Single-cell RNA sequencing reveals cadmium-induced cell-type-specific mechanisms of developmental neurotoxicity in human cortical organoids.

Ribosome biogenesis is involved in the progression of hepatocellular carcinoma (HCC), but the specific mechanisms and diagnostic values of ribosome biogenesis-related genes (RBRGs) in HCC remain unclear. We aimed to explore potential therapeutic targets in HCC from RBRGs. The differentially expressed RBRGs (DE-RBRGs) were explored using publicly available bulk RNA-sequencing data. Cox regression analysis was employed to evaluate the prognostic significance of the DE‑RBRGs. The optimal machine learning algorithm was selected to construct a prognostic model. The predictive performance of the model was assessed using Kaplan‑Meier analysis and receiver operating characteristic (ROC) curves. Single‑cell RNA‑sequencing data were subsequently utilized to identify key cell populations and the corresponding DE‑RBRGs. Bioinformatics analyses revealed 88 DE-RBRGs, predominantly enriched in ribosome biogenesis-related functions and pathways. The univariate Cox regression identified 12 DE-RBRGs with prognostic values. Following, the optimal machine learning algorithm (StepCox [forward] + SuperPC) was selected to construct a prognostic model. Survival analysis demonstrated that patients in the low-risk group exhibited markedly prolonged lifespan relative to their high-risk counterparts. ROC curves confirmed the predictive accuracy of this prognostic model in both training and validation cohorts. These 12 DE-RBRGs were significantly associated with immune cell infiltration, tumor immune evasion and drug sensitivity. Analysis of single-cell sequencing data identified hepatocytes as central mediators of HCC pathogenesis, which was associated with high expression of two DE-RBRGs: Nucleophosmin 1 (NPM1) and Ras-Related Nuclear Protein (RAN). NPM1 and RAN, which are highly expressed in hepatocytes, may serve as potential therapeutic targets in HCC. Their established roles in ribosome biogenesis could drive the development of novel therapies targeting this pathway.

Snail1, encoded by SNAI1 gene, is an essential protein that regulates epithelial-mesenchymal transition, which leads to extracellular matrix accumulation and kidney fibrosis, but with unclear cellular and molecular mechanisms. This study compared the cellular proteome of SNAI1-overexpressed renal tubular cells with that of vector-control cells by label-free quantitative proteomics, followed by functional assessments using various assays. A total of 233 proteins showed significant changes in their levels by ectopic SNAI1 expression. Of these, immunoblotting confirmed the decreases in HSP60 and HSP70 and the increase in DDX1. Bioinformatic analyses revealed the top 10 transcription factors as key upstream regulators of the altered cellular proteome, and translational regulation, ribosome, cell cycle regulation, and cellular senescence were primarily associated with these altered proteins. Gene ontology enrichment showed that focal adhesion, the structure where cells maintain their interior-extracellular matrix interactions, was one of the major affected cellular components. Experimental validations demonstrated that SNAI1-overexpressed cells displayed increases in nucleophosmin, nucleolar organizer regions, cell size, granularity, p21, γH2AX, MMP-9 secretion, and paxillin expression, confirming the bioinformatic predictions. This study has broadened our knowledge of Snail1 functions beyond its established role as the epithelial-mesenchymal transition regulator. In addition to alterations in the cellular proteome, ectopic SNAI1 expression induced nucleolar stress, ribosome biogenesis, senescence, and DNA damage response in renal tubular cells. Moreover, Snail1 also affected the dynamics of focal adhesion, which is imperative for cell migration, by regulating paxillin expression. These findings may offer new therapeutic targets related to Snail1-dependent mechanisms for effective management of kidney fibrosis.

Molecular mechanisms controlling kernel development in maize.

Transcriptomic and network analysis reveal methionine sulfoxide reductases dependent regulation of flagellar motility in Salmonella Typhimurium.

How does the cell coordinate its two major activities of cell growth and cell division? To explore this, we have genetically depleted yeast ribosomal protein Rpl32 of the 60S ribosomal subunit, which is an essential protein for cell proliferation. After 3-4 h of Rpl32 depletion, the cell cycle arrests at G1. We have undertaken a kinetic analysis of the early cellular events to deduce the pathway from Rpl32 depletion to G1 arrest. Rpl32 depletion blocks pre-rRNA processing of the initial 35S pre-rRNA, thus preventing ribosomal biogenesis and nuclear export of 60S ribosomal subunits. Interestingly, the Rpl25-GFP reporter transiently accumulates in a focal spot that resembles the nucleolar body/Cajal body. Amazingly, the inhibition of ribosome biogenesis in the nucleus is signalled to the cytoplasm, where mature 18S and 25S rRNAs are degraded in a ribophagy-independent manner; Rpl32 protease-degradation uses de-ubiquitination. Nonetheless, the ribosomes that remain after degradation are sufficient for translation, whose efficiency is unchanged through 6 h after Rpl32 depletion, and the cell size and vacuole increase in size. The level of cyclin 1 mRNA is rapidly diminished after Rpl32 depletion and is a likely factor for the arrest of the cell cycle at G1.

Insights from molecular dynamics and metadynamics simulations into nucleotide-regulated and species-specific conformational dynamics of Era GTPase.

Photodynamic therapy (PDT) is a minimally invasive cancer treatment modality with high spatial selectivity, whose therapeutic efficacy is largely governed by the photosensitizer's tissue penetration, singlet oxygen generation, and target specificity. In recent years, RNA has emerged as an attractive alternative target for PDT owing to its distinctive structural and biological features. In many cancers, ribosome biogenesis and nucleolar activity are markedly upregulated, leading to the accumulation of RNA species that are structurally exposed, highly abundant, and intrinsically susceptible to oxidative damage, thereby rendering RNA an efficient and accessible photodynamic target. RNA-targeted PDT enables selective photodamage without inducing permanent genomic lesions, reducing mutagenic risk while allowing light-triggered RNA degradation and precise spatiotemporal control of protein translation and cellular function. Moreover, unlike DNA damage, which can be partially repaired, oxidatively damaged RNA is typically eliminated through degradation rather than repair, enabling RNA-targeted PDT to circumvent repair-mediated resistance and achieve sustained cytotoxic effects. This Review summarizes recent advances in the molecular design of RNA-targeted photosensitizers, highlights their photophysical and biological mechanisms of action, and discusses the challenges and future opportunities for translating RNA-targeted PDT into clinical cancer therapy. • Recent advances in small-molecule RNA-targeted photosensitizers for photodynamic cancer therapy. • Structural design, binding mode, and photophysical properties of RNA-targeted photosensitizers. • RNA as a promising molecular target for precise PDT. • Advantages and mechanisms of RNA-targeted PDT strategies.

Transcriptomic regulatory mechanisms of Zostera caespitosa under different temperatures.

Skeletal muscle repair requires coordinated regulation of inflammation and protein synthesis, but the roles of ribosome biogenesis and protein composition remain poorly defined. To address this, mice underwent femoral artery ligation (FAL) to induce muscle regeneration over 28 days. In humans, tibialis anterior biopsies from patients with traumatic tibial fracture were subjected to RNA sequencing. Following FAL, c-Myc mRNA increased transiently, followed by increased ribosomal DNA transcription, leading to elevated total RNA levels. Skeletal muscle-specific ribosomal protein paralog RPL3L was replaced by the ubiquitously expressed RPL3 during the initial phases of recovery, but this shift was reversed by day 28. A substantial transcriptomic response was observed in human muscle injury, with heavy emphasis on MYC-induced anabolism and inflammation. This supports a model in which MYC-driven changes in ribosomal content and composition form a core anabolic module in skeletal muscle repair, potentially representing a targetable axis to enhance recovery after muscle injury.NEW & NOTEWORTHY Our findings establish ribosome biogenesis and ribosome remodeling as core components of the skeletal muscle regenerative program conserved across species. The rapid, MYC-driven induction of translational capacity, coupled with a transient switch in ribosomal protein composition, increases ribosome heterogeneity during skeletal muscle regeneration.

Venlafaxine reverses chemotherapy-induced alopecia through epithelial and dermal reprogramming at single-cell resolution.

RNA helicases are a large family of enzymes crucial for virtually all aspects of RNA metabolism, forming the backbone of gene expression regulation. Among them, DEAH-box helicase 33 (DHX33) has emerged as a pivotal player in fundamental cellular processes, including ribosomal biogenesis, transcription, and translation initiation. A compelling body of evidence now positions DHX33 as a significant oncoprotein, with its overexpression documented in a wide spectrum of human cancers such as lung carcinoma, hepatocellular carcinoma, glioblastoma, and acute myeloid leukemia. Its oncogenic drive is mediated through the transcriptional regulation of genes governing the cell cycle and apoptosis, its interplay with major signaling pathways like Wnt/β-catenin and PI3K/Akt/mTOR, and its role in metabolic reprogramming, notably the Warburg effect. Furthermore, DHX33 acts as a key downstream effector of potent oncogenes like c-Myc. Genetic or pharmacological inhibition of DHX33 consistently impedes tumor growth, underscoring its non-redundant role in oncogenesis. This review systematically synthesizes the current understanding of the mechanisms by which DHX33 promotes tumorigenesis. It delves into its regulation of core cellular processes, its integration into oncogenic signaling networks, and its recently discovered functions in epigenetic and metabolic reprogramming. By consolidating this knowledge, we aim to highlight the multifaceted nature of DHX33 in cancer biology and firmly establish its potential as a viable and promising therapeutic target for future anticancer strategies.

Botrytis cinerea is one of the most destructive pathogens that cause serious damage to fruits and vegetables. The effective management of B. cinerea thus requires the continuous development of new fungicides with novel structures or distinct modes of action. This study on nitropyridine chemistry led to the discovery of 6Bc-5 (HNPC-A0073). 6Bc-5 exhibits excellent fungicidal potency against B. cinerea (EC50 = 0.47 mg/L), superior to or comparable to the commercial products, such as procymidone, boscalid, and fluopyram. Notably, 6Bc-5 probably operates through a distinct fungicidal mechanism that does not affect energy metabolism but instead potently suppresses the ribosome biogenesis pathway of pathogenic fungi. This mechanism also allows 6Bc-5 to demonstrate a low toxicity to mammals, bees, and birds.

A simple oral STZ/alloxan-induced diabetic zebrafish model for chronic wound healing and therapeutic assessment.

8-Me-PIQ Expands Cord Blood CD34+ Hematopoietic Stem and Progenitor Cells via Metabolic Suppression and Inhibition of Ribosome Biogenesis.

Functional and protein interaction analysis of Nop7 in trypanosomatid parasites.

The nucleolus is essential for ribosome biogenesis and cellular homeostasis, and its dysfunction can induce nucleolar stress, a process implicated in cancer and other diseases. However, nucleolar stress is commonly inferred from morphological changes or a limited set of functional assays, and quantitative approaches based on gene expression profiles remain lacking. Here, we integrate literature curation with multi-dataset screening to define a nucleolar stress gene signature and develop a nucleolar stress score (NuS) applicable to bulk transcriptomics, single-cell transcriptomics, proteomics, and spatial transcriptomics. Using this framework, we show in colorectal cancer models that oxaliplatin induces nucleolar stress, suppresses nascent rRNA synthesis, and activates p53 signaling, whereas these responses are attenuated in oxaliplatin-resistant cells. Combined with a ribosome biogenesis activity score (RiboSis), NuS captures related but distinct dimensions of nucleolar function and stratifies tumors into functional states associated with clinical outcomes. NuS-based analysis of perturbational transcriptomes further prioritizes compounds with putative nucleolar stress-inducing activity. Collectively, this study provides a quantitative framework for evaluating nucleolar stress and illustrates its applications in disease stratification and drug mechanism discovery.

The RNA exosome is an essential and ubiquitous RNase with exonucleolytic activity that is involved in ribosome biogenesis and RNA quality control in eukaryotes. It is present both in the nucleus and cytoplasm and interacts with specific cofactors in each cell compartment, which are essential for the recruitment and activity control of the exosome. Post-translational modifications are known to regulate enzyme activity and protein interaction, although their precise roles are individually specific. In this study, we investigated the phosphorylation status of proteins associated with the nuclear (Rrp6) and core (Rrp46) subunits of the RNA exosome in Saccharomyces cerevisiae. Using coimmunoprecipitation followed by phosphopeptide enrichment and high-resolution mass spectrometry, we identified 114 phosphorylation sites on proteins functionally related to rRNA processing. Differential phosphorylation patterns between Rrp6 and Rrp46 coimmunoprecipitations are consistent with distinct exosome assemblies and suggest potential regulatory roles for phosphorylation. Several phosphosites were identified in exosome subunits and cofactors, revealing potential regulatory mechanisms for fine-tuning exosome function. The results shown here highlight the role of phosphorylation in the recruitment and control of the exosome in RNA processing and degradation, offering new insights into the post-transcriptional control of gene expression.

Cell-cell fusion, essential for diverse physiological events, requires high ATP levels. While mitochondrial activity increases in fusing cells, the mechanism driving mitochondrial ribosome (mitoribosome) biogenesis to support these energy demands remains unclear. Here, we identify angiogenin (ANG) as a mitochondrial tRNA (mt-tRNA) processing enzyme critical for mitoribosome biogenesis during myoblast and osteoclast fusion. Upon fusion initiation, ANG translocates to mitochondria, promoting mitoribosome biogenesis to support translation of respiratory complex proteins for ATP production. Using transcriptome-wide PARE and 5' RACE analyses, we show that ANG cleaves the tRNA 3'-end in mitochondrial pre-RNA transcripts bordering rRNAs and mRNAs, enabling their release for translation. Loss of ANG or disruption of its ribonucleolytic activity impairs osteoclast and myoblast fusion, disrupting bone and muscle homeostasis and skeletal muscle regeneration post-injury. Our findings establish ANG as an essential mitoribosome biogenesis regulator and highlight a novel mechanism of mitochondria energy regulation in high-energy-demand biological processes.

Huntington's Disease (HD), a neurodegenerative disorder, is caused by the expansion of a polyglutamine (polyQ) tract near the N-terminus of the huntingtin protein (HTT), resulting in HTT aggregation. While associated with neurodegeneration, HTT is expressed ubiquitously throughout the body, leading to potential peripheral consequences of aggregation. However, the impact on peripheral tissues remains poorly understood in comparison to the central nervous system. Here, a Caenorhabditis elegans (C. elegans) HD model that expresses an N-terminal HTT fragment (nonpathogenic 15Q or pathogenic 128Q) in body-wall muscle cells was used to evaluate proteome remodeling. Four conditions (15Q and 128Q on days 2 and 7 of adult worms, denoted as 15D2, 15D7, 128D2, and 128D7) were evaluated. In comparison to 15D2, 128D2 worms displayed decreased expression of ribosomal proteins and cytoskeletal components such as actin, profilin, calponin, and myosin, as well as overexpression of galectin, a stress- and inflammation-associated protein. By day 7, the 15D7 animals exhibited developmental signatures related to ribosome biogenesis, signal transduction, and vesicle trafficking, whereas abundance levels of proteins associated with stress response pathways such as proteostasis, protein folding, and cytoskeletal remodeling were observed to be increased in the 128D7 worms. These findings demonstrate the stage-dependent, nonlinear nature of HD-associated proteome disruption associated with peripheral expression of HD.