KAT8-catalyzed lactylation promotes eEF1A2-mediated protein synthesis and colorectal carcinogenesis.

Aberrant lysine lactylation (Kla) is associated with various diseases which are caused by excessive glycolysis metabolism. However, the regulatory molecules and downstream protein targets of Kla remain largely unclear. Here, we observed a global Kla abundance profile in colorectal cancer (CRC) that negatively correlates with prognosis. Among lactylated proteins detected in CRC, lactylation of eEF1A2K408 resulted in boosted translation elongation and enhanced protein synthesis which contributed to tumorigenesis. By screening eEF1A2 interacting proteins, we identified that KAT8, a lysine acetyltransferase that acted as a pan-Kla writer, was responsible for installing Kla on many protein substrates involving in diverse biological processes. Deletion of KAT8 inhibited CRC tumor growth, especially in a high-lactic tumor microenvironment. Therefore, the KAT8-eEF1A2 Kla axis is utilized to meet increased translational requirements for oncogenic adaptation. As a lactyltransferase, KAT8 may represent a potential therapeutic target for CRC.

Dendritic Cells but Not Macrophages Sense Tumor Mitochondrial DNA for Cross-priming through Signal Regulatory Protein α Signaling.

Inhibition of cytosolic DNA sensing represents a strategy that tumor cells use for immune evasion, but the underlying mechanisms are unclear. Here we have shown that CD47-signal regulatory protein α (SIRPα) axis dictates the fate of ingested DNA in DCs for immune evasion. Although macrophages were more potent in uptaking tumor DNA, increase of DNA sensing by blocking the interaction of SIRPα with CD47 preferentially occurred in dendritic cells (DCs) but not in macrophages. Mechanistically, CD47 blockade enabled the activation of NADPH oxidase NOX2 in DCs, which in turn inhibited phagosomal acidification and reduced the degradation of tumor mitochondrial DNA (mtDNA) in DCs. mtDNA was recognized by cyclic-GMP-AMP synthase (cGAS) in the DC cytosol, contributing to type I interferon (IFN) production and antitumor adaptive immunity. Thus, our findings have demonstrated how tumor cells inhibit innate sensing in DCs and suggested that the CD47-SIRPα axis is critical for DC-driven antitumor immunity.

Transcriptomic divergence of the Rheum palmatum complex derived from top-geoherb and non-geoherb areas provides the insights into geoherbalism properties of rhubarb.

Geoherb usually represents high-quality medicinal herbs with better clinical therapeutic effects, and elucidating the geoherbalism is essential for the quality improvement of traditional Chinese Medicine. However, few researches were conducted to clarify the geoherbalism based on a large scale of transcriptomics. In the present study, we compared the transcriptomes of Rheum palmatum complex derived from top-geoherb and non-geoherb areas to show the geoherbalism properties of rhubarb. A total of 412.32 Gb clean reads were obtained with unigene numbers of 100,615 after assembly. Based on the obtained transcriptome datasets, key enzyme-encoding genes involved in the anthraquinones biosynthesis were also obtained. We also found that 21 anthraquinone-related unigenes were differentially expressed between two different groups, and some of these DEGs were correlated to the content accumulation of five free anthraquinones, indicating that the gene expression profiles may promote the geoherbalism formation of rhubarb. In addition, the selective pressure analyses indicated that most paired orthologous genes between these two groups were subject to negative selection, and only a low proportion of orthologs under positive selection were detected. Functional annotation analyses indicated that these positive-selected genes related to the functions such as gene expression, substance transport, stress response and metabolism, indicating that discrepant environment also enhanced the formation of geoherbalism. Our study not only provided insights for the genetic mechanism of geoherbalism of rhubarb, but also laid more genetic cues for the future rhubarb germplasms improvement and utilization.

A chromosome-level genome reveals genome evolution and molecular basis of anthraquinone biosynthesis in Rheum palmatum.

BACKGROUND: Rhubarb is one of common traditional Chinese medicine with a diverse array of therapeutic efficacies. Despite its widespread use, molecular research into rhubarb remains limited, constraining our comprehension of the geoherbalism. RESULTS: We assembled the genome of Rheum palmatum L., one of the source plants of rhubarb, to elucidate its genome evolution and unpack the biosynthetic pathways of its bioactive compounds using a combination of PacBio HiFi, Oxford Nanopore, Illumina, and Hi-C scaffolding approaches. Around 2.8 Gb genome was obtained after assembly with more than 99.9% sequences anchored to 11 pseudochromosomes (scaffold N50 = 259.19 Mb). Transposable elements (TE) with a continuous expansion of long terminal repeat retrotransposons (LTRs) is predominant in genome size, contributing to the genome expansion of R. palmatum. Totally 30,480 genes were predicted to be protein-coding genes with 473 significantly expanded gene families enriched in diverse pathways associated with high-altitude adaptation for this species. Two successive rounds of whole genome duplication event (WGD) shared by Fagopyrum tataricum and R. palmatum were confirmed. We also identified 54 genes involved in anthraquinone biosynthesis and other 97 genes entangled in flavonoid biosynthesis. Notably, RpALS emerged as a compelling candidate gene for the octaketide biosynthesis after the key residual screening. CONCLUSION: Overall, our findings offer not only an enhanced understanding of this remarkable medicinal plant but also pave the way for future innovations in its genetic breeding, molecular design, and functional genomic studies.

Undergoing Lung Surgery (PSA-Lung) was appropriate for symptom assessment after discharge.

PURPOSE: To examine whether a 7-day or 24-h recall period of Perioperative Symptom Assessment for Patients Undergoing Lung Surgery (PSA-Lung) was appropriate for symptom assessment after discharge. METHODS: A total of 377 patients were recruited in a cohort study of patients who underwent lung surgery. We measured patient symptoms daily and weekly using the two recall period versions of the PSA-Lung scale, respectively. The psychometric properties of both versions were calculated. Spearman rank correlation coefficients and kappa (k) coefficients were used to measure the association between items score measured by the two version scales each week. Cohen's d effect size and mixed linear model were used to measure responsiveness to change over time. RESULTS: Spearman rank correlation coefficients between the symptom scores generated by the 7-day and 24-h versions (range 0.48-0.77; all P < 0.05). The correlations increased in patients in stable condition (weekly symptom change < 2). Cronbach's α coefficients for both ratings were > 0.87 and both had good test-retest reliability. The longitudinal analysis and Cohen's d effect sizes showed that both ratings had good ability to detect changes in all items. CONCLUSION: The 7-day retrospective scale was as effective as the 24-h retrospective scale in terms of psychometric performance. In the stage where the patient's symptoms change rapidly, it is recommended to use the 24-h retrospective scale for symptom monitoring. On the contrary, in a stable state, it can be considered to use the 7-day retrospective scale for monitoring to reduce the patient's burden.

Incoherent ultrafast energy transfer in phycocyanin 620 from Thermosynechococcus vulcanus revealed by polarization-controlled two dimensional electronic spectroscopy.

Phycocyanin 620 (PC620) is the outermost light-harvesting complex in phycobilisome of cyanobacteria, engaged in light collection and energy transfer to the core antenna, allophycocyanin. Recently, long-lived exciton-vibrational coherences have been observed in allophycocyanin, accounting for the coherent energy transfer [Zhu et al., Nat. Commun. 15, 3171 (2024)]. PC620 has a nearly identical spatial location of three α84-ß84 phycocyanobilin pigment pairs to those in allophycocyanin, inferring an existence of possible coherent energy transfer pathways. However, whether PC620 undergoes coherent or incoherent energy transfer remains debated. Furthermore, accurate determination of energy transfer rates in PC620 is still necessary owing to the spectral overlap and broadening in conventional time-resolved spectroscopic measurements. In this work, the energy transfer process within PC620 was directly resolved by polarization-controlled two dimensional electronic spectroscopy (2DES) and global analysis. The results show that the energy transfer from α84 to the adjacent ß84 has a lifetime constant of 400 fs, from ß155 to ß84 of 6-8 ps, and from ß155 to α84 of 66 ps, fully conforming to the Förster resonance energy transfer mechanism. The circular dichroism spectrum also reveals that the α84-ß84 pigment pair does not form excitonic dimer, and the observed oscillatory signals are confirmed to be vibrational coherence, excluding the exciton-vibrational coupling. Nodal line slope analysis of 2DES further reveals that all the vibrational modes participate in the energy dissipation of the excited states. Our results consolidate that the ultrafast energy transfer process in PC620 is incoherent, where the twisted conformation of α84 is suggested as the main cause for preventing the formation of α84-ß84 excitonic dimer in contrast to allophycocyanin.

Longitudinal patterns of patient-reported sleep disturbances after surgery for lung cancer.

PURPOSE: The purpose of this study was to identify longitudinal heterogeneous trajectories of sleep status, adjusted for the effect of pain over time, among patients who had surgery for lung cancer and to quantify how disturbed sleep in the hospital affects functional recovery after discharge. METHODS: We included patients from a surgical cohort (CN-PRO-Lung 1). All patients reported symptoms using the MD Anderson Symptom Inventory-Lung Cancer (MDASI-LC) daily during postoperative hospitalization. Group-based dual trajectory modeling was used to investigate trajectories of disturbed sleep and pain during the first 7 days of postoperative hospitalization. Cox regression was used to compare the recovery of walking ability between the different sleep trajectories. RESULTS: Among 421 patients, disturbed sleep trajectories comprised low (31%), moderate (52%), and high (17%) groups. The surgical approach and number of chest tubes were associated with pain, and the number of chest tubes was also associated with sleep disturbances (OR = 1.99; 95% CI: 1.08-3.67). Recovery of walking ability after discharge was significantly slower in the high (median days = 16; 95% CI: 5-NA) and moderate disturbed sleep trajectory groups (median days = 5; 95%CI: 4-6) than in the low group (median days = 3; 95% CI: 3-4). CONCLUSION: Changes in disturbed sleep among patients with lung cancer followed three distinct trajectories over the first 7 days of hospitalization after surgery. Dual trajectory analyses highlighted the high concordance between specific trajectories of disturbed sleep and pain. Patients at high sleep disturbance and high levels of pain may benefit from appropriate interventions for both symptoms in combination with the patient's surgical approach and the number of chest tubes.

The panda-derived Lactiplantibacillus plantarum BSG201683 improves LPS-induced intestinal inflammation and epithelial barrier disruption in vitro.

Captive pandas are suffering from intestinal infection due to intestinal microbiota characterized by a high abundance of Enterobacteriaceae induced by long-term captivity. Probiotic supplements showed improvement in intestinal barrier function and inflammation. However, the effects of panda-derived probiotics on the intestinal epithelium and inflammation have not been elucidated. In the present study, lipopolysaccharide (LPS) impaired Caco-2 and RAW264.7 inflammatory models were applied to assess the protection of Lactiplantibacillus plantarum BSG201683 (L. plantarum G83) on barrier disruption and inflammation. The results showed that treatment with L. plantarum G83 significantly decreased the paracellular permeability to fluorescein isothiocyanate conjugated dextran (MW 4000, FITC-D4) after LPS induction. Meanwhile, L. plantarum G83 alleviated the reduction in tight junction (TJ) proteins and downregulated proinflammatory cytokines caused by LPS in Caco-2 cells. L. plantarum G83 also significantly decreased the expression and secretion of pro-inflammatory cytokines in LPS-induced RAW264.7 cells. In addition, the IL-10 increased in both Caco-2 and RAW264.7 cells after L. plantarum G83 treatment. The phagocytosis activity of RAW264.7 cells was significantly increased after L. plantarum G83 treatment. Toll-like receptor 4/ nuclear factor kappa-B (TLR4/NF-κB) signaling pathways were significantly down-regulated after L. plantarum G83 intervention, and the phosphorylation of NF-κB/p65 was consistent with this result. Our findings suggest that L. plantarum G83 improves intestinal inflammation and epithelial barrier disruption in vitro.

Physiological ß-amyloid clearance by the liver and its therapeutic potential for Alzheimer's disease.

Cerebral amyloid-ß (Aß) accumulation due to impaired Aß clearance is a pivotal event in the pathogenesis of Alzheimer's disease (AD). Considerable brain-derived Aß is cleared via transporting to the periphery. The liver is the largest organ responsible for the clearance of metabolites in the periphery. Whether the liver physiologically clears circulating Aß and its therapeutic potential for AD remains unclear. Here, we found that about 13.9% of Aß42 and 8.9% of Aß40 were removed from the blood when flowing through the liver, and this capacity was decreased with Aß receptor LRP-1 expression down-regulated in hepatocytes in the aged animals. Partial blockage of hepatic blood flow increased Aß levels in both blood and brain interstitial fluid. The chronic decline in hepatic Aß clearance via LRP-1 knockdown specific in hepatocytes aggravated cerebral Aß burden and cognitive deficits, while enhancing hepatic Aß clearance via LRP-1 overexpression attenuated cerebral Aß deposition and cognitive impairments in APP/PS1 mice. Our findings demonstrate that the liver physiologically clears blood Aß and regulates brain Aß levels, suggesting that a decline of hepatic Aß clearance during aging could be involved in AD development, and hepatic Aß clearance is a novel therapeutic approach for AD.

Stokes shift spectroscopy and machine learning for label-free human prostate cancer detection.

The Stokes shift spectra (S3) of human cancerous and normal prostate tissues were collected label free at a selected wavelength interval of 40 nm to investigate the efficacy of the approach based on three key molecules-tryptophan, collagen, and reduced nicotinamide adenine dinucleotide (NADH)-as cancer biomarkers. S3 combines both fluorescence and absorption spectra in one scan. The S3 spectra were analyzed using machine learning (ML) algorithms, including principal component analysis (PCA), nonnegative matrix factorization (NMF), and support vector machines (SVMs). The components retrieved from the S3 spectra were considered principal biomarkers. The differences in the weights of the components between the two types of tissues were found to be significant. Sensitivity, specificity, and accuracy were calculated to evaluate the performance of SVM classification. This research demonstrates that S3 spectroscopy is effective for detecting the changes in the relative concentrations of the endogenous fluorophores in tissues due to the development of cancer label free.