-8, ligand-superfamily-member-15, and matrix-metalloproteinases-7,12 and 14. The effect in blood was not significant. Inhaled PDE4 inhibition by CHF6001 on top of triple therapy in patients with COPD and chronic bronchitis significantly modulated key inflammatory targets and pathways in the lung but not in blood. Mechanistically these findings support a targeted effect in the lung while minimising unwanted systemic class-effects. ClinicalTrial.gov, EudraCT, 2015-005550-35. Registered 15 July 2016. Show less