Genetic variation in voltage-gated sodium (Na) channels is a significant contributor to neurodevelopmental disorders. Na channel alpha subunits are encoded by the SCNxA family and four are predominately expressed in the brain: SCN1A, SCN2A, SCN3A, and SCN8A. Gene expression is developmentally regulated, and they are known to express functionally distinct transcript variants. Precision therapies targeting these genes and their transcript variants are currently in preclinical development, yet the developmental expression of these transcripts in the human brain is yet to be fully understood. Additionally, the functional consequences of some mutations differ depending on the studied channel isoform, suggesting differential transcript variant expression can affect disease prognoses. We characterise the expression of the four SCNxAs and their transcript variants in human, Rhesus monkey and mouse brain using publicly available RNA-sequencing data and analysis tools, demonstrating that this approach can be used to answer important biological questions of gene and transcript developmental regulation. We find that gene expression and transcript variant regulation are conserved across species at similar developmental stages and determine the developmental milestones for transcript variant expression. Our study provides a guide to researchers testing therapies and clinicians advising prognoses based on the expression of channel isoforms.
Download full-text PDF |
Source |
---|---|
http://dx.doi.org/10.1016/j.nbd.2022.105622 | DOI Listing |
Nat Cancer
January 2025
State Key Laboratory of Molecular Oncology, School of Life Sciences, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China.
Terminal exhaustion is a critical barrier to antitumor immunity. By integrating and analyzing single-cell RNA-sequencing and single-cell assay for transposase-accessible chromatin with sequencing data, we found that ETS variant 7 (ETV7) is indispensable for determining CD8 T cell fate in tumors. ETV7 introduction drives T cell differentiation from memory to terminal exhaustion, limiting antiviral and antitumor efficacy in male mice.
View Article and Find Full Text PDFNat Commun
January 2025
Biophysics Program, Stanford University, Stanford, CA, USA.
Understanding how proteins discriminate between preferred and non-preferred ligands ('selectivity') is essential for predicting biological function and a central goal of protein engineering efforts, yet the biophysical mechanisms underpinning selectivity remain poorly understood. Towards this end, we study how variants of the promiscuous transcription factor (TF) MAX (H. sapiens) alter DNA specificity and selectivity, yielding >1700 Ks and >500 rate constants in complex with multiple DNA sequences.
View Article and Find Full Text PDFPLoS Pathog
January 2025
Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom.
Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is a diverse family of variant surface antigens, encoded by var genes, that mediates binding of infected erythrocytes to human cells and plays a key role in parasite immune evasion and malaria pathology. The increased availability of parasite genome sequence data has revolutionised the study of PfEMP1 diversity across multiple P. falciparum isolates.
View Article and Find Full Text PDFPLoS One
January 2025
Arizona Humane Society, Phoenix, Arizona, United States of America.
SARS-CoV-2 is the cause of mild to severe acute respiratory disease that led to significant loss of human lives worldwide between 2019 and 2022. The virus has been detected in various animals including cats and dogs making it a major public health concern and a One Health issue. In this study, conjunctival and pharyngeal swabs (n = 350) and serum samples (n = 350) were collected between July and December 2020 from cats that were housed in an animal shelter and tested for the infection of SARS-CoV-2 using real time reverse-transcription polymerase chain reaction (rRT-PCR) that targeted the N1 and N2 genes, and a SARS-CoV-2 surrogate virus neutralization Test (sVNT), respectively.
View Article and Find Full Text PDFJ Med Chem
January 2025
State Key Laboratory of Antiviral Drugs, Pingyuan Laboratory, NMPA Key Laboratory for Research and Evaluation of Innovative Drug, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, China.
A novel 2'-α-fluoro-2'-β--(fluoromethyl) purine nucleoside phosphoramidate prodrug has been designed and synthesized to treat SARS-CoV-2 infection. The SARS-CoV-2 central replication transcription complex (C-RTC, nsp12-nsp7-nsp8) catalyzed in vitro RNA synthesis was effectively inhibited by the corresponding bioactive nucleoside triphosphate (). The cryo-electron microscopy structure of the C-RTC: complex was also determined.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!