Gastric cancer cell-derived exosomal miR-541-5p induces M2 macrophage polarization through DUSP3/JAK2/STAT3 pathway.

PURPOSE: Exosomal microRNAs have been identified as important mediators of communication between tumor cells and macrophages in the microenvironment. miR-541-5p was reported to be involved in hepatocellular carcinoma progression, but its role in gastric cancer (GC) and in GC cell-macrophage crosstalk is unknown. METHODS: Cell proliferation, migration and invasion were respectively assessed by CCK-8 assay, scratch and Transwell assays. RT-qPCR was used to detect the level of miR-541-5p, macrophage markers and DUSP3. The percentage of CD11b+CD206+ cell population was analyzed by flow cytometry. Western blotting was employed to evaluate DUSP3-JAK2/STAT3 pathway proteins and exosome markers. The interaction between miR-541-5p and DUSP3 was verified by luciferase assay. RESULTS: The results showed that miR-541-5p was upregulated in GC tissues and cells, and stimulated GC cell growth, migration and invasion in vitro. GC cells induce M2 macrophage polarization by secreting the exosomal miR-541-5p. Exosomal miR-541-5p maintained JAK2/STAT3 pathway activation in macrophages by targeting negative regulation of DUSP3. Inhibiting miR-541-5p significantly limited tumor growth in vivo. CONCLUSION: In conclusion, miR-541-5p promotes GC cell progression. GC cells may induce macrophage M2 polarization through the exosomal miR-541-5p-mediated DUSP3/JAK2/STAT3 pathway. miR-541-5p may be a potential therapeutic target for GC.

Primary intestinal T-cell and natural killer-cell lymphomas: Clinicopathologic and prognostic features of 79 cases in South China.

OBJECTIVES: Primary intestinal T-cell and natural killer-cell lymphomas (PITNKLs) are aggressive and make pathologic diagnoses in biopsy specimens challenging. We analyzed different subtypes' clinicopathologic features and treatment outcomes. METHODS: Seventy-nine PITNKL cases were characterized by clinical, morphologic, and immunohistochemical features. RESULTS: Among 79 cases of PITNKLs from 2008 to 2017 in our institution, 40 (50.63%) were extranodal NK/T-cell lymphoma, nasal type (ENKTL); 32 (40.51%) monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL); 6 (7.59%) intestinal T-cell lymphoma, not otherwise specified; and 1 (1.27%) indolent T-cell lymphoma of the gastrointestinal tract. Small intestine (n = 47) was the most common site. Monomorphic epitheliotropic intestinal T-cell lymphoma showed distinctive clinicopathologic features from other subtypes with high expression (96.88%) of spleen tyrosine kinase (SYK) and PD-L1 (87.5%) and the poorest prognosis (P < .001). CD30 was highly expressed in ENKTL (9/17, 57.94%) and irrelevant to prognosis (P > .05). CONCLUSIONS: Cases of PITNKL are biologically heterogeneous; most have a dismal prognosis. SYK and PD-L1 expression might be a significant marker for MEITL and helps differential diagnosis.

Association of serum interleukin-6 with negative symptoms in stable early-onset schizophrenia.

BACKGROUND: Accumulating evidence suggests that the inflammatory cytokine interleukin-6 (IL-6) contributes to the pathophysiology of psychiatric disorders. However, there was no study concerning the relationship between IL-6 concentrations and clinical features in the chronic phase of early-onset schizophrenia (EOS). AIM: To investigate the relationship between serum IL-6 concentration and the clinical features of EOS. METHODS: We measured serum IL-6 Levels from 74 patients with chronic schizophrenia, including 33 with age at onset < 21 years (EOS group) and 41 with onset ≥ 21 years in [adult-onset schizophrenia (AOS) group], and from 41 healthy controls. Symptom severities were evaluated using the Positive and Negative Syndrome Scale (PANSS). RESULTS: Serum IL-6 concentrations were higher in both EOS and AOS groups than healthy controls (F = 22.32, P < 0.01), but did not differ significantly between EOS and AOS groups (P > 0.05) after controlling for age, body mass index, and other covariates. Negative symptom scores were higher in the EOS group than the AOS group (F = 6.199, P = 0.015). Serum IL-6 concentrations in the EOS group were negatively correlated with both total PANSS-negative symptom score (r = -0.389, P = 0.032) and avolition/asociality subscore (r = -0.387, P = 0.026). CONCLUSION: Patients with EOS may have more severe negative symptoms than those with adult-onset schizophrenia during the chronic phase of the illness. IL-6 signaling may regulate negative symptoms and its avolition/asociality subsymptoms among the early-onset chronic schizophrenic patients.

Advances in the Structures, Pharmacological Activities, and Biosynthesis of Plant Diterpenoids.

More and more diterpenoids have attracted extensive attention due to the diverse chemical structures and excellent biological activities, and have been developed into clinical drugs or consumer products. The vast majority of diterpenoids are derived from plants. With the long-term development of plant medicinal materials, the natural resources of many plant diterpenoids are decreasing, and the biosynthetic mechanism of key active components has increasingly become a research hotspot. Using synthetic biology to engineer microorganisms into "cell factories" to produce the desired compounds is an essential means to solve these problems. In this review, we depict the plant-derived diterpenoids from chemical structure, biological activities, and biosynthetic pathways. We use representative plant diterpenes as examples to expound the research progress on their biosynthesis, and summarize the heterologous production of plant diterpenoids in microorganisms in recent years, hoping to lay the foundation for the development and application of plant diterpenoids in the future.

METTL1/FOXM1 promotes lung adenocarcinoma progression and gefitinib resistance by inhibiting PTPN13 expression.

INTRODUCTION: Lung adenocarcinoma (LUAD) is the most common malignant tumor in respiratory system. Methyltransferase-like 1 (METTL1) is a driver of m7G modification in mRNA. This study aimed to demonstrate the role of METTL1 in the proliferation, invasion and Gefitinib-resistance of LUAD. METHODS: Public datasets were downloaded from the Gene Expression Profiling Interactive Analysis (GEPIA) and GSE31210 datasets. Malignant tumor phenotypes were tested in vitro and in vivo through biological function assays and nude mouse with xenograft tumors. RNA immunoprecipitation assays were conducted to determine the interaction between METTL1 protein and FOXM1 mRNA. Public transcriptional database, Chromatin immunoprecipitation and luciferase report assays were conducted to detect the downstream target of a transcriptional factor FOXM1. Half maximal inhibitory concentration (IC50) was calculated to evaluate the sensitivity to Gefitinib in LUAD cells. RESULTS: The results showed that METTL1 was upregulated in LUAD, and the high expression of METTL1 was associated with unfavorable prognosis. Through the m7G-dependent manner, METTL1 improved the RNA stability of FOXM1, leading to the up-regulation of FOXM1. FOXM1 transcriptionally suppressed PTPN13 expression. The METTL1/FOXM1/PTPN13 axis reduced the sensitivity of LUAD cells to Gefitinib. Taken together, our data suggested that METTL1 plays oncogenic role in LUAD through inducing the m7G modification of FOXM1, therefore METTL1 probably is a new potential therapeutic target to counteract Gefitinib resistance in LUAD.

Sodium tanshinone IIA sulfonate protects vascular relaxation in ApoE-knockout mice by inhibiting the SYK-NLRP3 inflammasome-MMP2/9 pathway.

BACKGROUND: Hyperlipidemia damages vascular wall and serves as a foundation for diseases such as atherosclerosis, hypertension and stiffness. The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is implicated in vascular dysfunction associated with hyperlipidemia-induced vascular injury. Sodium tanshinone IIA sulfonate (STS), a well-established cardiovascular protective drug with recognized anti-inflammatory, antioxidant, and vasodilatory properties, is yet to be thoroughly investigated for its impact on vascular relaxant imbalance induced by hyperlipidemia. METHODS: In this study, we treated ApoE-knockout (ApoE-/-) mouse with STS and assessed the activation of the NLRP3 inflammasome, expression of MMP2/9, integrity of elastic fibers, and vascular constriction and relaxation. RESULTS: Our findings reveal that STS intervention effectively preserves elastic fibers, significantly restores aortic relaxation function in ApoE-/- mice, and reduces their excessive constriction. Furthermore, STS inhibits the phosphorylation of spleen tyrosine kinase (SYK), suppresses NLRP3 inflammasome activation, and reduces MMP2/9 expression. CONCLUSIONS: These results demonstrate that STS protects vascular relaxation against hyperlipidemia-induced damage through modulation of the SYK-NLRP3 inflammasome-MMP2/9 pathway. This research provides novel insights into the mechanisms underlying vascular relaxation impairment in a hyperlipidemic environment and uncovers a unique mechanism by which STS preserves vascular relaxation, offering valuable foundational research evidence for its clinical application in promoting vascular health.

Bioinformatics and systems biology approach to identify the pathogenetic link of neurological pain and major depressive disorder.

Neurological pain (NP) is always accompanied by symptoms of depression, which seriously affects physical and mental health. In this study, we identified the common hub genes (Co-hub genes) and related immune cells of NP and major depressive disorder (MDD) to determine whether they have common pathological and molecular mechanisms. NP and MDD expression data was downloaded from the Gene Expression Omnibus (GEO) database. Common differentially expressed genes (Co-DEGs) for NP and MDD were extracted and the hub genes and hub nodes were mined. Co-DEGs, hub genes, and hub nodes were analyzed for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment. Finally, the hub nodes, and genes were analyzed to obtain Co-hub genes. We plotted Receiver operating characteristic (ROC) curves to evaluate the diagnostic impact of the Co-hub genes on MDD and NP. We also identified the immune-infiltrating cell component by ssGSEA and analyzed the relationship. For the GO and KEGG enrichment analyses, 93 Co-DEGs were associated with biological processes (BP), such as fibrinolysis, cell composition (CC), such as tertiary granules, and pathways, such as complement, and coagulation cascades. A differential gene expression analysis revealed significant differences between the Co-hub genes ANGPT2, MMP9, PLAU, and TIMP2. There was some accuracy in the diagnosis of NP based on the expression of ANGPT2 and MMP9. Analysis of differences in the immune cell components indicated an abundance of activated dendritic cells, effector memory CD8+ T cells, memory B cells, and regulatory T cells in both groups, which were statistically significant. In summary, we identified 6 Co-hub genes and 4 immune cell types related to NP and MDD. Further studies are needed to determine the role of these genes and immune cells as potential diagnostic markers or therapeutic targets in NP and MDD.

Association between Branched-Chain amino acids and Epilepsy: A Mendelian randomized study.

BACKGROUND: Branched-chain amino acids (BCAAs) have been affected epilepsy, yet conclusions remain inconclusive, lacking causal evidence regarding whether BCAAs affect epilepsy. Systematic exploration of the causal relationship between BCAAs and epilepsy could hand out new ideas for the treatment of epilepsy. METHODS: Utilizing bidirectional Mendelian randomization (MR) study, we investigated the causal relationship between BCAA levels and epilepsy. BCAA levels from genome-wide association studies (GWAS), including total BCAAs, leucine levels, isoleucine levels, and valine levels, were employed. Causal relationships were explored applying the method of inverse variance-weighted (IVW) and MR-Egger, followed by sensitivity analyses of the results to evaluate heterogeneity and pleiotropy. RESULTS: Through strict genetic variant selection, we find some related SNPs, total BCAA levels (9), leucine levels (11), isoleucine levels (7), and valine levels (6) as instrumental variables for our MR analysis. Following IVW and sensitivity analysis, total BCAAs levels (OR = 1.14, 95 % CI = 1.019 âˆ¼ 1.285, P = 0.022) and leucine levels (OR = 1.15, 95 % CI = 1.018 âˆ¼ 1.304, P = 0.025) had significant correlation with epilepsy. CONCLUSIONS: There exists a causal relationship between the levels of total BCAAs and leucine with epilepsy, offering the new ideas into epilepsy potential mechanisms, holding significant implications for its prevention and treatment.

Evaluation of pathological response to neoadjuvant chemotherapy in locally advanced cervical cancer.

Neoadjuvant chemotherapy (NACT) is a viable therapeutic option for women diagnosed locally advanced cervical cancer (LACC). However, the factors influencing pathological response are still controversial. We collected pair specimens of 185 LACC patients before and after receiving NACT and conducted histological evaluation. 8 fresh tissues pre-treatment were selected from the entire cohort to conducted immune gene expression profiling. A novel pathological grading system was established by comprehensively assessing the percentages of viable tumor, inflammatory stroma, fibrotic stroma, and necrosis in the tumor bed. Then, 185 patients were categorized into either the good pathological response (GPR) group or the poor pathological response (PPR) group post-NACT, with 134 patients (72.4%, 134/185) achieving GPR. Increasing tumor-infiltrating lymphocytes (TILs) and tumor-infiltrating lymphocytes volume (TILV) pre-treatment were correlated with GPR, with TILV emerging as an independent predictive factor for GPR. Additionally, CIBERSORT analysis revealed noteworthy differences in the expression of immune makers between cPR and non-cPR group. Furthermore, a significantly heightened density of CD8 + T cells and a reduced density of FOXP3 + T cells were observed in GPR than PPR. Importantly, patients exhibiting GPR or inflammatory type demonstrated improved overall survival and disease-free survival. Notably, stromal type was an independent prognostic factor in multivariate analysis. Our study indicates the elevated TILV in pre-treatment specimens may predict a favorable response to NACT, while identifying stromal type in post-treatment specimens as an independent prognostic factor. Moreover, we proposed this pathological grading system in NACT patients, which may offer a more comprehensive understanding of treatment response and prognosis.

Sodium Tanshinone IIA Sulfonate alleviates vascular senescence in diabetic mice by modulating the A20-NFκB-NLRP3 inflammasome-catalase pathway.

Diabetes accelerates vascular senescence, which is the basis for atherosclerosis and stiffness. The activation of NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome and oxidative stress are closely associated with the deteriorative senescence in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs). For decades, Sodium Tanshinone IIA Sulfonate (STS) has been utilized as a cardiovascular medicine with acknowledged anti-inflammatory and anti-oxidative properties. Nevertheless, the impact of STS on vascular senescence remains unexplored in diabetes. Diabetic mice, primary ECs and VSMCs were transfected with the NLRP3 overexpression/knockout plasmid, the tumor necrosis factor alpha-induced protein 3 (TNFAIP3/A20) overexpression/knockout plasmid, and treated with STS to detect senescence-associated markers. In diabetic mice, STS treatment maintained catalase (CAT) level and vascular relaxation, reduced hydrogen peroxide probe (ROSgreen) fluorescence, p21 immunofluorescence, Senescence ß-Galactosidase Staining (SA-ß-gal) staining area, and collagen deposition in aortas. Mechanistically, STS inhibited NLRP3 phosphorylation (serine 194), NLRP3 dimer formation, NLRP3 expression, and NLRP3-PYCARD (ASC) colocalization. It also suppressed the phosphorylation of IkappaB alpha (IκBα) and NFκB, preserved A20 and CAT levels, reduced ROSgreen density, and decreased the expression of p21 and SA-ß-gal staining in ECs and VSMCs under HG culture. Our findings indicate that STS mitigates vascular senescence by modulating the A20-NFκB-NLRP3 inflammasome-CAT pathway in hyperglycemia conditions, offering novel insights into NLRP3 inflammasome activation and ECs and VSMCs senescence under HG culture. This study highlights the potential mechanism of STS in alleviating senescence in diabetic blood vessels, and provides essential evidence for its future clinical application.

Comparing shear wave elastography of breast tumors and axillary nodes in the axillary assessment after neoadjuvant chemotherapy in patients with node-positive breast cancer.

BACKGROUND: Accurately identifying patients with axillary pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) in breast cancer patients remains challenging. PURPOSE: To compare the feasibility of shear wave elastography (SWE) performed on breast tumors and axillary lymph nodes (LNs) in predicting the axillary status after NAC. MATERIALS AND METHODS: This prospective study included a total of 319 breast cancer patients with biopsy-proven positive node who received NAC followed by axillary lymph node dissection from 2019 to 2022. The correlations between shear wave velocity (SWV) and pathologic characteristics were analyzed separately for both breast tumors and LNs after NAC. We compared the performance of SWV between breast tumors and LNs in predicting the axillary status after NAC. Additionally, we evaluated the performance of the most significantly correlated pathologic characteristic in breast tumors and LNs to investigate the pathologic evidence supporting the use of breast or axilla SWE. RESULTS: Axillary pCR was achieved in 51.41% of patients with node-positive breast cancer. In breast tumors, there is a stronger correlation between SWV and collagen volume fraction (CVF) (r = 0.52, p < 0.001) compared to tumor cell density (TCD) (r = 0.37, p < 0.001). In axillary LNs, SWV was weakly correlated with CVF (r = 0.31, p = 0.177) and TCD (r = 0.29, p = 0.213). No significant correlation was found between SWV and necrosis proportion in breast tumors or axillary LNs. The predictive performances of both SWV and CVF for axillary pCR were found to be superior in breast tumors (AUC = 0.87 and 0.85, respectively) compared to axillary LNs (AUC = 0.70 and 0.74, respectively). CONCLUSION: SWE has the ability to characterize the extracellular matrix, and serves as a promising modality for evaluating axillary LNs after NAC. Notably, breast SWE outperform axilla SWE in determining the axillary status in breast cancer patients after NAC.

High bioavailable testosterone levels increase the incidence of isolated REM sleep behavior disorder: Results from multivariable and network Mendelian randomization analysis.

OBJECTIVES: To explore the causal relationships between sex hormone levels and incidence of isolated REM sleep behavior disorder (iRBD). METHODS: In our study, we utilized Genome-Wide Association Studies (GWAS) data for iRBD, including 9447 samples with 1061 cases of iRBD provided by the International RBD Study Group. Initially, we conducted a two-sample univariate MR analysis to explore the impact of sex hormone-related indicators on iRBD. This was followed by the application of multivariable MR methods to adjust for other hormone levels and potential confounders. Finally, we undertook a network MR analysis, employing brain structure Magnetic Resonance Imaging (MRI) characteristics as potential mediators, to examine whether sex hormones could indirectly influence the incidence of iRBD by affecting brain structure. RESULTS: Bioavailable testosterone (BioT) is an independent risk factor for iRBD (Odds Ratio [95 % Confidence Interval] = 2.437 [1.308, 4.539], P = 0.005, corrected-P = 0.020), a finding that remained consistent even after adjusting for other sex hormone levels and potential confounders. Additionally, BioT appears to indirectly increase the risk of iRBD by reducing axial diffusivity and increasing the orientation dispersion index in the left cingulum and cingulate gyrus. CONCLUSIONS: Our research reveals that elevated levels of BioT contribute to the development of iRBD. However, the specific impact of BioT on different sexes remains unclear. Furthermore, high BioT may indirectly lead to iRBD by impairing normal pathways in the left cingulum and cingulate gyrus and fostering abnormal pathway formation.

Dzip1 is dynamically expressed in the vertebrate germline and regulates the development of Xenopus primordial germ cells.

Primordial germ cells (PGCs) are the precursors of sperms and oocytes. Proper development of PGCs is crucial for the survival of the species. In many organisms, factors responsible for PGC development are synthesized during early oogenesis and assembled into the germ plasm. During early embryonic development, germ plasm is inherited by a few cells, leading to the formation of PGCs. While germline development has been extensively studied, how components of the germ plasm regulate PGC development is not fully understood. Here, we report that Dzip1 is dynamically expressed in vertebrate germline and is a novel component of the germ plasm in Xenopus and zebrafish. Knockdown of Dzip1 impairs PGC development in Xenopus embryos. At the molecular level, Dzip1 physically interacts with Dazl, an evolutionarily conserved RNA-binding protein that plays a multifaced role during germline development. We further showed that the sequence between amino acid residues 282 and 550 of Dzip1 is responsible for binding to Dazl. Disruption of the binding between Dzip1 and Dazl leads to defective PGC development. Taken together, our results presented here demonstrate that Dzip1 is dynamically expressed in the vertebrate germline and plays a novel function during Xenopus PGC development.

Correlation of Ktrans derived from dynamic contrast-enhanced MRI with treatment response and survival in locally advanced NSCLC patients undergoing induction immunochemotherapy and concurrent chemoradiotherapy.

PURPOSE: This study aimed to investigate the prognostic significance of pretreatment dynamic contrast-enhanced (DCE)-MRI parameters concerning tumor response following induction immunochemotherapy and survival outcomes in patients with locally advanced non-small cell lung cancer (NSCLC) who underwent immunotherapy-based multimodal treatments. MATERIAL AND METHODS: Unresectable stage III NSCLC patients treated by induction immunochemotherapy, concurrent chemoradiotherapy (CCRT) with or without consolidative immunotherapy from two prospective clinical trials were screened. Using the two-compartment Extend Tofts model, the parameters including Ktrans, Kep, Ve, and Vp were calculated from DCE-MRI data. The apparent diffusion coefficient was calculated from diffusion-weighted-MRI data. The receiver operating characteristic (ROC) curve and the area under the curve (AUC) were used to assess the predictive performance of MRI parameters. The Cox regression model was used for univariate and multivariate analysis. RESULTS: 111 unresectable stage III NSCLC patients were enrolled. Patients received two cycles of induction immunochemotherapy and CCRT, with or without consolidative immunotherapy. With the median follow-up of 22.3 months, the median progression-free survival (PFS) and overall survival (OS) were 16.3 and 23.8 months. The multivariate analysis suggested that Eastern Cooperative Oncology Group score, TNM stage and the response to induction immunochemotherapy were significantly related to both PFS and OS. After induction immunochemotherapy, 67 patients (59.8%) achieved complete response or partial response and 44 patients (40.2%) had stable disease or progressive disease. The Ktrans of primary lung tumor before induction immunochemotherapy yielded the best performance in predicting the treatment response, with an AUC of 0.800. Patients were categorized into two groups: high-Ktrans group (n=67, Ktrans＞164.3×10-3/min) and low-Ktrans group (n=44, Ktrans≤164.3×10-3/min) based on the ROC analysis. The high-Ktrans group had a significantly higher objective response rate than the low-Ktrans group (85.1% (57/67) vs 22.7% (10/44), p<0.001). The high-Ktrans group also presented better PFS (median: 21.1 vs 11.3 months, p=0.002) and OS (median: 34.3 vs 15.6 months, p=0.035) than the low-Ktrans group. CONCLUSIONS: Pretreatment Ktrans value emerged as a significant predictor of the early response to induction immunochemotherapy and survival outcomes in unresectable stage III NSCLC patients who underwent immunotherapy-based multimodal treatments. Elevated Ktrans values correlated positively with enhanced treatment response, leading to extended PFS and OS durations.

Developing an orbitally shaken bioreactor featuring a square vessel wall with a large circular chamfer.

The impact of orbitally shaking bioreactors (OSRs) on the biopharmaceutical industry is becoming increasingly important. In the preliminary exploration of the orbitally shaking bioreactor performance, the vessel wall shape has a crucial influence on the mixing and mass transfer in the bioreactor. However, the shape of OSRs still maintains a cylindrical structure, significantly limiting the advantages of the orbital shaking mixing. Therefore, in order to further improve the mixing and mass transfer performance of OSRs, a novel wall shape is proposed in this paper. This novel wall shape consists of cylindrical and square parts and looks like a square tank with a large circular chamfer (STCC), which was found could effectively enhance the efficiency of material mixing and mass transfer theoretically. Based on the same specific volumetric power consumption, a comparative analysis was conducted on the mixing time and oxygen transfer efficiency of OSRs with different shape walls using simulation and experimental methods. The results showed that the OSR with STCC was expected to perform higher mixing and oxygen transfer efficiency than the OSR with cylindrical wall. These findings suggested a promising prospect for the future application of the OSRs with STCC.

LINC00982-encoded protein PRDM16-DT regulates CHEK2 splicing to suppress colorectal cancer metastasis and chemoresistance.

Metastasis is one of the key factors of treatment failure in late-stage colorectal cancer (CRC). Metastatic CRC frequently develops resistance to chemotherapeutic agents. This study aimed to identify the novel regulators from "hidden" proteins encoded by long noncoding RNAs (lncRNAs) involved in tumor metastasis and chemoresistance. Methods: CRISPR/Cas9 library functional screening was employed to identify the critical suppressor of cancer metastasis in highly invasive CRC models. Western blotting, immunofluorescence staining, invasion, migration, wound healing, WST-1, colony formation, gain- and loss-of-function experiments, in vivo experimental metastasis models, multiplex immunohistochemical staining, immunohistochemistry, qRT-PCR, and RT-PCR were used to assess the functional and clinical significance of FOXP3, PRDM16-DT, HNRNPA2B1, and L-CHEK2. RNA-sequencing, co-immunoprecipitation, qRT-PCR, RT-PCR, RNA affinity purification, RNA immunoprecipitation, MeRIP-quantitative PCR, fluorescence in situ hybridization, chromatin immunoprecipitation and luciferase reporter assay were performed to gain mechanistic insights into the role of PRDM16-DT in cancer metastasis and chemoresistance. An oxaliplatin-resistant CRC cell line was established by in vivo selection. WST-1, colony formation, invasion, migration, Biacore technology, gain- and loss-of-function experiments and an in vivo experimental metastasis model were used to determine the function and mechanism of cimicifugoside H-1 in CRC. Results: The novel protein PRDM16-DT, encoded by LINC00982, was identified as a cancer metastasis and chemoresistance suppressor. The down-regulated level of PRDM16-DT was positively associated with malignant phenotypes and poor prognosis of CRC patients. Transcriptionally regulated by FOXP3, PRDM16-DT directly interacted with HNRNPA2B1 and competitively decreased HNRNPA2B1 binding to exon 9 of CHEK2, resulting in the formation of long CHEK2 (L-CHEK2), subsequently promoting E-cadherin secretion. PRDM16-DT-induced E-cadherin secretion inhibited fibroblast activation, which in turn suppressed CRC metastasis by decreasing MMP9 secretion. Cimicifugoside H-1, a natural compound, can bind to LEU89, HIS91, and LEU92 of FOXP3 and significantly upregulated PRDM16-DT expression to repress CRC metastasis and reverse oxaliplatin resistance. Conclusions: lncRNA LINC00982 can express a new protein PRDM16-DT to function as a novel regulator in cancer metastasis and drug resistance of CRC. Cimicifugoside H-1 can act on the upstream of the PRDM16-DT signaling pathway to alleviate cancer chemoresistance.

Photosensitizing metal covalent organic framework with fast charge transfer dynamics for efficient CO2 photoreduction.

Designing artificial photocatalysts for CO2 reduction is challenging, mainly due to the intrinsic difficulty of making multiple functional units cooperate efficiently. Herein, three-dimensional metal covalent organic frameworks (3D MCOFs) were employed as an innovative platform to integrate a strong Ru(ii) light-harvesting unit, an active Re(i) catalytic center, and an efficient charge separation configuration for photocatalysis. The photosensitive moiety was precisely stabilized into the covalent skeleton by using a rational-designed Ru(ii) complex as one of the building units, while the Re(i) center was linked via a shared bridging ligand with an Ru(ii) center, opening an effective pathway for their electronic interaction. Remarkably, the as-synthesized MCOF exhibited impressive CO2 photoreduction activity with a CO generation rate as high as 1840 µmol g-1 h-1 and 97.7% selectivity. The femtosecond transient absorption spectroscopy combined with theoretical calculations uncovered the fast charge-transfer dynamics occurring between the photoactive and catalytic centers, providing a comprehensive understanding of the photocatalytic mechanism. This work offers in-depth insight into the design of MCOF-based photocatalysts for solar energy utilization.

Fully dense generative adversarial network for removing artifacts caused by microwave dielectric effect in thermoacoustic imaging.

Microwave-induced thermoacoustic (TA) imaging (MTAI) combines pulsed microwave excitation and ultrasound detection to provide high contrast and spatial resolution images through dielectric contrast, which holds great promise for clinical applications. However, artifacts caused by microwave dielectric effect will seriously affect the accuracy of MTAI images that will hinder the clinical translation of MTAI. In this work, we propose a deep learning-based method fully dense generative adversarial network (FD-GAN) for removing artifacts caused by microwave dielectric effect in MTAI. FD-GAN adds the fully dense block to the generative adversarial network (GAN) based on the mutual confrontation between generator and discriminator, which enables it to learn both local and global features related to the removal of artifacts and generate high-quality images. The practical feasibility was tested in simulated, experimental data. The results demonstrate that FD-GAN can effectively remove the artifacts caused by the microwave dielectric effect, and shows superiority in denoising, background suppression, and improvement of image distortion. Our approach is expected to significantly improve the accuracy and quality of MTAI images, thereby enhancing the diagnostic accuracy of this innovative imaging technique.

Immune escape of avian oncogenic Marek's disease herpesvirus and antagonistic host immune responses.

Marek's disease virus (MDV) is a highly pathogenic and oncogenic alpha herpesvirus that causes Marek's disease (MD), which is one of the most important immunosuppressive and rapid-onset neoplastic diseases in poultry. The onset of MD lymphomas and other clinical diseases can be efficiently prevented by vaccination; these vaccines are heralded as the first demonstration of a successful vaccination strategy against a cancer. However, the persistent evolution of epidemic MDV strains towards greater virulence has recently resulted in frequent outbreaks of MD in vaccinated chicken flocks worldwide. Herein, we provide an overall review focusing on the discovery and identification of the strategies by which MDV evades host immunity and attacks the immune system. We have also highlighted the decrease in the immune efficacy of current MD vaccines. The prospects, strategies and new techniques for the development of efficient MD vaccines, together with the possibilities of antiviral therapy in MD, are also discussed.

LRG1 loss effectively restrains glomerular TGF-ß signaling to attenuate diabetic kidney disease.

Transforming growth factor (TGF)-ß signaling is a well-established pathogenic mediator of diabetic kidney disease (DKD). However, owing to its pleiotropic actions, its systemic blockade is not therapeutically optimal. The expression of TGF-ß signaling regulators can substantially influence TGF-ß's effects in a cell- or context-specific manner. Among these, leucine-rich α2-glycoprotein 1 (LRG1) is significantly increased in glomerular endothelial cells (GECs) in DKD. As LRG1 is a secreted molecule that can exert autocrine and paracrine effects, we examined the effects of LRG1 loss in kidney cells in diabetic OVE26 mice by single-cell transcriptomic analysis. Gene expression analysis confirmed a predominant expression of Lrg1 in GECs, which further increased in diabetic kidneys. Loss of Lrg1 led to the reversal of angiogenic and TGF-ß-induced gene expression in GECs, which were associated with DKD attenuation. Notably, Lrg1 loss also mitigated the increased TGF-ß-mediated gene expression in both podocytes and mesangial cells in diabetic mice, indicating that GEC-derived LRG1 potentiates TGF-ß signaling in glomerular cells in an autocrine and paracrine manner. Indeed, a significant reduction in phospho-Smad proteins was observed in the glomerular cells of OVE26 mice with LRG1 loss. These results indicate that specific antagonisms of LRG1 may be an effective approach to curb the hyperactive glomerular TGF-ß signaling to attenuate DKD.