The Role of Medical Image Modalities and AI in the Early Detection, Diagnosis and Grading of Retinal Diseases: A Survey.

Traditional dilated ophthalmoscopy can reveal diseases, such as age-related macular degeneration (AMD), diabetic retinopathy (DR), diabetic macular edema (DME), retinal tear, epiretinal membrane, macular hole, retinal detachment, retinitis pigmentosa, retinal vein occlusion (RVO), and retinal artery occlusion (RAO). Among these diseases, AMD and DR are the major causes of progressive vision loss, while the latter is recognized as a world-wide epidemic. Advances in retinal imaging have improved the diagnosis and management of DR and AMD. In this review article, we focus on the variable imaging modalities for accurate diagnosis, early detection, and staging of both AMD and DR. In addition, the role of artificial intelligence (AI) in providing automated detection, diagnosis, and staging of these diseases will be surveyed. Furthermore, current works are summarized and discussed. Finally, projected future trends are outlined. The work done on this survey indicates the effective role of AI in the early detection, diagnosis, and staging of DR and/or AMD. In the future, more AI solutions will be presented that hold promise for clinical applications

Genetic and phenotypic heterogeneity in autosomal recessive retinal disease

Molecular genetics has transformed our understanding of disease and is gradually changing the way medicine is practiced. Genetic mapping provides a powerful approach to discover genes and biological processes underlying human disorders. Recent advances in DNA microarray and sequencing technology have significantly increased the power of genetic mapping studies and have ushered in a new era for biomedicine. In this thesis, linkage analysis (including homozygosity mapping), exome sequencing and candidate gene sequencing have been utilised to genetically dissect autosomal recessive retinal disease. Subsequently, clinical findings from patients found to be similar in terms of molecular pathology have been pooled. DNA and basic phenotypic data from over 500 unrelated individuals were available for the project. Disease-causing variants in three genes that have not been previously associated with human recessive disorders are reported: (a) biallelic mutations in TRPM1 abrogate ON bipolar cell function and cause complete congenital stationary night blindness; (b) biallelic mutations in KCNJ13, a gene encoding an inwardly rectifying potassium channel subunit cause Leber congenital amaurosis; (c) biallelic mutations in PLA2G5, a gene encoding group V phospholipase A2, cause benign fleck retina. The consequences of mutations in these and other disease-related genes (RDH5, GRM6, KCNV2, OAT and SAG) on retinal structure (spectral domain optical coherence tomography, fundus autofluorescence imaging) and visual function (electrophysiology, perimetry testing) have been studied; features that may have mechanistic relevance have been identified. Additionally, DNA sequence variation of a highly polymorphic gene (C2ORF71), recently associated with photoreceptor degeneration, has been studied and quantified in patient and control samples. Basic bioinformatics tools to analyse genomic data have been developed (bash, perl, python and R programming languages). Overall, results presented in this thesis contribute to an understanding of Mendelian retinal disease that is not only observational but also mechanistic

A novel role for Adenomatous Polyposis Coli protein in the transport of mitochondria

Adenomatous Polyposis Coli (APC) is a multifunctional tumour suppressor protein, contributing to pathways in normal cell growth and differentiation. APC gene mutation is one of the earliest events in the progression of colorectal cancer (CRC), and typically gives rise to a truncated protein lacking C-terminal sequences, initiating deregulation of key cellular pathways. This thesis describes a new role for APC in mitochondrial transport. Silencing of wild-type APC by siRNA induced a redistribution of mitochondria from the cell periphery to the perinuclear region. Subsequently, novel interactions for APC were identified at the mitochondria with kinesin-motor complex proteins Miro/Milton. These interactions were mapped to the C-terminus of APC, correlating with defective mitochondrial transport and loss of Miro/Milton binding in CRC cells, which were restored by reconstitution of wild-type APC. Analysis by live cell imaging showed that loss of APC slowed the frequency of mitochondrial anterograde transport towards the cell periphery. It is proposed that APC drives mitochondria to the membrane to supply energy required for directed cell migration, a process disrupted in CRC. This opens up a new route through which CRC-associated APC mutations may contribute to carcinogenesis

A novel role for Adenomatous Polyposis Coli protein in the transport of mitochondria

Adenomatous Polyposis Coli (APC) is a multifunctional tumour suppressor protein, contributing to pathways in normal cell growth and differentiation. APC gene mutation is one of the earliest events in the progression of colorectal cancer (CRC), and typically gives rise to a truncated protein lacking C-terminal sequences, initiating deregulation of key cellular pathways. This thesis describes a new role for APC in mitochondrial transport. Silencing of wild-type APC by siRNA induced a redistribution of mitochondria from the cell periphery to the perinuclear region. Subsequently, novel interactions for APC were identified at the mitochondria with kinesin-motor complex proteins Miro/Milton. These interactions were mapped to the C-terminus of APC, correlating with defective mitochondrial transport and loss of Miro/Milton binding in CRC cells, which were restored by reconstitution of wild-type APC. Analysis by live cell imaging showed that loss of APC slowed the frequency of mitochondrial anterograde transport towards the cell periphery. It is proposed that APC drives mitochondria to the membrane to supply energy required for directed cell migration, a process disrupted in CRC. This opens up a new route through which CRC-associated APC mutations may contribute to carcinogenesis

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)

This work was supported by the National Institute of General Medical Sciences [GM131919].In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.PostprintPeer reviewe