MTR3D-AF2: Expanding the coverage of spatially derived missense tolerance scores across the human proteome using AlphaFold2.

The missense tolerance ratio (MTR) was developed as a novel approach to assess the deleteriousness of variants. Its three-dimensional successor, MTR3D, was demonstrated powerful at discriminating pathogenic from benign variants. However, its reliance on experimental structures and homologs limited its coverage of the proteome. We have now utilized AlphaFold2 models to develop MTR3D-AF2, which covers 89.31% of proteins and 85.39% of residues across the human proteome. This work has improved MTR3D's ability to distinguish clinically established pathogenic from benign variants. MTR3D-AF2 is freely available as an interactive web server at https://biosig.lab.uq.edu.au/mtr3daf2/.

Mutations in Glycosyltransferases and Glycosidases: Implications for Associated Diseases.

Glycosylation, a crucial and the most common post-translational modification, coordinates a multitude of biological functions through the attachment of glycans to proteins and lipids. This process, predominantly governed by glycosyltransferases (GTs) and glycoside hydrolases (GHs), decides not only biomolecular functionality but also protein stability and solubility. Mutations in these enzymes have been implicated in a spectrum of diseases, prompting critical research into the structural and functional consequences of such genetic variations. This study compiles an extensive dataset from ClinVar and UniProt, providing a nuanced analysis of 2603 variants within 343 GT and GH genes. We conduct thorough MTR score analyses for the proteins with the most documented variants using MTR3D-AF2 via AlphaFold2 (AlphaFold v2.2.4) predicted protein structure, with the analyses indicating that pathogenic mutations frequently correlate with Beta Bridge secondary structures. Further, the calculation of the solvent accessibility score and variant visualisation show that pathogenic mutations exhibit reduced solvent accessibility, suggesting the mutated residues are likely buried and their localisation is within protein cores. We also find that pathogenic variants are often found proximal to active and binding sites, which may interfere with substrate interactions. We also incorporate computational predictions to assess the impact of these mutations on protein function, utilising tools such as mCSM to predict the destabilisation effect of variants. By identifying these critical regions that are prone to disease-associated mutations, our study opens avenues for designing small molecules or biologics that can modulate enzyme function or compensate for the loss of stability due to these mutations.

AI-driven GPCR analysis, engineering, and targeting.

This article investigates the role of recent advances in Artificial Intelligence (AI) to revolutionise the study of G protein-coupled receptors (GPCRs). AI has been applied to many areas of GPCR research, including the application of machine learning (ML) in GPCR classification, prediction of GPCR activation levels, modelling GPCR 3D structures and interactions, understanding G-protein selectivity, aiding elucidation of GPCRs structures, and drug design. Despite progress, challenges in predicting GPCR structures and addressing the complex nature of GPCRs remain, providing avenues for future research and development.

Point-of-care computer-assisted design and manufacturing technology and its utility in post-traumatic mandibular reconstruction: An Australian public hospital experience.

Application of load-bearing osteosynthesis plates is the current gold-standard management for complex mandibular fractures. Traditionally, this has required a transcutaneous submandibular approach, carrying with it the risk of damage to the facial nerve and obvious extraoral scarring. The existing literature describes the use of computer-assisted design and manufacturing technology through external vendors to aid transoral mandibular reconstruction. However, the reliance on third-party manufacturers comes with significant drawbacks, notably increased financial costs and manufacturing delays. We describe our experience in using point-of-care three-dimensional-printed surgical models to aid with the application of mandibular reconstruction plates. Utilising a virtual three-dimensional reconstruction of the patient's preoperative computed tomography facial bones, we fabricate a custom model of the patient's mandible with the department's in-house three-dimensional printer. Stock plates are subsequently pre-bent and adapted to the three-dimensional model, with plate and screw position marked and screw lengths measured with callipers. By using a custom three-dimensional-printed surgical model to pre-contour the plates, we are able to position stock reconstruction plates via a transoral approach. Moreover, our unit's utilisation of in-house computer-assisted design and manufacturing software and hardware allows us deliver a same-day turnaround for both surgical planning and performing the operation. Patient-specific surgical planning guides can facilitate the safe and efficient transoral application of mandibular reconstruction plates. Moreover, the use of point-of-care computer-assisted design and manufacturing technology ensures timely and cost-effective manufacturing of the necessary biomodel.

A case of primary tracheal squamous cell carcinoma arising from malignant transformation of recurrent respiratory papillomatosis, with a complete response to concurrent chemoradiotherapy.

Recurrent respiratory papillomatosis is a human papillomavirus-mediated condition characterised by the development of benign squamous papillomata of the respiratory tract. Malignant transformation of recurrent respiratory papillomatosis, while rare, carries a poor prognosis and there are limited data surrounding treatment options, particularly in inoperable disease. We present the case of a 64-year-old male who developed malignant airway obstruction secondary to primary tracheal squamous cell carcinoma in the setting of a 5-year history of recurrent laryngotracheal papillomatosis, requiring placement of tracheostomy while on veno-venous extracorporeal membranous oxygenation. He was managed with cisplatin-based definitive chemoradiotherapy and had a complete metabolic response on post-treatment positron emission tomography/computed tomography, and remains free of recurrent squamous cell carcinoma at 16 months following treatment. This case supports the use of combined chemoradiotherapy as a potential therapeutic option for patients with primary tracheal squamous cell carcinoma, and emphasises the challenges associated with the long-term management of recurrent respiratory papillomatosis.

Chronic non-granulomatous supraglottitis of a male adolescent and its successful management with azathioprine.

Chronic non-granulomatous supraglottitis (CNGS) is a rare disorder of the supraglottic larynx, characterised by chronic supraglottic inflammation in the absence of granulomata, vasculitis, neoplasia, autoimmune disease or infective changes on histology. We present the case of a male adolescentwho attended with progressively worsening exertional dyspnoea, stridor and symptoms of obstructive sleep apnoea. Flexible nasendoscopy revealed marked supraglottic subepithelial thickening sparing the glottis and subglottis, confirmed on microlaryngoscopy. MRI of the head and neck demonstrated diffuse, homogenous supraglottic oedema. At the peak of his symptomology, the patient was admitted for further investigations and intravenous steroid therapy, and switched to prolonged oral steroids on discharge. Tracheostomy was avoided. After 3 months, he was successfully weaned from steroids to azathioprine with gradual symptomatic improvement. This case represents the first successful use of a steroid-sparing agent in the management of CNGS.