Two-dimensional heavy fermions in the van der Waals metal CeSiI.

Heavy-fermion metals are prototype systems for observing emergent quantum phases driven by electronic interactions1-6. A long-standing aspiration is the dimensional reduction of these materials to exert control over their quantum phases7-11, which remains a significant challenge because traditional intermetallic heavy-fermion compounds have three-dimensional atomic and electronic structures. Here we report comprehensive thermodynamic and spectroscopic evidence of an antiferromagnetically ordered heavy-fermion ground state in CeSiI, an intermetallic comprising two-dimensional (2D) metallic sheets held together by weak interlayer van der Waals (vdW) interactions. Owing to its vdW nature, CeSiI has a quasi-2D electronic structure, and we can control its physical dimension through exfoliation. The emergence of coherent hybridization of f and conduction electrons at low temperature is supported by the temperature evolution of angle-resolved photoemission and scanning tunnelling spectra near the Fermi level and by heat capacity measurements. Electrical transport measurements on few-layer flakes reveal heavy-fermion behaviour and magnetic order down to the ultra-thin regime. Our work establishes CeSiI and related materials as a unique platform for studying dimensionally confined heavy fermions in bulk crystals and employing 2D device fabrication techniques and vdW heterostructures12 to manipulate the interplay between Kondo screening, magnetic order and proximity effects.

Exogenous hydrogen sulfide alleviates hepatic endoplasmic reticulum stress via SIRT1/FoxO1/PCSK9 pathway in NAFLD.

High-fat-induced endoplasmic reticulum (ER) stress has been the main reason for the occurrence and development of nonalcoholic fatty liver disease (NAFLD). Hydrogen sulfide (H2 S) produces a marked effect on regulating lipid metabolism and antioxidation, whose effects on ER stress of NAFLD are still unclear. Here, we studied the influence of exogenous H2 S on NAFLD and its potential mechanism. In vivo, NAFLD model was induced by high-fat diet (HFD) for 12 weeks, followed by intraperitoneal injection of exogenous H2 S intervention for 4 weeks. HepG2 cells exposure to lipid mixture (LM) were used as vitro model to explore the potential mechanism. We found exogenous H2 S significantly inhibited the hepatic ER stress and improved the liver fat deposition of HFD-fed mice. These similar results were also observed in HepG2 cells dealt with LM after exogenous H2 S treatment. Further mechanism studies showed exogenous H2 S strengthened the combination of FoxO1 with the PCSK9 promoter gene through SIRT1-mediated deacetylation, thereby inhibiting the PCSK9 expression to relieve the hepatic ER stress. However, SIRT1 knockout eliminated the effects of exogenous H2 S on FoxO1 deacetylation, PCSK9 inhibition, and remission of hepatic ER stress and steatosis. In conclusion, exogenous H2 S improved NAFLD by inhibiting hepatic ER stress through SIRT1/FoxO1/PCSK9 pathway. Exogenous H2 S and ER stress may be potential drug and target for the treatment of NAFLD, respectively.

Transition Metal Functionalized C30N12S6 as High-Performance Trifunctional Catalysts with Integrated Descriptors toward Hydrogen Evolution, Oxygen Evolution, and Oxygen Reduction Reactions: A Case of High-Throughput First-Principles Screening within the Framework of TM-N2@C30N10S6.

In energy conversion and storage technologies, the design of highly efficient trifunctional electrocatalysts integrating with the high hydrogen evolution reaction (HER) and oxygen evolution/reduction reaction (OER/ORR) activities is highly desirable. Herein, utilizing first-principles computations, a novel periodically ordered macropore C30N12S6 monolayer was proposed, and the stability analysis attests to its good stability. Single transition metal (TM) atom anchored onto this newly proposed C30N12S6 monolayer to form single-atom catalysts, as achieved by TM-N2@C30N10S6, among which the Co-N2@C30N10S6 is the most promising multifunctional catalyst toward HER/OER/ORR with low overpotential of 0.01/0.59/0.3 V; meanwhile, the Rh-N2@C30N10S6 can be used as a bifunctional OER/ORR catalyst with low overpotential of 0.37/0.44 V, overmatching the landmark Pt (111) and IrO2/RuO2 catalysts. Particularly, the TM-d orbital in TM@CNS is remarkably hybridized with the O-p orbital of oxygenated intermediates, so that the lone electrons initially located at the antibonding orbital pair up and fill the downward bonding orbital, allowing OH* to be suitably adsorbed on TM@CNS, enhancing the catalytic performance. The relevant attributes, such as good stabilities and metallic features, ensured their applications in ambient conditions. Moreover, multilevel descriptors were constructed to clarify the origin of activity on TM@CNS, such as ΔGOH* (Gibbs free energy of OH*), εd (d-band center), COHP (crystal orbital Hamilton population), Nd/Nd + s (number of d/d + s electrons) and φ (descriptor), among which the filling of outer d-electrons of TM atom significantly affects the value of ΔGOH* that can determine the overpotential and, thus, become a key descriptor.

Kagome-like BiP3 Monolayer: An Emerging Quasi-Direct Auxetic Semiconductor Coupled with High Anisotropic Mobility toward Visible-Light-Driven Photoelectrocatalytic pH-Robust Overall Water-Splitting.

Two-dimensional (2D) Janus materials exhibit an outstanding potential that can meet the rigorous requirements of photocatalytic water splitting resulting from their unique atomic arrangement. However, these materials are quite scarce. Through ab initio density functional theory calculations, we introduce a kagome topology into the honeycomb lattice of blue phosphorene using phosphorus and bismuth atoms to build a hybrid honeycomb-like kagome lattice, realized by a hitherto unknown kagome-like Janus-like BiP3 monolayer with robust stability. Excitingly, the out-of-plane asymmetry benefiting from kagome and honeycomb topologies gives rise to a significantly negative out-of-plane Poisson's ratio and an obvious built-in electric field pointing from the sublayer of the P atom to the sublayer of the Bi atom. In conjunction with the investigations that encompass semiconducting properties, such as a quasi-direct gap, suitable band-edge positions, effective visible-light absorption, and high carrier mobility, the BiP3 monolayer achieves overall water splitting at pH 0-14 regardless of strain. Moreover, this intrinsic electric field provides a sufficient photogenerated carrier driving force for water splitting. The bare BiP3 comprises P and Bi atoms that function as catalysts for the hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) active sites, respectively. Upon exposure to light, the reaction of water into H2 and O2 can be observed across a pH range of 0-14. Meanwhile, by designing a transition-metal single-atom catalyst (TM@BiP3), our investigations have shown that embedding a single TM on BiP3 is a feasible route to improving the HER/OER activity by reducing the overpotentials to -0.039 and 0.58 eV for Mo and Os atoms, respectively. In this case, the positive value of the external potential acts as a sufficient OER driving force, i.e., in the light environment, the Os@BiP3 system can promote water molecules spontaneously oxidized into O2 at pH 0-14.

Comprehensive physiological, transcriptomic, and metabolomic analysis of the key metabolic pathways in millet seedling adaptation to drought stress.

Drought is one of the leading environmental constraints that affect the growth and development of plants and, ultimately, their yield and quality. Foxtail millet (Setaria italica) is a natural stress-resistant plant and an ideal model for studying plant drought resistance. In this study, two varieties of foxtail millet with different levels of drought resistance were used as the experimental material. The soil weighing method was used to simulate drought stress, and the differences in growth, photosynthetic physiology, metabolite metabolism, and gene transcriptional expression under drought stress were compared and analyzed. We aimed to determine the physiological and key metabolic regulation pathways of the drought-tolerant millet in resistance to drought stress. The results showed that drought-tolerant millet exhibited relatively stable growth and photosynthetic parameters under drought stress while maintaining a relatively stable level of photosynthetic pigments. The metabolomic, transcriptomic, and gene co-expression network analysis confirmed that the key to adaptation to drought by millet was to enhance lignin metabolism, promote the metabolism of fatty acids to be transformed into cutin and wax, and improve ascorbic acid circulation. These findings provided new insights into the metabolic regulatory network of millet adaptation to drought stress.

A novel model to assess disease activity in Takayasu arteritis based on 18F-FDG-PET/CT: a Chinese cohort study.

OBJECTIVE: To investigate the utility of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) in assessing disease activity in Takayasu arteritis (TA). METHODS: Ninety-one patients with TA were recruited from a Chinese cohort. Clinical data, acute-phase reactants and 18F-FDG-PET/CT findings were simultaneously recorded. The value of using 18F-FDG-PET/CT to identify active disease was evaluated, using ESR as a reference. Disease activity assessment models were constructed and concordance index (C-index), net reclassification index (NRI), and integrated discrimination index (IDI) were evaluated to compare the benefits of the new modes with ESR and the Kerr score. RESULTS: In total, 64 (70.3%) cases showed active disease. Higher levels of ESR and CRP, and lower IL-2 receptor (IL-2R) levels were observed in active cases. 18F-FDG-PET/CT parameters measured by determining the standard uptake value (SUV), including SUVmean, SUVratio1, SUVratio2, sum of SUVmean and sum of SUVmax, were significantly higher in active disease groups. The C-index threshold of ESR to indicate active disease was 0.78 (95% CI: 0.69, 0.88). The new activity assessment model combining ESR, sum of SUVmean and IL-2R showed significant improvement in C-index over the ESR method (0.96 vs 0.78, P < 0.01; NRI 1.63, P < 0.01; and IDI 0.48, P < 0.01). The new model also demonstrated modest superiority to the Kerr score assessment (0.96 vs 0.87, P = 0.03; NRI 1.19, P < 0.01; and IDI 0.33, P < 0.01). CONCLUSIONS: A novel 18F-FDG-PET/CT-based method that involves combining the sum of SUVmean with ESR score and IL-2R levels demonstrated superiority in identifying active TA compared with conventional methods.

The potential role of leflunomide in inhibiting vascular fibrosis by down-regulating type-II macrophages in Takayasu's arteritis.

OBJECTIVES: Inflammatory fibrosis of aortic lesions promoted by type II macrophages (M2) is one of the most serious incidents in Takayasu's arteritis (TAK), and the currently available therapies can not effectively block the inflammatory fibrosis. Here we explored whether leflunomide (LEF) could improve the fibrosis by down-regulating M2 in TAK. METHODS: Peripheral blood mono-nuclear cells (PBMCs) from 16 TAK patients were treated by leflunomide, and the ratio of M1/M2 macrophages and apoptosis of M2 were detected by flow cytometry. Supernatant levels of cytokines and chemokines secreted by M2 were measured by ELISAs. mRNA expression of profibrotic factors in M2 were analysed by real time PCR. Western blotting was used to analyse the activation of signal transducer activator of transcription (STAT)-6. RESULTS: LEF could inhibit M2 polarisation by curtailing STAT6 phosphorylation. LEF could also promote apoptosis of M2 and reduce the release of M2-derived CCL22 as well as the expression of profibrotic cytokines including CCL22 and TGF-ß in M2. CONCLUSIONS: LEF could potentially reduce vascular fibrosis by down-regulating the number and function of M2, which, eventually, could alleviate inflammatory fibrosis of aortic lesions in TAK patients.

CYR61/TGF-ß axis promotes adventitial fibrosis of Takayasu's arteritis in the IL-17 mediated inflammatory microenvironment.

OBJECTIVES: Takayasu's arteritis (TAK) is characterised by inflammation and fibrosis in the aortas, but its pathogenesis remains unclear. The aim of the study is to demonstrate the role of cysteine-rich protein 61 (CYR61), a novel proinflammatory factor, in the inflammation and fibrosis of TAK vessels. METHODS: CYR61 expression in the aortic vessel was compared between TA tissues and healthy samples by immunohistochemistry staining. The effect of CYR61 on the proliferation, migration and activation of adventitial fibroblasts (AFs) in the IL-17-mediated inflammatory microenvironment was studied in vitro. RESULTS: Here we found higher expression of CYR61 in the aortic adventitia in TAK patients than in healthy donors by immunohistochemistry staining. In vitro, recombinant human CYR61 (rhCYR61) significantly upregulated the proliferation of primary human aortic adventitial fibroblasts (AFs) and their expression of extracellular matrix (ECM) proteins such as collagen I, collagen III and fibronectin at the mRNA and protein levels, but rhCYR61 partly inhibited the migration of AFs. The integrin αvß1 was identified as a membrane receptor of CYR61 in AFs, and its downstream Erk1/2 pathway was found activated by detecting its phosphorylation level. Pretreatment with PD98059, an inhibitor of Erk1/2, down-regulated the mRNA and protein expression of ECM proteins in the rhCYR61-stimulated AFs. Furthermore, rhCYR61 up-regulated the expression of TGF-ß, and TGF-ß siRNA transfection obviously attenuated the profibrotic effect ofrhCYR61. Finally, to clarify the cooperation between CYR61 and classical proinflammatory factors, IL-17 was chosen as a co-stimulator in the culture of AFs. rhIL-17 promoted the mRNA and protein expression of CYR61 in AFs, and the collaboration of rhIL-17 and rhCYR61 dramatically boosted the synthesis of ECM and TGF-ß. CONCLUSIONS: Our findings suggest that CYR61 played a profibrotic role through the TGF-ß pathway and it enhanced IL-17-mediated inflammation and fibrosis in the mechanism of vascular impairment in TAK.

High melatonin levels are related to spinal ossification in patients with ankylosing spondylitis.

Objectives: To investigate associations of serum melatonin with spinal ossification and cytokines in ankylosing spondylitis (AS).Methods: Serum was obtained from 52 AS patients and 25 healthy controls. Melatonin was measured by ELISA kit; bone morphogenetic protein (BMP)-2, dickkopf-related protein (Dkk)-1, IL-1ß, IL-6, IL-17 and TNF-α concentrations were assayed using Luminex multiplex bead system. Osteocalcin and ß isomer of C-terminal telopeptide of type I collagen (ß-CTX) were measured using electrochemiluminescence immunoassay. Spinal damages were assessed using the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) on radiographs.Results: Serum melatonin was significantly increased in AS patients. Serum melatonin correlated positively with mSASSS after multivariate adjustment for age and disease duration (r = 0.70, p < .01). Patients with spinal bone bridge have higher levels of melatonin than those without spinal bone bridge [16.69 (4.65, 41.10) pg/ml vs. 7.43 (3.29, 15.30) pg/ml, p = .03]. The multiple linear regression analysis found that melatonin was a risk factor for spinal bone formation (ß = 0.35, p < .05). Additionally, melatonin correlated positively with osteocalcin (r = 0.34, p = .04) and IL-1ß (r = 0.39, p = .04) in AS.Conclusion: Melatonin is increased in AS patients, especially in patients with spinal bone bridge. It suggests that melatonin may play an important role in the pathological osteogenesis of AS.

Autophagy promotes aortic adventitial fibrosis via the IL-6/Jak1 signaling pathway in Takayasu's arteritis.

BACKGROUND: Autophagy is a ubiquitous and evolutionarily conserved self-rescue process. Studies have shown that autophagy is involved in the pathogenesis of multiple diseases; however, whether autophagy is associated with the pathogenesis of Takayasu's arteritis (TA), a large vessel idiopathic inflammatory disease characterized by vascular fibrosis, remains unclear. Moreover, although IL-6 is believed to be a direct target for TA treatment, anti-IL-6 treatment could not block TA-associated fibrosis in some cases, which impairs the aortic function of patients and can result in death. Thus, identify the mechanisms associated with TA is extremely important. Based on the relationship between autophagy and IL-6, we investigated the role of autophagy in the vascular fibrosis of TA induced by IL-6. METHODS: Autophagy proteins (LC3 and Atg3), IL-6, and markers of fibrosis (collagen 1 and α-SMA) were detected in tissues with TA lesions via immunochemistry, immunofluorescence, and Western blot, respectively. Different stages of autophagy were analyzed by the specific inhibitors, 3-methyladenosine (early stage), hydroxychloroquine sulfate (late stage), and bafilomycin A1 (late stage). Autophagosomes were detected using electron microscopy and a viral-vector transfection assay. The fibrosis profiles induced by IL-6-dependent autophagy was assessed with an ELISA. RESULTS: The expression of autophagy, IL-6, and fibrosis markers were elevated and correlated with each other in the adventitia tissues of TA patients. Furthermore, exogenous IL-6/IL-6Rα could significantly increase autophagy and fibrosis in vitro. An autophagy inhibitor was found to significantly block both autophagy and fibrosis induced by IL-6. Finally, IL-6 was found to significantly promote autophagy-induced fibrosis through the activation of the Jak1 pathway. CONCLUSIONS: IL-6-induced autophagy plays an important role in vascular fibrosis of TA. Targeting autophagy pathways might represent a novel therapeutic option for the treatment of TA.

Low Plasma Hydrogen Sulfide Is Associated with Impaired Renal Function and Cardiac Dysfunction.

BACKGROUND: Chronic kidney disease (CKD) has been proposed to associate with decreased hydrogen sulfide (H2S) level. Nevertheless, the role of H2S in the pathogenesis of CKD has not been fully investigated. Our study aimed to investigate the plasma level of endogenous H2S in patients with different stages of CKD, and to identify the role of H2S in the progression of CKD and its relationship with cardiovascular diseases. METHODS: A total of 157 non-dialysis CKD patients were recruited in our study, with 37 age- and sex-matched healthy individuals as control. Plasma concentration of H2S was measured with spectrophotometry. Sulfhemoglobin, the integration of H2S and hemoglobin, was characterized and measured by dual wavelength spectrophotometry. Serum levels of homocysteine (Hcy), cardiac troponin T (cTnT), and N-terminal pro B type natriuretic peptide were measured using automated analyzers. Conventional transthoracic echocardiography was performed and left ventricular ejection fraction (LVEF) was analyzed as a sensitive parameter of cardiac dysfunction. RESULTS: The plasma H2S level (µmol/L) in CKD patients was significantly lower than those in healthy controls (7.32 ± 4.02 vs. 14.11 ± 5.24 µmol/L, p < 0.01). Plasma H2S level was positively associated with estimated glomerular filtration rate (eGFR; ρ = 0.577, p < 0.01) and negatively associated with plasma indoxyl sulfate concentration (ρ = -0.554, p < 0.01). The mRNA levels of cystathionine ß-synthase and cystathionine γ-lyase, 2 catalytic enzymes of H2S formation, were significantly lower in blood mononuclear cells of CKD patients with respect to controls; however, the mRNA level of 3-mercaptopyruvate sulfurtransferase, as another H2S-producing enzyme, was significantly higher in CKD patients. The serum concentration of Hcy, acting as the substrate of H2S synthetase, was higher in the CKD group (p < 0.01). Specifically, the content of serum Hcy in CKD stages 3-5 patients was significantly higher than that in CKD stages 1-2, indicating an increasing trend of serum Hcy with the decline of renal function. Examination of ultrasonic cardiogram revealed a negative -correlation between plasma H2S level and LVEF (ρ = -0.204, p < 0.05) in CKD patients. The H2S level also correlated negatively with cTnT concentration (ρ = -0.249, p < 0.01). CONCLUSIONS: Plasma H2S level decreased with the decline of eGFR, which may contribute to the cardiac dysfunction in CKD -patients.

Sorafenib combined with radiofrequency ablation as treatment for patients with hepatocellular carcinoma: a systematic review and meta-analysis.

PURPOSE: To evaluate the safety and efficacy of a combination of sorafenib and radiofrequency ablation (RFA) in patients with hepatocellular carcinoma (HCC). METHODS: A systematic literature search was conducted using PubMed, Embase, the Cochrane Library, China National Knowledge Infrastructure (CNKI), China Biology Medicine disc (CBMdisc), WanFang Database, for all years up to January 2017. Pooled analyses of overall survival (OS), tumor- free survival, recurrence rates and adverse events were performed. RESULTS: IA total of 7 case control studies consisting of 1765 HCC patients were selected and included in this metaanalysis. Patients treated with sorafenib-RFA and sorafenib alone, RFA alone and surgery had no significant differences in 1-year OS (p=0.310), 2-year OS (p=0.262), 3-year OS (p=0.179), 4-year OS (p=0.238) and 5-year OS (p=0.933); 1-year recurrence rate (p=0.653), 2-year recurrence rate (p=0.416), 3-year recurrence rate (p=0.304), and 5-year recurrence rate (p=0.807); 1-year tumor-free survival rate (p=0.943), 3-year tumor-free survival rate (p=0.825), 5-year tumor-free survival rate (p=0.893) and overall adverse events (p=0.097). CONCLUSION: RFA-sorafenib combination may not be a better approach for patients with HCC. More well-designed randomized clinical trials (RCTs) should be performed before we finally arrive at a rational comprehension about the therapeutic value of the discussed options.

Generation of KCNH2 heterozygous knockout induced pluripotent stem cell (iPSC) line (Long and Short QT Syndrome).

KCNH2 (Potassium Voltage-Gated Channel Subfamily H Member) encodes a voltage-activated potassium channel role as rapidly activating-delayed rectifier potassium channel that plays an essential role in the final repolarization of the ventricular action potential. Mutations in this gene can cause long QT syndrome and short QT syndrome. Transcript variants encoding distinct isoforms were also identified. In this study, we generated induced pluripotent stem cells (iPSC) from a healthy individual by electroporation of peripheral blood mononuclear cells and generated a KCNH2 heterozygous knockout human iPSC line via CRISPR/Cas9 gene editing. The resulting iPSCs had a normal karyotype, were free of genomically integrated epitomal plasmids, expressed pluripotency markers, and maintained trilineage differentiation potential.

Iron-catalyzed N-alkylation using π-activated ethers as electrophiles.

A new method for the synthesis of diverse N-alkylation compounds was developed via an iron-catalyzed etheric C(sp(3))-O cleavage with the C-N bond formation in the reaction of π-activated ethers with various nitrogen-based nucleophiles. In addition, the mechanism of this reaction was investigated.

Identification of ferroptosis and drug resistance related hub genes to predict the prognosis in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Currently, overcoming the drug resistance in HCC is a critical challenge and ferroptosis has emerged as a promising therapeutic option for cancer. We aim to construct a new gene signature related to ferroptosis and drug resistance to predict the prognosis in HCC. The RNA-seq data of HCC patients was obtained from the Cancer Genome Atlas database. Using least absolute shrinkage and selection operator cox regression, Kaplan-Meier analysis, and differential analysis, we constructed a prognostic model consisting of six hub genes (TOP2A, BIRC5, VEGFA, HIF1A, FTH1, ACSL3) related to ferroptosis and drug resistance in HCC. Functional enrichment, pathway enrichment and GSEA analysis were performed to investigate the potential molecular mechanism, and construction of PPI, mRNA-miRNA, mRNA-RBP, mRNA-TF and mRNA-drugs interaction networks to predict its interaction with different molecules. Clinical prognostic characteristics were revealed by univariate, multivariate cox regression analysis and nomogram. We also analyzed the relationship between the signature, immune checkpoints, and drug sensitivity. The expression of the gene signature was detected in HCC cell lines and HPA database. Our prognostic model classified patients into high and low-risk groups based on the risk scores and found the expression level of the genes was higher in the high-risk group than the low-risk group, demonstrating that high expression of the hub genes was associated with poor prognosis in HCC. ROC analysis revealed its high diagnostic efficacy in both HCC and normal tissues. The proportional hazards model and calibration analysis confirmed that the model's prediction was most accurate for 1- and 3-years survival. QRT-PCR showed the high expression level of the gene signature in HCC. Our study built a novel gene signature with good potential to predict the prognosis of HCC, which may provide new therapeutic targets and molecular mechanism for HCC diagnosis and treatment.

The role of plateletcrit in Takayasu arteritis: A potential biomarker for disease activity and 6-month treatment response.

OBJECTIVES: To determine the role of plateletcrit as a potential biomarker for disease activity and treatment response in Takayasu arteritis (TAK). METHODS: Totally, 215 newly diagnosed TAK patients were consecutively enrolled. Demographic data, clinical manifestations, laboratory and imaging examinations, and treatment strategy were recorded at baseline and at each visit during the 6-month treatment period. Normal plateletcrit (0.1%-0.4%) and hyper-plateletcrit (>0.4%) observed at baseline were used as group criteria. RESULTS: At baseline, the overall plateletcrit was 0.32 (0.24-0.38)%, with a normal and high level observed in 172 (80.00%) and 43 (20.00%) patients, respectively. Baseline plateletcrit was significantly higher in patients with active disease and associated with inflammatory biomarkers, including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and interleukin (IL)-6 (all p < .01). At 6 months, complete remission was achieved in 171 (79.53%) patients, and a significant decrease in plateletcrit was observed in these cases (p < .01). Patients with a normal baseline plateletcrit were more likely to achieve complete remission compared to those with a high baseline plateletcrit (HR = 4.65, 95% CI: 2.38-19.08, p < .01). In addition, ESR (p = .01) and IL-6 (p = .02) levels were still higher in patients with a high baseline plateletcrit at 6 months. Progression of vascular lesions was indicated in 18 (8.37%) patients at 6 months, and these patients also had significantly higher baseline plateletcrit (p = .03). CONCLUSION: Plateletcrit levels were positively related to disease activity and inflammatory index in TAK. Importantly, patients with high baseline plateletcrit levels may show a worse treatment response at 6 months.

Time-reversal symmetry breaking superconductivity between twisted cuprate superconductors.

Twisted interfaces between stacked van der Waals (vdW) cuprate crystals present a platform for engineering superconducting order parameters by adjusting stacking angles. Using a cryogenic assembly technique, we construct twisted vdW Josephson junctions (JJs) at atomically sharp interfaces between Bi2Sr2CaCu2O8+x crystals, with quality approaching the limit set by intrinsic JJs. Near 45° twist angle, we observe fractional Shapiro steps and Fraunhofer patterns, consistent with the existence of two degenerate Josephson ground states related by time-reversal symmetry (TRS). By programming the JJ current bias sequence, we controllably break TRS to place the JJ into either of the two ground states, realizing reversible Josephson diodes without external magnetic fields. Our results open a path to engineering topological devices at higher temperatures.

A Mesoscale Study on the Dilation of Actively Confined Concrete under Axial Compression.

The confinement of concrete enhances its strength and ductility by restraining lateral dilation. The accuracy of a confinement model depends on how well it captures the dilation of concrete. In the current paper, a mesoscale model is established to study the dilation properties of concrete in active confinement, where the heterogeneity of concrete is considered. The stress-strain and lateral-axial strain curves of concrete in active confinement were used to demonstrate the validity of the mesoscale model. Subsequently, the distribution of lateral strain and the influences of the strength grade and confinement ratio on the dilation of concrete were investigated in a simulation. The results show that the distribution of the lateral strain along the radial or longitudinal directions is not uniform on the specimen when compressive failure occurs. The confinement ratio has a more significant influence on the concrete's transverse dilation than the strength grade. Finally, an expression of the lateral-axial strain relationship of concrete in active confinement is proposed. The proposed formula can reflect the simulation results of the mesoscale model and is in good agreement with the prediction of existing formulas.

The HN1/HMGB1 axis promotes the proliferation and metastasis of hepatocellular carcinoma and attenuates the chemosensitivity to oxaliplatin.

Hematological and neurological expressed 1 (HN1) is closely associated with the proliferation and metastasis of various tumors. However, the physiological functions and clinical significance of HN1 in hepatocellular carcinoma (HCC) remain indistinct. In this study, we investigated the role of HN1 in the pathogenesis of HCC and the underlying mechanism using clinical data from HCC patients, in vitro experiments utilizing HCC cell lines and in vivo animal models. We demonstrated that the overexpressed HN1 in HCC was correlated with patients' adverse outcomes. The gain and loss of function experiments indicated that HN1 could promote the proliferation, migration, and invasion of HCC cells in vitro. Furthermore, we found that HN1 knockdown sensitized HCC cells to oxaliplatin. Mechanically, HN1 prevented HMGB1 protein from ubiquitination and degradation via the autophagy-lysosome pathway, which was related to the interaction between HN1 protein and TRIM28 protein. In the nucleus, the downregulation of HMGB1 followed by HN1 knockdown resulted in increased DNA damage and cell death in the oxaliplatin-treated HCC cells. In the cytoplasm, HN1 regulated autophagy via HMGB1. Furthermore, HN1 knockdown in combination with HMGB1 overexpression restored the aggressive phenotypes of HCC cells and the sensitivity of these cells to oxaliplatin. HN1 knockdown inhibited the tumor growth and metastasis, and promoted the anticancer efficiency of oxaliplatin in vivo. In conclusion, our data suggest that the HN1/HMGB1 axis plays an important role in the development/progression and chemotherapy of HCC. Our findings indicate that the HN1/HMGB1 axis may be a promising therapeutic target for HCC treatment.

Potential Role of Macrophage Phenotypes and CCL2 in the Pathogenesis of Takayasu Arteritis.

Objectives: To investigate vascular macrophage phenotype as well as vascular and peripheral chemokine (C-C motif) ligand 2 (CCL2) expression during different stages of disease progression in patients with Takayasu Arteritis (TA). Methods: In this study, 74 patients with TA and 50 controls were recruited. TA disease activity was evaluated with Kerr scores. Macrophage phenotype and CCL2 expression were examined by immunohistochemistry in vascular specimens from 8 untreated and 7 treated TA patients, along with 4 healthy controls. Serum CCL2 were quantified by enzyme-linked immune-absorbent assay from TA patients at baseline (n=59), at 6-months (n=38), and from 46 healthy volunteers. Vascular macrophage phenotype, vascular CCL2 expression and serum CCL2 levels during different stages, as well as the relationship between serum CCL2 and disease activity or other inflammatory parameters (erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and interleukin 6 (IL-6)) were investigated. Results: In untreated patients, vascular M1 macrophages and CCL2 showed increased expression, mainly in the adventitia. In contrast, in treated patients, vascular adventitial M1 and CCL2 expression were decreased, while vascular medial M2 macrophages and CCL2 levels were increased. Distribution of macrophages and CCL2 was consistent within the TA vascular lesions regardless of the disease stage. Furthermore, peripheral CCL2 was elevated in patients with TA (TA: 160.30 ± 120.05 vs. Control: 65.58 ± 54.56 pg/ml, P < 0.001). CCL2 levels were found to correlate with ESR, CRP, and IL-6 (all R values between 0.55 and 0.6, all P < 0.001). Receiver operating curve analysis demonstrated that CCL2 (at the cut-off value of 100.36 pg/ml) was able to predict disease activity (area under the curve = 0.74, P = 0.03). Decrease in CCL2 level was observed in patients with clinical remission (CR), but not in patients without CR, after 6 months of treatment (CR patients: baseline 220.18 ± 222.69 vs. post-treatment 88.71 ± 55.89 pg/ml, P = 0.04; non-CR patients: baseline 142.45 ± 104.76 vs. post-treatment 279.49 ± 229.46 pg/ml, P = 0.02). Conclusions: Macrophages contribute to vascular pathological changes in TA by undergoing phenotype transformation. CCL2 is an important factor for recruiting macrophages and a potential biomarker for disease activity.