Delineation of functionally essential protein regions for 242 neurodevelopmental genes

Neurodevelopmental disorders (NDDs), including severe paediatric epilepsy, autism and intellectual disabilities are heterogeneous conditions in which clinical genetic testing can often identify a pathogenic variant. For many of them, genetic therapies will be tested in this or the coming years in clinical trials. In contrast to first-generation symptomatic treatments, the new disease-modifying precision medicines require a genetic test-informed diagnosis before a patient can be enrolled in a clinical trial. However, even in 2022, most identified genetic variants in NDD genes are "variants of uncertain significance'. To safely enrol patients in precision medicine clinical trials, it is important to increase our knowledge about which regions in NDD-associated proteins can "tolerate' missense variants and which ones are "essential' and will cause a NDD when mutated. In addition, knowledge about functionally indispensable regions in the 3D structure context of proteins can also provide insights into the molecular mechanisms of disease variants. We developed a novel consensus approach that overlays evolutionary, and population based genomic scores to identify 3D essential sites (Essential3D) on protein structures. After extensive benchmarking of AlphaFold predicted and experimentally solved protein structures, we generated the currently largest expert curated protein structure set for 242 NDDs and identified 14 377 Essential3D sites across 189 gene disorders associated proteins. We demonstrate that the consensus annotation of Essential3D sites improves prioritization of disease mutations over single annotations. The identified Essential3D sites were enriched for functional features such as intermembrane regions or active sites and discovered key inter-molecule interactions in protein complexes that were otherwise not annotated. Using the currently largest autism, developmental disorders, and epilepsies exome sequencing studies including > 360 000 NDD patients and population controls, we found that missense variants at Essential3D sites are 8-fold enriched in patients.In summary, we developed a comprehensive protein structure set for 242 NDDs and identified 14377 Essential3D sites in these. All data are available at https://es-ndd.broadinstitute.org for interactive visual inspection to enhance variant interpretation and development of mechanistic hypotheses for 242 NDDs genes. The provided resources will enhance clinical variant interpretation and in silico drug target development for NDD-associated genes and encoded proteins.Peer reviewe

Machine intelligence for nerve conduit design and production

Nerve guidance conduits (NGCs) have emerged from recent advances within tissue engineering as a promising alternative to autografts for peripheral nerve repair. NGCs are tubular structures with engineered biomaterials, which guide axonal regeneration from the injured proximal nerve to the distal stump. NGC design can synergistically combine multiple properties to enhance proliferation of stem and neuronal cells, improve nerve migration, attenuate inflammation and reduce scar tissue formation. The aim of most laboratories fabricating NGCs is the development of an automated process that incorporates patient-specific features and complex tissue blueprints (e.g. neurovascular conduit) that serve as the basis for more complicated muscular and skin grafts. One of the major limitations for tissue engineering is lack of guidance for generating tissue blueprints and the absence of streamlined manufacturing processes. With the rapid expansion of machine intelligence, high dimensional image analysis, and computational scaffold design, optimized tissue templates for 3D bioprinting (3DBP) are feasible. In this review, we examine the translational challenges to peripheral nerve regeneration and where machine intelligence can innovate bottlenecks in neural tissue engineering

Medical Image Segmentation Review: The success of U-Net

Automatic medical image segmentation is a crucial topic in the medical domain and successively a critical counterpart in the computer-aided diagnosis paradigm. U-Net is the most widespread image segmentation architecture due to its flexibility, optimized modular design, and success in all medical image modalities. Over the years, the U-Net model achieved tremendous attention from academic and industrial researchers. Several extensions of this network have been proposed to address the scale and complexity created by medical tasks. Addressing the deficiency of the naive U-Net model is the foremost step for vendors to utilize the proper U-Net variant model for their business. Having a compendium of different variants in one place makes it easier for builders to identify the relevant research. Also, for ML researchers it will help them understand the challenges of the biological tasks that challenge the model. To address this, we discuss the practical aspects of the U-Net model and suggest a taxonomy to categorize each network variant. Moreover, to measure the performance of these strategies in a clinical application, we propose fair evaluations of some unique and famous designs on well-known datasets. We provide a comprehensive implementation library with trained models for future research. In addition, for ease of future studies, we created an online list of U-Net papers with their possible official implementation. All information is gathered in https://github.com/NITR098/Awesome-U-Net repository.Comment: Submitted to the IEEE Transactions on Pattern Analysis and Machine Intelligence Journa

Wright State University\u27s Symposium of Student Research, Scholarship & Creative Activities from Thursday, October 26, 2023

The student abstract booklet is a compilation of abstracts from students\u27 oral and poster presentations at Wright State University\u27s Symposium of Student Research, Scholarship & Creative Activities on October 26, 2023.https://corescholar.libraries.wright.edu/celebration_abstract_books/1001/thumbnail.jp

DIAGNOSTICS OF DEMENTIA FROM STRUCTURAL AND FUNCTIONAL MARKERS OF BRAIN ATROPHY WITH MACHINE LEARNING

Dementia is a condition in which higher mental functions are disrupted. It currently affects an estimated 57 million people throughout the world. A dementia diagnosis is difficult since neither anatomical indicators nor functional testing is currently sufficiently sensitive or specific. There remains a long list of outstanding issues that must be addressed. First, multimodal diagnosis has yet to be introduced into the early stages of dementia screening. Second, there is no accurate instrument for predicting the progression of pre-dementia. Third, non-invasive testing cannot be used to provide differential diagnoses. By creating ML models of normal and accelerated brain aging, we intend to better understand brain development. The combined analysis of distinct imaging and functional modalities will improve diagnostics of accelerated decline with advanced data science techniques, which is the main objective of our study. Hypothetically, an association between brain structural changes and cognitive performance differs between normal and accelerated aging. We propose using brain MRI scans to estimate the cognitive status of the cognitively preserved examinee and develop a structure-function model with machine learning (ML). Accelerated ageing is suspected when a scanned individual’s findings do not align with the usual paradigm. We calculate the deviation from the model of normal ageing (DMNA) as the error of cognitive score prediction. Then the obtained data may be compared with the results of conducted cognitive tests. The greater the difference between the expected and observed values, the greater the risk of dementia. DMNA can discern between cognitively normal and mild cognitive impairment (MCI) patients. The model was proven to perform well in the MCI-versus-Alzheimer’s disease (AD) categorization. DMNA is a potential diagnostic marker of dementia and its types