Positive feedback loop PU.1-IL9 in Th9 promotes rheumatoid arthritis development.

OBJECTIVES: T helper 9 (Th9) cells are recognised for their characteristic expression of the transcription factor PU.1 and production of interleukin-9 (IL-9), which has been implicated in various autoimmune diseases. However, its precise relationship with rheumatoid arthritis (RA) pathogenesis needs to be further clarified. METHODS: The expression levels of PU.1 and IL-9 in patients with RA were determined by ELISA, western blotting (WB) and immunohistochemical staining. PU.1-T cell-conditional knockout (KO) mice, IL-9 KO and IL-9R KO mice were used to establish collagen antibody-induced arthritis (CAIA), respectively. The inhibitor of PU.1 and IL-9 blocking antibody was used in collagen-induced arthritis (CIA). In an in vitro study, the effects of IL-9 were investigated using siRNAs and IL-9 recombinant proteins. Finally, the underlying mechanisms were further investigated by luciferase reporter analysis, WB and Chip-qPCR. RESULTS: The upregulation of IL-9 expression in patients with RA exhibited a positive correlation with clinical markers. Using CAIA and CIA model, we demonstrated that interventions targeting PU.1 and IL-9 substantially mitigated the inflammatory phenotype. Furthermore, in vitro assays provided the proinflammatory role of IL-9, particularly in the hyperactivation of macrophages and fibroblast-like synoviocytes. Mechanistically, we uncovered that PU.1 and IL-9 form a positive feedback loop in RA: (1) PU.1 directly binds to the IL-9 promoter, activating its transcription and (2) Th9-derived IL-9 induces PU.1 via the IL-9R-JAK1/STAT3 pathway. CONCLUSIONS: These results support that the PU.1-IL-9 axis forms a positive loop in Th9 dysregulation of RA. Targeting this signalling axis presents a potential target approach for treating RA.

PU.1 promotes development of rheumatoid arthritis via repressing FLT3 in macrophages and fibroblast-like synoviocytes.

OBJECTIVES: To uncover the function and underlying mechanism of an essential transcriptional factor, PU.1, in the development of rheumatoid arthritis (RA). METHODS: The expression and localisation of PU.1 and its potential target, FMS-like tyrosine kinase 3 (FLT3), in the synovium of patients with RA were determined by western blot and immunohistochemical (IHC) staining. UREΔ (with PU.1 knockdown) and FLT3-ITD (with FLT3 activation) mice were used to establish collagen antibody-induced arthritis (CAIA). For the in vitro study, the effects of PU.1 and FLT3 on primary macrophages and fibroblast-like synoviocytes (FLS) were investigated using siRNAs. Mechanistically, luciferase reporter assays, western blotting, FACS and IHC were conducted to show the direct regulation of PU.1 on the transcription of FLT3 in macrophages and FLS. Finally, a small molecular inhibitor of PU.1, DB2313, was used to further illustrate the therapeutic effects of DB2313 on arthritis using two in vivo models, CAIA and collagen-induced arthritis (CIA). RESULTS: The expression of PU.1 was induced in the synovium of patients with RA when compared with that in osteoarthritis patients and normal controls. FLT3 and p-FLT3 showed opposite expression patterns compared with PU.1 in RA. The CAIA model showed that PU.1 was an activator, whereas FLT3 was a repressor, of the development of arthritis in vivo. Moreover, results from in vitro assays were consistent with the in vivo results: PU.1 promoted hyperactivation and inflammatory status of macrophages and FLS, whereas FLT3 had the opposite effects. In addition, PU.1 inhibited the transcription of FLT3 by directly binding to its promoter region. The PU.1 inhibitor DB2313 clearly alleviated the effects on arthritis development in the CAIA and CIA models. CONCLUSIONS: These results support the role of PU.1 in RA and may have therapeutic implications by directly repressing FLT3. Therefore, targeting PU.1 might be a potential therapeutic approach for RA.

The application of HER2 and CD47 CAR-macrophage in ovarian cancer.

BACKGROUND: The chimeric antigen receptor (CAR)-T therapy has a limited therapeutic effect on solid tumors owing to the limited CAR-T cell infiltration into solid tumors and the inactivation of CAR-T cells by the immunosuppressive tumor microenvironment. Macrophage is an important component of the innate and adaptive immunity, and its unique phagocytic function has been explored to construct CAR macrophages (CAR-Ms) against solid tumors. This study aimed to investigate the therapeutic application of CAR-Ms in ovarian cancer. METHODS: In this study, we constructed novel CAR structures, which consisted of humanized anti-HER2 or CD47 scFv, CD8 hinge region and transmembrane domains, as well as the 4-1BB and CD3ζ intracellular domains. We examined the phagocytosis of HER2 CAR-M and CD47 CAR-M on ovarian cancer cells and the promotion of adaptive immunity. Two syngeneic tumor models were used to estimate the in vivo antitumor activity of HER2 CAR-M and CD47 CAR-M. RESULTS: We constructed CAR-Ms targeting HER2 and CD47 and verified their phagocytic ability to ovarian cancer cells in vivo and in vitro. The constructed CAR-Ms showed antigen-specific phagocytosis of ovarian cancer cells in vitro and could activate CD8+ cytotoxic T lymphocyte (CTL) to secrete various anti-tumor factors. For the in vivo model, mice with human-like immune systems were used. We found that CAR-Ms enhanced CD8+ T cell activation, affected tumor-associated macrophage (TAM) phenotype, and led to tumor regression. CONCLUSIONS: We demonstrated the inhibition effect of our constructed novel HER2 CAR-M and CD47 CAR-M on target antigen-positive ovarian cancer in vitro and in vivo, and preliminarily verified that this inhibitory effect is due to phagocytosis, promotion of adaptive immunity and effect on tumor microenvironment.

Structural, electronic phase transitions and thermal spin transport properties in 2D NbSe2 and NbS2: a first-principles study.

How to effectively tune 2D electronic and magnetic properties is key to developing novel spintronic materials and devices. Although the strain induced metal-to-half-metal electronic phase transition (EPT) has been studied in 2H NbSe2 and NbS2 monolayers, the 1T phase, the Coulomb interaction and the transport properties have not been explored. Here, using first-principles calculations in junction with nonequilibrium Green's function, we present a comprehensive and comparative study on the strain tuned structural, electronic, magnetic and thermal spin transport properties for NbSe2 and NbS2 monolayers with and without Coulomb interaction. It is found that the Coulomb interaction makes the strain induced 2H-to-1T structural phase transition easier. Similar to the 2H phase, there is also a strain induced metal-to-half-metal EPT for the 1T phase without Coulomb interaction, and the Coulomb interaction makes the ETP easier. Remarkably, the 2H-NbSe2 monolayer with Coulomb interaction is a bipolar spin gapless semiconductor (SGS), and novel Dirac half-metal and usually SGS can be obtained by the tensile strain. In addition, we predict the excellent spin Seebeck effect and thermal spin diode effect in the bipolar SGS of the 2H-NbSe2 monolayer with Coulomb interaction, and expect the spin filtering effect and high magnetoresistance in the half-metals driven by the strain. We also discuss the strength of Coulomb interaction by comparing the theoretical and available experimental electronic states, indicating the indispensability of Coulomb interactions. These results suggest that 2D NbSe2 and NbS2 are promising candidates for phase-change spintronic materials and devices, and will stimulate extensive studies on this class of 2D systems.

Perylene-based molecular device: multifunctional spintronic and spin caloritronic applications.

Carbon-based magnetic molecular junctions are promising candidates for nanoscale spintronic applications because they are atomically thin and possess high stability and peculiar magnetism. Herein, based on first-principles and non-equilibrium Green's function, we designed a carbon-based molecular spintronic device composed of carbon atomic chains, zigzag-edged graphene nanoribbon (ZGNR), and a perylene molecule. Our results show that the device exhibits integrated spintronic and spin caloritronic functionalities, such as the bias-voltage driven spin filtering effect, negative differential resistance effect and giant magnetoresistance, temperature-gradient driven spin Seebeck effect, thermal spin filtering effect, high thermal magnetoresistance, and thermal colossal giant magnetoresistance. Furthermore, considering the phonon vibration effect, the spin and charge thermoelectric figure of merits (ZTsp and ZTch) can be enhanced and the peak of ZTsp is much larger than that of ZTch, indicating the excellent thermospin performance. The asymmetrical contact configuration between the carbon atomic chain and perylene/ZGNR inhibits the phonon thermal conductivity significantly, leading to the optimal ZTsp and ZTch of 2.4 and 0.5 at 300 K, respectively. These results suggest multifunctional spintronic and spin caloritronic applications for the perylene-based molecular device.

Ultrasensitive detection of multiple Alzheimer's disease biomarkers by SERS-LFA.

Alzheimer's disease (AD) is one of the top public health crises in the 21st century, especially in an aging society. Early diagnosis, prevention, and intervention can significantly reduce the risk of AD. Detection of multiple AD biomarkers in blood is an effective strategy and has drawn more and more attention in recent years. However, the concentration of AD biomarkers is very low, therefore, point-of-care testing (POCT) techniques are needed for sensitive detection. Herein, a lateral flow assay, based on Surface-enhanced Raman scattering nanotags (SERS-LFA), is proposed for the simultaneous quantification of multiple AD biomarkers including Amyloid-beta 42, Amyloid-beta 40, tau proteins, and neurofilament light chain. The limit of detection for four AD biomarkers is 138.1, 191.2, 257.1, and 309.1 fg mL-1, respectively, which are two orders of magnitude lower than their concentrations in blood. Compared with the existing detection technology, SERS-LFA has the advantages of high specificity, high sensitivity, low cost, multiple detection, and rapid detection. Therefore, SERS-LFA has a broad application prospect in the early diagnosis and monitoring of AD in the future.

Ultralow lattice thermal conductivity at room temperature in 2D KCuSe from first-principles calculations.

Ultralow lattice thermal conductivity is crucial for achieving a high thermoelectric figure of merit for thermoelectric applications. In this work, using first-principles calculations and the phonon Boltzmann transport theory, we investigate the phonon thermal transport properties of 2D KCuSe. Our calculations indicate that the strong acoustic-optical coupling, the low-lying acoustic phonon modes and the strong lattice anharmonic effect with a large Grüneisen parameter and phase space volume result in an ultralow lattice thermal conductivity of 0.021 W m-1 K-1 at 300 K for monolayer KCuSe, which is lower than those of recently reported KAgSe (0.26 W m-1 K-1 at 300 K) and TlCuSe (0.44 W m-1 K-1 at 300 K). Importantly, although the Coulomb interactions and the tensile biaxial strain lead to the increase of lattice thermal conductivity due to the increasing relaxation time (0.056 and 0.28 W m-1 K-1 at 300 K without and with 6% tensile strain, respectively), it is still lower than those of most 2D thermoelectric materials. The advantages of being cheap, environmentally friendly and having low lattice thermal conductivity compared to the KAgSe and TlCuSe derivatives make KCuSe a promising candidate for thermoelectric applications, which will stimulate more efforts toward theoretical and experimental studies on this class of 2D ternary semiconductors.

Prognostic Significance of Preoperative Integrated Liver Inflammatory Score in Patients with Hepatocellular Carcinoma.

BACKGROUND The Integrated Liver Inflammatory Score (ILIS), which includes 5 serum indicators (albumin, bilirubin, neutrophil count, alpha-fetoprotein [AFP], and alkaline phosphatase [ALP]), is a novel inflammation-based predictive model associated with poor survival in hepatocellular carcinoma (HCC) patients. Our study aimed to assess the prognostic value of ILIS in HCC patients undergoing radical hepatectomy and establish a nomogram and artificial neural network based on their ILIS scores. MATERIAL AND METHODS This multicenter retrospective study included patients from 2 institutions from 2007 to 2017. Independent risk factors associated with Recurrence-free survival (RFS) and overall survival (OS) were identified through univariate and multifactor analysis in the training and validation groups, respectively. Afterward, column line graphs and artificial neural networks (ANN) were constructed and validated using the validation group. RESULTS A total of 432 patients were included in this study (275 in the training group and 157 in the validation group). In both cohorts, ILIS was correlated with pathological features such as tumor size, degree of differentiation, Child-Pugh class classification, and BCLC staging. Moreover, ILIS was identified as an independent risk factor for OS. ILIS-based nomograms and artificial neural networks also showed the prognostic value of ILIS. CONCLUSIONS Preoperative ILIS is an independent and effective predictor of prognosis in HCC patients treated with radical hepatectomy, as shown by the fact that higher ILIS are associated with worse patient prognosis. We have also established nomograms and ANNs that predict HCC prognosis with high accuracy.

2D Nb2SiTe4and Nb2GeTe4: promising thermoelectric figure of merit and gate-tunable thermoelectric performance.

Recently, the experimentally synthesized Nb2SiTe4was found to be a stable layered narrow-gap semiconductor, and the fabricated field-effect transistors (FETs) based on few-layers Nb2SiTe4are good candidates for ambipolar devices and mid-infrared detection (Zhaoet al2019ACS Nano1310705-10). Here, we use first-principles combined with Boltzmann transport theory and non-equilibrium Green's function method to investigate the thermoelectric transport coefficients of monolayer Nb2XTe4(X = Si, Ge) and the gate voltage effect on the thermoelectric performance of the FET based on monolayer Nb2SiTe4. It is found that both monolayers have largep-type Seebeck coefficients due to the 'pudding-mold-type' valence band structure, and they both exhibit anisotropic thermoelectric behavior with optimal thermoelectric figure of merit of 1.4 (2.2) at 300 K and 2.8 (2.5) at 500 K for Nb2SiTe4(Nb2GeTe4). The gate voltage can effectively increase the thermoelectric performance for the Nb2SiTe4-based FET. The high thermoelectric figure of merit can be maintained in a wide temperature range under a negative gate voltage. Furthermore, the FET exhibits a good gate-tunable Seebeck diode effect. The present work suggests that Nb2XTe4monolayers are promising candidates for 2D thermoelectric materials and thermoelectric devices.

Epigenetic silencing of microRNA-204 by Helicobacter pylori augments the NF-κB signaling pathway in gastric cancer development and progression.

Helicobacter pylori infection induces gastric cancer (GC) development through a progressive cascade; however, the roles of the microRNAs that are involved in the cascade and the underlying mechanisms are still unclear. Here, we found that microRNA-204 was suppressed in gastric mucosal cells in response to H.pylori infection and downregulated in GC tissues due to aberrant methylation of the promoter of its host gene, TRPM3. Helicobacter pylori induced a progressive downregulation of microRNA-204 from superficial gastritis to intestinal metaplasia, with an accompanying increment of the methylated levels of CpG sites in the TRPM3 promoter. With the GC cellular models of AGS, MGC-803 or BGC-823, we found that microRNA-204 suppressed the tumor necrosis factor (TNF)-α-induced activation of NF-κB signaling pathways and, in animal models, inhibited tumor growth and metastasis. The conditional supernatant of microRNA-204 overexpression GC cells led to reduced tube formation of human umbilical vein endothelial cells. A target gene for microRNA-204 was BIRC2, and in GC cells, BIRC2 knockdown recapitulated the biological phenotype of microRNA-204 overexpression. BIRC2 overexpression promoted the metastasis of GC cells and rescued the inhibition activities of microRNA-204 on cell migration and the NF-κB signaling pathway. Moreover, lower microRNA-204 and higher BIRC2 expression levels were associated with a poorer prognosis of GC patients. These results demonstrate that epigenetic silencing of microRNA-204 induced by H.pylori infection augments the NF-κB signaling pathway in H.pylori-induced gastritis and GC, potentially providing novel intervention targets for these diseases. MicroRNA-204 was epigenetically down-regulated by H. pylori infection in gastric mucosal cells. It led to enhanced BIRC2 expression level and BIRC2/TNF-a/NF-kB signaling pathway activities, which promoted angiogenesis and metastasis of gastric cancer cells.

The half-metallicity and the spin filtering, NDR and spin Seebeck effects in 2D Ag-doped SnSe2 monolayer.

Two-dimensional SnSe2 has become more and more attractive due to the excellent electronic, optoelectronic, and thermoelectric properties. However, the study on magnetic properties is rare. Inspired by the recent experimental synthesis of SnSe2 monolayer and Ag-doped SnSe2 thin films, we use the first-principles calculations combined with the nonequilibrium Green's function method to investigate the structural, electronic, magnetic, and spin transport properties of an Ag-doped SnSe2 monolayer. It is found that the doped system exhibits half-metallic ferromagnetism with the energy gap of about 0.5 eV in the spin-down channel. The spin-polarized transport properties based on Ag-doped SnSe2 monolayers show an excellent spin filtering effect and a negative differential resistance effect under a bias voltage. Interestingly, under a temperature gradient, the spin Seebeck effect and the temperature-controlled reverse of spin polarization are also observed. These perfect spin transport properties can be understood from the calculated spin-polarized band structure and the spin-polarized transport spectrum. These studies indicate the potential spintronic and spin caloritronic applications for Ag-doped SnSe2 monolayer.

Prevention of prostate cancer by natural product MDM2 inhibitor GS25: in vitro and in vivo activities and molecular mechanisms.

Prostate cancer remains a major health problem in the USA and worldwide. There is an urgent need to develop novel approaches to preventing primary and metastatic prostate cancer. We have identified 25-OCH3-protopanaxadiol (GS25), the most active ginsenoside that has been identified so far; it has potent activity against human cancers, including prostate cancer. However, it has not been proven if GS25 could be a safe and effective agent for cancer prevention. In this study, we used the TRAMP model and clearly demonstrated that GS25 inhibited prostate tumorigenesis and metastasis with minimal host toxicity. Mechanistically, GS25 directly bound to the RING domain of MDM2, disrupted MDM2-MDMX binding and induced MDM2 protein degradation, resulting in strong inhibition of prostate cancer cell growth and metastasis, independent of p53 and androgen receptor status. In conclusion, our in vitro and in vivo data support the potential use of GS25 in prevention of primary and metastatic prostate cancer.

[Effects of pure total flavonoids from Citrus changshan-huyou on blood lipid metabolism in hyperlipidemic rats].

To observe and investigate the effects and mechanisms of the pure total flavonoids from Citrus changshan-huyou(PTFC) on blood lipid metabolism in hyperlipidemic rats. SD rats were fed with high fat diet for 4 weeks to induce hyperlipidemic rats model, meanwhile three dosages (50, 100, 200 mg•kg ⁻¹â€¢d ⁻¹) of PTFC were administrated intragastrically for 4 weeks respectively.After 2 weeks of modeling, their tail blood was taken and serum TC, TG, and HDL-C levels were detected by biochemical method and their body weight was measured. After 4 weeks of modeling, their body weight was measured and liver weight was measured, then the levels of TC, TG, HDL-C, LDL-C, ALT, AST, MDA and SOD in serum were detected to calculate lipid comprehensive index(LDL-C/HDL-C and LDL-C/TC ratios) and atherogenic index(AI); in addition, MDA and SOD levels were detected by biochemical method. The hitopathological changes of the liver tissues were observed by HE staining; the protein expression levels of PPAR-α, Lpl, and Lipc were detected by ELISA; and the mRNA expression levels of PPAR-α in the liver tissue were detected by Real-time PCR. The results showed that gavage administration of the PTFC significantly decreased the body weight, liver weight, liver index, serum ALT and AST activities, the levels of serum TC, TG, LDL-C, LDL-C/HDL-C, AI and increased serum HDL and LDL/TC level. Moreover, the PTFC significantly enhanced SOD activity and decreased the concentration of MDA in serum and liver tissue. Further mechanism investigation indicated that PTFC inhibited serum lipid accumulation by increasing the expressions PPAR-α, Lpl, Lipc protein and PPAR-α mRNA of the liver tissues. PTFC could actively regulate blood lipid metabolism by ameliorating hepatic function, improving the body's antioxidant capacity, lowering levels of oxidative stress, as well as positively regulating the expression levels of PPAR-α, Lpl, Lipc protein and PPAR-α mRNA of the liver tissues in rats.

Association of variants on ADIPOQ and AdipoR1 and the prognosis of gastric cancer patients after gastrectomy treatment.

Adiponectin is a protein hormone secreted exclusively by adipocytes and it is responsible for insulin sensitization in the human body. Deregulation of adiponectin and its downstream signaling pathway genes have been found to be involved in the gastric cancer carcinogenesis; however, whether the variants on adiponectin (ADIPOQ) and adiponectin receptor 1 (ADIPOR1) affect the prognosis of gastric cancer patients are still unknown. Here we have recruited 455 gastric cancer patients, who have received the gastrectomy treatment to evaluate the prognostic effects of variants on ADIPOQ (rs266729 and rs822395) and AdipoR1 (rs12733285 and rs1342387) for the gastric cancer patients. No significant association between the four variants and the overall survival of the gastric cancer patients was found. However, for those patients without a previous history of alcohol drinking, the rs266729 GG/CG genotype carriers showed a significantly decreased gastric cancer mortality compared to homogeneity CC patients (HR 0.74, 95 % CI 0.56-0.97; p = 0.032) after adjustment for variants age, sex, smoking status, tumor stage, tumor location and post-surgery chemotherapy. No significant association between the variant rs266729 genotypes and overall survival for the gastric cancer patients with an alcohol drinking habit. These data suggested that the variant rs266729 was an independent prognostic factor for the never drinking gastric cancer patients who received surgical treatment.

Flexible TWDM PON system with pluggable optical transceiver modules.

A flexible TWDM PON system is proposed which allows pay-as-you-grow in capacity, supports load balancing among different ODNs, and achieves significant power saving at OLT. Integrated OLT transceiver in enhanced CFP module and low-cost tunable ONU transceiver in SFP+ module are developed, for the first time, for cost effective deployment of TWDM PONs. System experiments demonstrate error free performance with 36 dB power budget in a flexible TWDM PON test bed.

CHIP functions as a novel suppressor of tumour angiogenesis with prognostic significance in human gastric cancer.

OBJECTIVE: CHIP (carboxy terminus of Hsc70 interacting protein) is an E3 ubiquitin ligase that can induce ubiquitination and degradation of several tumour related proteins, and acts as a suppressor of tumour metastasis. This study explored the biological function and clinical significance of CHIP in gastric cancer (GC). METHODS: The prognostic value of CHIP expression was evaluated using tissue microarray and immunohistochemical staining in two independent human GC cohorts. The role of CHIP on tumorigenicity and angiogenesis was determined in vitro and in vivo. RESULTS: CHIP expression was significantly decreased in GC lesions compared with paired non-cancerous tissues. Low tumoral CHIP expression significantly correlated with clinicopathological characteristics in patients, as well as with shorter overall survival in both cohorts. Multivariate Cox regression analysis revealed that CHIP expression was an independent prognostic factor for human GC patients. Moreover, CHIP overexpression impeded the formation of anchorage independent colonies in soft agar, suppressed the growth of xenografts in nude mice and inhibited endothelial cell growth and tube formation by suppressing nuclear factor κB (NF-κB) mediated interleukin 8 (IL-8) expression in vitro. In vivo studies also confirmed that CHIP inhibited blood vessel formation and recruitment of CD31 positive cells in matrigel plugs. Also, CHIP interacted with NF-κB/p65 and promoted its ubiquitination and degradation by proteasome, terminating NF-κB activity and inhibiting IL-8-induced angiogenesis, which correlated with subsequent tumour metastasis. CONCLUSIONS: Decreased CHIP expression in GC resulted in increased angiogenesis and contributed to GC progression and poor prognosis. CHIP expression is a GC candidate clinical prognostic marker and a putative treatment target.

Epigenetic Regulatory Axis MIR22-TET3-MTRNR2L2 Represses Fibroblast-Like Synoviocyte-Mediated Inflammation in Rheumatoid Arthritis.

OBJECTIVE: The specific role of fibroblast-like synoviocytes (FLSs) in the pathogenesis of rheumatoid arthritis (RA) is still not fully elucidated. This study aimed to explore the molecular mechanisms of epigenetic pathways, including three epigenetic factors, microRNA (miRNA)-22 (MIR22), ten-eleven translocation methylcytosine dioxygenase 3 (TET3), and MT-RNR2 like 2 (MTRNR2L2), in RA-FLSs. METHODS: The expression of MIR22, TET3, and MTRNR2L2 in the synovium of patients with RA and arthritic mice were determined by fluorescence in situ hybridization, quantitative polymerase chain reaction (qPCR), immunohistochemistry, and Western blot. Mir22-/- and Tet3+/- mice were used to establish a collagen antibody-induced arthritis (CAIA) model. Mir22 angomir and Tet3 small interfering RNA (siRNA) were used to illustrate the therapeutic effects on arthritis using a collagen-induced (CIA) model. Bioinformatics, luciferase reporter assay, 5-hydroxymethylcytosine (5hmC) dot blotting, chromatin immunoprecipitation-qPCR, and hydroxymethylated DNA immunoprecipitation were conducted to show the direct repression of MIR22 on the TET3 and transcriptional activation of TET3 on MTRNR2L2. RESULTS: The Mir22-/- CAIA model and RA-FLS-related in vitro experiments demonstrated the inhibitory effect of MIR22 on inflammation. MIR22 can directly inhibit the translation of TET3 in RA-FLSs by binding to its 3' untranslated region in TET3. The Tet3+/- mice-established CAIA model showed less severe symptoms of arthritis in vivo. In vitro experiments further confirmed the proinflammatory effect of TET3 in RA. In addition, the CIA model was used to validate the therapeutic effects of Mir22 angomir and Tet3 siRNA. Finally, TET3 exerts its proinflammatory effect by promoting 5hmC production in the promoter of its target MTRNR2L2 in RA-FLSs. CONCLUSION: The key role of the MIR22-TET3-MTRNR2L2 pathway in RA-FLSs provided an experimental basis for further studies into the pathogenesis and related targets of RA from the perspective of FLSs.

The network characteristics in schizophrenia with prominent negative symptoms: a multimodal fusion study.

Previous studies on putative neural mechanisms of negative symptoms in schizophrenia mainly used single modal imaging data, and seldom utilized schizophrenia patients with prominent negative symptoms (PNS).This study adopted the multimodal fusion method and recruited a homogeneous sample with PNS. We aimed to identify negative symptoms-related structural and functional neural correlates of schizophrenia. Structural magnetic resonance imaging (sMRI) and resting-state functional MRI (rs-fMRI) were performed in 31 schizophrenia patients with PNS and 33 demographically matched healthy controls.Compared to healthy controls, schizophrenia patients with PNS exhibited significantly altered functional activations in the default mode network (DMN) and had structural gray matter volume (GMV) alterations in the cerebello-thalamo-cortical network. Correlational analyses showed that negative symptoms severity was significantly correlated with the cerebello-thalamo-cortical structural network, but not with the DMN network in schizophrenia patients with PNS.Our findings highlight the important role of the cerebello-thalamo-cortical structural network underpinning the neuropathology of negative symptoms in schizophrenia. Future research should recruit a large sample and schizophrenia patients without PNS, and apply adjustments for multiple comparison, to verify our preliminary findings.

MDM2 is a useful prognostic biomarker for resectable gastric cancer.

Expression of MDM2 protein appears to be increased in malignancy and correlated to prognosis of tumors, but its role in gastric cancer remains controversial. Our recent investigations indicated that JWA was a novel candidate biomarker for gastric cancer. To evaluate the impact of MDM2 protein expression alone, and in combination with JWA, on the prognostic and predictive of patients with resectable gastric cancer, expression of MDM2 and JWA were examined by immunohistochemistry in three large cohorts (total n = 1131) of patient with gastric cancer. We found that MDM2 protein levels were significantly upregulated in gastric cancer (70.4%, 57 of 81) compared with adjacent non-cancerous tissues. High tumoral MDM2 expression significantly correlated with clinicopathologic characteristics, as well as with shorter overall survival (OS; P < 0.001 for all cohorts) in patients without adjuvant treatment. The effect of adjuvant fluorouracil-leucovorin-oxaliplatin (FLO) in improving OS compared with surgery alone was evident only in the high MDM2 group (hazard ratio = 0.57; 95% confidence interval, 0.37-0.89; P = 0.013). Furthermore, knockdown of MDM2 and overexpression of JWA had a synergistic effect on suppression of gastric cancer cell proliferation and migration. Patients with low MDM2 and high JWA expression had a better outcome of survival compared with the other groups (P < 0.001 for all cohorts). For the first time, our data suggest that MDM2 is a potent prognostic and predictive factor for benefit from adjuvant fluorouracil-leucovorin-oxaliplatin chemotherapy in resectable gastric cancer. The combination of MDM2 expression and JWA could serve as a more effective candidate prognostic biomarker for gastric cancer.