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270 results for “Disease Phenotypes”
Data from: Chronic Rapamycin administration via drinking water mitigates the pathological phenotype in a Krabbe disease mouse model through autophagy activation.
<p>ABSTRACT </p><p>Krabbe disease (KD) is a rare disorder caused by a deficiency of the lysosomal enzyme galactosylceramidase (GALC), resulting in the accumulation of the cytotoxic metabolite psychosine (PSY) in the nervous system. This accumulation triggers demyelination and neurodegeneration. Despite ongoing research, the underlying pathogenic mechanisms remain incompletely understood, and there is currently no cure available.</p><p>Previous studies from our lab revealed the presence of autophagy dysfunctions in KD pathogenesis, as evidenced by the presence of p62-tagged protein aggregates in the brains of KD mice and increased p62 levels in the KD sciatic nerve. We also demonstrated that the autophagy inducer Rapamycin (RAPA) can partially restore the wild-type (WT) phenotype in KD primary cells by reducing the number of p62 aggregates.</p><p>In this study, we tested RAPA in the Twitcher (TWI) mouse, a spontaneous KD mouse model. We administered the drug ad libitum via drinking water (15 mg/L) starting from post-natal day (PND) 21-23. We longitudinally monitored the motor performance of the mice through grip strength and rotarod tests, along with various biochemical parameters related to KD pathogenesis (i.e. autophagy markers expression, myelination, astrogliosis, and PSY accumulation).</p><p>Our findings demonstrate that RAPA significantly enhances motor functions at specific treatment time points and reduces astrogliosis in TWI brain, spinal cord, and sciatic nerves. Using western blot and immunohistochemistry, we observed a decrease in p62 aggregates in TWI nervous tissues, which corroborates our earlier in-vitro results. Furthermore, RAPA treatment partially reduces PSY levels in the spinal cord.</p><p>In conclusion, our results support the consideration of RAPA as a supportive therapy for KD. Importantly, as RAPA is already available in pharmaceutical formulations for clinical use, its potential for KD treatment can be promptly evaluated in clinical trials.</p>
Dautan et al 2024 " Gut-Initiated Alpha Synuclein Fibrils Drive Parkinson's Disease Phenotypes: Temporal Mapping of non-Motor Symptoms and REM Sleep Behavior Disorder"
<p><span>Parkinson’s disease (PD) is characterized by progressive motor as well as less recognized non-motor symptoms that arise often years before motor manifestation, including sleep and gastrointestinal disturbances. Despite the heavy burden on the patient’s quality of life, these non-motor manifestations are poorly understood. To elucidate the temporal dynamics of the disease, we employed a mice model involving injection of alpha-synuclein (αSyn) pre-formed fibrils (PFF) in the duodenum and antrum as a gut-brain model of Parkinsonism. Using anatomical mapping of αSyn PFF propagation and behavioral and physiological characterizations, we unveil a correlation between post-injection time the temporal dynamics of αSyn propagation and non-motor/motor manifestations of the disease. We highlight the concurrent presence of aggregates in key brain regions, expressing acetylcholine or dopamine and their functions in sleep duration, wakefulness, and particularly REM-associated atonia corresponging to REM behavioral disorder-like symptoms. This study presents a novel and in-depth exploration into the multifaceted nature of PD, unraveling the complex connections between α-synucleinopathies, gut-brain connectivity, and the emergence of non-motor phenotypes.</span></p>
# Single-cell network biology characterizes cell type gene regulation for drug repurposing and phenotype prediction in Alzheimer's disease
<p>Dysregulation of gene expression in Alzheimer’s disease (AD) remains elusive, especially at the cell type level. Gene regulatory network, a key molecular mechanism linking transcription factors (TFs) and regulatory elements to govern target gene expression, can change across cell types in the human brain and thus serve as a model for studying gene dysregulation in AD. However, it is still challenging to understand how cell type networks work abnormally under AD. To address this, we integrated single-cell multi-omics data and predicted the gene regulatory networks in AD and control for four major cell types, excitatory and inhibitory neurons, microglia and oligodendrocytes. Importantly, we applied network biology approaches to analyze the changes of network characteristics across these cell types, and between AD and control. For instance, many hub TFs target different genes between AD and control (rewiring). Also, these networks show strong hierarchical structures in which top TFs (master regulators) are largely common across cell types, whereas different TFs operate at the middle levels in some cell types (e.g., microglia). The regulatory logics of enriched network motifs (e.g., feed-forward loops) further uncover cell type-specific TF-TF cooperativities in gene regulation. The cell type networks are highly modular and several network modules with cell-type-specific expression changes in AD pathology are enriched with AD-risk genes and putative targets of approved and pending AD drugs, suggesting possible cell-type genomic medicine in AD. Finally, using the cell type gene regulatory networks, we developed machine learning models to classify and prioritize additional AD genes. We found that top prioritized genes predict clinical phenotypes (e.g., cognitive impairment) with reasonable accuracy. Overall, this single-cell network biology analysis provides a comprehensive map linking genes, regulatory networks, cell types and drug targets and reveals dysregulated cell type gene dysregulatory mechanisms in AD.</p>
Extraction of clinical phenotypes for Alzheimer disease dementia from clinical notes using natural language processing
<p><strong>Objectives</strong></p> <p>There is much interest in utilizing clinical data for developing prediction models for Alzheimer disease (AD) risk, progression, and outcomes. Existing studies have mostly utilized curated research registries, image analysis, and structured Electronic Health Record (EHR) data. However, much critical information resides in relatively inaccessible unstructured clinical notes within the EHR.</p> <p><strong>Materials and Methods</strong></p> <p>We developed a natural language processing (NLP)-based pipeline to extract AD-related clinical phenotypes, documenting strategies for success and assessing the utility of mining unstructured clinical notes. We evaluated the pipeline against gold-standard manual annotations performed by two clinical dementia experts for AD-related clinical phenotypes including medical comorbidities, biomarkers, neurobehavioral test scores, behavioral indicators of cognitive decline, family history, and neuroimaging findings.</p> <p><strong>Results</strong></p> <p>Documentation rates for each phenotype varied in the structured versus unstructured EHR. Inter-annotator agreement was high (Cohen's kappa = 0.72–1) and positively correlated with the NLP-based phenotype extraction pipeline's performance (average F1-score = 0.65-0.99) for each phenotype.</p> <p><strong>Discussion</strong></p> <p>We developed an automated NLP-based pipeline to extract informative phenotypes that may improve the performance of eventual machine-learning predictive models for AD. In the process, we examined documentation practices for each phenotype relevant to the care of AD patients and identified factors for success.</p> <p><strong>Conclusion</strong></p> <p>Success of our NLP-based phenotype extraction pipeline depended on domain-specific knowledge and focus on a specific clinical domain instead of maximizing generalizability. </p>
Medication and condition codes used to develop a computable phenotype for Crohn's Disease incident cases
<p>Lists of medication and condition concepts used for Crohn's disease incident case phenotyping as described in my Master's Thesis "Machine Learning Based Prediction of Incident Cases of Crohn’s Disease Using Electronic Health Records From a Large Integrated Health System".</p> <ul> <li>ibd_medication.csv contains medication names, OMOP Concept IDs, RxNorm codes and a flag indicating whether the medication is IBD-specific (i.e., antibiotics and glucocorticoides are marked as unspecific)</li> <li>ibd_conditions.csv contains condition names, OMOP Concept IDs, SNOMED CT codes and a categorical column indicating whether the condition refers to Crohn's Disease (CD), Ulcerative Colitis (UC), or Inflammatory bowel disease unclassified (IBD-U)</li> <li>ibd_symptoms.csv contains symptom names, OMOP Concept IDs, containing symptom group categories, and a flag indicating whether the symptom was added because it is a SNOMED CT descendent code of another code on the list. The list was created based on the IBD symptoms Read Code list provided by Blackwell et. al, 2021, doi:10.1093/ecco-jcc/jjaa146</li> </ul> <p>IBD, Inflammatory Bowel Disease; OMOP, Observational Medical Outcomes Partnership; SNOMED CT, Systematized Nomenclature of Medicine Clinial Terms.</p>
Extraction of clinical phenotypes for Alzheimer disease dementia from clinical notes using natural language processing
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Investigating the causal association between immune cell phenotypes and allergic diseases and non-allergic asthma using conventional Two-sample and Bayesian weighted Mendelian randomization
<p>Investigating the causal association between immune cell phenotypes and allergic diseases and non-allergic asthma using conventional Two-sample and Bayesian weighted Mendelian randomization</p>
Pathway-based, reaction-specific annotation of disease variants for elucidation of molecular phenotypes
<p>Supplementary Tables and Supplementary Methods for the research article "Pathway-based, reaction-specific annotation of disease variants for elucidation of molecular phenotypes" published in Database.</p>
Multimodal single cell analysis of the paediatric lower airway reveals novel immune cell phenotypes in early life health and disease
<p>RDS files of SingleCellExperiment objects containing raw single cell RNA-seq count data required to replicate the analyses presented at: <a href="https://oshlacklab.com/paed-cf-cite-seq/">https://oshlacklab.com/paed-cf-cite-seq/</a> and described in the pre-print titled: <em>"</em>Multimodal single cell analysis of the paediatric lower airway reveals novel immune cell phenotypes in early life health and disease<em>"</em>.<br> Instructions for how to incorporate the raw data into the analysis can be found at: <a href="https://oshlacklab.com/paed-cf-cite-seq/gettingStarted.html">https://oshlacklab.com/paed-cf-cite-seq/gettingStarted.html</a> and the complete analysis code and additional data files can be cloned/downloaded from: <a href="https://github.com/Oshlack/paed-cf-cite-seq">https://github.com/Oshlack/paed-cf-cite-seq</a>.</p>
DYRK1a inhibitor mediated rescue of Drosophila models of Alzheimer's disease-Down Syndrome phenotypes
<p>Alzheimer's disease (AD) is the most common neurodegenerative disease which is becoming increasingly prevalent due to ageing populations resulting in huge social, economic, and health costs to the community. Despite the pathological processing of genes such as Amyloid Precursor Protein (APP) into Amyloid-b and Microtubule Associated Protein Tau (MAPT) gene, into hyperphosphorylated Tau tangles being known for decades, there remains no treatments to halt disease progression. One population with increased risk of AD are people with Down syndrome (DS), who have a 90% lifetime incidence of AD, due to trisomy of human chromosome 21 (HSA21) resulting in three copies of APP and other AD-associated genes, such as DYRK1A (Dual specificity tyrosine-phosphorylation-regulated kinase 1A) overexpression. This suggests that blocking DYRK1A might have therapeutic potential. However, it is still not clear to what extent DYRK1A overexpression by itself leads to AD-like phenotypes and how these compare to Tau and Amyloid-b mediated pathology. Likewise, it is still not known how effective a DYRK1A antagonist may be at preventing or improving any Tau, Amyloid-b and DYRK1a mediated phenotype. To address these outstanding questions, we characterised Drosophila models with targeted overexpression of human Tau, human Amyloid-b or the fly orthologue of DYRK1A, called minibrain (mnb). We found targeted overexpression of these AD-associated genes caused degeneration of photoreceptor neurons, shortened lifespan, as well as causing loss of locomotor performance, sleep, and memory. Treatment with the experimental DYRK1A inhibitor PST-001 decreased pathological phosphorylation of human Tau (at serine (S) 262). PST-001 reduced degeneration caused by human Tau, Amyloid-b or mnb lengthening lifespan as well as improving locomotion, sleep and memory loss caused by expression of these AD and DS genes. This demonstrated PST-001 effectiveness as a potential new therapeutic targeting AD and DS pathology.</p>
Diseasome - Finding disease association based on Phenotypic and Genotypic clustering
<p>The final processed phenotypic clustered data (output.zip) from Orphanet is also added along side the genotypic clustering data.</p>
Interactive Heatmap of all Disease Phenolog Behavioural Phenotypes
<p><span><span>An interactive clustermap of behavioural tracking data for a panel of 25 <em>C. elegans</em> disease model phenologs (associated with the linked published paper). This is a static html file that can be opened in a browser and zoomed in for a detailed inspect of how the various strains differ from the control (N2). Mousing over the heatmap shows the name of features at each position so that a more intutive conclusion of the data, i.e., 'Strain A is slow' or 'Strain B is more curved', can be reached.</span></span><span></span></p>
Systematic creation and phenotyping of Mendelian disease models in C. elegans: towards large-scale drug repurposing
<p>Data collected for the eLife OpenAccess paper: Systematic creation and phenotyping of Mendelian disease models in <em>C. elegans</em>: towards large-scale drug repurposing. (doi: 10.7554/eLife.92491.1)</p> <p>Contains: extracted features, calculated stats, normalised z-scores and timerseries data of all the disease model mutants generated. In addition, there is a static .html file that allows for mousing over the clustermaps to easily view differences in strains compared to the N2 wild-type. Dataset also contains, metadata and feature summary/file name information of FDA-library drug screen and the confirmation screen of the hit from this (i.e., all data collected in published in the associated paper). </p>
High-throughput behavioural phenotyping of 25 C. elegans disease models including patient-specific mutations
<p>This repository contains: all code, phenomic data, extracted features, calculated stats, normalised z-scores and timerseries data for all of the disease mutant phenologs and data in our paper: High-throughput behavioural phenotyping of 25 C. elegans disease models including patient-specific mutations.</p>
DATASET RELATED TO ARTICLE "MISSENSE MUTATION IN ATXN2 GENE (C.2860C > T) IN AN AMYOTROPHIC LATERAL SCLEROSIS PATIENT WITH AGGRESSIVE DISEASE PHENOTYPE"
<p><strong>NGS_analysis PERFORMED AT fONDAZIONE BESTA AND CARRIED OUT AS PART OF THE STUDY MENTIONED AT TITLE</strong></p>
Post-marketing Surveillance of Ofev Capsules in Chronic Fibrosing Interstitial Lung Diseases With a Progressive Phenotype in Japan
ClinicalTrials.gov study NCT04559581. IPD Sharing: YES. Countries: 1. Publications: 0.
Investigation of Chronic Obstructive Pulmonary Disease (COPD) Phenotypes and Endotypes in China
ClinicalTrials.gov study NCT04853225. IPD Sharing: NO. Countries: 1. Publications: 1.
Apparent differential phenotypic responses by kelp forest grazers to disease-driven removal of sea star predators; [Data: Tegula shell morphology, GSI, stable isotope analysis]
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Data from: Complex disease and phenotype mapping in the domestic dog
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Genetic modifiers of somatic expansion and clinical phenotypes in Huntington’s disease reveal shared and tissue-specific effects
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Allen Brain Atlas
Allen Brain Atlas is an Allen Institute collection of brain map atlases, datasets, APIs, and analysis tools covering mouse, human, and non-human primate brain resources.
Annotated Behaviour and Observability Dataset (ABODe)
ABODe is a University of Edinburgh DataShare dataset for behavior classification in group-housed mice using home-cage video, identities, bounding boxes, ground-plate positions, and annotator labels.
DANDI Archive for NWB datasets
DANDI is a BRAIN Initiative archive for publishing and sharing neurophysiology data, including electrophysiology, optophysiology, and behavioral data packaged as NWB and related standards.
International Brain Laboratory public data
The International Brain Laboratory public data releases expose standardized mouse decision-making experiments, including Neuropixels recordings, widefield calcium imaging, behavior, and session metadata accessed through the ONE API.
OpenNeuro
OpenNeuro is a free, open platform for sharing neuroimaging datasets, with public search, dataset pages, and download paths for web, S3, DataLad, and the OpenNeuro CLI.