Ghrelin octanoylation by ghrelin O-acyltransferase: protein acylation impacting metabolic and neuroendocrine signalling

The acylated peptide hormone ghrelin impacts a wide range of physiological processes but is most well known for controlling hunger and metabolic regulation. Ghrelin requires a unique posttranslational modification, serine octanoylation, to bind and activate signalling through its cognate GHS-R1a receptor. Ghrelin acylation is catalysed by ghrelin O-acyltransferase (GOAT), a member of the membrane-bound O-acyltransferase (MBOAT) enzyme family. The ghrelin/GOAT/GHS-R1a system is defined by multiple unique aspects within both protein biochemistry and endocrinology. Ghrelin serves as the only substrate for GOAT within the human proteome and, among the multiple hormones involved in energy homeostasis and metabolism such as insulin and leptin, acts as the only known hormone in circulation that directly stimulates appetite and hunger signalling. Advances in GOAT enzymology, structural modelling and inhibitor development have revolutionized our understanding of this enzyme and offered new tools for investigating ghrelin signalling at the molecular and organismal levels. In this review, we briefly summarize the current state of knowledge regarding ghrelin signalling and ghrelin/GOAT enzymology, discuss the GOAT structural model in the context of recently reported MBOAT enzyme superfamily member structures, and highlight the growing complement of GOAT inhibitors that offer options for both ghrelin signalling studies and therapeutic applications.     

Bacterial Distribution in the Lungs of Children with Protracted Bacterial Bronchitis

Objectives

Flexible bronchoscopy with bronchoalveolar lavage (FB-BAL) is increasingly used for the microbiological confirmation of protracted bacterial bronchitis (PBB) in children with a chronic wet cough. At our centre, when performing FB-BAL for microbiological diagnosis we sample 6 lobes (including lingula) as this is known to increase the rate of culture positive procedures in children with cystic fibrosis. We investigated if this is also the case in children with PBB.

Methods

We undertook a retrospective case note review of 50 children investigated for suspected PBB between May 2011 and November 2013.

Results

The median (IQR) age at bronchoscopy was 2.9 (1.7–4.4) years and the median (IQR) duration of cough was 11 (8.0–14) months. Positive cultures were obtained from 41/50 (82%) and 16 (39%) of these patients isolated ≥2 organisms. The commonest organisms isolated were Haemophilus influenzae (25 patients), Moraxella catarrhalis (14 patients), Staphylococcus aureus (11 patients) and Streptococcus pneumoniae (8 patients). If only one lobe had been sampled (as per the European Respiratory Society guidance) 17 different organisms would have been missed in 15 patients, 8 of whom would have had no organism cultured at all. The FB-BAL culture results led to an antibiotic other than co-amoxiclav being prescribed in 17/41 (41%) patients.

Conclusions

Bacterial distribution in the lungs of children with PBB is heterogeneous and organisms may therefore be missed if only one lobe is sampled at FB-BAL. Positive FB-BAL results are useful in children with PBB and can influence treatment.     

Anaerobic digestion of animal waste: effect of mixing

Six laboratory scale biogas mixed anaerobic digesters were operated to study the effect of biogas recycling rates and draft tube height on their performance. The digesters produced methane at 0.40-0.45 L per liter of digester volume per day. A higher methane production rate was observed in unmixed digesters, while increased biogas circulation rate reduced methane production. However, different draft tube heights caused no difference in the methane production rate. Air infiltration (up to 15% oxygen in the biogas) was observed in the digesters mixed by biogas recirculation. Slight air permeability of tubing or leakage on the vacuum side of the air pump may have caused the observed air infiltration. The similar performance of the mixed and unmixed digesters might be the result of the low solids concentration (50 g dry solids per liter of slurry) in the fed animal slurry, which could be sufficiently mixed by the naturally produced biogas.     

The nonreceptor tyrosine kinase SRMS inhibits autophagy and promotes tumor growth by phosphorylating the scaffolding protein FKBP51

Nutrient-responsive protein kinases control the balance between anabolic growth and catabolic processes such as autophagy. Aberrant regulation of these kinases is a major cause of human disease. We report here that the vertebrate nonreceptor tyrosine kinase Src-related kinase lacking C-terminal regulatory tyrosine and N-terminal myristylation sites (SRMS) inhibits autophagy and promotes growth in a nutrient-responsive manner. Under nutrient-replete conditions, SRMS phosphorylates the PHLPP scaffold FK506-binding protein 51 (FKBP51), disrupts the FKBP51-PHLPP complex, and promotes FKBP51 degradation through the ubiquitin-proteasome pathway. This prevents PHLPP-mediated dephosphorylation of AKT, causing sustained AKT activation that promotes growth and inhibits autophagy. SRMS is amplified and overexpressed in human cancers where it drives unrestrained AKT signaling in a kinase-dependent manner. SRMS kinase inhibition activates autophagy, inhibits cancer growth, and can be accomplished using the FDA-approved tyrosine kinase inhibitor ibrutinib. This illuminates SRMS as a targetable vulnerability in human cancers and as a new target for pharmacological induction of autophagy in vertebrates.

This study describes the discovery and characterization of a nutrient-sensitive signaling pathway that drives growth and inhibits autophagy in mammalian cells. This pathway, which involves the non-receptor tyrosine kinase SRMS and the PHLPP scaffold protein FKBP51, promotes tumor growth and is amenable to pharmacological inhibition.     

Comparison of evoked vs. spontaneous tics in a patient with trigeminal neuralgia (tic doloureux)

A 53-year old woman with tic doloureaux, affecting her right maxillary division of the trigeminal nerve (V2), could elicit shooting pains by slightly tapping her teeth when off medication. The pains, which she normally rated as > 6/10 on a visual analog scale (VAS), were electric shock-like in nature. She had no other spontaneous or ongoing background pain affecting the region. Based on her ability to elicit these tics, functional magnetic resonance imaging (fMRI) was performed while she produced brief shocks every 2 minutes on cue (evoked pain) over a 20 min period. In addition, she had 1–2 spontaneous shocks manifested between these evoked pains over the course of functional image acquisition. Increased fMRI activation for both evoked and spontaneous tics was observed throughout cortical and subcortical structures commonly observed in experimental pain studies with healthy subjects; including the primary somatosensory cortex, insula, anterior cingulate, and thalamus. Spontaneous tics produced more decrease in signals in a number of regions including the posterior cingulate cortex and amygdala, suggesting that regions known to be involved in expectation/anticipation may have been activated for the evoked, but not spontaneous, tics. In this patient there were large increases in activation observed in the frontal regions, including the anterior cingulate cortex and the basal ganglia. Spontaneous tics showed increased activation in classic aversion circuitry that may contribute to increased levels of anxiety. We believe that this is the first report of functional imaging of brain changes in tic-doloureaux.     

A survey of gastrointestinal parasites of olive baboons (Papio anubis) in human settlement areas of Mole National Park, Ghana

Fecal samples from 55 free-ranging olive baboons (Papio anubis) in Mole National Park, Ghana, were collected 22 June-7 July 2008 and analyzed for gastrointestinal parasites. This is the first survey of baboon gastrointestinal parasites in Ghana and provides baseline data for this area. Ninety-three percent of samples were infected, leaving 7% with no parasites observed. Of those infected, there was a 76% prevalence of strongyles, 53% Strongyloides spp., 11% Abbreviata caucasica , 62% prevalence of Balantidium coli (trophozoites and cysts identified), 4% Entomeba hystolytica/dispar, and 47% unidentified protozoan parasites. Of the strongyle infections, 9% were identified as Oesophagostamum sp. One sample contained an unidentified spirurid nematode that resembled Gongylonema sp. Mole has a mixed forest-savanna habitat, and baboons frequently range into human areas, which makes them subject to parasites from each habitat and multiple sources of exposure. We found a high prevalence of nematode parasites, consistent with a wet or cooler forest environment, or high rates of fecal contamination. The presence of Strongyloides sp., E. hystolitica/dispar, and B. coli suggest potential public health risk from baboons, but molecular identification of these parasites, and documentation of their presence in local human populations, would be necessary to confirm zoonotic transmission.