Structural Basis for Mitotic Centrosome Assembly in Flies.

In flies, Centrosomin (Cnn) forms a phosphorylation-dependent scaffold that recruits proteins to the mitotic centrosome, but how Cnn assembles into a scaffold is unclear. We show that scaffold assembly requires conserved leucine zipper (LZ) and Cnn-motif 2 (CM2) domains that co-assemble into a 2:2 complex in vitro. We solve the crystal structure of the LZ:CM2 complex, revealing that both proteins form helical dimers that assemble into an unusual tetramer. A slightly longer version of the LZ can form micron-scale structures with CM2, whose assembly is stimulated by Plk1 phosphorylation in vitro. Mutating individual residues that perturb LZ:CM2 tetramer assembly perturbs the formation of these micron-scale assemblies in vitro and Cnn-scaffold assembly in vivo. Thus, Cnn molecules have an intrinsic ability to form large, LZ:CM2-interaction-dependent assemblies that are critical for mitotic centrosome assembly. These studies provide the first atomic insight into a molecular interaction required for mitotic centrosome assembly.

An endoscopically compatible fast-gelation powder forms Janus-adhesive hydrogel barrier to prevent postoperative adhesions.

Postoperative adhesions occur widely in various tissues, bringing the risk of secondary surgery and increased medical burden. Hydrogel barriers with Janus-adhesive ability can achieve physical isolation of adjacent tissues and are therefore considered an ideal solution. However, integrating endoscopic delivery convenience and viscoelastic Janus hydrogel formation remains a great challenge. Here, we present a report of the in situ formation of Janus-adhesive hydrogel barrier using a sprayable fast-Janus-gelation (FJG) powder. We first methacrylate the polysaccharide macromolecules to break the intermolecular hydrogen bonds and impart the ability of rapid hydration. FJG powder can rapidly absorb interfacial water and crosslink through borate ester bonds, forming a toughly adhesive viscoelastic hydrogel. The Janus barrier can be simply formed by further hydrating the upper powder with cationic solution. We construct rat models to demonstrate the antiadhesions efficiency of viscoelastic FJG hydrogels in organs with different motion modalities (e.g., intestine, heart, liver). We also developed a low-cost delivery device with a standardized surgical procedure and further validated the feasibility and effectiveness of FJG powder in minimally invasive surgery using a preclinical translational porcine model. Considering the advantages in terms of therapeutic efficacy, clinical convenience, and commercialization, our results reveal the great potential of Janus-gelation powder materials as a next-generation antiadhesions barrier.

MCM8 promotes lung cancer progression through upregulating DNAJC10.

MCM8 is a helicase, which participates in DNA replication and tumorigenesis and is upregulated in many human cancers, including lung cancer (LC); however, the function of MCM8 in LC tumour progression is unclear. In this study, we found that MCM8 was expressed at high levels in LC cells and tissues. Further, MCM8 upregulation was associated with advanced tumour grade and lymph node metastasis, and indicated poor prognosis. Silencing of MCM8 suppressed cell growth and migration in vitro and in vivo, while ectopic MCM8 expression promoted cell cycle progression, as well as cell migration, proliferation, and apoptosis. Mechanistically, DNAJC10 was identified as a downstream target of MCM8, using gene array and CO-IP assays. DNAJC10 overexpression combatted the inhibitory activity of MCM8 knockdown on LC progression, while silencing DNAJC10 alleviated the oncogenic function of MCM8 overexpression. MCM8 expression was positively correlated with that of DNAJC10 in LC samples from The Cancer Genome Atlas database, and DNAJC10 upregulation was also associated with poor overall survival of patients with LC. This study indicated that MCM8/DNAJC10 axis plays an important role in in LC development, and maybe as a new potential therapeutic target or a diagnostic biomarker for treating patients with LC.

Convolutional Neural Network-Driven Impedance Flow Cytometry for Accurate Bacterial Differentiation.

Impedance flow cytometry (IFC) has been demonstrated to be an efficient tool for label-free bacterial investigation to obtain the electrical properties in real time. However, the accurate differentiation of different species of bacteria by IFC technology remains a challenge owing to the insignificant differences in data. Here, we developed a convolutional neural networks (ConvNet) deep learning approach to enhance the accuracy and efficiency of the IFC toward distinguishing various species of bacteria. First, more than 1 million sets of impedance data (comprising 42 characteristic features for each set) of various groups of bacteria were trained by the ConvNet model. To improve the efficiency for data analysis, the Spearman correlation coefficient and the mean decrease accuracy of the random forest algorithm were introduced to eliminate feature interaction and extract the opacity of impedance related to the bacterial wall and membrane structure as the predominant features in bacterial differentiation. Moreover, the 25 optimized features were selected with differentiation accuracies of >96% for three groups of bacteria (bacilli, cocci, and vibrio) and >95% for two species of bacilli (Escherichia coli and Salmonella enteritidis), compared to machine learning algorithms (complex tree, linear discriminant, and K-nearest neighbor algorithms) with a maximum accuracy of 76.4%. Furthermore, bacterial differentiation was achieved on spiked samples of different species with different mixing ratios. The proposed ConvNet deep learning-assisted data analysis method of IFC exhibits advantages in analyzing a huge number of data sets with capacity for extracting predominant features within multicomponent information and will bring about progress and advances in the fields of both biosensing and data analysis.

Clonal expansion of shared T cell receptors reveals the existence of immune commonality among different lesions of synchronous multiple primary lung cancer.

The increase in the detection rate of synchronous multiple primary lung cancer (MPLC) has posed remarkable clinical challenges due to the limited understanding of its pathogenesis and molecular features. Here, comprehensive comparisons of genomic and immunologic features between MPLC and solitary lung cancer nodule (SN), as well as different lesions of the same patient, were performed. Compared with SN, MPLC displayed a lower rate of EGFR mutation but higher rates of BRAF, MAP2K1, and MTOR mutation, which function exactly in the upstream and downstream of the same signaling pathway. Considerable heterogeneity in T cell receptor (TCR) repertoire exists among not only different patients but also among different lesions of the same patient. Invasive lesions of MPLC exhibited significantly higher TCR diversity and lower TCR expansion than those of SN. Intriguingly, different lesions of the same patient always shared a certain proportion of TCR clonotypes. Significant clonal expansion could be observed in shared TCR clonotypes, particularly in those existing in all lesions of the same patient. In conclusion, this study provided evidences of the distinctive mutational landscape, activation of oncogenic signaling pathways, and TCR repertoire in MPLC as compared with SN. The significant clonal expansion of shared TCR clonotypes demonstrated the existence of immune commonality among different lesions of the same patient and shed new light on the individually tailored precision therapy for MPLC.

Ru Single-Atom Nanoarchitectonics on Co-Based Conducting Metal-Organic Frameworks for Enhanced Oxygen Evolution Reaction.

The development of oxygen evolution reaction (OER) electrocatalysts is essential for the production of green hydrogen from water electrolysis, but it is challenging. Herein, ruthenium (Ru) single-atom-modified Co-HHTP (HHTP = 2,3,6,7,10,11-hexahydroxytriphenylene) (Ru@Co-HHTP) was prepared via a solvothermal and ion exchange method. Systematic experiments highlight that the atomically dispersed Ru can optimize the electronic structure and electronic conductivity of Co-HHTP. As a result, the obtained Ru@Co-HHTP shows a low overpotential of 247 mV at 100 mA cm-2, a small Tafel slope of 38.14 mV dec-1, and good stability, which are superior to those of Co-HHTP, commercial IrO2, and most previously reported catalysts. This work provides a new avenue for designing highly efficient elongated OER electrocatalysts.

Single-cell dissection of cellular and molecular features underlying mesenchymal stem cell therapy in ischemic acute kidney injury.

Mesenchymal stem cells (MSCs) exert beneficial therapeutic effects in acute kidney injury (AKI), while the detailed repair mechanism remains unclear. Herein, we probed the underlying mechanisms of MSC therapy in AKI by performing unbiased single-cell RNA sequencing in IRI model with/without MSC treatment. Our analyses uncovered the tubular epithelial cells (TECs) and immune cells transcriptomic diversity and highlighted a repair trajectory involving renal stem/progenitor cell differentiation. Our findings also suggested that profibrotic TECs expressing pro-fibrotic factors such as Zeb2 and Pdgfb promoted the recruitment of inflammatory monocytes and Th17 cells to injured kidney tissue, inducing TGF-ß1 secretion and renal fibrosis. Finally, in addition to activating the repair properties of renal progenitor/stem cells, we uncovered a role for MSC-derived miR-26a-5p in mediating the therapeutic effects of MSCs by inhibiting Zeb2 expression and suppressing pro-fibrotic TECs and its subsequent recruitment of immune cell subpopulations. These findings may help to optimize future AKI treatment strategies.

Monovalent, bivalent and biparatopic nanobodies targeting S1 protein of porcine epidemic diarrhea virus efficiently neutralized the virus infectivity.

BACKGROUND: Porcine epidemic diarrhea virus (PEDV) is a highly contagious coronavirus that causes severe diarrhea and death in neonatal piglets, which has brought huge economic losses to the pork industry worldwide since its first discovery in the early 1970s in Europe. Passive immunization with neutralizing antibodies against PEDV is an effective prevention measure. To date, there are no effective therapeutic drugs to treat the PEDV infection. RESULTS: We conducted a screening of specific nanobodies against the S1 protein from a phage display library obtained from immunized alpacas. Through competitive binding to antigenic epitopes, we selected instead of chose nanobodies with high affinity and constructed a multivalent tandem. These nanobodies were shown to inhibit PEDV infectivity by the neutralization assay. The antiviral capacity of nanobody was found to display a dose-dependent pattern, as demonstrated by IFA, TCID50, and qRT-PCR analyses. Notably, biparatopic nanobody SF-B exhibited superior antiviral activity. Nanobodies exhibited low cytotoxicity and high stability even under harsh temperature and pH conditions, demonstrating their potential practical applicability to animals. CONCLUSIONS: Nanobodies exhibit remarkable biological properties and antiviral effects, rendering them a promising candidate for the development of anti-PEDV drugs.

Assessing patient information needs for new antidiabetic medications to inform shared decision-making: A best-worst scaling experiment in China.

BACKGROUND: Shared decision-making (SDM) is a patient-centred approach to improve the quality of care. An essential requirement for the SDM process is to be fully aware of patient information needs. OBJECTIVES: Our study aimed to assess patient information needs for new antidiabetic medications using the best-worst scaling (BWS) experiment. METHODS: BWS tasks were developed according to a literature review and the focus group discussion. We used a balanced incomplete block design and blocking techniques to generate choice sets. The final BWS contains 11 attributes, with 6-choice scenarios in each block. The one-to-one, face-to-face BWS survey was conducted among type 2 diabetic patients in Jiangsu Province. Results were analyzed using count-based analysis and modelling approaches. We also conducted a subgroup analysis to observe preference heterogeneity. RESULTS: Data from 539 patients were available for analysis. The most desired information domain was the comparative effectiveness of new antidiabetic medications. It consists of the incidence of macrovascular complications, the length of extended life years, changes in health-related quality of life, the incidence of microvascular complications, and the control of glycated haemoglobin. Of all the attributes, the incidence of macrovascular complications was the primary concern. Patients' glycemic control and whether they had diabetes complications exerted a significant influence on their information needs. CONCLUSIONS: Information on health benefits is of critical significance for diabetic patients. Patients have different information needs as their disease progresses. Personalized patient decision aids that integrate patient information needs and provide evidence of new antidiabetic medications are worthy of being established. PATIENT OR PUBLIC CONTRIBUTION: Before data collection, a pilot survey was carried out among diabetic patients to provide feedback on the acceptability and intelligibility of the attributes.

Acute kidney injury in hospitalized patients with nonmalignant pleural effusions: a retrospective cohort study.

BACKGROUND: Nonmalignant pleural effusion (NMPE) is common and remains a definite health care problem. Pleural effusion was supposed to be a risk factor for acute kidney injury (AKI). Incidence of AKI in NMPE patients and whether there is correlation between the size of effusions and AKI is unknown. OBJECTIVE: To assess the incidence of AKI in NMPE inpatients and its association with effusion size. STUDY DESIGN AND METHOD: We conducted a retrospective cohort study of inpatients admitted to the Chinese PLA General Hospital with pleural effusion from 2018-2021. All patients with pleural effusions confirmed by chest radiography (CT or X-ray) were included, excluding patients with diagnosis of malignancy, chronic dialysis, end-stage renal disease (ESRD), community-acquired AKI, hospital-acquired AKI before chest radiography, and fewer than two serum creatinine tests during hospitalization. Multivariate logistic regression and LASSO logistic regression models were used to identify risk factors associated with AKI. Subgroup analyses and interaction tests for effusion volume were performed adjusted for the variables selected by LASSO. Causal mediation analysis was used to estimate the mediating effect of heart failure, pneumonia, and eGFR < 60 ml/min/1.73m2 on AKI through effusion volume. RESULTS: NMPE was present in 7.8% of internal medicine inpatients. Of the 3047 patients included, 360 (11.8%) developed AKI during hospitalization. After adjustment by covariates selected by LASSO, moderate and large effusions increased the risk of AKI compared with small effusions (moderate: OR 1.47, 95%CI 1.11-1.94 p = 0.006; large: OR 1.86, 95%CI 1.05-3.20 p = 0.028). No significant modification effect was observed among age, gender, diabetes, bilateral effusions, and eGFR. Volume of effusions mediated 6.8% (p = 0.005), 4.0% (p = 0.046) and 4.6% (p < 0.001) of the effect of heart failure, pneumonia and low eGFR on the development of AKI respectively. CONCLUSION: The incidence of AKI is high among NMPE patients. Moderate and large effusion volume is independently associated with AKI compared to small size. The effusion size acts as a mediator in heart failure, pneumonia, and eGFR.

Early warm-season mesoscale convective systems dominate soil moisture-precipitation feedback for summer rainfall in central United States.

Land-atmosphere interactions play an important role in summer rainfall in the central United States, where mesoscale convective systems (MCSs) contribute to 30 to 70% of warm-season precipitation. Previous studies of soil moisture-precipitation feedbacks focused on the total precipitation, confounding the distinct roles of rainfall from different convective storm types. Here, we investigate the soil moisture-precipitation feedbacks associated with MCS and non-MCS rainfall and their surface hydrological footprints using a unique combination of these rainfall events in observations and land surface simulations with numerical tracers to quantify soil moisture sourced from MCS and non-MCS rainfall. We find that early warm-season (April to June) MCS rainfall, which is characterized by higher intensity and larger area per storm, produces coherent mesoscale spatial heterogeneity in soil moisture that is important for initiating summer (July) afternoon rainfall dominated by non-MCS events. On the other hand, soil moisture sourced from both early warm-season MCS and non-MCS rainfall contributes to lower-level atmospheric moistening favorable for upscale growth of MCSs at night. However, soil moisture sourced from MCS rainfall contributes to July MCS rainfall with a longer lead time because with higher intensity, MCS rainfall percolates into deeper soil that has a longer memory. Therefore, early warm-season MCS rainfall dominates soil moisture-precipitation feedback. This motivates future studies to examine the contribution of early warm-season MCS rainfall and associated soil moisture anomalies to predictability of summer rainfall in the major agricultural region of the central United States and other continental regions frequented by MCSs.

Combining Functional Units to Design Organic Materials with Dynamic Room-Temperature Phosphorescence under Continuous Ultraviolet Irradiation.

Developing materials with dynamic room-temperature phosphorescence (RTP) properties is crucial for expanding the applications of organic light-emitting materials. In this study, we designed and synthesized two novel RTP molecules by combining functional units, incorporating the folded unit thianthrene into the classic luminescent cores thioxanthone or anthraquinone to construct TASO and TA2O. In this combination, the TA unit contributes to the enhancement of spin-orbit coupling (SOC), while the luminescent core governs the triplet energy level. After the strategic manipulation of SOC using the thianthrene unit, the target molecules exhibited a remarkable enhancement in RTP performance. This strategy led to the successful development of TASO and TA2O molecules with outstanding dynamic RTP properties when exposed to continuous ultraviolet irradiation, a result that can be ascribed to their efficient RTP, improved absorption ability, and oxygen-sensitive RTP properties. Leveraging the oxygen-mediated ultraviolet-radiation-induced RTP enhancement in TASO-doped polymer films, we developed a novel time-resolved detection technique for identifying phase separation in polymers with varying oxygen permeability. This research offers a promising approach for constructing materials with dynamic RTP properties.

Photoactivatable Engineering of CRISPR/Cas9-Inducible DNAzyme Probe for In Situ Imaging of Nuclear Zinc Ions.

DNAzyme-based fluorescent probes for imaging metal ions in living cells have received much attention recently. However, employing in situ metal ions imaging within subcellular organelles, such as nucleus, remains a significant challenge. We developed a three-stranded DNAzyme probe (TSDP) that contained a 20-base-pair (20-bp) recognition site of a CRISPR/Cas9, which blocks the DNAzyme activity. When Cas9, with its specialized nuclear localization function, forms an active complex with sgRNA within the cell nucleus, it cleaves the TSDP at the recognition site, resulting in the in situ formation of catalytic DNAzyme structure. With this design, the CRISPR/Cas9-inducible imaging of nuclear Zn2+ is demonstrated in living cells. Moreover, the superiority of CRISPR-DNAzyme for spatiotemporal control imaging was demonstrated by integrating it with photoactivation strategy and Boolean logic gate for dynamic monitoring nuclear Zn2+ in both HeLa cells and mice. Collectively, this conceptual design expands the DNAzyme toolbox for visualizing nuclear metal ions and thus provides new analytical methods for nuclear metal-associated biology.

The PI3K-Akt-mTOR pathway mediates renal pericyte-myofibroblast transition by enhancing glycolysis through HKII.

BACKGROUND: Pericyte-myofibroblast transition (PMT) has been confirmed to contribute to renal fibrosis in several kidney diseases, and transforming growth factor-ß1 (TGF-ß1) is a well-known cytokine that drives PMT. However, the underlying mechanism has not been fully established, and little is known about the associated metabolic changes. METHODS: Bioinformatics analysis was used to identify transcriptomic changes during PMT. PDGFRß + pericytes were isolated using MACS, and an in vitro model of PMT was induced by 5 ng/ml TGF-ß1. Metabolites were analyzed by ultraperformance liquid chromatography (UPLC) and tandem mass spectrometry (MS). 2-Deoxyglucose (2-DG) was used to inhibit glycolysis via its actions on hexokinase (HK). The hexokinase II (HKII) plasmid was transfected into pericytes for HKII overexpression. LY294002 or rapamycin was used to inhibit the PI3K-Akt-mTOR pathway for mechanistic exploration. RESULTS: An increase in carbon metabolism during PMT was detected through bioinformatics and metabolomics analysis. We first detected increased levels of glycolysis and HKII expression in pericytes after stimulation with TGF-ß1 for 48 h, accompanied by increased expression of α-SMA, vimentin and desmin. Transdifferentiation was blunted when pericytes were pretreated with 2-DG, an inhibitor of glycolysis. The phosphorylation levels of PI3K, Akt and mTOR were elevated during PMT, and after inhibition of the PI3K-Akt-mTOR pathway with LY294002 or rapamycin, glycolysis in the TGF-ß1-treated pericytes was decreased. Moreover, PMT and HKII transcription and activity were blunted, but the plasmid-mediated overexpression of HKII rescued PMT inhibition. CONCLUSIONS: The expression and activity of HKII as well as the level of glycolysis were increased during PMT. Moreover, the PI3K-Akt-mTOR pathway regulates PMT by increasing glycolysis through HKII regulation.

Preoperative Assessment of Blood Vessels and Intratumoral Microbleeds in Brain Tumors Based on a 3D Contrast-Enhanced T1 -Weighted Flow-Sensitive Black-Blood Sequence.

BACKGROUND: Three-dimensional (3D) contrast-enhanced T1 -weighted flow-sensitive black-blood (CE-T1 WI FSBB) is a newly developed black blood sequence by adding motion probing gradient pulses to gradient echo (GRE) sequences, which has important value for the preoperative assessment of tumor brain blood supply vessels and intratumoral microbleeds. PURPOSE: To compare 3D CE-T1 WI FSBB and 3D contrast-enhanced fast spin echo (FSE) sequence for T1 WI for preoperative assessment of blood vessels and microbleeds in brain tumors and to investigate the correlation between visible vessels and microbleeds. STUDY TYPE: Prospective. SUBJECTS: One hundred and seventy-five patients with brain tumors, 65 were male, 110 were female. Including histologically confirmed 73 meningiomas, 23 schwannomas, 20 gliomas, 7 hemangioblastomas, 5 metastases, 2 lymphomas, 2 hemangiopericytomas, 2 germ cell tumors, 1 craniopharyngioma, and 1 cholesteatoma. FIELD STRENGTH/SEQUENCE: A 3-T, CE-T1 WI FSBB, GRE; 3-T, CE-T1 WI, FSE. ASSESSMENT: Three neuroradiologists counted the number of intratumoral vessels on CE-T1 WI and CE-T1 WI FSBB images separately, and they counted the number of intratumoral microbleeds on CE-T1 WI FSBB images. Brain tumors were classified into grade I, grade II, and grade IV according to the World Health Organization (WHO) grading. Differences in the ability of CE-T1 WI FSBB and CE-T1 WI to display intratumoral vessels were compared. The mean counts of three observers were used to study the correlation between vessels and microbleeds. STATISTICAL TESTS: Two-way random intraclass correlation coeficient (ICC) was used for inter-reader agreement regarding intratumoral vessel and microbleed counts, and the linear regression analysis (with F-test) was used to study the correlation between intratumoral vessels and microbleeds based on CE-T1 WI FSBB (α = 0.05). RESULTS: Inter-reader agreements for intratumoral vessel count on CE-T1 WI (ICC = 0.93) and CE-T1 WI FSBB (ICC = 0.92), and the agreement for intratumoral microbleed count on CE-T1 WI FSBB (ICC = 0.99) were excellent. There were statistically significant differences in intratumoral vessel counts between CE-T1 WI and CE-T1 WI FSBB using Mann-Whitney U -test: image readers could identify more intratumoral vessels on CE-T1 WI FSBB images, particularly for meningiomas, schwannomas, gliomas, and WHO grade I tumors. The number of intratumoral vessels had a significant positive effect on the number of intratumoral microbleeds (microbleeds = 5.024 + 1.665 × vessels; F = 11.51). DATA CONCLUSION: More intratumoral vessels could potentially be identified using a 3D CE-T1 WI FSBB sequence compared to a CE-T1 WI sequence, and the number of intratumoral vessels showed a positive linear relationship with the number of intratumoral microbleeds, which might suggest that brain tumors with rich blood supply were more prone to intratumoral microbleeds. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 3.

Recent advances in portable devices for fruit firmness assessment.

Fruit firmness is of vital importance in various links of the fruit supply chain, such as determining harvest time, choosing packaging and transportation methods, regulating storage conditions and predicting shelf life. Portable devices are useful tools to perform on-site measurements of fruit firmness to guide production, optimize processing procedures, improve handling practices and formulate supply strategies. This paper reviews the recent advances in the design and development of portable devices to evaluate fruit firmness based on sensing mechanical, sonic, vibrational and optical properties of fruits. The principle, structure, composition, application and performance of different portable devices are presented. Since each sensor has its merits and limitations, the integration of multiple microsensors to develop a miniaturized, low-cost and facile-operation device may achieve higher sensing performance in determining fruit firmness.

Resistive switching modulation by incorporating thermally enhanced layer in HfO2-based memristor.

Oxide-based memristors by incorporating thermally enhanced layer (TEL) have showed great potential in electronic devices for high-efficient and high-density neuromorphic computing owing to the improvement of multilevel resistive switching. However, research on the mechanism of resistive switching regulation is still lacking. In this work, based on the method of finite element numerical simulation analysis, a bilayer oxide-based memristor Pt/HfO2(5 nm)/Ta2O5(5 nm)/Pt with the Ta2O5TEL was proposed. The oxygen vacancy concentrates distribution shows that the fracture of conductive filaments (CF) is at the interface where the local temperature is the highest during the reset process. The multilevel resistive switching properties were also obtained by applying different stop voltages. The fracture gap of CF can be enlarged with the increase of the stopping voltage, which is attributed to the heat-gathering ability of the TEL. Moreover, it was found that the fracture position of oxygen CF is dependent on the thickness of TEL, which exhibits a modulation of device RS performance. These results provide a theoretical guidance on the suitability of memristor devices for use in high-density memory and brain-actuated computer systems.

Trapping and diffusion of hydrogen in iron-doped Y2O3.

Y2O3 is a promising material for use as a tritium permeation barrier (TPB) coating and as dispersed particles in oxide dispersion strengthened steels for experimental fusion reactors. By using first-principles approaches, we found that substituting Fe for Y in Y2O3 is the most energetically favourable under O-deficient and H-rich conditions, leading to easier formation of the nearby O vacancies. These O vacancies serve as effective trapping sites for H atoms with a formation energy of -2.36 eV. The presence of Fe defects also makes it more difficult for H atoms to migrate in Y2O3 from three possible H-related defects. These findings suggest that incorporating Fe into Y2O3 could yield a better TPB and provide insight into the improved H trapping ability of Y2O3 with Fe dopants.

Cxcl10 deficiency attenuates renal interstitial fibrosis through regulating epithelial-to-mesenchymal transition.

IFN-γ-inducible protein 10 (IP-10, CXCL10) has been widely demonstrated to be involved in multiple kidney pathological processes. However, the role of CXCL10 in renal fibrosis remains unclear. In this study, Cxcl10-deficient (Cxcl10-/-) mice were used to generate the unilateral ureteral obstruction (UUO) model. The level of renal fibrosis and inflammatory cell infiltration was examined in vivo and the effects of CXCL10 on EMT process of HK-2 cells was investigated in vitro. We observed that the injury degree of renal tissue and the collagen deposition levels were lighter and the expression of α-SMA, collagen I and fibronectin was significantly reduced in Cxcl10-/- mice, while the expression of E-cadherin was increased. However, interstitial F4/80-positive macrophages and CD4-positive T lymphocytes were unaffected by knockout of Cxcl10. Furthermore, IFN-γ or CXCL10 stimulation could obviously promote the expression of α-SMA, collagen I, fibronectin and reduce the expression of E-cadherin in HK-2 cells, which could be inhibited by transfection of Cxcl10-siRNA. Our findings suggested Cxcl10 knockout could reduce renal dysfunction and inhibit renal fibrosis through regulating EMT process of renal tubular epithelial cells in murine UUO model. These results may provide a novel insight into the mechanism and a potential therapy target of renal fibrosis.

14-Deoxygarcinol improves insulin sensitivity in high-fat diet-induced obese mice via mitigating NF-κB/Sirtuin 2-NLRP3-mediated adipose tissue remodeling.

Interleukin (IL)-1ß is a culprit of adipose tissue inflammation, which in turn causes systematic inflammation and insulin resistance in obese individuals. IL-1ß is mainly produced in monocytes and macrophages and marginally in adipocytes, through cleavage of the inactive pro-IL-1ß precursor by caspase-1, which is activated via the NLRP3 inflammasome complex. The nuclear factor-κB (NF-κB) transcription factor is the master regulator of inflammatory responses. Brindle berry (Garcinia cambogia) has been widely used as health products for treating obesity and related metabolic disorders, but its active principles remain unclear. We previously found a series of polyisoprenylated benzophenones from brindle berry with anti-inflammatory activities. In this study we investigated whether 14-deoxygarcinol (DOG), a major polyisoprenylated benzophenone from brindle berry, alleviated adipose tissue inflammation and insulin sensitivity in high-fat diet fed mice. The mice were administered DOG (2.5, 5 mg · kg-1 · d-1, i.p.) for 4 weeks. We showed that DOG injection dose-dependently improved insulin resistance and hyperlipidemia, but not adiposity in high-fat diet-fed mice. We found that DOG injection significantly alleviated adipose tissue inflammation via preventing macrophage infiltration and pro-inflammatory polarization of macrophages, and adipose tissue fibrosis via reducing the abnormal deposition of extracellular matrix. In LPS plus nigericin-stimulated THP-1 macrophages, DOG (1.25, 2.5, 5 µM) dose-dependently suppressed the activation of NLRP3 inflammasome and NF-κB signaling pathway. We demonstrated that DOG bound to and activated the deacetylase Sirtuin 2, which in turn deacetylated and inactivated NLRP3 inflammasome to reduce IL-1ß secretion. Moreover, DOG (1.25, 2.5, 5 µM) dose-dependently mitigated inflammatory responses in macrophage conditioned media-treated adipocytes and suppressed macrophage migration toward adipocytes. Taken together, DOG might be a drug candidate to treat metabolic disorders through modulation of adipose tissue remodeling.