Biology subjects

Ackerman, H.

Publications and source records attributed to Ackerman, H..

6 recordsLinked to original sources

bioRxiv2026

Conserved sequence elements in the final exon of MDM2-eight-exon skipping event reveal a cassette regulon model of alternative splicing controlled by a distal regulatory element.

Modern sequencing technologies have revealed that cancers exhibit widespread dysregulation of alternative splicing, which plays a significant role in driving tumor hallmarks. Alternative splicing enables a single gene to generate multiple mRNA variants, a fundamental mechanism that shapes the distinctive characteristics of normal cells as well as cancer cells. These splicing events are governed by complex interactions between cis- and trans-acting factors and understanding these mechanisms is crucial for effectively targeting cancer cells. This study highlights a unique splicing event in which genotoxic stress induces the skipping of eight-exons in the proto-oncogene MDM2, resulting in the formation of MDM2-ALT1, an isoform that is overexpressed in various cancers. To effectively target this splicing event, it is important to unfold the regulatory mechanism behind it. We hypothesize that the event occurs either by the autonomous regulation of individual exons (Exon autonomous model), where each exon is regulated independently or by the coordinated exclusion of an eight-exon-regulon unit (Exon Regulon model). Utilizing in-silico tools, a comprehensive modular minigene system, CRISPR-mutated cell line, and murine models, we demonstrate that this complex MDM2 splicing event is regulated by sequences within a distal terminal exon, which emerge as critical regulators, orchestrating the alternative splicing of MDM2. Constitutive expression of the Mdm2-MS2 isoform (the mouse ortholog of the human MDM2-ALT1 splice variant), achieved by mutating the Srsf2 binding-site on exon 11, modulates proliferation and apoptosis dynamics in NIH3T3 cells. Moreover, in a p53-wildtype in-vivo setting, this isoform confers a protective effect against age-induced neoplasia. Our findings support the Exon Regulon model of MDM2 splicing, regulated by distal elements analogous to distal enhancer elements that control transcription. These finding sheds light on intricacies in the splicing code that could have significant implications for developing splice variant targeting cancer therapies.

molecular biology↗

bioRxiv2025

EnrichMET: R Package for Integrated Pathway and Network Analysis for Metabolomics

Advances in metabolomics have significantly improved our understanding of cellular processes by enabling the identification of hundreds of metabolites in a single experiment. These developments provide valuable insights into complex metabolic networks. While efforts have been made to develop pathway enrichment analysis (PEA), existing implementation often require multiple steps, rely on web-based interfaces, or depend on R packages configuration that may affect reproducibility and ease of use. To overcome these limitations, we introduce EnrichMet, an R package for fast, flexible, and reproducible pathway enrichment analysis. EnrichMet modules support over-representation analysis of pathways, metabolite set enrichment analysis (MetSEA), and network-based pathway analysis. The package streamlines the workflow by combining curated pathway information from the Kyoto Encyclopedia of Genes and Genomics (KEGG) and employs Fishers Exact Test to identify significantly enriched pathways. Benchmark analyses show that enrichment on sample data completes in approximately 3 seconds. EnrichMet offers both a command-line and a user-friendly Shiny interface, enabling accessibility for users with or without programming experience. Through case studies on experimental metabolomics datasets, we demonstrated that EnrichMet delivers accurate and comprehensive pathway enrichment results while minimizing computational time and simplifying user interaction. Furthermore, its flexible framework supports extensions to other data types and knowledge bases beyond KEGG, as illustrated through a lipidomics case study. By unifying performance, reproducibility, usability, and visualization within a single package, EnrichMet facilitates deeper insights and promotes efficient, transparent, and reproducible research practices. Availability and implementation(https://github.com/biodatalab/enrichmet.git)

bioinformatics↗

bioRxiv2025

Discovery of an Adaptive Neuroimmune Response Driving Itch and Fast Tick Removal with Implications for Preventing Pathogen Transmission

Acquired tick resistance (ATR) is well characterized in tick-exposed animals, compromising tick fitness through antibody-mediated activation of basophils. Yet, anti-tick vaccines inducing ATR have had limited success. Here, we describe a neuroimmune event preceding ATR that leads to rapid host-mediated tick removal. Tick-sensitized guinea pigs mechanically remove ticks within 3-6 hours via an acquired neuroimmune-induced itch response that correlates with increased dermal expression of itch-associated genes like OSM and skin infiltration by T cells and macrophages, independently of IgG and IgE antibodies. When we expose humans to ticks, a similar immune response is observed. Blocking T cells before tick sensitization prevents immune cell infiltration to bite sites and abrogates scratching and tick removal. This neuroimmune response is independent of Trpv1 as tick-sensitized guinea pigs treated with resiniferatoxin remove ticks effectively. Itch-induced tick removal or IITR offers a novel approach to tick-borne disease prevention through early tick detection and removal.

neuroscience↗

bioRxiv2024

iModMix: Integrative Module Analysis for Multi-omics Data

SummaryIntegrative Module Analysis for Multi-omics Data (iModMix) is a biology-agnostic framework that enables the discovery of novel associations across any type of quantitative abundance data, including but not limited to transcriptomics, proteomics, and metabolomics. Instead of relying on pathway annotations or prior biological knowledge, iModMix constructs data-driven modules using graphical lasso to estimate sparse networks from omics features. These modules are summarized into eigenfeatures and correlated across datasets for horizontal integration, while preserving the distinct feature sets and interpretability of each omics type. iModMix operates directly on matrices containing expression or abundances for a wide range of features, including but not limited to genes, proteins, and metabolites. Because it does not rely on annotations (e.g., KEGG identifiers), it can seamlessly incorporate both identified and unidentified metabolites, addressing a key limitation of many existing metabolomics tools. iModMix is available as a user-friendly R Shiny application requiring no programming expertise (https://imodmix.moffitt.org), and as an R package for advanced users (https://github.com/biodatalab/iModMix). The tool includes several public and in-house datasets to illustrate its utility in identifying novel multi-omics relationships in diverse biological contexts. Availability and implementationShiny application: https://imodmix.moffitt.org. The R package and source code: https://github.com/biodatalab/iModMix.

bioinformatics↗

bioRxiv2021

Oral Lisinopril Raises Tissue Levels of ACE2, the SARS-CoV-2 Receptor, in Healthy Male and Female Mice

Angiotensin-converting enzyme 2 (ACE2) is the established cellular receptor for SARS-CoV-2. However, it is unclear whether ACE1 inhibitors (e.g., lisinopril) or angiotensin receptor blockers (e.g., losartan) alter tissue ACE2 expression. This study sought to determine whether lisinopril or losartan, as monotherapies or in combination, change tissue levels of ACE2 in healthy male and female mice. Mice received lisinopril (10 mg/kg/day), losartan (10 mg/kg/day), or both for 21 days via drinking water. A control group received water without drug. ACE2 protein index (ACE2 protein / total protein) was determined on small intestine, lung, kidney, and brain. Oral lisinopril increased ACE2 protein index across all tissues (p < 0.0001 vs control). In contrast, the combination of lisinopril plus losartan did not increase ACE2 levels in any tissue (p = 0.89 vs control) and even decreased tissue expression of the Ace2 gene (p < 0.001 vs control). Tissue ACE2 remained elevated in mice 21 days after cessation of lisinopril (p = 0.02). Across both cohorts, plasma ACE2 did not correlate with ACE2 protein index in any tissue. A sex difference was observed: kidney ACE2 levels were higher in males than females (p < 0.0001). Oral lisinopril increases ACE2, the cellular receptor for SARS-CoV-2, in tissues that are relevant to the transmission and pathogenesis of COVID-19. Remarkably, the addition of losartan prevented lisinopril-induced increases in ACE2 across tissues. These results suggest that ACE inhibitors and angiotensin receptor blockers interact to determine tissue levels of ACE2.

pharmacology and toxicology↗

bioRxiv2021

Endothelial alpha globin is a nitrite reductase

Small artery vasodilation in response to hypoxia is essential for matching oxygen supply to tissue oxygen demand. One source of hypoxic dilation via nitric oxide (NO) signaling is nitrite reduction by erythrocytic hemoglobin (2{beta}2). However, the alpha subunit of hemoglobin is also expressed in resistance artery endothelium and localized to myoendothelial junctions, a subcellular domain that contacts underlying vascular smooth muscle cells. We hypothesized that nitrite reduction mediated by endothelial alpha globin may occur at myoendothelial junctions to regulate hypoxic vasodilation. To test this concept, we created two novel mouse strains: one lacking alpha globin specifically in endothelium (EC Hba1{Delta}/{Delta}) and one where alpha globin is mutated such that its inhibitory association with endothelial NO synthase (eNOS) is prevented (Hba1WT/{Delta}36-39). In EC Hba1{Delta}/{Delta} or Hba1WT/{Delta}36-39 mice hemoglobin levels, hematocrit and erythrocyte counts were unchanged from littermate controls. Loss of the full alpha globin protein from the endothelium in the EC Hba1{Delta}/{Delta} model was associated with decreased exercise capacity and decreased intracellular nitrite utilization in hypoxic conditions. These effects were not seen in Hba1WT/{Delta}36-39 animals. Hypoxia induced vasodilation was decreased by 60% in isolated thoracodorsal arteries from EC Hba1{Delta}/{Delta}, while infusion of erythrocytes only partially rescued the dilatory response. Lastly, unlike other models where blood pressure is decreased, EC Hba1{Delta}/{Delta} blood pressure was not altered in response to hypoxia. Overall, we conclude that alpha globin in the resistance artery endothelium can act as a nitrite reductase to provide a local vasodilatory response to hypoxia.

physiology↗