Biology subjects

Ramani, A. K.

Publications and source records attributed to Ramani, A. K..

3 recordsLinked to original sources

bioRxiv2022

Conserved transcriptional programming across sex and species after peripheral nerve injury predicts treatments for neuropathic pain

Chronic pain is a devastating problem affecting 1 in 5 individuals around the globe, with neuropathic pain the most debilitating and poorly treated type of chronic pain. Advances in transcriptomics and data mining have contributed to cataloging diverse cellular pathways and transcriptomic alterations in response to peripheral nerve injury but have focused on phenomenology and classifying transcriptomic responses. Here, with the goal of identifying new types of pain-relieving agents, we compared transcriptional reprogramming changes in the dorsal spinal cord after peripheral nerve injury cross-sex and cross-species and imputed commonalities, as well as differences in cellular pathways and gene regulation. We identified 93 transcripts in the dorsal horn that were increased by peripheral nerve injury in male and female mice and rats. Following gene ontology and transcription factor analyses, we constructed a pain interactome for the proteins encoded by the differentially expressed genes, discovering new, conserved signaling nodes. We interrogated the interactome with the Drug-Gene database to predict FDA-approved medications that may modulate key nodes within the network. The top hit from the analysis was fostamatinib, the molecular target of which is the non-receptor tyrosine kinase Syk, which our analysis had identified as a key node in the interactome. We found that intrathecally administrating the active metabolite of fostamatinib, R406, significantly reversed pain hypersensitivity in both sexes. Thus, we have identified and shown the efficacy of an agent that could not have been previously predicted to have analgesic properties. One sentence summaryUnbiased approach to predicting safe therapies for neuropathic pain

neuroscience↗

bioRxiv2020

FORCAST: a fully integrated and open source pipeline to design Cas-mediated mutagenesis experiments

Cas-mediated genome editing has enabled researchers to perform mutagenesis experiments with relative ease. Effective genome editing requires tools for guide RNA selection, off-target prediction, and genotyping assay design. While independent tools exist for these functions, there is still a need for a comprehensive platform to design, view, evaluate, store, and catalogue guides and their associated primers. The Finding Optimizing and Reporting Cas Targets (FORCAST) application integrates existing open source tools such as JBrowse, Primer3, BLAST, bwa, and Silica to create a complete allele design and quality assurance pipeline. FORCAST is a fully integrated software that allows researchers performing Cas-mediated genome editing to generate, visualize, store, and share information related to guides and their associated experimental parameters. It is available from a public GitHub repository and as a Docker image, for ease of installation and portability.

bioinformatics↗

bioRxiv2019

Found in Transcription: Gene fusions arise through defects in RNA processing in the absence of chromosomal rearrangements.

Recent advancements in high throughput sequencing analysis have enabled the characterization of cancer-driving fusions, improving our understanding of cancer development. Most fusion calling methods, however, examine either RNA or DNA information alone and are limited to a rigid definition of what constitutes a fusion. For this study we developed a pipeline that incorporates several fusion calling methods and considers both RNA and DNA to capture a more complete representation of the tumour fusion landscape. Interestingly, most of the fusions we identified were specific to RNA, with no evidence of corresponding genomic restructuring. Further, while the average total number of fusions in tumour and normal brain tissue samples is comparable, their overall fusion profiles vary significantly. Tumours have an over-representation of fusions occurring between coding genes, whereas fusions involving intergenic or non-coding regions comprised the vast majority of those in normals. Tumours were also more abundant in unique, sample-specific fusions compared to normals, though several fusions exhibited strong recurrence in the tumour type examined (diffuse intrinsic pontine glioma; DIPG) and were absent from both normal tissues and other cancers. Intriguingly, tumours also show broad up- or down-regulation of spliceosomal gene expression, which significantly correlates with fusion number (p=0.007). Our results show that RNA-specific fusions are abundant in both tumour and normal tissue and are associated with spliceosomal gene dysregulation. RNA-specific fusions should be considered as a potential mechanism that may contribute to cancer formation initiation and maintenance alongside more traditional structural events.

genomics↗