Study on the mechanism of liver cancer immune escape mediated by MINDY1 through regulation of PD-L1 ubiquitination level.

The novel deubiquitinase enzyme, motif interacting with ubiquitin-containing novel DUB family-1 (MINDY1), is highly expressed in liver cancer tissues and plays a crucial role in maintaining the stemness of liver cancer cells. Programmed death ligand-1 (PD-L1) is an immunosuppressive molecule overexpressed by tumour cells. The potential role of MINDY1 in inhibiting the stemness of liver cancer cells by deubiquitinating PD-L1 has not yet been reported. To investigate the mechanism by which MINDY1 mediates immune escape in liver cancer through the regulation of PD-L1 ubiquitination, we examined the expression levels of MINDY1 and PD-L1 in liver cancer and adjacent tissues from 50 hepatocellular carcinoma (HCC) patients using protein imprinting and immunohistochemistry. We analyzed the relationship between the expression levels of MINDY1 and PD-L1 in liver cancer tissues and their correlation with the 5-year tumor-free survival rates of patients. Subsequently, MINDY1 expression was knocked down in Huh7 cells using small interfering RNA (siRNA) interference or upregulated through transfection with a MINDY1 overexpression plasmid. The effects of MINDY1 knockdown or overexpression on the proliferation, apoptosis, migration, and invasion of HCC cells, as well as the regulation of PD-L1 binding and ubiquitination, were assessed. The 5-year tumor-free survival rates were significantly lower in both the high MINDY1 expression group and the high PD-L1 expression group (χ2 = 4.919 and 13.158, respectively). A significant difference in survival was observed between the high and low MINDY1 expression groups (χ2= 27.415). MINDY1 was found to directly interact with PD-L1, with MINDY1 gene knockdown promoting PD-L1 ubiquitination and MINDY1 overexpression inhibiting PD-L1 ubiquitination. All comparisons yielded statistically significant results (P < 0.05). In conclusion, MINDY1 inhibits the malignant progression of liver cancer by inhibiting PD-L1 ubiquitination and mediating immune escape.

Paeoniflorin inhibited GSDMD to alleviate ANIT-induced cholestasis via pyroptosis signaling pathway.

BACKGROUND: Cholestasis (CT) is a group of disorders caused by impaired production, secretion or excretion of bile. This may result in the deposition of bile components in the blood and liver, which in turn causes damage to liver cells and other tissues. If untreated, CT can progress to severe complications, including cirrhosis, liver failure, and potentially life-threatening conditions. OBJECTIVE: This research was intended to elucidate the function and mechanism of Paeoniflorin (PF) in ameliorating ANIT-induced pyroptosis in CT. METHODS: CT models were established in SD rats and HepG2 cells through ANIT treatment. Histological examination was conducted using haematoxylin and eosin (HE) staining to assess the histopathological alterations in the liver. Network pharmacology was employed to identify potential PF targets in CT treatment. To evaluate pyroptosis levels, various methods were used, including serum biochemical analysis, Enzyme-Linked Immunosorbent Assay (ELISA), immunofluorescence (IF), immunohistochemistry (IHC), Western blotting, transmission electron microscopy (TEM), and scanning electron microscopy (SEM). The HuProt™ 20K Chip was utilized to pinpoint potential PF-binding targets. PF's direct mechanisms in CT treatment were explored using molecular docking (MD), molecular dynamics simulations (MDS), Cellular Thermal Shift Assay (CETSA), and Surface Plasmon Resonance (SPR). RESULTS: PF administration was found to alleviate ANIT-induced liver pathology, enhance liver function markers, and improve cell viability. Network pharmacology and pyroptosis inhibitor studies suggested that PF might mitigate CT via the NLRP3-dependent pyroptosis pathway. This hypothesis was further supported by Western blotting, IF, and IHC analyses, which indicated PF's potential to inhibit NLRP3-dependent pyroptosis in CT. GSDMD was identified as a target through HuProt™ 20K Chip screening. The binding affinity of PF to GSDMD was validated through MD, MDS, CETSA, and SPR techniques. Additionally, the regulatory impact of GSDMD on downstream inflammatory pathways was confirmed by ELISA and IHC. CONCLUSION: PF exhibited a hepatoprotective effect in ANIT-induced CT, primarily by targeting GSDMD, thereby suppressing ANIT-induced pyroptosis and the subsequent release of inflammatory mediators.

Phase 3 study of gilteritinib versus salvage chemotherapy in predominantly Asian patients with relapsed/refractory FLT3-mutated acute myeloid leukemia.

The phase 3 COMMODORE trial evaluated gilteritinib versus salvage chemotherapy (SC) in a predominantly Asian relapsed/refractory (R/R) FLT3-mutated (FLT3mut+) acute myeloid leukemia (AML) patient population. The primary endpoint was overall survival (OS); secondary endpoints included event-free survival (EFS) and complete remission (CR) rate. As of June 30, 2020 (interim analysis: 32.2 months after study initiation), 234 patients were randomized (gilteritinib, n = 116; SC, n = 118). Median OS was significantly longer with gilteritinib versus SC (9.6 vs. 5.0 months; HR 0.566 [95% CI: 0.392, 0.818]; p = 0.00211) with a median follow-up of 10.3 months. Median EFS was also significantly longer with gilteritinib (2.8 vs. 0.6 months; HR 0.551 [95% CI: 0.395, 0.769]; p = 0.00004). CR rates with gilteritinib and SC were 16.4% and 10.2%, respectively; composite CR rates were 50.0% and 20.3%, respectively. Exposure-adjusted grade ≥3 adverse event (AE) rates were lower with gilteritinib (58.38 events/patient-year [E/PY]) versus SC (168.30 E/PY). Common AEs with gilteritinib were anemia (77.9%) and thrombocytopenia (45.1%). Gilteritinib plasma concentration peaked ~4 h postdose; ~3-fold accumulation occurred with multiple dosing. The COMMODORE trial demonstrated that gilteritinib significantly improved OS and EFS in predominantly Asian patients, validating the outcomes of gilteritinib from the ADMIRAL trial in R/R FLT3mut+ AML.

Paeoniflorin protects hepatocytes from APAP-induced damage through launching autophagy via the MAPK/mTOR signaling pathway.

BACKGROUND: Drug-induced liver injury (DILI) is gradually becoming a common global problem that causes acute liver failure, especially in acute hepatic damage caused by acetaminophen (APAP). Paeoniflorin (PF) has a wide range of therapeutic effects to alleviate a variety of hepatic diseases. However, the relationship between them is still poorly investigated in current studies. PURPOSE: This work aimed to explore the protective effects of PF on APAP-induced hepatic damage and researched the potential molecular mechanisms. METHODS: C57BL/6J male mice were injected with APAP to establish DILI model and were given PF for five consecutive days for treatment. Aiming to clarify the pharmacological effects, the molecular mechanisms of PF in APAP-induced DILI was elucidated by high-throughput and other techniques. RESULTS: The results demonstrated that serum levels of ALP, γ-GT, AST, TBIL, and ALT were decreased in APAP mice by the preventive effects of PF. Moreover, PF notably alleviated hepatic tissue inflammation and edema. Meanwhile, the results of TUNEL staining and related apoptotic factors coincided with the results of transcriptomics, suggesting that PF inhibited hepatocyte apoptosis by regulated MAPK signaling. Besides, PF also acted on reactive oxygen species (ROS) to regulate the oxidative stress for recovery the damaged mitochondria. More importantly, transmission electron microscopy showed the generation of autophagosomes after PF treatment, and PF was also downregulated mTOR and upregulated the expression of autophagy markers such as ATG5, ATG7, and BECN1 at the mRNA level and LC3, p62, ATG5, and ATG7 at the protein level, implying that the process by which PF exerted its effects was accompanied by the occurrence of autophagy. In addition, combinined with molecular dynamics simulations and western blotting of MAPK, the results suggested p38 as a direct target for PF on APAP. Specifically, PF-activated autophagy through the downregulation of MAPK/mTOR signaling, which in turn reduced APAP injury. CONCLUSIONS: Paeoniflorin mitigated liver injury by activating autophagy to suppress oxidative stress and apoptosis via the MAPK/mTOR signaling pathway. Taken together, our findings elucidate the role and mechanism of paeoniflorin in DILI, which is expected to provide a new therapeutic strategy for the development of paeoniflorin.

Equol exerts anti-tumor effects on choriocarcinoma cells by promoting TRIM21-mediated ubiquitination of ANXA2.

Choriocarcinoma is a malignant cancer that belongs to gestational trophoblastic neoplasia (GTN). Herein, serum metabolomic analysis was performed on 29 GTN patients and 30 healthy individuals to characterize the metabolic variations during GTN progression. Ultimately 24 differential metabolites (DMs) were identified, of which, Equol was down-regulated in GTN patients, whose VIP score is the 3rd highest among the 24 DMs. As an intestinal metabolite of daidzein, the anticancer potential of Equol has been demonstrated in multiple cancers, but not choriocarcinoma. Hence, human choriocarcinoma cell lines JEG-3 and Bewo were used and JEG-3-derived subcutaneous xenograft models were developed to assess the effect of Equol on choriocarcinoma. The results suggested that Equol treatment effectively suppressed choriocarcinoma cell proliferation, induced cell apoptosis, and reduced tumorigenesis. Label-free quantitative proteomics showed that 136 proteins were significantly affected by Equol and 20 proteins were enriched in Gene Ontology terms linked to protein degradation. Tripartite motif containing 21 (TRIM21), a E3 ubiquitin ligase, was up-regulated by Equol. Equol-induced effects on choriocarcinoma cells could be reversed by TRIM21 inhibition. Annexin A2 (ANXA2) interacted with TRIM21 and its ubiquitination was modulated by TRIM21. We found that TRIM21 was responsible for proteasome-mediated degradation of ANXA2 induced by Equol, and the inhibitory effects of Equol on the malignant behaviors of choriocarcinoma cells were realized by TRIM21-mediated down-regulation of ANXA2. Moreover, ß-catenin activation was inhibited by Equol, which also depended on TRIM21-mediated down-regulation of ANXA2. Taken together, Equol may be a novel candidate for the treatment for choriocarcinoma.

Efficacy and prognostic factors of stereotactic body radiotherapy combined with immunotherapy for pulmonary oligometastases: a preliminary retrospective cohort study.

Background: Stereotactic body radiotherapy (SBRT) combined immunotherapy has a synergistic effect on patients with stage IV tumors. However, the efficacy and prognostic factors analysis of SBRT combined immunotherapy for patients with pulmonary oligometastases have rarely been reported in the studies. The purpose of this study is to explore the efficacy and prognostic factors analysis of SBRT combined immunotherapy for patients with oligometastatic lung tumors. Methods: A retrospective analysis was conducted on 43 patients with advanced tumors who received SBRT combined with immunotherapy for pulmonary oligometastases from October 2018 to October 2021. Local control (LC), progression-free survival (PFS), and overall survival (OS) were assessed using the Kaplan-Meier method. Univariate and multivariate analyses of OS were performed using the Cox regression model, and the P value <0.05 was considered statistically significant. The receiver operating characteristic (ROC) curve of neutrophil-to-lymphocyte ratio (NLR) after SBRT was generated. Spearman correlation analysis was used to determine the relationship of planning target volume (PTV) with absolute lymphocyte count (ALC) before and after SBRT and with neutrophil count (NE) after SBRT. Additionally, linear regression was used to examine the relationship between ALC after SBRT and clinical factors. Results: A total of 43 patients with pulmonary oligometastases receiving SBRT combined with immunotherapy were included in the study. The change in NLR after SBRT was statistically significant (P<0.001). At 1 and 2 years, respectively, the LC rates were 90.3% and 87.5%, the OS rates were 83.46% and 60.99%, and the PFS rates were 69.92% and 54.25%, with a median PFS of 27.00 (17.84-36.13) months. Univariate and multivariate Cox regression analyses showed that a shorter interval between radiotherapy and immunization [≤21 days; hazard ratio (HR) =1.10, 95% confidence interval (CI): 0.06-0.89; P=0.02] and a low NLR after SBRT (HR =0.24, 95% CI: 1.01-1.9; P=0.03) were associated with improved OS. The ROC curve identified 4.12 as the cutoff value for predicting OS based on NLR after SBRT. NLR after SBRT ≤4.12 significantly extended OS compared to NLR after SBRT >4.12 (log-rank P=0.001). Spearman correlation analysis and linear regression analysis showed that PTV was negatively correlated with ALC after SBRT. Conclusions: Our preliminary research shows that SBRT combined with immunotherapy has a good effect, and NLR after SBRT is a poor prognostic factor for OS. Larger PTV volume is associated with decreased ALC after SBRT.

Role of the lncRNA/Wnt signaling pathway in digestive system cancer: a literature review.

The long noncoding RNA (lncRNA)/Wingless (Wnt) axis is often dysregulated in digestive system tumors impacting critical cellular processes. Abnormal expression of specific Wnt-related lncRNAs such as LINC01606 (promotes motility), SLCO4A1-AS1 (promotes motility), and SH3BP5-AS1 (induces chemoresistance), plays a crucial role in these malignancies. These lncRNAs are promising targets for cancer diagnosis and therapy, offering new treatment perspectives. The lncRNAs, NEF and GASL1, differentially expressed in plasma show diagnostic potential for esophageal squamous cell carcinoma and gastric cancer, respectively. Additionally, Wnt pathway inhibitors like XAV-939 have demonstrated preclinical efficacy, underscoring their therapeutic potential. This review comprehensively analyzes the lncRNA/Wnt axis, highlighting its impact on cell proliferation, motility, and chemoresistance. By elucidating the complex molecular mechanisms of the lncRNA/Wnt axis, we aim to identify potential therapeutic targets for digestive system tumors to pave the way for the development of targeted treatment strategies.

Transition Metal-Gallium Intermetallic Compounds with Tailored Active Site Configurations for Electrochemical Ammonia Synthesis.

Gallium (Ga) with a low melting point can serve as a unique metallic solvent in the synthesis of intermetallic compounds (IMCs). The negative formation enthalpy of transition metal-Ga IMCs endows them with high catalytic stability. Meanwhile, their tunable crystal structures offer the possibility to tailor the configurations of active sites to meet the requirements for specific catalytic applications. Herein, we present a general method for preparing a range of transition metal-Ga IMCs, including Co-Ga, Ni-Ga, Pt-Ga, Pd-Ga, and Rh-Ga IMCs. The structurally ordered CoGa IMCs with body-centered cubic (bcc) structure are uniformly dispersed on the nitrogen-doped reduced graphene oxide substrate (O-CoGa/NG) and deliver outstanding nitrate reduction reaction (NO3RR) performance, making them excellent catalysts to construct highly efficient rechargeable Zn-NO3- battery. Operando studies and theoretical simulations demonstrate that the electron-rich environments around the Co atoms enhance the adsorption strength of *NO3 intermediate and simultaneously suppress the formation of hydrogen, thus improving the NO3RR activity and selectivity.

Phylogeographic analysis reveals multiple origins of the desert shrub Reaumuria songarica in northern Xinjiang, involving homoploid and tetraploid hybrids.

Hybrid speciation plays an important role in species diversification. The establishment of reproductive isolation is crucial for hybrid speciation, and the identification of diverse types of hybrids, particularly homoploid hybrid species, contributes to a comprehensive understanding of this process. Reaumuria songarica is a constructive shrub widespread in arid Central Asia. Previous studies have inferred that the R. songarica populations in the Gurbantunggut Desert (GuD) originated from homoploid hybridizations between its eastern and western lineages and may have evolved into an incipient species. To further elucidate the genetic composition of different hybrid populations and to determine the species boundary of this hybrid lineage, we investigated the overall phylogeographic structure of R. songarica based on variation patterns of five cpDNA and one nrITS sequences across 32 populations. Phylogenetic analyses demonstrated that within the GuD lineage, the Wuerhe population evolved directly from ancestral lineages, whereas the others originated from hybridizations between the eastern and western lineages. PCoA and genetic barrier analysis supported the subdivision of the GuD lineage into the southern (GuD-S) and northern (GuD-N) groups. Populations in the GuD-S group had a consistent genetic composition and the same ancestral female parent, indicating that they belonged to a homoploid hybrid lineage. However, the GuD-N group experienced genetic admixture of the eastern and western lineages on nrITS and cpDNA, with some populations inferred to be allopolyploid based on ploidy data. Based on cpDNA haplotypes, BEAST analyses showed that the GuD-S and GuD-N groups originated after 0.5 Ma. Our results suggest that multiple expansions and contractions of GuD, driven by Quaternary climatic oscillations and the Kunlun-Yellow River tectonic movement, are important causes of the complex origins of R. songarica populations in northern Xinjiang. This study highlights the complex origins of the Junggar Basin flora and the underappreciated role of hybridization in increasing its species diversity.

A predictive model for L-T4 dose in postoperative DTC after RAI therapy and its clinical validation in two institutions.

Purpose: To develop a predictive model using machine learning for levothyroxine (L-T4) dose selection in patients with differentiated thyroid cancer (DTC) after resection and radioactive iodine (RAI) therapy and to prospectively validate the accuracy of the model in two institutions. Methods: A total of 266 DTC patients who received RAI therapy after thyroidectomy and achieved target thyroid stimulating hormone (TSH) level were included in this retrospective study. Sixteen clinical and biochemical characteristics that could potentially influence the L-T4 dose were collected; Significant features correlated with L-T4 dose were selected using machine learning random forest method, and a total of eight regression models were established to assess their performance in prediction of L-T4 dose after RAI therapy; The optimal model was validated through a two-center prospective study (n=263). Results: Six significant clinical and biochemical features were selected, including body surface area (BSA), weight, hemoglobin (HB), height, body mass index (BMI), and age. Cross-validation showed that the support vector regression (SVR) model was with the highest accuracy (53.4%) for prediction of L-T4 dose among the established eight models. In the two-center prospective validation study, a total of 263 patients were included. The TSH targeting rate based on constructed SVR model were dramatically higher than that based on empirical administration (Rate 1 (first rate): 52.09% (137/263) vs 10.53% (28/266); Rate 2 (cumulative rate): 85.55% (225/263) vs 53.38% (142/266)). Furthermore, the model significantly shortens the time (days) to achieve target TSH level (62.61 ± 58.78 vs 115.50 ± 71.40). Conclusions: The constructed SVR model can effectively predict the L-T4 dose for postoperative DTC after RAI therapy, thus shortening the time to achieve TSH target level and improving the quality of life for DTC patients.

Dehydroevodiamine Alleviates Ulcerative Colitis by Inhibiting the PI3K/AKT/NF-κB Signaling Pathway via Targeting AKT1 and Regulating Gut Microbes and Serum Metabolism.

Ulcerative colitis (UC) is a typical inflammatory bowel disease (IBD), impairing the quality of life of patients. Dehydroevodiamine (DHE) is an active alkaloid isolated from Tetradium ruticarpum that exerts significant anti-inflammatory effects in gastrointestinal diseases. However, the effect and mechanisms of DHE on UC remain unclear. We performed a DSS-induced experimental UC rat model to reveal the efficacy and potential mechanisms of DHE on UC. HE and AB-PAS staining were used for the evaluation of pathologies, and 16S rRNA sequencing was used to detect changes in gut microbes. Metabolomics was used to detect changes in serum metabolites. Network pharmacology and transcriptomics were conducted to reveal the underlying mechanisms of DHE for UC. HuProt proteome microarrays, molecular docking, and SPR were used to reveal the targets of action of DHE. WB, RT-qPCR, and IHC were used to assess the action effects of DHE. DHE demonstrated significant alleviation of DSS-induced colitis symptoms in rats by suppressing inflammatory and oxidative stress responses, amending colonic barrier injury, and inhibiting apoptosis. In terms of gut microbial modulation, DHE decreased the abundance of Allobaculum, Clostridium, Escherichia, Enterococcus, and Barnesiella and increased the abundance of Lactobacillus, Bifidobacterium, and SMB5. Moreover, metabolomics suggested that the regulation of DHE in DSS-induced UC rats mainly involved aminoacyl-tRNA biosynthesis, vitamin B6 metabolism, phenylalanine, tyrosine, and so on. Mechanically, DHE alleviated UC in rats by targeting AKT1, thereby inhibiting the PI3K/AKT/NF-κB signaling pathway.

The molecular regulatory mechanism of reed canary grass under salt, waterlogging, and combined stress was analyzed by transcriptomic analysis.

BACKGROUND: Reed canary grass has been identified as a suitable species for restoring plateau wetlands and understanding plant adaptation mechanisms in wetland environments. In this study, we subjected a reed canary grass cultivar 'Chuanxi' to waterlogging, salt, and combined stresses to investigate its phenotypic characteristics, physiological indices, and transcriptome changes under these conditions. RESULTS: The results revealed that the growth rate was slower under salt stress than under waterlogging stress. The chlorophyll content and energy capture efficiency of the PS II reaction center decreased with prolonged exposure to each stress. Conversely, while the activities of enzymes associated with respiratory metabolism, as well as MDA, PRO, Na+, and K+-ATPase, increased. The formation of distinct aerenchyma was observed under waterlogging stress and combined stress. Transcriptome sequencing analysis identified 5,379, 4,169, and 14,993 DEGs under CK vs. W, CK vs. S, and CK vs. SW conditions, respectively. The WRKY was found to be the most abundant under waterlogging stress, whereas the MYB predominated under salt stress and combined stress. Glutathione metabolic pathways and Plant hormone signal transduction have also been found to play important roles in stress. CONCLUSION: By integrating phenotypic, physiological, anatomical, and transcriptomic, this research provides valuable insights into how reed canary grass responds to salt, waterlogging, and combined stresses. These findings may inform the ecological application of reed canary grass in high-altitude wetlands and for breeding purposes.

A new exploration: characterization of the differentiation trajectory of prostate cancer cells.

Prostate cancer is one of the most common malignant tumors in men, and in-depth study of its gene expression patterns is crucial for understanding the formation and development of prostate cancer. Although single-cell transcriptomics has deeply explored the heterogeneous expression characteristics of prostate cancer, given that normal epithelial cells themselves have different states of differentiation, these normal differentiation characteristics may lead to confusion with heterogeneous tumor characteristics. In this study, we used single-cell data from the GEO database to analyze in detail the heterogeneity of prostate cancer tumor cells/tumor-associated epithelium cells (TAECs), with a particular focus on the differentiation state of epithelial cells in matching normal tissue. We found that after subtype pairing analysis of normal tissue and tumor tissue epithelium based on differentiation status, the characteristics identified later were not consistent with the general characteristics originally exhibited by different TAECs subpopulations. Among them, all TAECs subpopulations showed P53 enrichment and downregulation of the apoptotic pathway, and expressed higher levels of EGFR, ERBB2, interferon receptors, MIF, and cell adhesion-related signals; through transcription factor regulatory network analysis, we observed that YY1, NKX3-1, and EHF had higher transcriptional activity in TAECs subpopulations than normal epithelial cells at the same differentiation stage, while ATF3 was the opposite. Among them, YY1 may act as an upstream regulator of the MIF signaling pathway, and ATF3 is a key upstream transcriptional regulator of differentially expressed genes in the P53 and apoptotic pathways. Immune infiltration analysis showed that the above four transcription factors were significantly correlated with the infiltration of immune cells in prostate cancer, and pan-cancer analysis showed that their expression-related survival risks were widely present in different cancers. It is worth noting that this is merely a preliminary, exploratory study, which inevitably has some deficiencies and limitations. Despite this, this study is committed to bringing a novel and unique perspective to the field through this work, with the hope of opening up new levels of understanding and stimulating more in-depth research and discussion.

Simplified Gambogic Acid Prodrug Nanoparticles to Improve Efficiency and Reduce Toxicity for Clinical Translation Potential.

Poor in vivo characteristics of gambogic acid (GA) and difficulties in industrial manufacturing of its nanocarriers have hindered its clinical translation. Therefore, a reproducible nano-drug delivery system must be developed to realize simpler manufacture and address inherent defects of GA, such as short circulation and severe side effects, in order to facilitate its clinical application. Herein, a drug self-assembled nanoparticles (NPs) consisting of a hydrophobic prodrug based on GA and oleyl alcohol (OA), as well as vitamin E-polyethylene glycol succinate (TPGS) as a shield to improve the stability of the NPs is reported. The preparation method is simple enough to stably facilitate large-scale manufacturing. The self-assembled NPs exhibit a remarkably high drug-loading capacity, and their prolonged circulation enables the NPs to demonstrate superior antitumor efficacy in both cellular and animal models. The flexible hydrophobic long chain wraps GA groups, which mitigates vascular irritation and reduces hemolysis rates. Consequently, the prodrug nano-system addresses GA-related concerns regarding stability, efficacy, and safety, offering a simple, stable, and secure nano-platform for similar candidate drugs.

Metagenomic analysis reveals high diversity of gut viromes in yaks (Bos grunniens) from the Qinghai-Tibet Plateau.

The Qinghai-Tibet Plateau (QTP), renowned for its exceptional biological diversity, is home to numerous endemic species. However, research on the virology of vulnerable vertebrates like yaks remains limited. In this study, our objective was to use metagenomics to provide a comprehensive understanding of the diversity and evolution of the gut virome in yak populations across different regions of the QTP. Our findings revealed a remarkably diverse array of viruses in the gut of yaks, including those associated with vertebrates and bacteriophages. Notably, some vertebrate-associated viruses, such as astrovirus and picornavirus, showed significant sequence identity across diverse yak populations. Additionally, we observed differences in the functional profiles of genes carried by the yak gut virome across different regions. Moreover, the virus-bacterium symbiotic network that we discovered holds potential significance in maintaining the health of yaks. Overall, this research expands our understanding of the viral communities in the gut of yaks and highlights the importance of further investigating the interactions between viruses and their hosts. These data will be beneficial for revealing the crucial role that viruses play in the yak gut ecology in future studies.

Machine Learning-Driven discovery of immunogenic cell Death-Related biomarkers and molecular classification for diabetic ulcers.

In this study, we redefine the diagnostic landscape of diabetic ulcers (DUs), a major diabetes complication. Our research uncovers new biomarkers linked to immunogenic cell death (ICD) in DUs by utilizing RNA-sequencing data of Gene Expression Omnibus (GEO) analysis combined with a comprehensive database interrogation. Employing a random forest algorithm, we have developed a diagnostic model that demonstrates improved accuracy in distinguishing DUs from normal tissue, with satisfactory results from ROC analysis. Beyond mere diagnosis, our model categorizes DUs into novel molecular classifications, which may enhance our comprehension of their underlying pathophysiology. This study bridges the gap between molecular insights and clinical practice. It sets the stage for transformative strategies in DUs management, marking a significant step forward in personalized medicine for diabetic patients.

Interactions between mild depressive symptoms and amyloid pathology on the trajectory of neurodegeneration, cognitive decline, and risk of Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) was driven by the interplay between modifiable environmental factors and ß-amyloid (Aß) pathology. We aimed to investigate the interaction effects of mild depressive symptoms (MDS) with Aß on AD development. METHODS: Longitudinal data of 1746 non-demented adults (mean age = 73 years, female = 53 %, maximum = 10 years) were derived from the Alzheimer's Disease Neuroimaging Initiative cohort. MDS was separately defined by the baseline status, longitudinal latent class, and average intensity during follow-up. Amyloid-positive (A+) status was determined based on cerebrospinal fluid levels of ß-amyloid. Regression models were employed to analyze the interactive effects of MDS with A+ on cognitive decline, neurodegeneration, and AD incidence. RESULTS: Individuals with both A+ status and MDS at baseline experienced the fastest neurodegeneration (p < 0.01), cognitive decline (p < 0.05), and a higher risk of developing AD (HR = 5.23, p < 0.001). Furthermore, A+ participants with the trajectory of increasing depressive symptoms demonstrated more pronounced neurodegeneration (p < 0.001), cognitive decline (p < 0.01), and elevated risk of AD (HR = 10.45, p < 0.001). Finally, A+ status in combination with a higher average intensity of depressive symptoms was associated with faster brain atrophy (p < 0.01) and brain metabolism decline (p < 0.05), cognitive decline (p < 0.05), and higher AD risk (HR = 13.99, p < 0.001). CONCLUSION: These findings emphasized that the MDS-Aß interaction relationship should be considered in risk stratification, prediction, and early management of neurodegeneration and cognitive decline in the pre-dementia stage.

Exploring Evolutionary Pathways and Abiotic Stress Responses through Genome-Wide Identification and Analysis of the Alternative Oxidase (AOX) Gene Family in Common Oat (Avena sativa).

The alternative oxidase (AOX), a common terminal oxidase in the electron transfer chain (ETC) of plants, plays a crucial role in stress resilience and plant growth and development. Oat (Avena sativa), an important crop with high nutritional value, has not been comprehensively studied regarding the AsAOX gene family. Therefore, this study explored the responses and potential functions of the AsAOX gene family to various abiotic stresses and their potential evolutionary pathways. Additionally, we conducted a genome-wide analysis to explore the evolutionary conservation and divergence of AOX gene families among three Avena species (Avena sativa, Avena insularis, Avena longiglumis) and four Poaceae species (Avena sativa, Oryza sativa, Triticum aestivum, and Brachypodium distachyon). We identified 12 AsAOX, 9 AiAOX, and 4 AlAOX gene family members. Phylogenetic, motif, domain, gene structure, and selective pressure analyses revealed that most AsAOXs, AiAOXs, and AlAOXs are evolutionarily conserved. We also identified 16 AsAOX segmental duplication pairs, suggesting that segmental duplication may have contributed to the expansion of the AsAOX gene family, potentially preserving these genes through subfunctionalization. Chromosome polyploidization, gene structural variations, and gene fragment recombination likely contributed to the evolution and expansion of the AsAOX gene family as well. Additionally, we hypothesize that AsAOX2 may have potential function in resisting wounding and heat stresses, while AsAOX4 could be specifically involved in mitigating wounding stress. AsAOX11 might contribute to resistance against chromium and waterlogging stresses. AsAOX8 may have potential fuction in mitigating ABA-mediated stress. AsAOX12 and AsAOX5 are most likely to have potential function in mitigating salt and drought stresses, respectively. This study elucidates the potential evolutionary pathways of the AsAOXs gene family, explores their responses and potential functions to various abiotic stresses, identifies potential candidate genes for future functional studies, and facilitates molecular breeding applications in A. sativa.

Dehydroevodiamine targeting IKKß to alleviate acute gastric injury via inhibiting the p65/NLRP3 axis.

BACKGROUND: Acute gastric injury, a common and recurring global digestive disorder, significantly impairs patient quality of life and overall health. Dehydroevodiamine (DHE), a bioactive natural product derived from Tetradium ruticarpum (A. Juss.) Hartley, shows potential therapeutic effects on acute gastric injury. This study investigates the underlying mechanisms of DHE's alleviating effects on acute gastric injury. METHODS: The gastric mucosal protective effect of DHE was confirmed through in vivo and in vitro acute gastric injury models. Biotin pulldown MS and molecular dynamics simulations identified DHE's target. CETSA and SPR assays validated DHE's affinity for IKKß. Protein site mutation validation and MST pinpointed the direct binding sites of DHE on IKKß. Additionally, the potential mechanism by which DHE ameliorates acute gastric injury was elucidated using WB, IHC, and IF methods, and further confirmed by rescue experiments. RESULTS: DHE effectively ameliorated IDO-induced gastric injury in GES-1 cells and rat gastric mucosa, both in vitro and in vivo. Biotin pulldown MS identified IKKß as the target of DHE in alleviating gastric injury. CETSA and SPR assays confirmed DHE's direct binding to IKKß. Molecular dynamics simulations, protein mutation experiments, and MST results pinpointed GLU-149, GLU-49, and ASP-103 in the ATP-binding pocket as the binding sites of DHE on IKKß. Notably, DHE was found to competitively bind to IKKß with ATP. Mechanistically, DHE attenuated IDO-induced gastric injury by inhibiting the IKKß-p65/NLRP3 signaling pathway. Importantly, exogenous activation of IKKß reversed the therapeutic effect of DHE, indicating that DHE's efficacy depends on IKKß. CONCLUSION: DHE attenuated IDO-induced gastric injury by inhibiting the IKKß-p65/NLRP3 signaling pathway. Notably, DHE is a novel ATP-competitive IKKß inhibitor that prevents phosphorylation by targeting GLU-149, GLU-49, and ASP-103 in the ATP-binding pocket. This study reveals new targets of action for DHE, providing a new molecular basis for using DHE in treating inflammation-related diseases.

The essential roles of lncRNAs/PI3K/AKT axis in gastrointestinal tumors.

The role of long noncoding RNA (lncRNA) in tumors, particularly in gastrointestinal tumors, has gained significant attention. Accumulating evidence underscores the interaction between various lncRNAs and diverse molecular pathways involved in cancer progression. One such pivotal pathway is the PI3K/AKT pathway, which serves as a crucial intracellular mechanism maintaining the balance among various cellular physiological processes for normal cell growth and survival. Frequent dysregulation of the PI3K/AKT pathway in cancer, along with aberrant activation, plays a critical role in driving tumorigenesis. LncRNAs modulate the PI3K/AKT signaling pathway through diverse mechanisms, primarily by acting as competing endogenous RNA to regulate miRNA expression and associated genes. This interaction significantly influences fundamental biological behaviors such as cell proliferation, metastasis, and drug resistance. Abnormal expression of numerous lncRNAs in gastrointestinal tumors often correlates with clinical outcomes and pathological features in patients with cancer. Additionally, these lncRNAs influence the sensitivity of tumor cells to chemotherapy in multiple types of gastrointestinal tumors through the abnormal activation of the PI3K/AKT pathway. These findings provide valuable insights into the mechanisms underlying gastrointestinal tumors and potential therapeutic targets. However, gastrointestinal tumors remain a significant global health concern, with increasing incidence and mortality rates of gastrointestinal tumors over recent decades. This review provides a comprehensive summary of the latest research on the interactions of lncRNA and the PI3K/AKT pathway in gastrointestinal tumor development. Additionally, it focuses on the functions of lncRNAs and the PI3K/AKT pathway in carcinogenesis, exploring expression profiles, clinicopathological characteristics, interaction mechanisms with the PI3K/AKT pathway, and potential clinical applications.