Publications by Year: 2026

Oncogenic Kaposi's sarcoma-associated herpesvirus (KSHV) employs a biphasic life cycle consisting of latency and lytic replication to achieve lifelong infection. Despite its essential role in KSHV persistence and tumorigenicity, much remains unknown about how KSHV lytic reactivation is regulated. Leveraging high-throughput transcriptomics, we identify microRNA-31-5p (miRNA-31-5p) as a key regulator of KSHV lytic reactivation, capable of modulating expression of KSHV lytic genes and progression through the lytic cascade. Mechanistically, miR-31-5p controls the KSHV lytic switch by regulating expression of the RNA-binding protein KHDRBS3. miR-31-5p-mediated KHDRBS3 repression results in decreased nascent transcription of crucial viral lytic genes including the main KSHV transcription factor RTA. We characterize KHDRBS3 as a major host factor that is critical for KSHV lytic replication and uncover its key role in KSHV lytic gene transcription. Our results highlight a pivotal role for the miR-31-5p/KHDRBS3 axis in modulating KSHV reactivation and provide insights into gene-expression regulation of lytic KSHV.

Cutaneous melanoma, a highly aggressive and therapy-resistant skin cancer, is characterized by its remarkable cellular plasticity, enabling tumour cells to switch between different phenotypic states. This plasticity contributes to tumour heterogeneity and is regulated by key transcription factors. Long non-coding RNAs (lncRNAs) are emerging as crucial regulators in melanoma progression, yet much remains to be explored regarding their role in phenotype switching. In this study, we analysed long non-coding RNAs (lncRNAs) across different murine melanoma cell lines, identifying a set of lncRNAs potentially involved in regulating melanoma phenotypic state through cis-regulation of neighbouring protein-coding genes. We demonstrated that the lncRNA Dlx4os regulates genes associated with melanoma plasticity, favouring a mesenchymal-like, undifferentiated state. Dlx4os knockdown redirected melanoma cells to a more differentiated and less malignant phenotype, confirmed by differential expression of phenotypic state markers (Sox10, Mitf, Tgfβ, Sox6, Mlana), reduced their invasive and migratory potential, and delayed tumour progression in vivo. Furthermore, we identified a human orthologue of Dlx4os. Our findings highlight the potential of Dlx4os as both a biomarker and therapeutic target, capable of modulating melanoma's phenotypic plasticity to influence treatment response and metastasis.

Peptide nucleic acid (PNA) is a synthetic mimic of DNA where the deoxyribose-phosphodiester backbone is replaced with N-(2-aminoethyl) glycine units. The lack of deoxyribose-phosphodiester bonds enhances enzymatic stability and improves binding affinity of PNA with complementary DNA and RNA strands. To enhance target binding, conformational stability, and pharmacological activity, several chemical modifications have been introduced into PNA. Modified PNAs have demonstrated promising preclinical potential as antisense and anti-gene agents, supporting their use in diverse biomedical applications. The limited in vivo biodistribution and cellular uptake of PNA have significantly hindered its clinical development. Enhancing PNA biodistribution using nanoformulations and bioconjugate-based delivery strategies has resulted in substantial in vivo pharmacological effects. Further, with advancements in chemistry and delivery techniques, PNA holds promise in treating genetic diseases, metabolic disorders, cancers, and infectious diseases. This review summarizes PNA's pharmacological mechanisms, chemical modifications, delivery strategies, and therapeutic applications while addressing limitations for clinical translation.

The human prefrontal cortex (PFC), whose laminar organization is essential for cognitive function, is among the first regions to show age-related functional decline1,2. Single-cell sequencing studies revealed cell type-dependent aging effects but lacked spatial specificity3-6. Spatial transcriptomics (ST) advanced our molecular understanding of the human PFC7, yet whether aging-driven changes differ across PFC layers remains unclear. Here, we performed whole-transcriptome ST on postmortem PFC from 37 individuals across the adult lifespan. We mapped cortical layers and revealed aging mechanisms across layers. This represents one of the largest and most comprehensive lifespan ST analysis of the human PFC brain, offering crucial insight into how the brain ages and identifying potential molecular targets to mitigate cognitive aging and extend healthspan.

BRCA1/2 -mutated breast cancers exhibit homologous recombination deficiency (HRD), making them initially sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. However, 40-70% of patients develop resistance, necessitating combination strategies and predictive biomarkers. We first investigated approaches to overcome PARP resistance and then explored spatial microRNA (miRNA) profiling as a prognostic tool. Using the K14-Cre Brca1 f/f Trp53 f/f model with tumors that acquired PARP resistance, we evaluated PARP inhibitor combinations with either PI3K inhibition or Poly(I:C) in vivo . Both combinations improved antitumor activity compared to PARP inhibition alone. Next, to predict resistance we applied a sensitive assay that quantifies and spatially profiles miRNA expression in situ onto FFPE sections from tumors treated for 10 days using nanoliter well arrays with functionalized hydrogel posts. We developed a spatial miRNA analysis framework integrating latent Dirichlet allocation (LDA) and principal component analysis (PCA) to develop "topics" that stratify early tumors as either PARP inhibitor-sensitive or - resistant and distinguish their treatment regimens. We also incorporated immune architecture using Structural Similarity Index Measure (SSIM) maps that revealed co-localization of immune infiltration and miRNA topics. This integrative approach highlights how miRNA-based spatial analysis can predict PARP inhibitor resistance and provide a promising biomarker to inform therapeutic strategies for BRCA1/2- related breast cancers.

Increasing lifespans make health problems in the elderly such as opioid misuse a more prominent concern. Understanding the effects that opioids may have on the aged brain can help us address age-related concerns of opioid exposure. This study aimed to assess potential interactions between aging and opioid exposure. Three-month-old (young adult) and 19-month-old (aged) C57BL/6JN mice were assigned to either a morphine (3 mg/kg, i.p.) or saline group. A conditioned placed preference (CPP) task was used to assess reward sensitivity, while rotarod and beam walk tests were used to assess sensorimotor coordination. To assess for potential age-dependent effects of morphine on gene expression, we performed RNA sequencing in the prefrontal cortex (PFC). We found that morphine induced CPP in both age groups. Our results indicate impaired motor coordination in aged mice; however, morphine did not significantly affect motor coordination in either age group, although a trend toward an increased number of slips was observed in morphine-treated aged mice. Transcriptomic analysis revealed more robust effects of morphine on gene expression in the aged brain compared to the young brain. Interestingly, we found limited overlap between morphine-regulated genes in young and old mice, suggesting that the molecular effects of morphine are age-dependent. Taken together, while we found no significant interactions between morphine (at the tested dose) and aging in the behavioral assays, morphine caused age-dependent gene expression changes. Our findings suggest that age should be considered when prescribing opioids and that age-specific therapeutics may help address opioid use disorder in the elderly.