Podocyte-Specific Silencing of Acid Sphingomyelinase Gene to Abrogate Hyperhomocysteinemia-Induced NLRP3 Inflammasome Activation and Glomerular Inflammation.

Acid Sphingomyelinase has been reported to increase tissue ceramide and thereby mediate hHcy-induced glomerular NLRP3 inflammasome activation, inflammation, and sclerosis. In the present study, we tested whether somatic podocyte-specific silencing of Smpd1 gene attenuates hHcy-induced NLRP3 inflammasome activation and associated exosome release in podocytes and thereby suppresses glomerular inflammatory response and injury. In vivo, somatic podocyte-specific Smpd1 gene silencing almost blocked hHcy-induced glomerular NLRP3 inflammasome activation in Podocre mice compared to control littermates. By nanoparticle tracking analysis, floxed Smpd1 shRNA transfection was found to abrogate hHcy-induced elevation of urinary exosome excretion in Podocre mice. In addition, Smpd1 gene silencing in podocytes prevented hHcy-induced immune cell infiltration into glomeruli, proteinuria, and glomerular sclerosis in Podocre mice. In cell studies, we also confirmed that Smpd1 gene knockout or silencing prevented Hcy-induced elevation of exosome release in the primary cultures of podocyte isolated from Smpd1-/- mice or podocytes of Podocre mice transfected with floxed Smpd1 shRNA compared to WT/WT podocytes. Smpd1 gene overexpression amplified Hcy-induced exosome secretion from podocytes of Smpd1trg/Podocre mice, which was remarkably attenuated by transfection of floxed Smpd1 shRNA. Mechanistically, Hcy-induced elevation of exosome release from podocytes was blocked by ASM inhibitor, but not by NLRP3 inflammasome inhibitors. Super-resolution microscopy also showed that ASM inhibitor, but not NLRP3 inflammasome inhibitors, prevented the inhibition of lysosome-multivesicular body interaction by Hcy in podocytes. In conclusion, our findings suggest that ASM in podocytes plays a crucial role in the control of NLRP3 inflammasome activation and exosome release.

Consolidation chemotherapy after definitive concurrent chemoradiotherapy in patients with inoperable esophageal squamous cell carcinoma: a multicenter non-inferiority phase III randomized clinical trial.

BACKGROUND: Definitive concurrent chemoradiotherapy (dCCRT) is the gold standard for the treatment of locally advanced esophageal squamous cell carcinoma (ESCC). However, the potential benefits of consolidation chemotherapy after dCCRT in patients with esophageal cancer remain debatable. Prospective randomized controlled trials comparing the outcomes of dCCRT with or without consolidation chemotherapy in patients with ESCC are lacking. In this study, we aim to generate evidence regarding consolidation chemotherapy efficacy in patients with locally advanced, inoperable ESCC. METHODS: This is a multicenter, prospective, open-label, phase-III randomized controlled trial comparing non-inferiority of dCCRT alone to consolidation chemotherapy following dCCRT. In total, 600 patients will be enrolled and randomly assigned in a 1:1 ratio to receive either consolidation chemotherapy after dCCRT (Arm A) or dCCRT alone (Arm B). Overall survival will be the primary endpoint, whereas progression-free survival, locoregional progression-free survival, distant metastasis-free survival, and treatment-related toxicity will be the secondary endpoints. DISCUSSION: This study aid in further understanding the effects of consolidation chemotherapy after dCCRT in patients with locally advanced, inoperable ESCC. TRIAL REGISTRATION: ChiCTR1800017646.

RNA N6-methyladenosine-modified-binding protein YTHDF1 promotes prostate cancer progression by regulating androgen function-related gene TRIM68.

PURPOSE: There is no report about the direct relationship between m6A modification and androgen receptor (AR)-related genes in prostate cancer (PC). We aimed to study the mechanisms of m6A methylation in regulating the pathogenesis of PC from the perspective of AR-related genes. METHODS: qRT-PCR was applied to detect the expression of m6A-related genes in PC cell with or without AR inhibitor. The effects of YTHDF1 knockdown on PC cell viability, apoptosis, migration and invasion were investigated using flow cytometry, wound healing and transwell assays, respectively. The mechanism of YTHDF1 action was investigated using m6A RNA immunoprecipitation (MeRIP) sequencing. The biological functions of YTHDF1 were also explored through in vivo experiments. RESULTS: YTHDF1 was significantly down-regulated in AR inhibitor group. YTHDF1 knockdown significantly decreased AR level, viability and m6A methylation level of PC cells. TRIM68 was identified as a direct target of YTHDF1. Both YTHDF1 and TRIM68 knockdown increased apoptosis, and decreased cell viability, migration, and invasion of PC cells, while TRIM68 overexpression reversed the effects of YTHDF1 knockdown on PC cells. In addition, knockdown of YTHDF1 or TRIM68 significantly decreased the m6A methylation level, and mRNA and protein levels of YTHDF1, TRIM68 and AR in PC cells, while TRIM68 overexpression increased the expression levels above. Furthermore, subcutaneous xenografts of nude mice also revealed that TRIM68 could reverse the effects of YTHDF1 knockdown in PC in vivo. CONCLUSION: This study suggested the key role of YTHDF1-mediated m6A modification in PC progression by regulating androgen function-related gene TRIM68 in PC.

The D ~ Sense ex-vivo viability assay application in a patient with stage IV lung adenocarcinoma: a case report.

BACKGROUND: The treatment resistance is a problem for lung cancer. In this study, we used a vitro tissue culturing system to select a new therapy strategy for a patient with tyrosine kinase inhibitors (TKIs) resistance. CASE PRESENTATION: A 42-year-old male Asian patient was diagnosed with advanced lung adenocarcinoma harboring an exon 19 deletion in the epidermal growth factor receptor (EGFR) gene. The patient was treated with Gefitinib, resulting in an almost complete remission for over a year. The patient relapsed after 13 months treatment, and received four cycles of chemotherapy. At 20 months, the patient had developed multiple lung metastases and a solitary cerebellar metastasis. An EGFR T790M mutation was identified in the peripheral blood sample. Subsequent treatment with Osimertinib resulted in a complete response of the intracranial metastasis. By 33 months, the patient had developed a mediastinal tumor mass that responded well to local radiotherapy. By 39 months, an EGFR C797S cis-mutation had been identified and the patient was treated with Brigatinib and Cetuximab. By 44 months, the tumor cells from the pleural effusion had been tested for sensitivity against 30 targeted and cytostatic drugs using the D ~ Sense ex-vivo viability assay. The assay identified 8 drugs with moderate to high sensitivity. Combination therapy of Gemcitabin and Lobaplatin had resulted in disease stabilization. CONCLUSIONS: The case showed that individualized treatment aided by D ~ Sense ex-vivo viability assay can be a viable option for patients with advanced lung adenocarcinoma with pleural effusions.

Nimotuzumab plus concurrent chemo-radiotherapy in unresectable locally advanced oesophageal squamous cell carcinoma (ESCC): interim analysis from a Phase 3 clinical trial.

BACKGROUND: This prospectively randomised, double-blinded, placebo-controlled, multicenter Phase 3 clinical trial was conducted to assess the efficacy and safety profile of nimotuzumab (nimo) plus concurrent chemo-radiotherapy (CCRT) in patients with unresectable locally advanced ESCC. METHODS: Patients were randomly assigned (1:1) to receive CCRT plus nimotuzumab or placebo. The primary endpoint was overall survival (OS). In addition, interim analysis for short-term response rate was pre-defined. RESULTS: A total of 201 patients were randomised into two groups. Eighty patients in the nimo group and eighty-two in the placebo group were evaluable. Three to six months after treatment, 26 (32.5%) patients achieved complete response (CR) in the nimo group, and 10 (12.2%) in the placebo group (P = 0.002). The ORR of the nimo group was significantly higher than the placebo group (93.8% vs. 72.0%, P < 0.001). The two groups' grade 3-5 adverse drug reactions were 11.1% vs. 10.9% (P > 0.05). CONCLUSIONS: Nimotuzumab, in combination with chemo-radiotherapy, increased the CRR and ORR with a good safety profile. The OS is needed to be followed and finally analysed. CLINICAL TRIAL REGISTRATION: NCT02409186.

Multi-engineered Graphene Extended-Gate Field-Effect Transistor for Peroxynitrite Sensing in Alzheimer's Disease.

The expression of ß-amyloid peptides (Aß), a pathological indicator of Alzheimer's disease (AD), was reported to be inapparent in the early stage of AD. While peroxynitrite (ONOO-) is produced excessively and emerges earlier than Aß plaques in the progression of AD, it is thus significant to sensitively detect ONOO- for early diagnosis of AD and its pathological research. Herein, we unveiled an integrated sensor for monitoring ONOO-, which consisted of a commercially available field-effect transistor (FET) and a high-performance multi-engineered graphene extended-gate (EG) electrode. In the configuration of the presented EG electrode, laser-induced graphene (LIG) intercalated with MnO2 nanoparticles (MnO2/LIG) can improve the electrical properties of LIG and the sensitivity of the sensor, and graphene oxide (GO)-MnO2/Hemin nanozyme with ONOO- isomerase activity can selectively trigger the isomerization of ONOO- to NO3-. With this synergistic effect, our EG-FET sensor can respond to the ONOO- with high sensitivity and selectivity. Moreover, taking advantage of our EG-FET sensor, we modularly assembled a portable sensing platform for wireless tracking ONOO- levels in the brain tissue of AD transgenic mice at earlier stages before massive Aß plaques appeared, and we systematically explored the complex role of ONOO- in the occurrence and development of AD.

Children's Daily Living Routine Mediates the Relations Between Parent-Child Relationships and Child Adjustment Problems During School Suspension in Hong Kong.

Young children's adjustment problems were found to be prevalent during the COVID-19 pandemic. Such adjustment problems may be dependent on children's relationships with their parents and children's daily living routine in the family during the pandemic-related school suspension period. This study examines how children's routine mediated the associations between parent-child relationships and child adjustment problems during the fifth wave of the COVID-19 pandemic in Hong Kong, when schools were suspended. The study collected data from 937 parents (87.8% mothers) of children aged 5-12 (M = 7.35 years, SD = 2.09; 50.5% girls). Parents reported on parent-child relationships, children's daily living routine, and child adjustment problems in an online survey. Our findings from structural equation modeling indicate that parent-child closeness was negatively related to child adjustment problems, whereas conflict was positively related to child adjustment problems. Children's routine mediated the associations between parent-child relationships (i.e., closeness and conflict) and child externalizing problems. However, children's routine did not mediate the associations between parent-child relationships (i.e., closeness and conflict) and child internalizing problems. The findings show that parents should be helped to establish routine, especially in difficult times when young children experience turbulence in their daily life, so as to reduce their adjustment problems, in particular of an externalizing nature.

Ultrafast Electronic Dynamics in Anisotropic Indirect Interlayer Excitonic States of Monolayer WSe2/ReS2 Heterojunctions.

Understanding ultrafast electronic dynamics of the interlayer excitonic states in atomically thin transition metal dichalcogenides is of importance in engineering valleytronics and developing excitonic integrated circuits. In this work, we experimentally explored the ultrafast dynamics of indirect interlayer excitonic states in monolayer type II WSe2/ReS2 heterojunctions using time-resolved photoemission electron microscopy, which reveals its anisotropic behavior. The ultrafast cooling and decay of excited-state electrons exhibit significant linear dichroism. The ab initio theoretical calculations provide unambiguous evidence that this linear dichroism result is primarily associated with the anisotropic nonradiative recombination of indirect interlayer excitonic states. Measuring time-resolved photoemission energy spectra, we have further revealed the ultrafast evolution of excited-state electrons in anisotropic indirect interlayer excitonic states. The findings have important implications for controlling the interlayer moiré excitonic effects and designing anisotropic optoelectronic devices.

The level of serum total bile acid is related to atherosclerotic lesions, prognosis and gut Lactobacillus in acute coronary syndrome patients.

BACKGROUND: Bile acids play crucial roles in various metabolisms, as well as Lactobacillus in the intestine. But studies on their roles in acute coronary syndrome (ACS) are still insufficient. The aim of this study was to investigate their role and potential association with the severity of coronary lesions and the prognosis of ACS. METHODS: Three hundred and sixty ACS patients were selected. Detection of gut Lactobacillus levels was done through 16S rDNA sequence analysis. Evaluation of the extent of lesions was done using the SYNTAX (SS) score. Mediation analysis was used to assess the relationship between serum total bile acid (TBA), Lactobacillus, atherosclerotic lesions and prognosis of ACS. RESULTS: Logistic regressive analysis disclosed that serum TBA and Lactobacillus were independent predictors of coronary lesions (high vs. low SS: serum TBA adjusted odds ratio (aOR) = 0.8, 95% confidence interval (CI): 0.6-0.9, p < .01; Lactobacillus: aOR = 0.9, 95% CI: 0.9-1.0, p = .03). According to multivariate Cox regression analysis, they were negatively correlated with the overall risk of all-cause death (serum TBA: adjusted hazard ratio (aHR) = 0.1, 95% CI: 0.0-0.6, p = .02; Lactobacillus: aHR = 0.6, 95% CI: 0.4-0.9, p = .01), especially in acute myocardial infarction (AMI) but not in unstable angina pectoris (UAP). Ulteriorly, mediation analysis showed that serum TBA played an important role as a mediation effect in the following aspects: Lactobacillus (17.0%, p < .05) â†’ SS association (per 1 standard deviation (SD) increase), Lactobacillus (43.0%, p < .05) â†’ all-cause death (per 1 SD increase) and Lactobacillus (45.4%, p < .05) â†’ cardiac death (per 1 SD increase). CONCLUSIONS: The lower serum TBA and Lactobacillus level in ACS patients, especially in AMI, was independently linked to the risk of coronary lesions, all-cause death and cardiac death. In addition, according to our mediation model, serum TBA served as a partial intermediate in predicting coronary lesions and the risk of death by Lactobacillus, which is paramount to further exploring the mechanism of Lactobacillus and bile acids in ACS.KEY MESSAGESLower level of serum total bile acid (TBA) was highly associated with the severity of coronary lesions, myocardial damage, inflammation and gut Lactobacillus in acute coronary syndrome (ACS) patients, especially in acute myocardial infarction (AMI).Lower level of serum TBA was highly associated with mortality (including all-cause death and cardiac death) in patients with ACS, especially with AMI.Serum TBA had a partial mediating effect rather than regulating effect between gut Lactobacillus and coronary lesions and prognosis of ACS.

Regulation of NLRP3 Inflammasome Activation and Inflammatory Exosome Release in Podocytes by Acid Sphingomyelinase During Obesity.

The activation of nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome has been reported to importantly contribute to glomerular inflammation and injury under different pathological conditions such as obesity. However, the mechanism mediating NLRP3 inflammasome activation in podocytes and subsequent glomerular injury remains poorly understood. Given that the ceramide signaling pathway has been reported to be implicated in obesity-related glomerulopathy (ORG), the present study was designed to test whether the ceramide-producing enzyme, acid sphingomyelinase (ASM), determines NLRP3 inflammasome activation and inflammatory exosome release in podocytes leading to glomerular inflammation and injury during ORG. In Smpd1trg/Podocre mice, podocyte-specific overexpression of Smpd1 gene which encodes ASM significantly exaggerated high-fat diet (HFD)-induced NLRP3 inflammasome activation in podocytes and immune cell infiltration in glomeruli compared to WT/WT mice. Smpd1 gene deletion, however, blocked these pathological changes induced by HFD in Smpd1-/- mice. Accompanied with NLRP3 inflammasome activation and glomerular inflammation, urinary excretion of exosomes containing podocyte marker and NLRP3 inflammasome products (IL-1ß and IL-18) in Smpd1trg/Podocre mice on the HFD was much higher than that in WT/WT mice. In contrast, Smpd1-/- mice on the HDF had significantly lower urinary exosome excretion than WT/WT mice. Correspondingly, HFD-induced podocyte injury, glomerular sclerosis, and proteinuria were more severe in Smpd1trg/Podocre mice, but milder in Smpd1-/- mice compared to WT/WT mice. Using podocytes isolated from these mice, we demonstrated that visfatin, a prototype pro-inflammatory adipokine, induced NLRP3 inflammasome activation and enrichment of multivesicular bodies (MVBs) containing IL-1ß in podocytes, which was much stronger in podocytes from Smpd1trg/Podocre mice, but weaker in those from Smpd1-/- mice than WT/WT podocytes. By quantitative analysis of exosomes, it was found that upon visfatin stimulation, podocytes from Smpd1trg/Podocre mice released much more exosomes containing NLRP3 inflammasome products, but podocytes from Smpd1-/- mice released much less exosomes compared to WT/WT podocytes. Super-resolution microscopy demonstrated that visfatin inhibited lysosome-MVB interaction in podocytes, indicating impaired MVB degradation by lysosome. The inhibition of lysosome-MVB interaction by visfatin was amplified by Smpd1 gene overexpression but attenuated by Smpd1 gene deletion. Taken together, our results suggest that ASM in podocytes is a crucial regulator of NLRP3 inflammasome activation and inflammatory exosome release that instigate glomerular inflammation and injury during obesity.

Mucilage secretion by aerial roots in sorghum (Sorghum bicolor): sugar profile, genetic diversity, GWAS and transcriptomic analysis.

Aerial root mucilage can enhance nitrogen fixation by providing sugar and low oxygen environment to the rhizosphere microbiome in Sierra Mixe maize. Aerial root mucilage has long been documented in sorghum (Sorghum bicolor), but little is known about the biological significance, genotypic variation, and genetic regulation of this biological process. In the present study, we found that a large variation of mucilage secretion capacity existed in a sorghum panel consisting of 146 accessions. Mucilage secretion occurred primarily in young aerial roots under adequately humid conditions but decreased or stopped in mature long aerial roots or under dry conditions. The main components of the mucilage-soluble were glucose and fructose, as revealed by sugar profiling of cultivated and wild sorghum. The mucilage secretion capacity of landrace grain sorghum was significantly higher than that of wild sorghum. Transcriptome analysis revealed that 1844 genes were upregulated and 2617 genes were downregulated in mucilage secreting roots. Amongst these 4461 differentially expressed genes, 82 genes belonged to glycosyltransferases and glucuronidation pathways. Sobic.010G120200, encoding a UDP-glycosyltransferase, was identified by both GWAS and transcriptome analysis as a candidate gene, which may be involved in the regulation of mucilage secretion in sorghum through a negative regulatory mechanism.

Identification of lncRNA, miRNA and mRNA expression profiles and ceRNA Networks in small cell lung cancer.

BACKGROUND: Small cell lung cancer (SCLC) is a highly lethal malignant tumor. It accounts for approximately 15% of newly diagnosed lung cancers. Long non-coding RNAs (lncRNAs) can regulate gene expression and contribute to tumorigenesis through interactions with microRNAs (miRNAs). However, there are only a few studies reporting the expression profiles of lncRNAs, miRNAs, and mRNAs in SCLC. Also, the role of differentially expressed lncRNAs, miRNAs, and mRNAs in relation to competitive endogenous RNAs (ceRNA) network in SCLC remain unclear. RESULTS: In the present study, we first performed next generation sequencing (NGS) with six pairs of SCLC tumors and adjacent non-cancerous tissues obtained from SCLC patients. Overall, 29 lncRNAs, 48 miRNAs, and 510 mRNAs were found to be differentially expressed in SCLC samples (|log2[fold change] |> 1; P < 0.05). Bioinformatics analysis was performed to predict and construct a lncRNA-miRNA-mRNA ceRNA network, which included 9 lncRNAs, 11 miRNAs, and 392 mRNAs. Four up-regulated lncRNAs and related mRNAs in the ceRNA regulatory pathways were selected and validated by quantitative PCR. In addition, we examined the role of the most upregulated lncRNA, TCONS_00020615, in SCLC cells. We found that TCONS_00020615 may regulate SCLC tumorigenesis through the TCONS_00020615-hsa-miR-26b-5p-TPD52 pathway. CONCLUSIONS: Our study provided the comprehensive analysis of the expression profiles of lncRNAs, miRNAs, and mRNAs of SCLC tumors and adjacent non-cancerous tissues. We constructed the ceRNA networks which may provide new evidence for the underlying regulatory mechanism of SCLC. We also found that the lncRNA TCONS_00020615 may regulate the carcinogenesis of SCLC.

Genomic architecture of leaf senescence in sorghum (Sorghum bicolor).

KEY MESSAGE: Leaf senescence in sorghum is primarily controlled by the progression, but not by the onset of senescence. The senescence-delaying haplotypes of 45 key genes accentuated from landraces to improved lines. Leaf senescence is a genetically programmed developmental process and plays a central role for plant survival and crop production by remobilising nutrients accumulated in senescent leaves. In theory, the ultimate outcome of leaf senescence is determined by the onset and progression of senescence, but how these two processes contribute to senescence is not fully illustrated in crops and the genetic basis for them is not well understood. Sorghum (Sorghum bicolor), which is known for the remarkable stay-green trait, is ideal for dissecting the genomic architecture underlying the regulation of senescence. In this study, a diverse panel of 333 sorghum lines was explored for the onset and progression of leaf senescence. Trait correlation analysis showed that the progression of leaf senescence, rather than the onset of leaf senescence, significantly correlated with variations of the final leaf greenness. This notion was further supported by GWAS, which identified 31 senescence-associated genomic regions containing 148 genes, of which 124 were related to the progression of leaf senescence. The senescence-delaying haplotypes of 45 key candidate genes were enriched in lines with extremely prolonged senescence duration, while senescence-promoting haplotypes in those with extremely accelerated senescence. Haplotype combinations of these genes could well explain the segregation of the senescence trait in a recombinant inbred population. We also demonstrated that senescence-delaying haplotypes of candidate genes were under strong selection during sorghum domestication and genetic improvement. Together, this research advanced our understanding of crop leaf senescence and provided a suite of candidate genes for functional genomics and molecular breeding.

The prediction value of platelet-derived growth factor for major adverse cardiovascular events in patients with acute non-ST-segment elevation myocardial infarction.

BACKGROUND: The value of plasma Platelet-Derived Growth Factor (PDGF) as a biomarker in predicting major adverse cardiovascular events (MACEs) in patients with acute non-ST-segment elevation myocardial infarction (NSTEMI) remains unclear. METHODS: A total of 242 patients with NSTEMI were enrolled in this observational cohort study. The correlation between PDGF and MACEs was evaluated during a five-year follow-up. Kaplan-Meier survival analysis with Cox proportional-hazards regression was used to identify predictive values of PDGF. RESULTS: The mean follow-up of NSTEMI patients was 1334 days. It was found that as the PDGF level increased, a significant uptrend in the incidence of MACEs and all-cause death, including the MACEs of 30 days, 180 days, 1 year, 5 years and the death of 1 year and 5 years (All Log-rank p < .05). Subgroup analysis further showed that PDGF had better predictive value for patients with age >65 years, GRACE score ≥140 and platelet count (PLT) >200 × 109/L. CONCLUSION: PDGF levels can predict short-term and long-term MACEs in NSTEMI patients after discharge, especially for patients with older age, higher GRACE score and baseline PLT > 200 × 109/L.Key messagesPDGF is a risk factor for short- and long-term MACEs in patients with STEMI.PDGF has a better prognostic value in patients with older age and PLT > 200 × 109/L.Baseline plasma PDGF levels were positively correlated with GRACE score.

Thermo-sensitive amylase-starch double-layer polymer nanoparticles with self-polishing and protein corona-free property for drug delivery applications.

Protein corona formation can lead to obstructive screening of targeting groups of nanoparticles (NPs). Also, the targeting groups are subjected to physiochemical interactions when exposed to solvents. Here, these two factors can influence NP targeting efficiency. Therefore, it is necessary to prepare a general method of preparing an anti-fouling NPs with protected targeting groups. Here, we designed α-amylase-starch double-layer coated poly (methyl methacrylate-co-acrylic acid) NPs (α-ams-SCMMA NPs), functionalized with aptamer targeting groups and doped with Tetrakis(para-hydraoxylphenyl) porphyrin (TPPOH) as a payload drug. Natural polysaccharide starch and enzyme α-amylase were applied here for thermo-sensitive activation of starch hydrolyzation in order to render the NPs' self-polishing from protein corona effects. During incubation with serum media, the protein corona was formed at the exterior shell of NPs, while the self-polishing process was activated to remove the "protein fouling" when the incubation temperature increased to 37 °C (body temperature). Mechanistically, the starch layer of α-ams-SCMMA NPs was readily hydrolysed by α-amylase, whereby the adsorbed protein corona could be efficiently eliminated and the targeting groups were then presented. With this unique self-polishing NP design, we believe our method can be applied for potential NP applications in cancer therepy due to excellent antifouling property and protected targeting groups.

Overexpression of lncRNA TUG1 enhances the efficacy of DC-CIK immunotherapy in neuroblastoma in vitro and in vivo.

BACKGROUND: Long non-coding RNA (LncRNA) TUG1 plays a critical role in the development of human cancers. This study explored whether TUG1 is involved in the cytotoxicity of dendritic cells and cytokine-induced killer cells (DCs-CIK), an immunotherapy approach, in neuroblastoma. METHODS: A TUG1 expression plasmid was transfected into DCs. Neuroblastoma SK-N-SH cells were incubated with CIK cells, DCs-CIK cells, and TUG1-overexpressing DCs-CIK cells, with or without irradiation. SK-N-SH cell viability, colony formation, migration, and apoptosis were analyzed using CCK-8, colony formation assay, transwell assay, and flow cytometry, respectively. Production of IL-12, IL-2 and IFN-γ in the supernatants was determined using ELISA. A dual luciferase activity assay was performed to confirm the molecular interactions between TUG1 and miR-204. Tumor-bearing mice were established by injection of SK-N-SH cells followed by stimulation with CIK cells, DC-CIK cells, and TUG1-overexpressing DCs-CIK cells. RESULTS: Compared to CIK alone or DC-CIK therapy, overexpression of TUG1 significantly suppressed tumor cell proliferation, colony formation, and migration of neuroblastoma cells. Moreover, upregulation of TUG1 robustly induced apoptosis and altered key molecules associated with apoptosis and epithelial-mesenchymal transition. Contents of IL-12, IL-2 and IFN-γ were dramatically elevated in the supernatants in the coculturing system upon transfection with TUG1. In addition, TUG1 was found to be act as miR-204 sponge. Furthermore, in vivo experiments demonstrated that upregulation of TUG1 potentiated the antitumor activity of DC-CIK immunotherapy. CONCLUSION: Overexpression of TUG1 promotes DC maturation and enhances CIK cytotoxicity, suggesting that TUG1 may be a novel target for enhancing DC-CIK based immunotherapy for neuroblastoma.

Correction: Efficiently increasing the radiative rate of TADF material with metal coordination.

Correction for 'Efficiently increasing the radiative rate of TADF material with metal coordination' by Xian-Bao Cai et al., Chem. Commun., 2022, 58, 8970-8973, https://doi.org/10.1039/D2CC02930H.

Hippocampal morphological atrophy and distinct patterns of structural covariance network in Alzheimer's disease and mild cognitive impairment.

Elucidating distinct morphological atrophy patterns of Alzheimer's disease (AD) and its prodromal stage, namely, mild cognitive impairment (MCI) helps to improve early diagnosis and medical intervention of AD. On that account, we aimed to obtain distinct patterns of voxel-wise morphological atrophy and its further perturbation on structural covariance network in AD and MCI compared with healthy controls (HCs). T1-weighted anatomical images of matched AD, MCI, and HCs were included in this study. Gray matter volume was obtained using voxel-based morphometry and compared among three groups. In addition, structural covariance network of identified brain regions exhibiting morphological difference was constructed and compared between pairs of three groups. Thus, patients with AD have a reduced hippocampal volume and an increased rate of atrophy compared with MCI and HCs. MCI exhibited a decreased trend in bilateral hippocampal volume compared with HCs and the accelerated right hippocampal atrophy rate than HCs. In AD, the hippocampus further exhibited increased structural covariance connected to reward related brain regions, including the anterior cingulate cortex, the putamen, the caudate, and the insula compared with HCs. In addition, the patients with AD exhibited increased structural covariance of left hippocampus with the bilateral insula, the inferior frontal gyrus, the superior temporal gyrus, and the cerebellum than MCI. These results reveal distinct patterns of morphological atrophy in AD and MCI, providing new insights into pathology of AD.

Wall-associated kinase-like gene RL1 contributes to red leaves in sorghum.

Red leaves are common in trees but rare in cereal crops. Red leaves can be used as raw materials for anthocyanin extraction and may have some adaptive significance for plants. In this study, we discovered a red leaf phenotype in the F1 hybrids derived from a cross between two sorghum accessions with green leaf. Histological analysis of red leaves and green leaves showed that red compounds accumulate in mesophyll cells and gradually spreads to the entire leaf blade. In addition, we found chloroplasts degraded more quickly in red leaves than in green leaves based on transmission electron microscopy. Metabolic analysis revealed that flavonoids including six anthocyanins are more abundant in red leaves. Moreover, transcriptome analysis revealed that expression of flavonoid biosynthesis genes was upregulated in red leaves. These observations indicate that flavonoids and anthocyanins in particular, are ideal candidates for the red compounds accumulating in red leaves. Segregation analysis of the red leaf phenotype suggested a genetic architecture consisting of three dominant genes, one (RL1 for RED LEAF1) of which we mapped to a 55-kb region on chromosome 7 containing seven genes. Sequencing, reverse transcription-polymerase chain reaction, and transcriptome analysis suggested Sobic.007G214300, encoding a wall-associated kinase, as the most likely candidate for RL1. Fine mapping the red leaf gene and identifying the metabolites that cause red leaf in sorghum provide us with a better understanding of the red leaf phenotype in the natural population of sorghum.