Joint Exposure to Ambient Air Pollutants, Genetic Risk, and Ischemic Stroke: A Prospective Analysis in UK Biobank.

BACKGROUND: Our primary objective was to assess the association between joint exposure to various air pollutants and the risk of ischemic stroke (IS) and the modification of the genetic susceptibility. METHODS: This observational cohort study included 307 304 British participants from the United Kingdom Biobank, who were stroke-free and possessed comprehensive baseline data on genetics, air pollutant exposure, alcohol consumption, and dietary habits. All participants were initially enrolled between 2006 and 2010 and were followed up until 2022. An air pollution score was calculated to assess joint exposure to 5 ambient air pollutants, namely particulate matter with diameters equal to or <2.5 µm, ranging from 2.5 to 10 µm, equal to or <10 µm, as well as nitrogen oxide and nitrogen dioxide. To evaluate individual genetic risk, a polygenic risk score for IS was calculated for each participant. We adjusted for demographic, social, economic, and health covariates. Cox regression models were utilized to estimate the associations between air pollution exposure, polygenic risk score, and the incidence of IS. RESULTS: Over a median follow-up duration of 13.67 years, a total of 2476 initial IS events were detected. The hazard ratios (95% CI) of IS for per 10 µg/m3 increase in particulate matter with diameters equal to or <2.5 µm, ranging from 2.5 to 10 µm, equal to or <10 µm, nitrogen dioxide, and nitrogen oxide were 1.73 (1.33-2.14), 1.24 (0.88-1.70), 1.13 (0.89-1.33), 1.03 (0.98-1.08), and 1.04 (1.02-1.07), respectively. Furthermore, individuals in the highest quintile of the air pollution score exhibited a 29% to 66% higher risk of IS compared with those in the lowest quintile. Notably, participants with both high polygenic risk score and air pollution score had a 131% (95% CI, 85%-189%) greater risk of IS than participants with low polygenic risk score and air pollution score. CONCLUSIONS: Our findings suggested that prolonged joint exposure to air pollutants may contribute to an increased risk of IS, particularly among individuals with elevated genetic susceptibility to IS.

General Design Concepts for CAPodes as Ionologic Devices.

Capacitive analogues of semiconductor diodes (CAPodes) present a new avenue for energy-efficient and nature-inspired next-generation computing devices. Here, we disclose the generalized concept for bias-direction-adjustable n- and p-CAPodes based on selective ion sieving. Controllable-unidirectional ion flux is realized by blocking electrolyte ions from entering sub-nanometer pores. The resulting CAPodes exhibit charge-storage characteristics with a high rectification ratio (96.29 %). The enhancement of capacitance is attributed to the high surface area and porosity of an omnisorbing carbon as counter electrode. Furthermore, we demonstrate the use of an integrated device in a logic gate circuit architecture to implement logic operations ('OR', 'AND'). This work demonstrates CAPodes as a generalized concept to achieve p-n and n-p analogue junctions based on selective ion electrosorption, provides a comprehensive understanding and highlights applications of ion-based diodes in ionologic architectures.

Tracer-specific reference tissues selection improves detection of 18 F-FDG, 18 F-florbetapir, and 18 F-flortaucipir PET SUVR changes in Alzheimer's disease.

This study sought to identify a reference tissue-based quantification approach for improving the statistical power in detecting changes in brain glucose metabolism, amyloid, and tau deposition in Alzheimer's disease studies. A total of 794, 906, and 903 scans were included for 18 F-FDG, 18 F-florbetapir, and 18 F-flortaucipir, respectively. Positron emission tomography (PET) and T1-weighted images of participants were collected from the Alzheimer's disease Neuroimaging Initiative database, followed by partial volume correction. The standardized uptake value ratios (SUVRs) calculated from the cerebellum gray matter, centrum semiovale, and pons were evaluated at both region of interest (ROI) and voxelwise levels. The statistical power of reference tissues in detecting longitudinal SUVR changes was assessed via paired t-test. In cross-sectional analysis, the impact of reference tissue-based SUVR differences between cognitively normal and cognitively impaired groups was evaluated by effect sizes Cohen's d and two sample t-test adjusted by age, sex, and education levels. The average ROI t values of pons were 86.62 and 38.40% higher than that of centrum semiovale and cerebellum gray matter in detecting glucose metabolism decreases, while the centrum semiovale reference tissue-based SUVR provided higher t values for the detection of amyloid and tau deposition increases. The three reference tissues generated comparable d images for 18 F-FDG, 18 F-florbetapir, and 18 F-flortaucipir and comparable t maps for 18 F-florbetapir and 18 F-flortaucipir, but pons-based t map showed superior performance in 18 F-FDG. In conclusion, the tracer-specific reference tissue improved the detection of 18 F-FDG, 18 F-florbetapir, and 18 F-flortaucipir PET SUVR changes, which helps the early diagnosis, monitoring of disease progression, and therapeutic response in Alzheimer's disease.

FXR/ASS1 axis attenuates the TAA-induced liver injury through arginine metabolism.

Previous studies demonstrated that arginine biosynthesis was frequently impaired in acute liver injury. However, the underlying mechanisms remain elusive. In this study, we found that Argininosuccinate synthetase 1 (ASS1), a rate-limiting enzyme in arginine metabolism, was downregulated in the TAA-induced liver injury model. Single-cell RNA-seq data found that ASS1 was highly enriched in the hepatocytes. The reduction of ASS1 was attributed to the decreased expression of Farnesoid X receptor (FXR), which is a bile acid-activated nuclear hormone receptor with high expression in the liver. Subsequent studies demonstrated that activation of FXR by its agonist obeticholic acid (OCA) directly promoted ASS1 transcription and enhanced arginine synthesis, leading to the alleviation of TAA-mediated liver injury. Further experiments found that OCA, ASS1, and arginine supplement can rescue TAA-mediated hepatocytes apoptosis by decreasing the protein levels of Cyto C, PARP, and Caspase 3. Taken together, our study illustrated a protective role of the FXR/ASS1 axis in TAA-induced liver injury by targeting arginine metabolism, which might shed light on the development of novel therapeutic approaches for acute liver injury.

Bioactive Ion-Based Switchable Supercapacitors.

Switchable supercapacitors (SCs) enable a reversible electrically-driven uptake/release of bioactive ions by polarizing porous carbon electrodes. Herein we demonstrate the first example of a bioactive ion-based switchable supercapacitor. Based on choline chloride and porous carbons we unravel the mechanism of physisorption vs. electrosorption by nuclear magnetic resonance, Raman, and impedance spectroscopy. Weak physisorption facilitates electrically-driven electrolyte depletion enabling the controllable uptake/release of electrolyte ions. A new 4-terminal device is proposed, with a main capacitor and a detective capacitor for monitoring bioactive ion adsorption in situ. Ion-concentration control in printed choline-based switchable SCs realizes switching down to 8.3 % residual capacitance. The exploration of adsorption mechanisms in printable microdevices will open an avenue of manipulating bioactive ions for the application of drug delivery, neuromodulation, or neuromorphic devices.

Li/Garnet Interface Stabilization by Thermal-Decomposition Vapor Deposition of an Amorphous Carbon Layer.

Applying interlayers is the main strategy to address the large area specific resistance (ASR) of Li/garnet interface. However, studies on eliminating the Li2 CO3 and LiOH interfacial lithiophobic contaminants are still insufficient. Here, thermal-decomposition vapor deposition (TVD) of a carbon modification layer on Li6.75 La3 Zr1.75 Ta0.25 O12 (LLZTO) provides a contaminant-free surface. Owing to the protection of the carbon layer, the air stability of LLZTO is also improved. Moreover, owing to the amorphous structure of the low graphitized carbon (LGC), instant lithiation is achieved, and the ASR of the Li/LLZTO interface is reduced to 9â€…Ω cm2 . Lithium volatilization and Zr4+ reduction are also controllable during TVD. Compared with its high graphitized carbon counterpart (HGC), the LGC-modified Li/LLZTO interface displays a higher critical current density of 1.2 mA cm-2 , as well as moderate Li plating and stripping, which provides enhanced polarization voltage stability.

Modular architecture of metabolic brain network and its effects on the spread of perturbation impact.

Metabolic brain network, which is based on functional correlation patterns of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) images, has been widely applied in both basic and clinical neuroscience. Exploring the properties of the metabolic brain network can provide valuable insight to the physiologic and pathologic processes of the brain. Based on the network theory, modular architecture has the ability to limit the spread of local perturbation impact and therefore modular networks are more robust against external damage. However, whether the metabolic brain network has modular architecture remains unknown. METHODS: 77 rats performed 18F-FDG PET brain imaging. The metabolic brain network was then constructed by measuring interregional metabolic correlation in inter-subject manner. Afterwards, modular architecture of the network was detected by a greedy algorithm. Further, we perturbed the metabolic brain network by inducing focal photothrombotic ischemia in the bilateral motor cortex and then measured the glucose metabolic change of each brain region using FDG-PET. RESULTS: A significant modular architecture was found in the metabolic brain network. The network could be divided into four modules which corresponding approximately to executive, learning/memory, visual/auditory and sensorimotor processing functional domains. After inducing the focal ischemia on the bilateral motor cortex, most of the significantly changed brain regions (13 of 17) belong to the sensorimotor module. CONCLUSION: Our results revealed an inherent modular architecture in the metabolic brain network and gave an experimental evidence that the modularity of the metabolism brain network could limit the spread of local perturbation impact.

Gray matter reduction related to decreased serum creatinine and increased triglyceride, Hemoglobin A1C, and low-density lipoprotein in subjects with obesity.

PURPOSE: Altered brain volume and metabolic variables have been found in subjects with obesity. However, the role of metabolic parameters in gray matter volume (GMV) has been poorly investigated. This study aimed to investigate the relationship between the metabolic parameters and brain volume in subjects with obesity. METHODS: Thirty-seven subjects with obesity and 39 age and sex matched normal-weight controls were included in this study. Eighteen of the 37 participants who underwent sleeve gastrectomy were included in the longitudinal analysis. Blood samples and high-resolution 3T T1-weighted magnetic resonance images were collected. Metabolic parameters in plasma and GMV were measured. RESULTS: Multiple linear regression analysis showed that gray matter reduction in several cognition-related cortices including right angular gyrus, superior occipital cortex, superior parietal cortex, and cerebellum was related to decreased creatinine, as well as increased triglyceride, HbA1c, and low-density lipoprotein in plasma in subjects with obesity. Weight loss after the surgery induced significant recovery of altered metabolic parameters and decreased gray matter volume. Furthermore, changes in the four metabolic parameters before and after the surgery were associated with changes in gray matter volume. CONCLUSION: Our results suggest that the gray matter reduction is related to decreased creatinine as well as increased triglyceride, HbA1c, and low-density lipoprotein in plasma in subjects with obesity.

High-Energy Rechargeable Metallic Lithium Battery at -70 °C Enabled by a Cosolvent Electrolyte.

Lithium metal is an ideal anode for high-energy rechargeable batteries at low temperature, yet hindered by the electrochemical instability with the electrolyte. Concentrated electrolytes can improve the oxidative/reductive stability, but encounter high viscosity. Herein, a co-solvent formulation was designed to resolve the dilemma. By adding electrochemically "inert" dichloromethane (DCM) as a diluent in concentrated ethyl acetate (EA)-based electrolyte, the co-solvent electrolyte demonstrated a high ionic conductivity (0.6 mS cm-1 ), low viscosity (0.35 Pa s), and wide range of potential window (0-4.85 V) at -70 °C. Spectral characterizations and simulations show these unique properties are associated with the co-solvation structure, in which high-concentration clusters of salt in the EA solvent were surrounded by mobile DCM diluent. Overall, this novel electrolyte enabled rechargeable metallic Li battery with high energy (178 Wh kg-1 ) and power (2877 W kg-1 ) at -70 °C.

Anchoring an Artificial Solid-Electrolyte Interphase Layer on a 3D Current Collector for High-Performance Lithium Anodes.

The application of Li anodes is hindered by dendrite growth and side reactions between Li and electrolyte, despite its high capacity and low potential. A simple approach for this challenge is now demonstrated. In our strategy, the garnet-type Li6.4 La3 Zr1.4 Ta0.6 O12 (LLZTO)-based artificial solid-electrolyte interphase (SEI) is anchored on Cu foam by sintering the Cu foam coated with LLZTO particles. The heat treatment leads to the interdiffusion of Cu and Ta2 O5 at the Cu/LLZTO interface, through which LLZTO layer is fixed on Cu foam. 3D structure lowers the current density, and meanwhile the SEI reduces the contact of Li and electrolyte. Furthermore, the anchoring construction can endure Li-deposition-induced volume change. Therefore, LLZTO-modified Cu foam shows much improved Li plating/stripping performance, including long lifespan (2400 h), high rate (maximum current density of 20 mA cm-2 ), high areal capacity (8 mA h cm-2 for 100 cycles), and high efficiency (over 98 %).

Islet-1 overexpression in human mesenchymal stem cells promotes vascularization through monocyte chemoattractant protein-3.

The LIM-homeobox transcription factor islet-1 (ISL1) has been proposed to mark a cardiovascular progenitor cell lineage that gives rise to cardiomyocytes, endothelial cells, and smooth muscle cells. The aim of this study was to investigate whether forced expression of ISL1 in human mesenchymal stem cells (hMSCs) influenced the differentiation capacity and angiogenic properties of hMSCs. The lentiviral vector, EF1α-ISL1, was constructed using the Multisite Gateway System and used to transduce hMSCs. We found that ISL1 overexpression did not alter the proliferation, migration, or survival of hMSCs or affect their ability to differentiate into osteoblasts, adipocytes, cardiomyocytes, or endotheliocytes. However, ISL1-hMSCs differentiated into smooth muscle cells more efficiently than control hMSCs. Furthermore, conditioned medium from ISL1-hMSCs greatly enhanced the survival, migration, and tube-formation ability of human umbilical vein endothelial cells (HUVECs) in vitro. In vivo angiogenesis assays also showed much more vascular-like structures in the group cotransplanted with ISL1-hMSCs and HUVECs than in the group cotransplanted with control hMSCs and HUVECs. Quantitative RT-PCR and antibody arrays detected monocyte chemoattractant protein-3 (MCP3) at a higher level in conditioned medium from ISL1-hMSCs cultures than in conditioned medium from control hMSCs. Neutralization assays showed that addition of an anti-MCP3 antibody to ISL1-hMSCs-conditioned medium efficiently abolished the angiogenesis-promoting effect of ISL1-hMSCs. Our data suggest that overexpression of ISL1 in hMSCs promotes angiogenesis in vitro and in vivo through increasing secretion of paracrine factors, smooth muscle differentiation ability, and enhancing the survival of HUVECs.

Association between household size and risk of incident dementia in the UK Biobank study.

Currently, the relationship between household size and incident dementia, along with the underlying neurobiological mechanisms, remains unclear. This prospective cohort study was based on UK Biobank participants aged ≥ 50 years without a history of dementia. The linear and non-linear longitudinal association was assessed using Cox proportional hazards regression and restricted cubic spline models. Additionally, the potential mechanisms driven by brain structures were investigated by linear regression models. We included 275,629 participants (mean age at baseline 60.45 years [SD 5.39]). Over a mean follow-up of 9.5 years, 6031 individuals developed all-cause dementia. Multivariable analyses revealed that smaller household size was associated with an increased risk of all-cause dementia (HR, 1.06; 95% CI 1.02-1.09), vascular dementia (HR, 1.08; 95% CI 1.01-1.15), and non-Alzheimer's disease non-vascular dementia (HR, 1.09; 95% CI 1.03-1.14). No significant association was observed for Alzheimer's disease. Restricted cubic splines demonstrated a reversed J-shaped relationship between household size and all-cause and cause-specific dementia. Additionally, substantial associations existed between household size and brain structures. Our findings suggest that small household size is a risk factor for dementia. Additionally, brain structural differences related to household size support these associations. Household size may thus be a potential modifiable risk factor for dementia.

Molecular circuit for exponentiation based on the domain coding strategy.

DNA strand displacement (DSD) is an efficient technology for constructing molecular circuits. However, system computing speed and the scale of logical gate circuits remain a huge challenge. In this paper, a new method of coding DNA domains is proposed to carry out logic computation. The structure of DNA strands is designed regularly, and the rules of domain coding are described. Based on this, multiple-input and one-output logic computing modules are built, which are the basic components forming digital circuits. If the module has n inputs, it can implement 2n logic functions, which reduces the difficulty of designing and simplifies the structure of molecular logic circuits. In order to verify the superiority of this method for developing large-scale complex circuits, the square root and exponentiation molecular circuits are built. Under the same experimental conditions, compared with the dual-track circuits, the simulation results show that the molecular circuits designed based on the domain coding strategy have faster response time, simpler circuit structure, and better parallelism and scalability. The method of forming digital circuits based on domain coding provides a more effective way to realize intricate molecular control systems and promotes the development of DNA computing.

Messenger RNA electroporated hepatitis B virus (HBV) antigen-specific T cell receptor (TCR) redirected T cell therapy is well-tolerated in patients with recurrent HBV-related hepatocellular carcinoma post-liver transplantation: results from a phase I trial.

BACKGROUND AND AIMS: Liver transplantation (LT) is the primary curative option for cirrhotic patients with early-stage hepatocellular carcinoma (HCC). However, tumor recurrence occurs in 15-20% of cases with unfavorable prognosis. We have developed a library of T cell receptors (TCRs) specific for different hepatitis B virus (HBV) antigens, restricted by different molecules of human leucocyte antigen (HLA)-class I, to redirect T cells against HBV antigens (Banu in Sci Rep 4:4166, 2014). We further demonstrated that these transiently functional T cells specific for HBV obtained through messenger RNA (mRNA) electroporation can eliminate HCC cells expressing HBV antigens in vitro and in vivo (Kah in J Clin Invest 127:3177-3188, 2017). A phase I clinical trial for patients with HCC recurrence post-liver transplant was conducted to assess the safety, tolerability, and anti-tumor efficacy of transiently functional HBV-TCR T cells. Here, we report the clinical findings with regard to the safety and anti-tumor efficacy of mRNA electroporated HBV-specific TCR-T cells. (ClinicalTrials.gov identifier: NCT02719782). PATIENTS AND METHODS: A total of six patients with HBV-positive recurrent HCC post-liver transplant and HLA-matched to TCR targeting hepatitis B surface antigen (HBsAg) or hepatitis B core antigen (HBcAg) (HLA-A*02:01/HBsAg, HLA-A*11:01/HBcAg, HLA-B*58:01/HBsAg or HLA-C*08:01/HBsAg) were enrolled in this study. The primary objective was to assess the safety of short-lived mRNA electroporated HBV-TCR T cells based on the incidence and severity of the adverse event (AE) graded per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 4.0. The secondary objective was to determine the effectiveness of HBV-TCR T cells as per RECIST 1.1 criteria. Patients were followed up for survival for 2 years post-end of treatment. RESULTS: The median age of the six patients was 35.5 years (range: 28-47). The median number of HBV-TCR T cell infusions administered was 6.5 (range: 4-12). The treatment-related AE included grade 1 pyrexia. This study reported no cytokine release syndrome nor neurotoxicity. One patient remained alive and five were deceased at the time of the data cutoff (30 April 2020). CONCLUSION: This study has demonstrated that multiple infusions of mRNA electroporated HBV-specific TCR T cells were well-tolerated in patients with HBV-positive recurrent HCC post-liver transplant.

The pathway toward practical application of lithium-metal anodes for non-aqueous secondary batteries.

The revolution of automotive vehicles (from petrol vehicles to electric vehicles) has set high demands for the performance of batteries. Lithium-metal batteries (LMBs) show great potential owing to their high energy density but encounter poor cycle life and safety issues. It is of great significance to reveal LMB failure mechanisms and understand their relationship with battery performance. This review presents an overview of the state-of-the-art Li-metal anodes, with an emphasis on two typical failure modes: capacity degradation and dendritic growth of Li metal. The critical correlations between the composition, structure and failure are explained point by point. The chemical and electrochemical stabilities of the lithium anode are discussed. Particularly, for the first time, five types of lithium-metal anodes are classified to develop a comprehensive understanding of LMBs. Furthermore, strategies are suggested to improve the practical performance of LMBs, including material innovation, electrolyte modification and advanced characterization.

PCBP1 is associated with rheumatoid arthritis by affecting RNA products of genes involved in immune response in Th1 cells.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by persistent synovitis, in which T helper 1 (Th1) can promote the development of a pro-inflammatory microenvironment. Poly(rC)-binding protein 1 (PCBP1) has been identified as a promising biomarker of RA, while its molecular mechanisms in RA development are unknown. As a canonical RNA binding protein, we propose that PCBP1 could play roles in RA by affecting both expression and alternative splicing levels in Th1 cells. Here, microarray datasets (GSE15573 and GSE23561), including 102 peripheral blood mononuclear cell samples from 39 RA patients and 63 controls, were used to evaluate the PCBP1 expression changes in RA patients. High throughput sequencing data (GSE84702) of iron driven pathogenesis in Th1 cells were downloaded and reanalyzed, including two Pcbp1 deficiency samples and two control samples in Th1 cells. In addition, CLIP-seq data of PCBP1 in Jurkat T cells was also analyzed to investigate the regulatory mechanisms of PCBP1. We found PCBP1 were down-regulated in RA specimens compared with control. The result of differentially expressed genes (DEGs) showed that Pcbp1 silencing in Th1 cells affected the expression of genes involved in immune response pathway. Alternative splicing analysis also revealed that PCBP1-regulated alternative splicing genes (RASGs) were enriched in TNF-a/NF-κB signaling pathway, T cell activation, T cell differentiation and T cell differentiation associated immune response pathways, which were highly associated with RA. DEGs and RASGs by Pcbp1 deficiency in mice were validated in PBMCs specimens of RA patients by RT-qPCR. Investigation of the CLIP-seq data revealed PCBP1 preferred to bind to 3'UTR and intron regions. PCBP1-bound genes were also significantly associated with RASGs, identifying 102 overlapped genes of these two gene sets. These genes were significantly enriched in several immune response related pathways, including myeloid cell differentiation and positive regulation of NF-κB transcription factor activity. Two RA-related genes, PML and IRAK1, were screened from the above immune related pathways. These results together support our hypothesis that PCBP1 can regulate the expression of genes involved in immune response pathway, and can bind to and regulate the alternative splicing of immune response related genes in immune T cells, and ultimately participate in the molecular mechanism of RA, providing new research ideas and directions for clinical diagnosis and treatment.

Clinical Prediction of Heart Failure in Hemodialysis Patients: Based on the Extreme Gradient Boosting Method.

Background: Heart failure (HF) is the main cause of mortality in hemodialysis (HD) patients. However, it is still a challenge for the prediction of HF in HD patients. Therefore, we aimed to establish and validate a prediction model to predict HF events in HD patients. Methods: A total of 355 maintenance HD patients from two hospitals were included in this retrospective study. A total of 21 variables, including traditional demographic characteristics, medical history, and blood biochemical indicators, were used. Two classification models were established based on the extreme gradient boosting (XGBoost) algorithm and traditional linear logistic regression. The performance of the two models was evaluated based on calibration curves and area under the receiver operating characteristic curves (AUCs). Feature importance and SHapley Additive exPlanation (SHAP) were used to recognize risk factors from the variables. The Kaplan-Meier curve of each risk factor was constructed and compared with the log-rank test. Results: Compared with the traditional linear logistic regression, the XGBoost model had better performance in accuracy (78.5 vs. 74.8%), sensitivity (79.6 vs. 75.6%), specificity (78.1 vs. 74.4%), and AUC (0.814 vs. 0.722). The feature importance and SHAP value of XGBoost indicated that age, hypertension, platelet count (PLT), C-reactive protein (CRP), and white blood cell count (WBC) were risk factors of HF. These results were further confirmed by Kaplan-Meier curves. Conclusions: The HF prediction model based on XGBoost had a satisfactory performance in predicting HF events, which could prove to be a useful tool for the early prediction of HF in HD.

Super-enhancer-driven lncRNA-DAW promotes liver cancer cell proliferation through activation of Wnt/ß-catenin pathway.

Aberrant expression of long non-coding RNAs (lncRNAs) has been reported in multiple cancers. However, the underlying mechanisms mediated by super-enhancers remain elusive. Here we sought to define the role of a novel lncRNA termed lncRNA-DAW in tumorigenesis. Our results revealed that lncRNA-DAW was driven by a liver-specific super-enhancer and transcriptionally activated by HNF4G, leading to frequent elevation in hepatocellular carcinoma (HCC) specimens. Ectopic expression of lncRNA-DAW promoted both in vivo and in vitro tumor growth. By using RNA sequencing, Wnt2 was screened out as a downstream effector of lncRNA-DAW. We next found that lncRNA-DAW physically interacted with EZH2, a negative regulator of Wnt2. This interplay subsequently potentiated CDK1-EZH2 interaction, leading to the phosphorylation and ubiquitination of EZH2. The lncRNA-DAW-mediated EZH2 degradation facilitated the de-repression of Wnt2 transcription, which eventually activated the Wnt/ß-catenin pathway. Furthermore, we verified that Wnt2 potentiated in vitro and in vivo cancer cell growth by activating the Wnt/ß-catenin pathway. Finally, Wnt2 amplification was confirmed as a common event in liver cancer, and the expression of lncRNA-DAW was positively correlated with Wnt2 in HCC specimens. Collectively, we are the first to identify lncRNA-DAW as a novel candidate oncogene in liver cancer, and this lncRNA may serve as a novel clinical diagnosis biomarker for liver cancer.

Altered Default Mode Network Is Associated With Cognitive Impairment in CADASIL as Revealed by Multimodal Neuroimaging.

Background and Purpose: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy caused by mutations in the NOTCH3 gene is a hereditary cerebral small vessel disease, manifesting with stroke, cognitive impairment, and mood disturbances. Functional or structural changes in the default mode network (DMN), which plays important role in cognitive and mental maintenance, have been found in several neurological and mental diseases. However, it remains unclear whether DMN is altered in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Methods: Multimodal imaging methods, including MRI and positron emission tomography (PET), were applied to evaluate the functional, structural, and metabolic characteristics of DMN in 25 patients with CADASIL and 42 healthy controls. Results: Compared with controls, patients with CADASIL had decreased nodal efficiency and degree centrality of the dorsal medial pre-frontal cortex and hippocampal formation within DMN. Structural MRI and diffusion tensor imaging (DTI) showed decreased gray matter volume and fiber tracks presented in the bilateral hippocampal formation. Meanwhile, PET imaging showed decreased metabolism within the whole DMN in CADASIL. Furthermore, correlation analyses showed that these nodal characteristics, gray matter volume, and metabolic signals of DMN were related to cognitive scores in CADASIL. Conclusions: Our results suggested that altered network characteristics of DMN might play important roles in cognitive deficits of CADASIL.

The clinical implication of gamma-glutamyl transpeptidase in COVID-19.

BACKGROUND AND AIM: Coronavirus disease 2019 (COVID-19) is a life-threatening disease that predominantly causes respiratory failure. The impact of COVID-19 on other organs remains elusive. Herein, we aimed to investigate the effects of COVID-19 on the hepatobiliary system. METHODS: In the current study, we obtained the clinical records and laboratory results from 66 laboratory-confirmed patients with COVID-19 at the Wuhan Tongji Hospital between 10 February 2020 and 28 February 2020. The detailed clinical features and laboratory findings were collected for analysis. Bioinformatics analysis was conducted to evaluate the correlation between gamma-glutamyl transferase (GGT) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry receptor angiotensin-converting enzyme 2 (ACE2). RESULTS: In this cohort, 30 (51.7%) patients had abnormal liver function on admission, which was associated with disease severity and enriched in the male and diabetic patients. The elevated levels of direct bilirubin (P = 0.029) and GGT (P = 0.004) were common in patients with severe pneumonia when compared with those with mild pneumonia. In addition, elevated levels of GGT (P = 0.003) and aspartate aminotransferase (AST) (P = 0.007) were positively associated with longer hospital stay. The expression of ACE2 was closely associated with GGT in various human tissues because they shared the common transcriptional regulator hepatic nuclear factor-1ß (HNF1B). CONCLUSIONS: Increased GGT levels were common in severe cases and elevated GGT levels were positively associated with prolonged hospital stay and disease severity. Due to the consistent expression with ACE2, GGT is a potent biomarker indicating the susceptibility of SARS-CoV-2 infection.