Science China Life Sciences最新文献

Despite advancements in CAR-T therapy, over half of the lymphoma patients still face drug resistance or relapse. Seventy-nine Chinese patients with B-cell lymphoma provided 192 serum samples for circulating tumor DNA (ctDNA) detection to identify the genomic features linked to prognosis during CAR-T cell therapy. Patients in complete remission and noncomplete remission groups were analyzed, and those with >10 ctDNA gene mutations before CAR-T cell therapy had significantly worse overall survival and progression-free survival rates than those with fewer mutations. MYD88, FAT1, and BTG2 mutations were correlated with poorer OS, whereas MUC16 mutations were correlated with better OS. Patients with TP53 mutation pretreatment had significantly lower CR rates than those without TP53 mutations (33.3% vs. 68.1%, P=0.02). However, TP53 mutation pretreatment did not affect long-term patient survival. All patients with TP53 mutations 4 weeks after CAR-T cell therapy failed to achieve CR, with poorer OS (1-year OS rate: 37.5% vs. 66.4%; 2-year OS rate: 12.5% vs. 56.3%, P=0.0023). Among patients with CR, those with BCR mutations at 4 weeks post-treatment exhibited poorer OS (2-year OS rate: 40.9% vs. 76.1%, P=0.035). One week after CAR-T cell therapy, patients without CDKN2A, CBLB, APC, SPEN, KMT2D, CARD11, FOXO1, or PDGFRB mutations were more likely to achieve CR (76.6% vs. 28.6%, P<0.001) and had better OS (1-year OS rate: 81.5% vs. 38.9%, 2-year OS rate: 62.2% vs. 5%, P<0.001) and PFS (1-year PFS rate: 67.2% vs. 0%, P<0.001). This study evaluated the genomic features and screened a gene set to predict CAR-T cell therapy efficacy in B-cell lymphoma, aiding clinicians in accurately evaluating efficacy and treatment decision-making.

Colorectal cancer (CRC) is a prevalent malignancy characterized by rising incidence and mortality rates worldwide. The involvement of RNA pseudouridine synthase enzymes in CRC development is well-documented, yet the transcriptomic profile of pseudouridine (Ψ) in CRC remains largely unexplored. This study explored the transcriptomic landscape of Ψ in CRC by analyzing 21 biopsies and their corresponding adjacent healthy tissues, along with blood samples from 10 patients using PRAISE, a quantitative pseudouridine sequencing technology at base resolution. Our findings revealed significant differences in Ψ distribution and levels between CRC samples and adjacent normal tissues, correlating with the expression levels of DKC1, PUS7L, and PUS10. Notably, distinct Ψ levels of snoRNAs could serve as potential tumor biomarkers. Furthermore, we assessed the clinical utility of Ψ in both tumor and blood samples. Differentiated Ψ levels showed promising correlations with clinical markers such as cancer antigen 125, cancer antigen 153, and cancer antigen 199 in tumors, whereas Ψ sites in blood revealed enhanced correlations with routine blood indicators like white blood cells (WBCs) and alpha-fetoprotein (AFP). These findings underscore the significant role of RNA Ψ in CRC, providing valuable insights into its potential applications for clinical diagnosis and treatment.

Lignin, an energy-rich and adaptable polymer comprising phenylpropanoid monomers utilized by plants for structural reinforcement, water conveyance, and defense mechanisms, ranks as the planet's second most prevalent biopolymer, after cellulose. Despite its prevalence, lignin is frequently underused in the process of converting biomass into fuels and chemicals. Instead, it is commonly incinerated for industrial heat due to its intricate composition and resistance to decomposition, presenting obstacles for targeted valorization. In contrast to chemical catalysts, biological enzymes show promise not only in selectively converting lignin components but also in seamlessly integrating into cellular structures, offering biocatalysis as a potentially efficient pathway for lignin enhancement. This review comprehensively summarizes cutting-edge biostrategies, ligninolytic enzymes, metabolic pathways, and lignin-degrading strains or consortia involved in lignin degradation, while critically evaluating the underlying mechanisms. Metabolic and genetic engineering play crucial roles in redirecting lignin and its derivatives towards metabolic pathways like the tricarboxylic acid cycle, opening up novel avenues for its valorization. Recent advancements in lignin valorization are scrutinized, highlighting key challenges and promising solutions. Furthermore, the review underscores the importance of innovative approaches, such as leveraging digital systems and synthetic biology, to unlock the commercial potential of lignin-derived raw materials as sustainable feedstocks. Artificial intelligence-driven technologies offer promise in overcoming current challenges and driving widespread adoption of lignin valorization, presenting an alternative to sugar-based feedstocks for bio-based manufacturing in the future. The utilization of available lignin residue for synthesis of high-value chemicals or energy, even alternative food, addresses various crises looming in the food-energy-water nexus.

Ruminant livestock provide a rich source of products, such as meat, milk, and wool, and play a critical role in global food security and nutrition. Over the past few decades, genomic studies of ruminant livestock have provided valuable insights into their domestication and the genetic basis of economically important traits, facilitating the breeding of elite varieties. In this review, we summarize the main advancements for domestic ruminants in reference genome assemblies, population genomics, and the identification of functional genes or variants for phenotypic traits. These traits include meat and carcass quality, reproduction, milk production, feed efficiency, wool and cashmere yield, horn development, tail type, coat color, environmental adaptation, and disease resistance. Functional genomic research is entering a new era with the advancements of graphical pangenomics and telomere-to-telomere (T2T) gap-free genome assembly. These advancements promise to improve our understanding of domestication and the molecular mechanisms underlying economically important traits in ruminant livestock. Finally, we provide new perspectives and future directions for genomic research on ruminant genomes. We suggest how ever-increasing multiomics datasets will facilitate future studies and molecular breeding in livestock, including the potential to uncover novel genetic mechanisms underlying phenotypic traits, to enable more accurate genomic prediction models, and to accelerate genetic improvement programs.

Although disturbances in the gut microbiome have been implicated in multiple sclerosis (MS), little is known about the changes and interactions between the gut microbiome and blood metabolome, and how these changes affect disease-modifying therapy (DMT) in preventing the progression of MS. In this study, the structure and composition of the gut microbiota were evaluated using 16S rRNA gene sequencing and an untargeted metabolomics approach was used to compare the serum metabolite profiles from patients with relapsing-remitting MS (RRMS) and healthy controls (HCs). Results indicated that RRMS was characterized by phase-dependent α-phylogenetic diversity and significant disturbances in serum glycerophospholipid metabolism. Notably, α-phylogenetic diversity was significantly decreased in RRMS patients during the chronic phase (CMS) compared with those in the acute phase (AMS). A distinctive combination of two elevated genera (Slackia, Lactobacillus) and five glycerophospholipid metabolism-associated metabolites (four increased: GPCho(22:5/20:3), PC(18:2(9Z,12Z)/16:0), PE(16:0/18:2(9Z,12Z)), PE(18:1(11Z)/18:2(9Z,12Z)); one decreased: PS(15:0/22:1(13Z))) in RRMS patients when comparing to HCs. Moreover, a biomarker panel consisting of four microbial genera (three decreased: Lysinibacillus, Parabacteroides, UBA1819; one increased: Lachnoanaerobaculum) and two glycerophospholipid metabolism-associated metabolites (one increased: PE(P-16:0/22:6); one decreased: CL(i-12:0/i-16:0/i-17:0/i-12:0)) effectively discriminated CMS patients from AMS patients, which indicate correlation with higher disability. Additionally, DMTs appeared to attenuate MS progression by reducing UBA1819 and upregulating CL(i-12:0/i-16:0/i-17:0/i-12:0). These findings expand our understanding of the microbiome and metabolome roles in RRMS and may contribute to identifying novel diagnostic biomarkers and promising therapeutic targets.

China, with its large geographic span, possesses rich genetic diversity across vast frontier regions in addition to the Han Chinese majority. Importantly, demographic events and various natural and cultural environments in Chinese frontier regions have shaped the genomic diversity of ethnic minorities via local adaptations. Thus, insights into the genetic diversity and adaptive evolution of these under-represented ethnic groups are crucial for understanding evolutionary scenarios and biomedical implications in East Asian populations. Here, we focus on ethnic minorities in Chinese frontier regions and review research advances regarding genomic diversity, genetic structure, population history, genetic admixture, and local adaptation. We first provide an overview of the extensive genetic diversity across populations in different Chinese frontier regions. Next, we summarize research progress regarding genetic ancestry, demographic history, the adaptive process, and the archaic identification of multiple ethnic minorities in different Chinese frontier regions. Finally, we discuss the gaps and opportunities in genomic studies of Chinese populations and the need for a more comprehensive understanding of genomic diversity and the evolution of populations of East Asian ancestry in the post-genomic era.

Despite considerable research underscoring the importance of carbohydrate intake in relation to the risk of type 2 diabetes (T2D), a comprehensive assessment of this relationship is currently lacking. We aimed to examine the associations of various types and food sources of dietary carbohydrate intake with the risk of T2D, to evaluate potential effect modification by other factors, including genetic susceptibility, and to explore the potential mediators for such associations. The present study included 161,872 participants of the UK Biobank who were free of prevalent cancer, cardiovascular disease, or diabetes, and had at least one validated 24-h dietary recall assessment. Multivariable-adjusted age-stratified Cox proportional hazard regression models were applied to estimate hazard ratios (HRs) and 95% confidence intervals (CI) for the associations of various types and food sources of dietary carbohydrate intake with risk of T2D. During a median follow-up of 13.6 years, 4,176 incident cases of T2D were identified. In the multivariable-adjusted models, a greater intake of fiber, carbohydrates from whole grains, and carbohydrates from non-starchy vegetables was significantly associated with a lower risk of T2D (highest vs. lowest quantile, HR [95% CI]=0.70 [0.62-0.79], 0.74 [0.67-0.82], and 0.83 [0.75-0.92], respectively, all P for trend <0.005). In contrast, a higher intake of starch and carbohydrate from starchy vegetables was associated with an increased risk of T2D (highest vs. lowest quantile, HR [95% CI]=1.31 [1.16-1.48] and 1.19 [1.09-1.31], respectively, both P for trend <0.005). Replacing one serving of refined grains or starchy vegetables with an equal amount of whole grains or non-starchy vegetables was associated with 4% to 10% lower risk of T2D (all P values <0.001). The observed associations were generally similar across population subgroups, including individuals with different genetic susceptibility to T2D. Mediation analyses of the inverse association between T2D risk and isocaloric substitution of carbohydrates from refined grains with carbohydrate from whole grains demonstrated that 39.6%, 43.4%, 44.0%, 27.8%, and 34.9% were mediated through body mass index, waist-to-hip ratio, glycosylated hemoglobin, high-density lipoprotein cholesterol, and C-reactive protein, respectively. In addition, the inverse association between the isocaloric substitution of carbohydrates from starchy vegetables with carbohydrates from non-starchy vegetables and T2D was partially mediated through high-density lipoprotein cholesterol (15.9%). These findings underscore the importance of dietary modifications of carbohydrates, particularly considering types and food sources of carbohydrate intake, in the primary prevention of T2D.

Innate immunity serves as a crucial defense mechanism against invading pathogens, yet its negative regulatory network remains under explored. In this study, we identify BEN domain-containing protein 6 (BEND6) as a novel negative regulator of innate immunity through a genome-scale CRISPR knockout screen for host factors essential for viral replication. We show that BEND6 exhibits characteristics of an interferon-stimulated gene (ISG), with its mRNA and protein levels upregulated by RNA virus-induced IFN-β. BEND6 targets IRF3 and inhibits its recruitment by TBK1, thus preventing IRF3 phosphorylation and dimerization. Additionally, BEND6 directly binds to ISRE, thereby hindering the DNA binding activity of IRF3 and blocking the subsequent activation of IFN-β transcription. Taken together, our study reveals the mechanism of BEND6 in promoting the replication of various RNA viruses and provides a potential therapeutic target for RNA virus infection.