Biomedical subjects

Xin Gao

Publications and source records attributed to Xin Gao.

7 recordsLinked to original sources

PubMed2026

Key enzyme optimization and multi-node metabolic flux regulation drive l-arginine production in Escherichia coli.

Microbial production of l-arginine is often constrained by tight metabolic regulation and insufficient precursor supply. Here a plasmid-free, non-auxotrophic Escherichia coli strain for high-level production of l-arginine was rationally engineered, based on our previous constructed strain G0 with 12.4 g/L l-arginine production in flask. Glucose metabolism and glutamate/aspartate uptake were initially enhanced, with subsequent semi-rational engineering of key enzymes, ornithine acetyltransferase (OAT) and argininosuccinate synthase (ASS), to promote ATP synthesis. OAT was firstly rational engineered by introducing amide group for the residues near substrate-binding pocket to stabilize oxyanion transition states, with achieving that variant Y386Q showed Km/kcat at 6.58 mM-1 min-1, 2 times higher than that of wild type. Variant Y332L of ASS was novelty fused with argininosuccinate lyase via GGGGS linker for ASS activity measurement, which helped improve l-arginine titer to 17.5 g/L. With further studies by screening of rate-limiting nodes on the genome-scale level based on sRNA strategy, aspartate and glutamate pathways were synergistically enhanced, along with utilizing carbon dioxide recycling for carbamoyl phosphate synthesis to drive ammonia donor supply. The obtained final plasmid-free and non-auxotrophic strain G16 produced 21.1 g/L l-arginine in flask, 76.6% higher than that of original strain G0. In 5 L fermenter, 125.6 g/L l-arginine was produced by fed-batch fermentation, with a yield of 0.53 g/g glucose. This study underscores that the convergence of mechanistic enzyme redesign and systems-level pathway optimization is critical to unlocking high-efficient amino acid production, offering a transferable blueprint for rational strain engineering in industrial biotechnology.

Argininosuccinate synthase↗

PubMed2026

Chromosome-scale genomes and population resequencing resolve subgenome diversity and halophyte adaptation in Salicornia.

Amid escalating water scarcity and groundwater depletion, halophytes such as Salicornia (Amaranthaceae) represent valuable models for extreme salt tolerance and hold promise for saltwater-based agriculture. Here, we show chromosome-scale genome assemblies for six Salicornia species, revealing four distinct subgenomes, reconciling our assemblies with two existing reference genomes (S. ramosissima UK and S. europaea China), correcting chromosome numbering and orientation. Comparative analyses across ploidy levels demonstrate genome expansion in North American lineages driven by Gypsy retrotransposons, and lineage-specific expansions of two gene families implicated in stress metabolism. Phylogenetic and population-structure analyses of a global resequencing panel of 318 accessions resolve interspecific relationships and establish curated germplasm collections for future crop breeding. Genetic analyses uncover a contrasting population-genetic signal on chromosome 6A between two species, highlighting an OSCA calcium-permeable channel gene as a candidate locus for osmotic adaptation. Together, these resources establish a genomic framework for Salicornia that supports evolutionary studies of halophyte adaptation and crop development.

Chenopodiaceae↗

PubMed2026

Clinical translation of senescence-related pan-cancer multi-omics: tools for assessment and immunotherapy prediction.

Cellular senescence (CS) exerts dual roles in tumorigenesis, yet its pan-cancer molecular characteristics and clinical value remain unclear, hindering its translation to oncology and personalized therapy. To address the lack of specific and universal tools for senescence assessment and immunotherapy response prediction, this study systematically analyzed 1259 CS-related genes from the CellAge database across 31 cancer types by integrating multi-omics data, including bulk RNA-seq, single-cell/spatial transcriptomics, and CRISPR screening. We developed a rank-based algorithm SenScoreR (publicly available at https://gxhub.shinyapps.io/SenScoreR/ ) for senescence quantification, validated with 10 independent datasets, and constructed a machine learning-based predictive model CS.Sig for immunotherapy response. Results showed that tumors had significantly lower Rank-based Senescence Score (RSS) than normal tissues across 31 cancers (average diagnostic AUC = 0.895), with low RSS linked to poor survival; high RSS correlated with reduced genomic instability, enriched CD8⁺ T/NK cell/macrophage infiltration, upregulated PD-L1 expression, and elevated immune cytolytic activity. CS.Sig demonstrated robust performance in predicting ICI response (AUC = 0.716 across 10 cohorts), outperforming 13 existing signatures, while CRISPR screening identified 17 senescence-related targets (e.g., CEP55, PPP1CC) whose knockout enhanced anti-tumor immunity. Our findings clarify CS's role in maintaining tumor genomic stability and shaping immune microenvironments, and the developed SenScoreR, CS.Sig, and identified targets bridge basic CS research with clinical oncology, providing a translational resource and hypothesis basis for future experimental and clinical validation.

Journal Article↗

PubMed2026

Effects of permissive hypercapnia on intraoperative cerebral oxygenation and early postoperative cognitive function in older patients with fragile brain function during the non-acute phase undergoing laparoscopic colorectal surgery: A randomized controlled trial.

BACKGROUND AND PURPOSE: Older adults with non-acute fragile brain function (NFBF) may be particularly susceptible to perioperative disturbances in cerebral oxygenation and postoperative neurocognitive decline. Permissive hypercapnia (PHC) may enhance cerebral oxygenation, but its effects in this population remain unclear. We examined whether PHC-based ventilation improves intraoperative regional cerebral oxygen saturation (rSO2) and early postoperative cognitive outcomes in older patients with NFBF undergoing elective laparoscopic colorectal surgery. METHODS: In this single-center, single-blind randomized trial, 76 patients were assigned in a 1:1 ratio to PHC-based or conventional ventilation. The primary outcome was the absolute change in rSO2 from baseline (T0) to the end of surgery (T4). Analyses followed the intention-to-treat principle, with prespecified per-protocol sensitivity analysis. Secondary outcomes included intraoperative rSO2 trajectories, cerebral oxygen extraction-related indices, early postoperative cognitive screening, serum neuron-specific enolase and interleukin-6, and safety outcomes. RESULTS: PHC significantly increased rSO2 relative to conventional ventilation (left: adjusted mean difference [aMD] 10.64, 95% CI 8.96-12.33; right: aMD 10.16, 95% CI 8.22-12.11; both P < 0.001), with consistent sensitivity results. Repeated-measures analyses showed persistently higher intraoperative rSO2 in the PHC group. Cerebral oxygen extraction-related indices were generally lower with PHC. However, early postoperative cognitive outcomes and serum biomarkers did not differ between groups. Emergence time was modestly longer with PHC, whereas adverse events were comparable. CONCLUSIONS: PHC-based ventilation favorably modified intraoperative cerebral oxygenation and oxygen-extraction profiles but did not translate into detectable early postoperative cognitive or biomarker benefits in older adults with NFBF.

Humans↗

PubMed2025

Yeast growth is controlled by the proportional scaling of mRNA and ribosome concentrations.

Despite growth being fundamental to all aspects of cell biology, we do not yet know its organizing principles in eukaryotic cells. Classic models derived from the bacteria E. coli posit that protein-synthesis rates are set by mass-action collisions between charged tRNAs produced by metabolic enzymes and mRNA-bound ribosomes. These models show that faster growth is achieved by simultaneously raising both ribosome content and peptide elongation speed. Here, we test if these models are valid for eukaryotes by combining single-molecule tracking, spike-in RNA sequencing, and proteomics in 15 carbon- and nitrogen-limited conditions using the budding yeast S. cerevisiae. Ribosome concentration increases linearly with growth rate, as in bacteria, but the peptide elongation speed remains constant (~9 amino acids/s) and charged tRNAs are not limiting. Total mRNA concentration rises in direct proportion to ribosomes, driven by enhanced RNA polymerase II occupancy of the genome. We show that a simple kinetic model of mRNA-ribosome binding predicts both the fraction of active ribosomes, the growth rate, and responses to transcriptional perturbations. Yeast accelerate growth by coordinately and proportionally co-up-regulating total mRNA and ribosome concentrations, not by speeding elongation. Taken together, our work establishes a new framework for eukaryotic growth control and resource allocation.

Journal Article↗

PubMed2025

The mRNA export pathway licenses viral mimicry response and antitumor immunity by actively exporting nuclear retroelement transcripts.

Nuclear retroelement transcripts (RTs), which can be elicited both transcriptionally and posttranscriptionally, form double-stranded RNA (dsRNA) in cytosol to trigger the viral mimicry response (VMR) and antitumor immunity. However, the strength of the induced VMR varies tremendously across tumor types, and the underlying mechanisms remain poorly understood. Here, we demonstrate that the mRNA export pathway modulates the VMR through actively exporting nuclear RTs for cytosolic dsRNA formation after their induction. Tumor cells hijack this process for immune evasion through aberrant coactivator-associated arginine methyltransferase 1 (CARM1) expression. Mechanistically, we show that the cytoplasmic transportation of RTs by the mRNA export pathway is counteracted by the RNA exosome, which cleaves multiple transcripts within this pathway, including those encoding the essential DExD-box helicase 39A (DDX39A) and the adaptor protein ALYREF. CARM1 enhances the RNA exosome activity to attenuate the nuclear export of RTs by the mRNA export pathway through two synergistic mechanisms: (i) transcriptionally activating several RNA exosome components and (ii) posttranslationally methylating arginine 6 of the RNA exosome subunit EXOSC1, which protects it from proteasome-mediated degradation. Collectively, our study highlights the critical active regulatory role of the mRNA export pathway in transporting nuclear RTs into the cytosol for triggering the VMR and tumor immunity. Furthermore, we propose that enhancing the mRNA export pathway activity, either through CARM1 inhibition or RNA exosome modulation, could reinforce the therapeutic agent-induced VMR, thus holding the promise for overcoming tumor immune evasion and immunotherapy resistance.

Humans↗

PubMed2024

An isoform-resolution transcriptomic atlas of colorectal cancer from long-read single-cell sequencing.

Colorectal cancer (CRC) ranks as the second leading cause of cancer deaths globally. In recent years, short-read single-cell RNA sequencing (scRNA-seq) has been instrumental in deciphering tumor heterogeneities. However, these studies only enable gene-level quantification but neglect alterations in transcript structures arising from alternative end processing or splicing. In this study, we integrated short- and long-read scRNA-seq of CRC samples to build an isoform-resolution CRC transcriptomic atlas. We identified 394 dysregulated transcript structures in tumor epithelial cells, including 299 resulting from various combinations of splicing events. Second, we characterized genes and isoforms associated with epithelial lineages and subpopulations exhibiting distinct prognoses. Among 31,935 isoforms with novel junctions, 330 were supported by The Cancer Genome Atlas RNA-seq and mass spectrometry data. Finally, we built an algorithm that integrated novel peptides derived from open reading frames of recurrent tumor-specific transcripts with mass spectrometry data and identified recurring neoepitopes that may aid the development of cancer vaccines.

Colorectal Neoplasms↗