Application of metagenomic next-generation sequencing technology in the etiological diagnosis of peritoneal dialysis-associated peritonitis.

Pathogens detected by metagenomic next-generation sequencing (mNGS) and the laboratory blood culture flask method were compared to understand the advantages and clinical significance of mNGS assays in the etiological diagnosis of peritoneal dialysis-associated peritonitis (PDAP). The study involved a total of 37 patients from the hospital's peritoneal dialysis centre, six of whom were patients with non-peritoneal dialysis-associated peritonitis. Peritoneal dialysis samples were collected from the 37 patients, who were divided into two groups. One group's samples were cultured using conventional blood culture flasks, and the other samples underwent pathogen testing using mNGS. The results showed that the positive rate of mNGS was 96.77%, while that of the blood culture flask method was 70.97% (p < 0.05). A total of 29 pathogens were detected by mNGS, namely 24 bacteria, one fungus, and four viruses. A total of 10 pathogens were detected using the bacterial blood culture method, namely nine bacteria and one fungus. The final judgment of the PDAP's causative pathogenic microorganism was made by combining the clinical condition, response to therapy, and the whole-genome sequencing findings. For mNGS, the sensitivity was 96.77%, the specificity was 83.33%, the positive predictive value was 96.77%, and the negative predictive value was 83.33%. For the blood culture flask method, the sensitivity was 70.97%, the specificity was 100%, the positive predictive value was 100%, and the negative predictive value was 0%. In conclusion, mNGS had a shorter detection time for diagnosing peritoneal dialysis-related peritonitis pathogens, with a higher positive rate than traditional bacterial cultures, providing significant advantages in diagnosing rare pathogens.

Effect of Postoperative Prolonged sedation with Dexmedetomidine after successful reperfusion with Endovascular Thrombectomy on long-term prognosis in patients with acute ischemic stroke (PPDET): study protocol for a randomized controlled trial.

BACKGROUND: Endovascular thrombectomy (EVT) is a standard treatment for acute ischemic stroke (AIS) with large vessel occlusion. Hypertension and increased blood pressure variability within the first 24 h after successful reperfusion are related to a higher risk of symptomatic intracerebral hemorrhage and higher mortality. AIS patients might suffer from ischemia-reperfusion injury following reperfusion, especially within 24 h. Dexmedetomidine (DEX), a sedative commonly used in EVT, can stabilize hemodynamics by inhibiting the sympathetic nervous system and alleviate ischemia-reperfusion injury through anti-inflammatory and antioxidative properties. Postoperative prolonged sedation for 24 h with DEX might be a potential pharmacological approach to improve long-term prognosis after EVT. METHODS: This single-center, open-label, prospective, randomized controlled trial will include 368 patients. The ethics committee has approved the protocol. After successful reperfusion (modified thrombolysis in cerebral infarction scores 2b-3, indicating reperfusion of at least 50% of the affected vascular territory), participants are randomly assigned to the intervention or control group. In the intervention group, participants will receive 0.1~1.0 µg/kg/h DEX for 24 h. In the control group, participants will receive an equal dose of saline for 24 h. The primary outcome is the functional outcome at 90 days, measured with the categorical scale of the modified Rankin Scale, ranging from 0 (no symptoms) to 6 (death). The secondary outcome includes (1) the changes in stroke severity between admission and 24 h and 7 days after EVT, measured by the National Institute of Health Stroke Scale (ranging from 0 to 42, with higher scores indicating greater severity); (2) the changes in ischemic penumbra volume/infarct volume between admission and 7 days after EVT, measured by neuroimaging scan; (3) the length of ICU/hospital stay; and (4) adverse events and the all-cause mortality rate at 90 days. DISCUSSION: This randomized clinical trial is expected to verify the hypothesis that postoperative prolonged sedation with DEX after successful reperfusion may promote the long-term prognosis of patients with AIS and may reduce the related socio-economic burden. TRIAL REGISTRATION: ClinicalTrials.gov NCT04916197. Prospectively registered on 7 June 2021.

Safety, immunogenicity, and efficacy of a modified COVID-19 mRNA vaccine, SW-BIC-213, in healthy people aged 18 years and above: a phase 3 double-blinded, randomized, parallel controlled clinical trial in Lao PDR (Laos).

Background: The mRNA vaccine has demonstrated significant effectiveness in protecting against SARS-CoV-2 during the pandemic, including against severe forms of the disease caused by emerging variants. In this study, we examined safety, immunogenicity, and relative efficacy of a heterologous booster of the lipopolyplex (LPP)-based mRNA vaccine (SW-BIC-213) versus a homologous booster of an inactivated vaccine (BBIBP) in Laos. Methods: In this phase 3 clinical trial, which was randomized, parallel controlled and double-blinded, healthy adults aged 18 years and above were recruited from the Southern Savannakhet Provincial Hospital and Champhone District Hospital. The primary outcomes were safety and immunogenicity, with efficacy as an exploratory endpoint. Participants who were fully immunized with a two-dose inactivated vaccine for more than 6 months were assigned equally to either the SW-BIC-213 group (25 µg) or BBIBP group. The primary safety endpoint was to describe the safety profile of all participants in each group up to 6 months post-booster immunization. The primary immunogenic outcome was to demonstrate the superiority of the neutralizing antibody response, in terms of geometric mean titers (GMTs) of SW-BIC-213, compared with BBIBP 28 days after the booster dose. The exploratory efficacy endpoint aimed to assess the relative efficacy of SW-BIC-213 compared to BBIBP against virologically confirmed symptomatic COVID-19 over a 6-month period. The trial was registered with ClinicalTrials.gov (NCT05580159). Findings: Between October 10, 2022, and January 13, 2023, 1200 participants were assigned to SW-BIC-213 group and 1203 participants in the BBIBP group. All adverse reactions observed during the study were tolerable, transient, and resolved spontaneously. Solicited local reactions were the main adverse reactions in both the SW-BIC-213 group (43.8%) and BBIBP group (14.8%) (p < 0.001). Heterologous boosting with SW-BIC-213 induced higher live virus neutralizing antibodies to SARS-CoV-2 wildtype and BA.5 strains with GMTs reaching 750.1 and 192.9 than homologous boosting with BBIBP with GMTs of 131.5 (p < 0.001) and 47.5 (p < 0.001) on day 29. The statistical findings revealed that, following a period of 14-day to 6-month after booster vaccination, the SW-BIC-213 group exhibited a relative vaccine efficacy (VE) of 70.1% (95% CI: 34.2-86.4) against symptomatic COVID-19 when compared to the BBIBP group. Interpretation: A heterologous booster with the COVID-19 mRNA vaccine SW-BIC-213 manifests a favorable safety profile and proves highly immunogenic and efficacious in preventing symptomatic COVID-19 in individuals who have previously received two doses of inactivated vaccine. Funding: Shanghai Strategic Emerging Industries Development Special Fund, Biomedical Technology Support Special Project of Shanghai "Science and Technology Innovation Action Plan", Shanghai Municipal Science and Technology Commission.

Development of a model based on the age-adjusted Charlson comorbidity index to predict survival for resected perihilar cholangiocarcinoma.

BACKGROUND: Perihilar cholangiocarcinoma (pCCA) has a poor prognosis and urgently needs a better predictive method. The predictive value of the age-adjusted Charlson comorbidity index (ACCI) for the long-term prognosis of patients with multiple malignancies was recently reported. However, pCCA is one of the most surgically difficult gastrointestinal tumors with the poorest prognosis, and the value of the ACCI for the prognosis of pCCA patients after curative resection is unclear. AIM: To evaluate the prognostic value of the ACCI and to design an online clinical model for pCCA patients. METHODS: Consecutive pCCA patients after curative resection between 2010 and 2019 were enrolled from a multicenter database. The patients were randomly assigned 3:1 to training and validation cohorts. In the training and validation cohorts, all patients were divided into low-, moderate-, and high-ACCI groups. Kaplan-Meier curves were used to determine the impact of the ACCI on overall survival (OS) for pCCA patients, and multivariate Cox regression analysis was used to determine the independent risk factors affecting OS. An online clinical model based on the ACCI was developed and validated. The concordance index (C-index), calibration curve, and receiver operating characteristic (ROC) curve were used to evaluate the predictive performance and fit of this model. RESULTS: A total of 325 patients were included. There were 244 patients in the training cohort and 81 patients in the validation cohort. In the training cohort, 116, 91 and 37 patients were classified into the low-, moderate- and high-ACCI groups. The Kaplan-Meier curves showed that patients in the moderate- and high-ACCI groups had worse survival rates than those in the low-ACCI group. Multivariable analysis revealed that moderate and high ACCI scores were independently associated with OS in pCCA patients after curative resection. In addition, an online clinical model was developed that had ideal C-indexes of 0.725 and 0.675 for predicting OS in the training and validation cohorts. The calibration curve and ROC curve indicated that the model had a good fit and prediction performance. CONCLUSION: A high ACCI score may predict poor long-term survival in pCCA patients after curative resection. High-risk patients screened by the ACCI-based model should be given more clinical attention in terms of the management of comorbidities and postoperative follow-up.

Deafness-Associated ADGRV1 Mutation Impairs USH2A Stability through Improper Phosphorylation of WHRN and WDSUB1 Recruitment.

The ankle-link complex (ALC) consists of USH2A, WHRN, PDZD7, and ADGRV1 and plays an important role in hair cell development. At present, its architectural organization and signaling role remain unclear. By establishing Adgrv1 Y6236fsX1 mutant mice as a model of the deafness-associated human Y6244fsX1 mutation, the authors show here that the Y6236fsX1 mutation disrupts the interaction between adhesion G protein-coupled receptor V subfamily member 1 (ADGRV1) and other ALC components, resulting in stereocilia disorganization and mechanoelectrical transduction (MET) deficits. Importantly, ADGRV1 inhibits WHRN phosphorylation through regional cAMP-PKA signaling, which in turn regulates the ubiquitination and stability of USH2A via local signaling compartmentalization, whereas ADGRV1 Y6236fsX1 does not. Yeast two-hybrid screening identified the E3 ligase WDSUB1 that binds to WHRN and regulates the ubiquitination of USH2A in a WHRN phosphorylation-dependent manner. Further FlAsH-BRET assay, NMR spectrometry, and mutagenesis analysis provided insights into the architectural organization of ALC and interaction motifs at single-residue resolution. In conclusion, the present data suggest that ALC organization and accompanying local signal transduction play important roles in regulating the stability of the ALC.

Hsa_circ_0007334 Promotes the Osteogenic Differentiation and Proliferation of Human Bone Marrow Mesenchymal Stem Cells by Sponging miR-144-3p.

This study aimed to identify the possible function and the molecular mechanism of hsa_circ_0007334 in human bone marrow mesenchymal stem cells (hBMSCs) osteogenic differentiation. The level of hsa_circ_0007334 was detected by means of quantitative real-time polymerase chain reaction (RT-qPCR). Alkaline phosphatase (ALP), RUNX2, osterix (OSX), and osteocalcin (OCN) were monitored to analyze the degree of osteogenic differentiation under routine culture or under the control of hsa_circ_0007334. The proliferation of hBMSCs was tested with a cell counting kit-8 (CCK-8) assay. The migration of hBMSCs was tested using the Transwell assay. Bioinformatics analysis was used to predict the possible targets of hsa_circ_0007334 or miR-144-3p. Dual-luciferase reporter assay system was used to analyze the combination between hsa_circ_0007334 and miR-144-3p. Hsa_circ_0007334 was upregulated in osteogenic differentiation of hBMSCs. Osteogenic differentiation increased by hsa_circ_0007334 in vitro was confirmed with levels of ALP and bone markers (RUNX2, OCN, OSX). hsa_circ_0007334 overexpression promoted osteogenic differentiation, proliferation, and migration of hBMSCs, and knockdown of hsa_circ_0007334 has the opposite effects. miR-144-3p was identified as the target of hsa_circ_0007334. The targeting genes of miR-144-3p are involved in osteogenic-differentia-tion-related biological processes (such as bone development, epithelial cell proliferation, and mesenchymal cell apoptotic prosess) and pathways (including FoxO and VEGF signaling pathway). Hsa_circ_0007334, therefore, presents itself as a promising biological for osteogenic differentiation.

Characterization of laser cooling in microgravity via long-term operations in TianGong-2 space lab.

The invention of laser cooling has fundamentally influenced the research frontier of atomic physics and quantum physics, and recently an intense focus has been on the studies of cold atom physics in microgravity environments. Herein, we report the results of our laser cooling experiment in TianGong-2 space lab, which operated for 34 consecutive months in orbit. Over such an extended operation time, the quality of laser cooling did not experience any significant decline, while the properties of laser cooling in orbital microgravity were systematically studied. In particular, we demonstrate magneto-optical trapping and polarization-gradient cooling in orbit and carefully examine their performances. A comparison of the in-orbit and on-ground results indicates that a higher cooling efficiency exists in microgravity, including a smaller loss rate during the trapping and cooling process and lower ultimate temperature of laser-cooled atoms. Our progress has laid the technical foundations for future applications of cold atoms in space missions with operation times of the order of years.

Model and online calculator for prediction of fistula maturation based on vein dilation and age: A retrospective cohort study in a single-center.

OBJECTIVE: A model that considers the characteristics of dialysis patients may help predict successful fistula maturation. We evaluated factors associated with radiocephalic arteriovenous fistula (RCAVF) maturation at 3 months in dialysis patients with end-stage renal disease (ESRD). METHODS: A total of 184 patients who received an initial RCAVF at Beijing Haidian Hospital (Haidian Section of Peking University Third Hospital) were recruited. Fistula maturation was assessed within 3 months. Patient characteristics and preoperative vascular assessment indices were examined. Factors associated with fistula maturation were analyzed using logistic regression and least absolute shrinkage and selection operator (LASSO) binary logistic regression. Boostrapping was used for internal validation. RESULTS: The development data consisted of 184 ESRD patients receiving an initial RCAVF, 140 (76%) of whom achieved fistula maturation. The main predictors of RCAVF maturation in the final model were sex, age-adjusted vein dilation (eVD), radial artery volume (Vartery), and diastolic blood pressure. The difference of vein diameter with and without a tourniquet was significantly larger in the mature RCAVF group (3.0 ± 0.5 vs. 2.2 ± 0.5 mm). The area under receiver operating characteristic (AUROC) curve for prediction of fistula maturation was 0.77, and the Hosmer-Lemeshow statistic indicated agreement between observed and predicted values (P = 0.792). Analysis of internal validation using bootstrapping indicated the C-index was 0.75. CONCLUSION: The ratio of vein dilation and age were the major predictors of fistula maturation at 3 months in our patients. The resulting online prediction model may help in clinical decision-making for patients receiving a RCAVF.

[Correlations of 18F-FDG PET/CT Metabolic Parameters and Metabolic Heterogeneity with Human Epidermal Growth Factor Receptor 2 Expression in Patients with Gastric Cancer].

Objective To investigate the value of 18F-FDG PET/CT metabolic parameters and metabolic heterogeneity for predicting the expression of human epidermal growth factor receptor 2 (HER2) in patients with gastric cancer. Methods A total of 45 patients with gastric cancer confirmed by surgical pathology between September 2016 and May 2021 were enrolled in this study.All the patients underwent 18F-FDG PET/CT examination before surgery.The maximum standardized uptake value (SUVmax),metabolic tumor volume (MTV),and total lesion glycolysis (TLG) of primary gastric cancer were measured,and the linear regression slope of MTV corresponding to different SUVmax thresholds (40% SUVmax and 80% SUVmax) was calculated.The absolute value of the slope was deemed to represent the metabolic heterogeneity of primary gastric cancer,termed the heterogeneity index (HI).Univariate and multivariate Logistic regression analyses were conducted to evaluate the correlations of 18F-FDG PET/CT metabolic parameters and HI with HER2 expression. Results The 45 patients included 10 with positive HER2 expression and 35 with negative result.The MTV (P=0.043) and HI (P=0.048) were lower in the patients with positive HER2 expression than in the patients with negative HER2 expression.The MTV and HI had the optimal thresholds of 12.10 cm3 and 3.71,respectively,which respectively showed the accuracy of 62.2% and 57.8% for predicting HER2 expression.The univariate Logistic regression showed that the tumor differentiation degree,MTV,and HI were correlated with HER2 expression,while the multivariate Logistic regression showed that only the tumor differentiation degree (OR=20.130,95%CI=1.843-219.860,P=0.014) was an independent predictor for HER2 expression.A further stratified analysis of the tumor differentiation degree showed that HER2 expression only varied among different MTV threshold groups in patients with moderately/well differentiated gastric cancer (P=0.031). Conclusions MTV and HI were associated with HER2 expression in gastric cancer,whereas neither played an independent predictive role.Therefore,these factors should be combined with clinicopathological characteristics of patients to jointly guide treatment decisions.

[Spatiotemporal variations of fish feeding guilds in Yellow River basin]. / 黄河流域鱼类食性同资源种团的时空变化.

Conservation of fish resources is the key to ecological protection and high-quality development of Yellow River basin. From 1960 to 2019, Yellow River basin distributed 201 fish species, belonging to 16 orders, 35 families. The species number of Cypriniformes was the largest (accounting for 60.7%), followed by Perciformes (accounting for 10.0%). From 1960 to 1980, there were 182 fish species belonging to 15 orders, 28 families. During 1980-2019, there were 112 species, belonging to 10 orders, 23 families. The total number of fish species in source area, midstream and downstream decreased significantly, while that in the upper reaches increased slightly. Jaccard's similarity index of source area, upstream, midstream and downstream between two periods were 34.2%, 46.0%, 42.4% and 35.7%, respectively. Based on feeding preference characteristic, fish species could be divided into eight feeding guilds: phytobenthivores, herbivores, phytoplanktivores, zooplanktivores, omnivorous, insectivores, zoobenthivores, and piscivores. Compared with the period from 1960 to 1980, the proportion of insectivores decreased significantly in the Yellow River basin during 1980-2019, while that of phytobenthivores, herbivores, phytoplanktivores, omnivorous and piscivores increased significantly. From 1960 to 1980, the proportion of insectivores was higher than other reaches at source area and upstream, then began to decrease along the river continuum from reaches with elevation of 2000-3000 m; while the proportion of piscivores was lower than other reaches at source area and upstream, then began to increase along the river continuum from reaches with elevation of 2000-3000 m. From 1980 to 2019, the proportion of insectivores decreased along river continuum from source area, and that of piscivores increased from source area to midstream but decreased in downstream. Development of cascade hydropower, water pollution, insufficient water flow, overfishing and invasion of alien fish were important factors causing the spatiotemporal variations of fish feeding guilds in Yellow River basin.

Celeribacter litoreus sp. nov., isolated from intertidal sediment.

A Gram-negative, aerobic, non-flagellated and rod-shaped bacterium, strain ASW11-22T, was isolated from an intertidal sediment collected from a coastal area of Qingdao, PR China. The strain grew at 15-40 °C (optimum, 37 °C), at pH 6.0-9.0 (optimum, pH 7.0) and with 0.5-10 % (w/v) NaCl (optimum, 1.0 %). It hydrolysed gelatin and aesculin but did not reduce nitrate to nitrite. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain ASW11-22T belonged to the genus Celeribacter, showing the highest sequence similarity to the type strains of Celeribacter halophilus MCCC 1A06432T (98.20 %) and Celeribacter ethanolicus NH195T (97.84 %). The genomic DNA G+C content was 59.1 mol%. The major cellular fatty acid (>10 %) of the strain was summed feature 8 (C18 : 1 ω7c and/or C18 : 1 ω6c) and its main polar lipids were phosphatidylglycerol and one unidentified aminolipid. The sole respiratory quinone of strain ASW11-22T was ubiquinone-10. On the basis of the polyphasic evidence presented in this paper, strain ASW11-22T represents a novel Celeribacter species, for which the name Celeribacter litoreus sp. nov. is proposed. The type strain is ASW11-22T (=KCTC 82495T=MCCC 1K05584T).

FLO8 deletion leads to decreased adhesion and virulence with downregulated expression of EPA1, EPA6, and EPA7 in Candida glabrata.

BACKGROUND: The Candida glabrata does not develop into a pathogenic hiphal form; however, it has become the second most common pathogen of fungal infections in humans, partly because of its adhesion ability and virulence. OBJECTIVES: The present study aimed to determine whether Flo8, a transcription factor that plays an important role in the virulence and drug resistance in Candida albicans, has a similar role in C. glabrata. METHODS: We constructed FLO8 null strains of a C. glabrata standard strain and eight clinical strains from different sources, and a FLO8 complemented strain. Real-time quantitative PCR, biofilm formation assays, hydrophobicity tests, adhesion tests, Caenorhabditis elegans survival assay, and drug-susceptibility were then performed. RESULTS: Compared with the wild-type strains, the biofilm formation, hydrophobicity, adhesion, and virulence of the FLO8-deficient strains decreased, accompanied by decreased expression of EPA1, EPA6, and EPA7. On the other hand, it showed no changes in antifungal drug resistance, although the expression levels of CDR1, CDR2, and SNQ2 increased after FLO8 deletion. CONCLUSIONS: These results indicated that Flo8 is involved in the adhesion and virulence of C. glabrata, with FLO8 deletion leading to decreased expression of EPA1, EPA6, and EPA7 and decreased biofilm formation, hydrophobicity, adhesion, and virulence.

The Anti-Tumor Effect and Mechanism of Triterpenoids in Rhus chinensis Mill. on Reversing Effector CD8+ T-cells Dysfunction by Targeting Glycolysis Pathways in Colorectal Cancer.

Rhus chinensis Mill. is a traditional Chinese medicine (TCM) which is commonly used for cancer treatments. Our previous work had proven that triterpenoids of Rhus chinensis (TER) could effectively regulate glycolysis involved in colorectal cancer (CRC) and play an important role in the prevention of T-cells dysfunction. This study aimed to systematically investigate the effects and mechanisms of TER on glucose metabolism in CRC, while the regulatory mechanisms of TER on restoring T-cells function and activity in CRC were explored as well. The extract of triterpenoids from Rhus chinensis was obtained, and production of lactic acid and glucose uptake were assayed. Also, the expression of CD8+ T-cells surface markers, cytokines secreted by CD8+ T cells, and the expression of key glycolytic enzymes and glucose deprivation induced by tumor cells were further examined. Notably, results showed that TER prevented the dysfunction in CD8+ T cells by enhancing mTOR activity and subsequent cellular metabolism. Furthermore, our findings also demonstrated that TER promoted glycolytic gene expression in CD8+ T cells in vivo, and significantly inhibited tumor growth. Altogether, our studies suggested that TER not only reversed effector CD8+ T-cells dysfunction and enhanced T-cells recognition, but also improved tumor microenvironment, thereby providing new insight into the prevention and treatment of CRC with TCM.

Efficient tandem organic light-emitting diodes with non-doped structures.

Highly efficient tandem organic light-emitting diodes (TOLEDs) were achieved based on a non-doped charge generation unit (CGU) consisting of LiF/Al/C60/4,4',4"-tris(N-3-methylphenyl-N-phenyl-amino) triphenylamine (m-MTDATA) and ultrathin emitting layers. The current-voltage characteristics of the CGU devices and electron-only devices and the capacitance-voltage characteristics of the CGU-based capacitance devices were characterized to explore the charge generation and injection mechanisms. The charge generation process occurs at the interface of C60/m-MTDATA through electron transferring from the highest occupied molecular orbital of m-MTDATA to the lowest unoccupied molecular orbital of C60. It is found that the thinner C60 layer contributes to efficient electron injection. Under the optimal structure, the blue TOLEDs exhibit a maximum current efficiency (CEmax) of 43.3 cd/A. The CEmax and maximum external quantum efficiency (EQEmax) of the white TOLEDs reach 84.6 cd/A and 26.7%, respectively.

Effects and mechanisms of fatty acid metabolism­mediated glycolysis regulated by betulinic acid­loaded nanoliposomes in colorectal cancer.

Although previous studies have demonstrated that triterpenoids, such as betulinic acid (BA), can inhibit tumor cell growth, their potential targets in colorectal cancer (CRC) metabolism have not been systematically investigated. In the present study, BA­loaded nanoliposomes (BA­NLs) were prepared, and their effects on CRC cell lines were evaluated. The aim of the present study was to determine the anticancer mechanisms of action of BA­NLs in fatty acid metabolism­mediated glycolysis, and investigate the role of key targets, such as acyl­CoA synthetase (ACSL), carnitine palmitoyltransferase (CPT) and acetyl CoA, in promoting glycolysis, which is activated by inducing hexokinase (HK), phosphofructokinase­1 (PFK­1), phosphoenolpyruvate (PEP) and pyruvate kinase (PK) expression. The results demonstrated that BA­NLs significantly suppressed the proliferation and glucose uptake of CRC cells by regulating potential glycolysis and fatty acid metabolism targets and pathways, which forms the basis of the anti­CRC function of BA­NLs. Moreover, the effects of BA­NLs were further validated by demonstrating that the key targets of HK2, PFK­1, PEP and PK isoenzyme M2 (PKM2) in glycolysis, and of ACSL1, CPT1a and PEP in fatty acid metabolism, were blocked by BA­NLs, which play key roles in the inhibition of glycolysis and fatty acid­mediated production of pyruvate and lactate. The results of the present study may provide a deeper understanding supporting the hypothesis that liposomal BA may regulate alternative metabolic pathways implicated in CRC adjuvant therapy.

The effects and mechanisms of isoliquiritigenin loaded nanoliposomes regulated AMPK/mTOR mediated glycolysis in colorectal cancer.

In this study, isoliquiritigenin (ISL) incorporated nanoliposomes were prepared and their effects on colorectal cancer (CRC) cell lines were investigated. Herein, we sought to explore the anti-cancer mechanisms of ISL loaded nanoliposomes (ISL-NLs) on AMP-activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) pathways mediated glycolysis. Also, the key targets such as caveolin 1 (CAV1), glucose transporters and Akt/mTOR that promote glycolysis, and are activated via the induction of α-enolase (ENO1), fructose bisphosphate aldolase A (ALDOA) and monocarboxylate transporter 4 (MCT4) expressions were also investigated. It was shown that ISL-NLs significantly suppressed the proliferation and glucose uptake of CRC cell by potentially regulating the glycolysis and lactate targets as well as pathways that formed the basis of the anti-CRC effects of ISL-NLs. The mechanism underlying this effect was further validated via the regulation of some key targets such as ENO1, ALDOA, lactate dehydrogenase A (LDHA) and MCT4 in glycolysis coupled with cellular myelocytomatosis oncogene (c-myc), hypoxia-inducible factor 1-alpha (HIF-1α) in protein kinase B/mTOR (Akt/mTOR) pathways. Moreover, the AMPK proteins were identified to be up-regulated while the lactic acid production was suppressed by ISL-NLs in the CRC cells, indicating that ISL-NLs had an inhibitory effect on AMPK mediated glycolysis and lactate production. Altogether, these results have provided insights into the mechanism underlying the key role that liposomal ISL played in the multiple inhibition of AMPK and Akt/mTOR mediated glycolysis and lactate generation, which may be regulated as the alternative metabolic pathways of CRC as well as serve as adjuvant therapy for the disease.

Comparison between endovascular versus hybrid thrombectomy for arteriovenous graft under complete ultrasound guidance.

BACKGROUND: Endovascular treatment of acute thrombosed arteriovenous grafts performed completely under ultrasound guidance has rarely been reported. We compared the efficacy of a new endovascular thrombectomy technique (percutaneous manual thromboaspiration through the introducer sheath) with classical hybrid thrombectomy (minimally invasive surgical thrombectomy combined with high-pressure angioplasty) performed completely under ultrasound guidance, for arteriovenous graft thrombosis. METHODS: This was a retrospective cohort study involving patients receiving hemodialysis who underwent arteriovenous graft thrombectomy between January 2014 and December 2017. We divided 130 participants into an intervention (endovascular) group (N.=65) and a control (classical hybrid) group (N.=65) according to the thrombectomy technique. The procedural success rate, immediate outcomes and patency were compared between the groups. RESULTS: There was no significant difference in the procedural success rate (92.31% vs. 89.23%, P=0.55) between the intervention and control groups, respectively. No major complications were noted, but two cases of vessel rupture occurred in the control group and three cases of vessel rupture occurred in the intervention group. The procedure time in the intervention group was significantly shorter than that in the control group (74±14.21 min vs. 109.05±19.20 min, respectively; P<0.05). During the 6-month follow-up, we found no significant difference in the postintervention primary patency rate (48.33% vs. 55.17%; P=0.51) or the postintervention second patency rate (83.33% vs. 84.49%; P=0.79) between the intervention and control groups, respectively. Dialysis clearance and ≥50% stenosis were predictors of postintervention primary patency (hazard ratio, 7.80; 95% confidence interval: 1.75-34.81; P=0.01; and hazard ratio, 6.43; 95% confidence interval: 2.43-17.03; P<0.001), respectively. CONCLUSIONS: Completely ultrasound-guided percutaneous manual thromboaspiration through the introducer sheath can be used for thrombosed arteriovenous grafts. This approach has the advantage of shorter operative time compared with hybrid treatment.

Cognitive impairment and associated risk factors in older adult hemodialysis patients: a cross-sectional survey.

The clinical epidemiological features of cognitive impairment in Chinese older adult patients undergoing hemodialysis are not clear, we aimed to identify the extent and patterns of cognitive impairment among those patients. We conducted a cross-sectional study of 613 hemodialysis patients aged 50 to 80 from 11 centers in Beijing. A neuropsychological battery of 11 tests covering domains of attention/processing speed, executive function, memory, language, and visuospatial function was applied, patients were classified as none, mild, or major cognitive impairment according to the fifth version of the Diagnostic and Statistical Manual of Mental Disorders criteria for cognitive impairment. Compared with Chinese population norms, 37.2% of the participants had mild cognitive impairment, 43.7% had major cognitive impairment. Memory and language were the most severe impaired domains in the mild cognitive impairment group, attention and visuospatial function domains were the most serious impaired domains in the major cognitive impairment group. Concomitant impairment across multiple cognitive domains was common. Factors associated with major cognitive impairment included age, education level, history of stroke and hypertension, dialysis vintage, and single-pool Kt/V. There is a high frequency of cognitive impairment in Chinese older adult hemodialysis patients, with varying severity and concomitant impairment across multiple domains.

The Antitumor Activity of Betulinic Acid-Loaded Nanoliposomes Against Colorectal Cancer In Vitro and In Vivo via Glycolytic and Glutaminolytic Pathways.

The purpose of this study is to develop betulinic acid loaded nanoliposomes to improve the chemotherapy effect of colorectal cancer. The cellular uptake and anti-tumor effects of betulinic acid loaded nanoliposomes in vitro were characterized and evaluated, and their effects on glycolysis, glutamine decomposition and key anti-cancer targets were analyzed. Moreover, their anticancer efficacy was assessed in vivo. Compared with free betulinic acid in vitro, the cellular uptake and anti-tumor activity of betulinic acid-loaded nanoliposomes were significantly enhanced; these nanoliposomes significantly suppressed the proliferation and glucose uptake of colorectal cancer cells. Mechanistically, the anti-colorectal cancer effect of betulinic acid-loaded nanoliposomes was confirmed by their triggering of cellular apoptosis and regulating the potential glycolytic and glutaminolytic targets and pathways. After tumor proliferation was inhibited and colorectal cancer cells apoptosis, the anticancer effect of betulinic acid loaded nanoliposomes in vivo was significantly enhanced. All in all, betulinic acid loaded nanoliposomes are expected to be an effective drug delivery system for colorectal cancer treatment.

Transcriptomic analysis reveals recovery strategies in strawberry roots after using a soil amendment in continuous cropping soil.

BACKGROUND: In strawberry cultivation, continuous cropping (CC) obstacles seriously threaten production. A patented soil amendment (SA) can effectively relieve the CC obstacles to strawberry cultivation, but knowledge of the recovery mechanisms underlying this phenomenon is limited. RESULTS: In this study, transcriptomic profiling of strawberry roots in soil with and without the SA was conducted using RNA-Seq technology to reveal gene expression changes in response to SA treatment. In total, 188 differentially expressed genes (DEGs), including 144 upregulated and 44 downregulated DEGs, were identified. SA treatment resulted in genotype-dependent responses, and the response pattern, including an overall increase in the expression of nutrient transport genes and a decrease in the expression of defense response genes, may be a possible mechanism underlying recovery strategies in strawberry roots after the application of the SA to CC soil. We also found that 9 Hsp genes involved in plant defense pathways were all downregulated in the SA-treated roots. CONCLUSIONS: This research indicated that strawberry plants reallocated defense resources to development when SA treatment alleviated the stress caused by a CC soil environment. The present study provides an opportunity to reveal the fundamental mechanisms of the tradeoff between growth and defense in strawberry.