Biology subjects

Rahim, A.

Publications and source records attributed to Rahim, A..

5 recordsLinked to original sources

bioRxiv2026

DNA Adenine Methylation Clock in Brain Aging and Alzheimer's Disease Progression

N6-methyldeoxyadenosine (N6medA) is a recently identified endogenous DNA modification widely found in bacteria, plants, and eukaryotes. In mammals, N6medA has been implicated in brain function, immunity, and response to environmental stress, but its relevance to gene regulation and mammalian aging remains controversial due to its extremely low abundance (< 1 per 10 million adenines) and an uncertainty regarding its genomic origin. We have developed and validated an ultrasensitive isotope dilution nano liquid chromatography-nanospray ionization Orbitrap mass spectrometry methodology to quantify N6medA in genomic DNA. Applying this approach to human prefrontal cortex tissues, we found that genomic N6medA levels increase linearly with chronological age (Pearson correlation coefficient, 0.95). Individuals with mild cognitive impairment (MCI) and Alzheimers disease (AD) exhibited a trend toward elevated cortical N6medA levels relative to age-matched controls. Genome-wide profiling of N6medA in human prefrontal cortex was conducted using two independent methods: NAME-Seq and MeDIP-Seq, which revealed age associated adenine methylation changes reminiscent of established epigenetic aging signatures such as the 5-methylcytosine clocks. N6medA mapping experiments identified a subset of genomic loci that were altered in MCI and AD. Pathway analysis of cross-validated adenine methylation sites revealed an enrichment of genes involved in neuronal function and age-related neurological processes, including glutamatergic synapse, axon guidance, and long-term depression. Finally, mass-spectrometry-based photoaffinity proteomics with synthetic DNA representing a region of the APP gene identified N6medA reader proteins with known roles in DNA repair, replication and transcription. Together, these findings identify N6medA as an age-associated DNA modification in the human brain and suggest that its accumulation and recognition by specific protein readers may contribute to molecular processes underlying brain aging and age-related neurodegeneration.

biochemistry↗

bioRxiv2025

Citizen science gamers enable automated flow cytometry gating through machine learning

Manual flow cytometry gating requires up to one hour per sample with 32% inter-expert variability, creating critical bottlenecks in immunological research reproducibility. To address this, we developed flowMagic, a machine learning algorithm for automated gating that is trained on both expert-curated data (template data) and crowdsourced annotations from citizen science gaming. Through EVE Online, 839,199 players analyzed 52,178 bivariate plots from 37 studies, generating 31,703 quality-controlled training plots. Evaluated against 92,203 expert-validated files spanning 79 immune populations (i.e., a biologically defined cell subset within each bivariate plot), flowMagic achieved 90% accuracy for abundant populations and 65% for rare populations, outperforming existing methods. The algorithm reproduced biological patterns including neutrophil dynamics in COVID-19 patients and immune development in newborns. This gaming-based approach demonstrates that crowd-sourced pattern recognition generates robust training data for complex biomedical applications, offering transformative potential for standardizing flow cytometry analysis and accelerating immunological discovery.

bioinformatics↗

bioRxiv2024

TET1 Functions as a Tumor Suppressor in Lung Adenocarcinoma Through Epigenetic Remodeling and Immune Modulation

Ten-Eleven Translocation (TET1-3) dioxygenases oxidize 5-methylcytosine (5mC) in DNA to generate 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC), initiating DNA demethylation. The three proteins share significant sequence homology and catalyze the same chemical reaction utilizing alpha-ketoglutarate cofactor and non-heme iron to oxidize the methyl group of 5mC. Since their discovery in 2009, there have been contradictory reports regarding the roles of TET proteins in cancer. TET genes have been characterized as tumor suppressor genes because their expression levels are reduced in many human cancers including lymphoma, prostate, and pancreas, and TET2 gene mutations are common in hematological cancers. However, TET1 was recently reported to be overexpressed in triple negative breast cancer and to act as a protooncogene in lung cancer. In the present study, we employed genetic approaches to directly address the function of TET1 protein in lung adenocarcinoma. We found that overexpression of TET1 in human lung adenocarcinoma (H441) cells decreased their proliferation and inhibited colony formation, cell migration, and 3D spheroid tumorigenesis. In contrast, TET1 knockout in lung adenocarcinoma accelerated cell growth and promoted colony formation, cell migration, and 3D spheroid tumorigenesis. Transcriptomics and proteomics analyses revealed that TET1 overexpression was associated with overexpression of immune markers, primarily via activation of TNF and NF-kB signaling pathways. TET1 knockout in lung adenocarcinoma cells induces the expression of genes involved in cellular metabolism and cell growth. Our results are consistent with a tumor suppressor role of TET1 gene in lung adenocarcinoma and reveal its role in activating antitumor immunity.

cancer biology↗

bioRxiv2019

High-throughput phenotyping reveals expansive genetic and structural underpinnings of immune variation

By developing a high-density murine immunophenotyping platform compatible with high-throughput genetic screening, we have established profound contributions of genetics and structure to immune variation. Specifically, high-throughput phenotyping of 530 knockout mouse lines identified 140 monogenic \"hits\" (>25%), most of which had never hitherto been implicated in immunology. Furthermore, they were conspicuously enriched in genes for which humans show poor tolerance to loss-of-function. The immunophenotyping platform also exposed dense correlation networks linking immune parameters with one another and with specific physiologic traits. By limiting the freedom of individual immune parameters, such linkages impose genetically regulated \"immunological structures\", whose integrity was found to be associated with immunocompetence. Hence, our findings provide an expanded genetic resource and structural perspective for understanding and monitoring immune variation in health and disease.

immunology↗

bioRxiv2018

Gene therapy in argininosuccinic aciduria

Argininosuccinate lyase (ASL) belongs to the liver-based urea cycle detoxifying ammonia, and the citrulline-nitric oxide cycle synthesising nitric oxide (NO). ASL-deficient patients present argininosuccinic aciduria characterised by hyperammonaemia and a multi-organ disease with neurocognitive impairment. Current therapeutic guidelines aim to control ammonaemia without considering the systemic NO imbalance. Here, we observed a neuronal disease with oxidative/nitrosative stress in ASL-deficient mouse brains. A single systemic injection of gene therapy mediated by an adeno-associated viral vector serotype 8 (AAV8) in adult or neonatal mice demonstrated the long-term correction of the urea cycle and the citrulline-NO cycle in the brain, respectively. The neuronal disease persisted if ammonaemia only was normalised but was dramatically reduced after correction of both ammonaemia and neuronal ASL activity. This was correlated with behavioural improvement and a decrease of the cortical cell death rate. Thus, the cerebral disease in argininosuccinic aciduria involves neuronal oxidative/nitrosative stress not mediated by hyperammonaemia, which is reversed by AAV gene transfer targeting the brain and the liver, acting on two different metabolic pathways via a single vector delivered systemically. This approach provides new hope for hepatocerebral metabolic diseases.

genetics↗