Chen Tang

Here, we present a multi-modal deep generative model, the single-cell Multi-View Profiler (scMVP), which is designed for handling sequencing data that simultaneously measure gene expression and chromatin accessibility in the same cell, including SNARE-seq, sci-CAR, Paired-seq, SHARE-seq, and Multiome from 10X Genomics. scMVP generates common latent representations for dimensionality reduction, cell clustering, and developmental trajectory inference and generates separate imputations for differential analysis and cis-regulatory element identification. scMVP can help mitigate data sparsity issues with imputation and accurately identify cell groups for different joint profiling techniques with common latent embedding, and we demonstrate its advantages on several realistic datasets.

The fungus Verticillium dahliae causes vascular wilt disease on hundreds of plant species. Homologs of the bZIP transcription factor Atf1 are required for virulence in most pathogenic fungi, but the molecular basis for their involvement is largely unknown. We performed targeted gene deletion, expression analysis, biochemistry and pathogenicity assays to demonstrate that VdAtf1 governs pathogenesis via the regulation of nitrosative resistance and nitrogen metabolism in V. dahliae. VdAtf1 controls pathogenesis via the regulation of nitric oxide (NO) resistance and inorganic nitrogen metabolism rather than oxidative resistance and is important for penetration peg formation in V. dahliae. VdAtf1 affects ammonium and nitrate assimilation in response to various nitrogen sources. VdAtf1 may be involved in regulating the expression of VdNut1. VdAtf1 responds to NO stress by strengthening the fungal cell wall, and by causing over-accumulation of methylglyoxal and glycerol, which in turn impacts NO detoxification. We also verified that the VdAtf1 ortholog in Fusarium graminearum mediates nitrogen metabolism, suggesting conservation of this function in related plant pathogenic fungi. Our findings revealed new functions of VdAtf1 in pathogenesis, response to nitrosative stress and nitrogen metabolism in V. dahliae. The results provide novel insights into the regulatory mechanisms of the transcription factor VdAtf1 in virulence.

Synthetic lethality is emerging as an important cancer therapeutic paradigm, while the comprehensive selective treatment opportunities for various tumors have not yet been explored. We develop the Synthetic Lethality Knowledge Graph (SLKG), presenting the tumor therapy landscape of synthetic lethality (SL) and synthetic dosage lethality (SDL). SLKG integrates the large-scale entity of different tumors, drugs and drug targets by exploring a comprehensive set of SL and SDL pairs. The overall therapy landscape is prioritized to identify the best repurposable drug candidates and drug combinations with literature supports, in vitro pharmacologic evidence or clinical trial records. Finally, cladribine, an FDA-approved multiple sclerosis treatment drug, is selected and identified as a repurposable drug for treating melanoma with CDKN2A mutation by in vitro validation, serving as a demonstrating SLKG utility example for novel tumor therapy discovery. Collectively, SLKG forms the computational basis to uncover cancer-specific susceptibilities and therapy strategies based on the principle of synthetic lethality.

Laryngeal cancers are mostly squamous cell carcinomas. Although targeting radio-resistant cancer cells is important for improving the treatmental efficiency, the signaling pathway- and therapeutic strategy-related to laryngeal carcinoma still require further study. Galangin is an active pharmacological ingredient, isolated from propolis and Alpinia officinarum Hance, and has been reported to have anticancer and anti-oxidative properties through regulation of cell cycle, resulting in angiogenesis, apoptosis, invasion and migration without triggering any toxicity in normal cells. PI3K/AKT and p38 are important signaling pathways to modulate cancer cell apoptosis and proliferation through caspase-3, NF-κB and mTOR signal pathways. Autophagy is also enhanced by activating LC3s and Beclin 1. In the present study, galangin was found to suppress laryngeal cancer cell proliferation. Also, flow cytometry, immunohistochemical and western blot analysis indicated that cell apoptosis was induced for galangin administration, promoting caspase-3 expression through regulating PI3K/AKT/NF-κB. Furthermore, galangin inhibited laryngeal cancer cell proliferation, related to p38 inactivation by galangin treatment. Additionally, mTOR activation regulated by PI3K/AKT was reduced by galangin, suppressing cancer cell transcription and proliferation. Our data also indicated that the tumor volume and weight in nude mice were reduced for galangin use in vivo accompanied by Ki-67 decrease and TUNEL increase in tumor tissues. Together, our data indicated that galangin has a potential role in suppressing human laryngeal cancer via inhibiting tumor cell proliferation, activating apoptosis and autophagy, which were regulated by p38 and AKT/NF-κB/mTOR pathways, providing a therapeutic strategy for human laryngeal cancer treatment.