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Continuous cell division is a hallmark of cancer, and the underlying mechanism is tumor genomics instability. Cell cycle checkpoints are critical for enabling an orderly cell cycle and maintaining genome stability during cell division. Based on their distinct functions in cell cycle control, cell cycle checkpoints are classified into two groups: DNA damage checkpoints and DNA replication stress checkpoints. The DNA damage checkpoints (ATM-CHK2-p53) primarily monitor genetic errors and arrest cell cycle progression to facilitate DNA repair. Unfortunately, genes involved in DNA damage checkpoints are frequently mutated in human malignancies. In contrast, genes associated with DNA replication stress checkpoints (ATR-CHK1-WEE1) are rarely mutated in tumors, and cancer cells are highly dependent on these genes to prevent replication catastrophe and secure genome integrity. At present, poly (ADP-ribose) polymerase inhibitors (PARPi) operate through “synthetic lethality” mechanism with mutant DNA repair pathways genes in cancer cells. However, an increasing number of patients are acquiring PARP inhibitor resistance after prolonged treatment. Recent work suggests that a combination therapy of targeting cell cycle checkpoints and PARPs act synergistically to increase the number of DNA errors, compromise the DNA repair machinery, and disrupt the cell cycle, thereby increasing the death rate of cancer cells with DNA repair deficiency or PARP inhibitor resistance. We highlight a combinational strategy involving PARP inhibitors and inhibition of two major cell cycle checkpoint pathways, ATM-CHK2-TP53 and ATR-CHK1-WEE1. The biological functions, resistance mechanisms against PARP inhibitors, advances in preclinical research, and clinical trials are also reviewed.

Sulfolobus islandicus is a model microorganism in the TACK superphylum of the Archaea, a key lineage in the evolutionary history of cells. Here we report a genome-wide identification of the repertoire of genes essential to S. islandicus growth in culture. We confirm previous targeted gene knockouts, uncover the non-essentiality of functions assumed to be essential to the Sulfolobus cell, including the proteinaceous S-layer, and highlight essential genes whose functions are yet to be determined. Phyletic distributions illustrate the potential transitions that may have occurred during the evolution of this archaeal microorganism, and highlight sets of genes that may have been associated with each transition. We use this comparative context as a lens to focus future research on archaea-specific uncharacterized essential genes that may provide valuable insights into the evolutionary history of cells. Sulfolobus islandicus is a model organism within the TACK superphylum of the Archaea. Here, the authors perform a genome-wide analysis of essential genes in this organism, show that the proteinaceous S-layer is not essential, and explore potential stages of evolution of the essential gene repertoire in Archaea.

As a type of “cold tumor” with limited immune cell infiltration, ovarian cancer has historically shown limited efficacy in immunotherapy. In this study, we report that exosomes from ovarian cancer can specifically target omentum which is the predilection site for ovarian cancer to metastasize and combat subsequently implanted tumor. Furthermore, we found a substantial increase in the proportion of CD3 + T cells, particularly CD8 + T cells, within the omental tissue where exosomes homed. This increase was accompanied by a significant enhancement in granzyme B levels within CD8 + T cells. Additionally, there was a notable elevation in the concentration of interferon-gamma (IFN-γ) in peripheral blood. In vitro results indicated that exosomes could be internalized by dendritic cells (DCs), promote DC differentiation, and subsequently induce the production of granzyme B and IFN-γ in T cells. Surprisingly, we also observed high expression of programmed death ligand 1 (PD-L1) in the omentum. Therefore, we discovered whether combining PD-L1 blockade led to further tumor regression. However, although the combination group showed complete tumor regression, this difference did not reach statistical significance. But in general, we emphasize that in the case of pre-injection, exosomes have great potential to combat the famous “cold tumor”, ovarian cancer, via targeting omentum and activating anti-tumor immunity, offering a novel avenue for overcoming ovarian cancer.

Deciphering the biology of natural microbial communities is limited by the lack of functional data. While transcriptomics enables gene expression profiling, mRNA levels often fail to predict protein abundance, the primary indicator of microbial function. Prior studies addressed this by calculating RNA-to-protein (RTP) conversion factors using conserved protein-to-RNA (ptr) ratios across bacterial strains, but their cross-species and cross-domain utility remained unknown. We generated comprehensive transcriptomic and proteomic data sets from seven bacteria and one archaeon spanning diverse metabolisms and ecological niches. We identified orthologous genes with conserved ptr ratios, enabling the discovery of RTP conversion factors that significantly improved protein prediction from mRNA, even between distant species and domains. This reveals previously unrecognized conservation in ptr ratios across domains and eliminates the need for paired proteomic data in many cases. Our approach offers a broadly applicable framework to enhance functional prediction in microbiomes using only transcriptomic data.

Endoplasmic reticulum (ER) stress is implicated in the pathogenesis of many diseases, including myocardial ischemia/reperfusion injury. We hypothesized that human umbilical cord mesenchymal stromal cells derived extracellular vesicles (HuMSC-EVs) could protect cardiac cells against hyperactive ER stress induced by hypoxia/reoxygenation (H/R) injury. The H/R model was generated using the H9c2 cultured cardiac cell line. HuMSC-EVs were extracted using a commercially available exosome isolation reagent. Levels of apoptosis-related signaling molecules and the degree of ER stress were assessed by western blot. The role of the PI3K/Akt pathway was investigated using signaling inhibitors. Lactate dehydrogenase leakage and 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) analysis were used for evaluating the therapeutic effects of HuMSC-EVs in vitro. The results showed that ER stress and the rate of apoptosis were increased in the context of H/R injury. Treatment with HuMSC-EVs inhibited ER stress and increased survival in H9c2 cells exposed to H/R. Mechanistically, the PI3K/Akt pathway was activated by treatment with HuMSC-EVs after H/R. Inhibition of the PI3K/Akt pathway by a specific inhibitor, LY294002, partially reduced the protective effect of HuMSC-EVs. Our findings suggest that HuMSC-EVs could alleviate ER stress–induced apoptosis during H/R via activation of the PI3K/Akt pathway.

The S-layer is considered to be the sole component of the cell wall in Sulfolobales , a taxonomic group within the Crenarchaeota whose cellular features have been suggested to have a close relationship to the last archaea-eukaryote common ancestor. In this study, we genetically dissect how the two previously characterized S-layer genes as well as a newly identified S-layer-associated protein-encoding gene contribute to the S-layer architecture in Sulfolobus . We provide genetic evidence for the first time showing that the slaA gene is a key cell morphology determinant and may play a role in Sulfolobus cell division or/and cell fusion. Rediscovery of the ancient evolutionary relationship between archaea and eukaryotes has revitalized interest in archaeal cell biology. Key to the understanding of archaeal cells is the surface layer (S-layer), which is commonly found in Archaea but whose in vivo function is unknown. Here, we investigate the architecture and cellular roles of the S-layer in the hyperthermophilic crenarchaeon Sulfolobus islandicus . Electron micrographs of mutant cells lacking slaA or both slaA and slaB confirm the absence of the outermost layer (SlaA), whereas cells with intact or partially or completely detached SlaA are observed for the Δ slaB mutant. We experimentally identify a novel S-layer-associated protein, M164_1049, which does not functionally replace its homolog SlaB but likely assists SlaB to stabilize SlaA. Mutants deficient in the SlaA outer layer form large cell aggregates, and individual cell size varies, increasing significantly up to six times the diameter of wild-type cells. We show that the Δ slaA mutant cells exhibit more sensitivity to hyperosmotic stress but are not reduced to wild-type cell size. The Δ slaA mutant contains aberrant chromosome copy numbers not seen in wild-type cells, in which the cell cycle is tightly regulated. Together, these data suggest that the lack of SlaA results in either cell fusion or irregularities in cell division. Our studies show the key physiological and cellular functions of the S-layer in this archaeal cell. IMPORTANCE The S-layer is considered to be the sole component of the cell wall in Sulfolobales , a taxonomic group within the Crenarchaeota whose cellular features have been suggested to have a close relationship to the last archaea-eukaryote common ancestor. In this study, we genetically dissect how the two previously characterized S-layer genes as well as a newly identified S-layer-associated protein-encoding gene contribute to the S-layer architecture in Sulfolobus . We provide genetic evidence for the first time showing that the slaA gene is a key cell morphology determinant and may play a role in Sulfolobus cell division or/and cell fusion.

Lactylation, a newly identified post‐translational modification, plays a multifaceted role in cancer biology by integrating epigenetic and non‐epigenetic mechanisms. This review summarizes the latest research progress on lactylation, including its functions in epigenetic regulation and its broader impact on cellular processes. Lactate, as a metabolic byproduct, not only serves as an energy source for tumor cells but also acts as a signaling molecule driving various oncogenic processes. Lactylation facilitates cancer metabolic reprogramming, enabling tumor cells to adapt to hypoxic and nutrient‐deprived microenvironments. Moreover, lactylation mediates immune suppression in the tumor microenvironment, promoting immune evasion and therapy resistance. This review further explores the clinical potential of targeting lactylation, offering new avenues for innovation in cancer research and treatment. These findings highlight the pivotal role of lactylation in cancer progression and its significant value as a potential therapeutic target.

Myocardial ischemia-reperfusion injury (MIRI), which occurs when the blood supply is restored in the ischemic myocardium, is a major medical concern for patients with acute myocardial infarction (AMI). Despite the use of extracellular vesicles (EVs) from mesenchymal stromal cells (MSCs), which can be used to treat MIRI, the application of EVs still has limited use in clinical practice. Melatonin (MT), however, not only exerts a significant protective effect in the treatment of cardiovascular diseases but also enhances biological functions of MSCs through pretreatment. Therefore, in the current study, we sought to determine whether MT improves the paracrine effect of MSCs through pretreatment. Our research provides evidence to support the therapeutic effect of MT-pretreated MSCs-derived extracellular vesicles (MT-EVs) in ameliorating hypoxia/reoxygenation (H/R) injury in human umbilical vein endothelial cells (HuVECs). We also performed a metabolomic analysis using ultra-high-performance liquid chromatography/Q Exactive HF-X Hybrid Quadrupole-Orbitrap Mass (UHPLC-QE-MS/MS) to explore metabolism profiling of H/R cell model with MT-EVs or EVs from MSCs (NC-EVs) treatment. We found 932 differential metabolites (DEMs) in the MT-EVs group compared with the NC-EVs group. Metabolic profiling analysis showed these metabolites were engaged in the ABC transporters, nucleotide metabolism, purine metabolic pathway, and glycerophospholipid metabolism. Furthermore, we observed increased levels of palmitoylcarnitine (fatty acid-derived mitochondrial substrate) and gabapentin in the MT-EVs group, which may play a therapeutic role in HuVECs during H/R. In conclusion, the results demonstrated that MT-EVs can protect endothelial cells from H/R injury by affecting the metabolic pathways. Graphical Abstract This study addresses how MT-EVs attenuated H/R injury by affecting metabolic pathways in HuVECs. EVs from MT-preconditioned HuMSCs (MT-EVs) were applied to treat HuVECs during H/R, ultimately increasing cell viability, attenuating cell injury, and reducing apoptosis. UHPLC-QE-MS/MS was used to explore the metabolism profiling of HuVECs treated. MT-EVs affected ABC transporters, purine metabolism, and glycerophospholipid metabolism in HuVECs. In addition, palmitoylcarnitine and gabapentin were upregulated. These may have therapeutic effects on HuVECs during H/R.

The intratumoral microbe-host interaction plays crucial role in the development of cancer. The microbiome can influence cancer development by modulating inflammation, immune responses and metabolic pathways. Therefore, we aim to delineate the landscape and role of intratumoral microbiota in cervical cancer (CC). The presence of bacterial community in CC tissues was confirmed by fluorescence hybridization (FISH). Then 16s rRNA and RNA-Seq were used to characterize the composition of intratumoral microbiota. Combined with cervical squamous cell carcinoma (CESC) data from the Tumor Cancer Genome Atlas (TCGA), the clinical signatures of intratumoral microbiota and DEGs were further analyzed. Finally, the effect of the up-regulated Fibrinogen beta chain (FGB) expressed fragment peptide on the biological behavior of cancer was verified We found the composition heterogeneity of bacteria in CC tumors. was most highly enriched in CC tissues and grouped according to the relative abundance level. The clinical characteristics of patients with relatively high abundance of had the higher levels of fibrinogen and lower levels of white blood cell (WBC) and albumin (ALB) expression. Combining transcriptome data from the two our collective CC and TCGA-CESC cohorts, we found that abundance was significantly associated with fibrinogen beta peptide expression and worse overall survival in CC patients. experiment revealed that could promote the proliferation and migration of cervical cancer cells through overexpression of FGB. We characterized the composition of the intratumoral microbiota in CC tissues and identified the most significantly differentially abundant bacteria between cancerous and non-cancerous tissues. Our findings provide novel insights into the relationship between intratumoral and the tumorigenesis of CC. A deeper understanding of the tumor microenvironment and its associated microbiota may reveal new potential therapeutic targets and improve clinical outcomes.

Background Sinorhizobium meliloti is noted for its exceptional capacity to produce unsaturated fatty acids (UFAs). Earlier studies have indicated that S. meliloti primarily employs the FabA-FabB pathway for UFA synthesis, however, the mechanisms remain elusive. This study was conducted to elucidate these mechanisms responsible for the significant UFA production in S. meliloti . Methods The genes encoding enoyl-acyl carrier protein (ACP) reductase (ENR) were disrupted using the suicide plasmid pK18mobsacB, followed by the creation of single-crossover and double-crossover mutants. The ENR proteins were expressed in Escherichia coli BL21(DE3) strains and subsequently purified. Their enzymatic activities were assessed through gel electrophoresis and NADH oxidation assays. Additionally, the fatty acid composition was determined using gas chromatography-mass spectrometry (GC-MS) and thin-layer chromatography. Results Our findings demonstrate that the heterologous expression of fabI2 in a temperature-sensitive E. coli fabI mutant results in a significant enhancement of UFA production. Genetic analyses confirmed that fabI2 is an indispensable gene in the S. meliloti genome, as it cannot be disrupted. Interestingly, we observed that fabI2 could only be functionally replaced by the Enterococcus faecalis fabI gene and not by the homologous fabI1 from S. meliloti ,  E. coli fabI , or Pseudomonas aeruginosa fabV. Furthermore, we validated that the deletion of fabI1 in S. meliloti triggered an increase in UFA production compared to the wild-type strain Rm1021. Conclusions In this study, we identified the ENR, encoded by the S. meliloti SMc00326 gene ( fabI2 ), as playing a pivotal role in the biosynthesis of UFAs. Additionally, the FabI1 enzyme, encoded by SMc00005, was found to modulate the fatty acid composition within S. meliloti . Together, these discoveries establish a foundation for the development of a model that explains the significant contribution of FabI2 to the robust synthesis of UFAs in S. meliloti .