Biology subjects

Mari, T.

Publications and source records attributed to Mari, T..

5 recordsLinked to original sources

bioRxiv2024

Neuromuscular dysfunction in patient-derived FUSR244RR-ALS iPSC model via axonal downregulation of neuromuscular junction proteins

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative condition characterized by the progressive degeneration of motor neurons, ultimately resulting in death due to respiratory failure. A common feature among ALS cases is the early loss of axons, pointing to defects in axonal transport and translation as initial disease indicators. Here, we established a FUSR244RR-ALS hiPSC-derived model that recapitulates the motor neuron survival and muscle contractility defects characteristic of ALS patients. Analysis of the protein and mRNA expression profiles in axonal and somatodendritic compartments of ALS-afflicted and isogenic control motor neurons revealed a selective downregulation of proteins essential for the neuromuscular junction function in FUS-ALS axons. Furthermore, analysis of FUS CLIP and RIP data showed that FUS binds mRNAs encoding these proteins. This work shed light on the pathogenic mechanisms of ALS and emphasized the importance of axonal gene expression analysis in elucidating the mechanisms of neurodegenerative disorders.

cell biology↗

bioRxiv2023

External Validation of Machine Learning and EEG for Continuous Pain Intensity Prediction in Healthy Individuals

Previous research has predicted subjective pain intensity from electroencephalographic (EEG) data using machine learning (ML) models. However, there is a paucity of externally validated ML models for pain assessment, particularly for continuous pain prediction (e.g., decoding pain ratings on a 101-point scale). We aimed to conduct the first external validation paradigm for ML regression models for pain intensity prediction from EEG data. Ninety-one subjects were recruited across three samples. Sample one (n = 40) was used for model development, sample two (n = 51) was used as a cross-subject external validation set, whilst sample three (n = 25) was used as a within-subjects temporal external validation set. Pneumatic pressure stimuli were delivered to the left-hand index fingernail bed at 10 graded intensity levels. Single-trial time-frequency features of peri-stimulus EEG were used to train a Random Forest (RF) model and long short-term memory (LSTM) network to predict pain intensity responses. Results demonstrated that both the RF model and LSTM network predicted pain intensity significantly more accurately than a random prediction model, with the mean absolute error (MAE) of the RF (best performing model) at 19.59, 21.29, and 18.90 for internal validation, cross-subject external validation, and within-subject external validation, respectively. However, neither model was able to predict pain intensity better than a baseline dummy model, which predicted the mean behavioural rating of the training set and did not have access to neural data. Moreover, in a replication of our recent work, we developed a RF model for the classification of low and high-pain trials, which demonstrated internal and external validation accuracies up to 64% and 58%, respectively. Taken together, our results suggest that using ML and EEG to predict continuous pain ratings is not currently feasible. However, classification models demonstrate some potential, consistently outperforming chance across validation samples. Further improvements such as composite measures are required to elevate ML performance to a clinically meaningful level.

neuroscience↗

bioRxiv2022

In vitro Kinase-to-Phosphosite database (iKiP-DB) predicts kinase activity in phosphoproteomic datasets

Phosphoproteomics routinely quantifies changes in the levels of thousands of phosphorylation sites, but functional analysis of such data remains a major challenge. While databases like PhosphoSitePlus contain information about many phosphorylation sites, the vast majority of known sites are not assigned to any protein kinase. Assigning changes in the phosphoproteome to the activity of individual kinases therefore remains a key challenge.. A recent large-scale study systematically identified in vitro substrates for most human protein kinases. Here, we reprocessed and filtered these data to generate an in vitro Kinase-to-Phosphosite database (iKiP-DB). We show that iKiP-DB can accurately predict changes in kinase activity in published phosphoproteomic datasets for both well-studied and poorly characterized kinases. We apply iKiP-DB to a newly generated phosphoproteomic analysis of SARS-CoV-2 infected human lung epithelial cells and provide evidence for coronavirus-induced changes in host cell kinase activity. In summary, we show that iKiP-DB is widely applicable to facilitate the functional analysis of phosphoproteomic datasets.

bioinformatics↗

bioRxiv2021

Neuroblastoma signalling models unveil combination therapies targeting feedback-mediated resistance

Very high risk neuroblastoma is characterised by increased MAPK signalling, and targeting MAPK signalling is a promising therapeutic strategy. We used a deeply characterised panel of neuroblastoma cell lines and found that the sensitivity to MEK inhibitors varied drastically between these cell lines. By generating quantitative perturbation data and mathematical modelling, we determined potential resistance mechanisms. We found that negative feedbacks within MAPK signalling and to the IGF receptor mediate re-activation of MAPK signalling upon treatment in resistant cell lines. By using cell-line specific models, we predict that combinations of MEK inhibitors with RAF or IGFR inhibitors can overcome resistance, and tested these predictions experimentally. In addition, phospo-proteomics profiles confirm the cell-specific feedback effects and synergy of MEK and IGFR targeted treatements. Our study shows that a quantitative understanding of signalling and feedback mechanisms facilitated by models can help to develop and optimise therapeutic strategies, and our findings should be considered for the planning of future clinical trials introducing MEKi in the treatment of neuroblastoma.

cancer biology↗

bioRxiv2020

Bulk and single-cell gene expression profiling of SARS-CoV-2 infected human cell lines identifies molecular targets for therapeutic intervention

The coronavirus disease 2019 (COVID-19) pandemic, caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an ongoing global health threat with more than two million infected people since its emergence in late 2019. Detailed knowledge of the molecular biology of the infection is indispensable for understanding of the viral replication, host responses, and disease progression. We provide gene expression profiles of SARS-CoV and SARS-CoV-2 infections in three human cell lines (H1299, Caco-2 and Calu-3 cells), using bulk and single-cell transcriptomics. Small RNA profiling showed strong expression of the immunity and inflammation-associated microRNA miRNA-155 upon infection with both viruses. SARS-CoV-2 elicited approximately two-fold higher stimulation of the interferon response compared to SARS-CoV in the permissive human epithelial cell line Calu-3, and induction of cytokines such as CXCL10 or IL6. Single cell RNA sequencing data showed that canonical interferon stimulated genes such as IFIT2 or OAS2 were broadly induced, whereas interferon beta (IFNB1) and lambda (IFNL1-4) were expressed only in a subset of infected cells. In addition, temporal resolution of transcriptional responses suggested interferon regulatory factors (IRFs) activities precede that of nuclear factor-{kappa}B (NF-{kappa}B). Lastly, we identified heat shock protein 90 (HSP90) as a protein relevant for the infection. Inhibition of the HSP90 charperone activity by Tanespimycin/17-N-allylamino-17-demethoxygeldanamycin (17-AAG) resulted in a reduction of viral replication, and of TNF and IL1B mRNA levels. In summary, our study established in vitro cell culture models to study SARS-CoV-2 infection and identified HSP90 protein as potential drug target for therapeutic intervention of SARS-CoV-2 infection.

systems biology↗