A5077485626- Tuberculosis Research and Epidemiology
- Antibiotic Resistance in Bacteria
- RNA and protein synthesis mechanisms
- Protein Structure and Dynamics
- vaccines and immunoinformatics approaches
- Evolution and Genetic Dynamics
- SARS-CoV-2 and COVID-19 Research
- Computational Drug Discovery Methods
- Mycobacterium research and diagnosis
- Genomics and Rare Diseases
- Bioinformatics and Genomic Networks
- Cancer Genomics and Diagnostics
- Microbial Metabolic Engineering and Bioproduction
- Genetics and Neurodevelopmental Disorders
- Bacterial Genetics and Biotechnology
- CRISPR and Genetic Engineering
- Pneumonia and Respiratory Infections
- RNA modifications and cancer
- Pneumocystis jirovecii pneumonia detection and treatment
- Glycosylation and Glycoproteins Research
- Virology and Viral Diseases
- Viral Infections and Vectors
- PI3K/AKT/mTOR signaling in cancer
- Machine Learning in Bioinformatics
- Epigenetics and DNA Methylation
Baker Heart and Diabetes Institute
2019-2025
The University of Queensland
2022-2025
The University of Melbourne
2018-2023
Peter Doherty Institute
2023
Mater Dei Hospital
2023
Australian Cancer Research Foundation
2020
London School of Hygiene & Tropical Medicine
2018
Abstract Proteins are intricate, dynamic structures, and small changes in their amino acid sequences can lead to large effects on folding, stability dynamics. To facilitate the further development evaluation of methods predict these changes, we have developed ThermoMutDB, a manually curated database containing >14,669 experimental data thermodynamic parameters for wild type mutant proteins. This represents an increase 83% unique mutations over previous databases includes information...
Multidrug-resistant bacterial pathogens like vancomycin-resistant Enterococcus faecium (VREfm) are a critical threat to human health1. Daptomycin is last-resort antibiotic for VREfm infections with novel mode of action2, but which resistance has been widely reported unexplained. Here we show that rifaximin, an unrelated used prophylactically prevent hepatic encephalopathy in patients liver disease3, causes cross-resistance daptomycin VREfm. Amino acid changes arising within the RNA...
Nicotinamide adenine dinucleotide (NAD) is essential for embryonic development. To date, biallelic loss-of-function variants in 3 genes encoding nonredundant enzymes of the NAD de novo synthesis pathway - KYNU, HAAO, and NADSYN1 have been identified humans with congenital malformations defined as deficiency disorder (CNDD). Here, we 13 further individuals predicted to be damaging, phenotypes ranging from multiple severe complete absence malformation. Enzymatic assessment variant...
Membrane contact sites between organelles are critical for the transfer of biomolecules. Lipid droplets store fatty acids and form contacts with mitochondria, which regulate acid oxidation adenosine triphosphate production. Protein compartmentalization at lipid droplet-mitochondria their effects on biological processes poorly described. Using proximity-dependent biotinylation methods, we identify 71 proteins sites, including a multimeric complex containing extended synaptotagmin (ESYT) 1,...
Abstract Genomic studies of Mycobacterium tuberculosis bacteria have revealed loci associated with resistance to anti-tuberculosis drugs. However, the molecular consequences polymorphism within these candidate remain poorly understood. To address this, we used computational tools quantify effects point mutations conferring three major drugs, isoniazid (n = 189), rifampicin 201) and D-cycloserine 48), their primary targets, katG , rpoB alr . Notably, mild biophysical brought about by high...
Abstract Rifampicin resistance is a major therapeutic challenge, particularly in tuberculosis, leprosy, P. aeruginosa and S. aureus infections, where it develops via missense mutations gene rpoB. Previously we have highlighted that these reduce protein affinities within the RNA polymerase complex, subsequently reducing nucleic acid affinity. Here, used insights to develop computational rifampicin predictor capable of identifying resistant even outside well-defined determining region (RRDR),...
Abstract Drug discovery is a lengthy, costly and high-risk endeavour that further convoluted by high attrition rates in later development stages. Toxicity has been one of the main causes failure during clinical trials, increasing drug time costs. To facilitate early identification optimisation toxicity profiles, several computational tools emerged aiming at improving success timely pre-screening candidates. Despite these efforts, there an demand for platforms capable assessing both...
Abstract Missense mutations are known contributors to diverse genetic disorders, due their subtle, single amino acid changes imparted on the resultant protein. Because of this, understanding impact these protein stability and function is crucial for unravelling disease mechanisms developing targeted therapies. The Critical Assessment Genome Interpretation (CAGI) provides a valuable platform benchmarking state-of-the-art computational methods in predicting disease-related thermodynamics. Here...
Rifampin resistance in leprosy may remain undetected due to the lack of rapid and effective diagnostic tools. A quick reliable method is essential determine impacts emerging detrimental mutations drug targets. The functional consequences missense β-subunit RNA polymerase (RNAP) Mycobacterium leprae (M. leprae) contribute phenotypic rifampin leprosy. Here, we report in-silico saturation mutagenesis all residues RNAP other 19 amino acid types (generating 21,394 for 1126 residues) predict their...
Phosphate and tensin homolog on chromosome ten (PTEN) germline mutations are associated with an overarching condition known as PTEN hamartoma tumor syndrome. Clinical phenotypes this syndrome range from macrocephaly autism spectrum disorder to Cowden syndrome, which manifests multiple noncancerous tumor-like growths (hamartomas), increased predisposition certain cancers. It is unclear, however, the basis by might lead these very diverse phenotypic outcomes. Here we show that, considering...
The past few years have revolutionised the utility of protein structural information in assessing disease risk. Such efforts been pioneered by DeepMind and Meta teams, who initially developed accurate prediction tools AlphaFold ESMFold, respectively. More recently, both readapted to create AlphaMissene ESM1b, through which, pathogenicity potential all possible missense mutations within human proteome has predicted. Similarly, VESPA was created as an alignment-agnostic predictor, which infers...
Kinases play crucial roles in cellular signalling and biological processes with their dysregulation associated diseases, including cancers. Kinase inhibitors, most notably those targeting ABeLson 1 (ABL1) kinase chronic myeloid leukemia, have had a significant impact on cancer survival, yet emergence of resistance mutations can reduce effectiveness, leading to therapeutic failure. Limited effort, however, has been devoted developing tools accurately identify ABL1 mutations, as well providing...
Rabies virus phosphoprotein (P protein) is a multifunctional protein that plays key roles in replication as the polymerase cofactor binds to complex of viral genomic RNA and nucleoprotein (N protein), evading innate immune response by binding STAT transcription factors. These interactions are mediated C-terminal domain P CTD ). The colocation these sites small globular raises question how underlying evasion, central infection, coordinated and, potentially, coregulated. While direct data on...
Amyotrophic lateral sclerosis (ALS) is a progressively fatal, neurodegenerative disease associated with both motor and non-motor symptoms, including frontotemporal dementia. Approximately 10% of cases are genetically inherited (familial ALS), while the majority sporadic. Mutations across wide range genes have been associated; however, underlying molecular effects these mutations their relation to phenotypes remain poorly explored.We initially curated an extensive list (n=1343) missense...
Abstract Alzheimer's disease (AD) is one of the most common forms dementia and neurodegenerative diseases, characterized by formation neuritic plaques neurofibrillary tangles. Many different proteins participate in this complicated pathogenic mechanism, missense mutations can alter folding functions these proteins, significantly increasing risk AD. However, many methods to identify AD‐causing variants did not consider effect from perspective a protein three‐dimensional environment. Here, we...
SUMMARY The emergence of the COVID-19 pandemic has spurred a global rush to uncover basic biological mechanisms, inform effective vaccine and drug development. Despite viral novelty, sequencing efforts have already identified genomic variation across isolates. To enable easy exploration spatial visualization potential implications SARS-CoV-2 mutations on infection, host immunity development we developed COVID-3D ( http://biosig.unimelb.edu.au/covid3d/ ).
Abstract Multidrug-resistant bacterial pathogens like vancomycin-resistant Enterococcus faecium (VREfm) are a critical threat to human health. Daptomycin is last-resort antibiotic for VREfm infections with novel mode-of-action, but which resistance has surprisingly been widely reported unexplained. Here we show that rifaximin, an unrelated used prophylactically prevent hepatic encephalopathy in liver disease patients, causes cross-resistance daptomycin VREfm. Amino acid changes arising...
Abstract Background: Mutations within the Von Hippel-Lindau (VHL) tumor suppressor gene are known to cause VHL disease, which is characterized by formation of cysts and tumors in multiple organs body, particularly clear cell renal carcinoma (ccRCC). A major challenge clinical practice determining risk from a given mutation gene. Previous efforts have been hindered limited available data technological constraints. Methods: To overcome this, we initially manually curated largest set clinically...