LncRNA HCG18 promotes inflammation and apoptosis in intervertebral disc degeneration via the miR-495-3p/FSTL1 axis.

Intervertebral disc degeneration (IDD) causes pain in the back and neck. This study investigated the role of long non-coding RNA HLA complex group 18 (HCG18) in a cell model of IDD. An IDD model was established by stimulating nucleus pulposus (NP) cells with interleukin (IL)-1ß. MTT assay was performed to evaluate NP cell viability. The apoptosis was detected by flow cytometry. The expressions of HCG18, microRNA (miR)-495-3p, and follistatin-like protein-1 (FSTL1) were measured by RT-qPCR. The interactions of miR-495-3p with HCG18 and FSTL1 were analyzed by luciferase reporter assay. IL-1ß stimulation upregulated HCG18 and FSTL1, but downregulated miR-495-3p in NP cells. Silencing of HCG18 or FSTL1, as well as miR-495-3p overexpression in NP cells alleviated IL-1ß-induced apoptosis and inflammation of NP cells. Both HCG18 and FSTL1 had binding sites for miR-495-3p. Overexpression of FSTL1 abolished the effects of HCG18 silencing on IL-1ß-induced apoptosis and inflammation. The HCG18/miR-495-3p/FSTL1 axis is essential for IDD development. Therapeutic strategies targeting this axis may be used for IDD treatment.

SWI/SNF complex gene variations are associated with a higher tumor mutational burden and a better response to immune checkpoint inhibitor treatment: a pan-cancer analysis of next-generation sequencing data corresponding to 4591 cases.

BACKGROUND: Genes related to the SWItch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex are frequently mutated across cancers. SWI/SNF-mutant tumors are vulnerable to synthetic lethal inhibitors. However, the landscape of SWI/SNF mutations and their associations with tumor mutational burden (TMB), microsatellite instability (MSI) status, and response to immune checkpoint inhibitors (ICIs) have not been elucidated in large real-world Chinese patient cohorts. METHODS: The mutational rates and variation types of six SWI/SNF complex genes (ARID1A, ARID1B, ARID2, SMARCA4, SMARCB1, and PBRM1) were analyzed retrospectively by integrating next-generation sequencing data of 4591 cases covering 18 cancer types. Thereafter, characteristics of SWI/SNF mutations were depicted and the TMB and MSI status and therapeutic effects of ICIs in the SWI/SNF-mutant and SWI/SNF-non-mutant groups were compared. RESULTS: SWI/SNF mutations were observed in 21.8% of tumors. Endometrial (54.1%), gallbladder and biliary tract (43.4%), and gastric (33.9%) cancers exhibited remarkably higher SWI/SNF mutational rates than other malignancies. Further, ARID1A was the most frequently mutated SWI/SNF gene, and ARID1A D1850fs was identified as relatively crucial. The TMB value, TMB-high (TMB-H), and MSI-high (MSI-H) proportions corresponding to SWI/SNF-mutant cancers were significantly higher than those corresponding to SWI/SNF-non-mutant cancers (25.8 vs. 5.6 mutations/Mb, 44.3% vs. 10.3%, and 16.0% vs. 0.9%, respectively; all p < 0.0001). Furthermore, these indices were even higher for tumors with co-mutations of SWI/SNF genes and MLL2/3. Regarding immunotherapeutic effects, patients with SWI/SNF variations showed significantly longer progression-free survival (PFS) rates than their SWI/SNF-non-mutant counterparts (hazard ratio [HR], 0.56 [95% confidence interval {CI} 0.44-0.72]; p < 0.0001), and PBRM1 mutations were associated with relatively better ICI treatment outcomes than the other SWI/SNF gene mutations (HR, 0.21 [95% CI 0.12-0.37]; p = 0.0007). Additionally, patients in the SWI/SNF-mutant + TMB-H (HR, 0.48 [95% CI 0.37-0.54]; p < 0.0001) cohorts had longer PFS rates than those in the SWI/SNF-non-mutant + TMB-low cohort. CONCLUSIONS: SWI/SNF complex genes are frequently mutated and are closely associated with TMB-H status, MSI-H status, and superior ICI treatment response in several cancers, such as colorectal cancer, gastric cancer, and non-small cell lung cancer. These findings emphasize the necessity and importance of molecular-level detection and interpretation of SWI/SNF complex mutations.

Phosphoserine phosphatase as a prognostic biomarker in patients with gastric cancer and its potential association with immune cells.

BACKGROUND: Because of dismal prognosis in gastric cancer, identifying relevant prognostic factors is necessary. Phosphoserine phosphatase (PSPH) exhibits different expression patterns in many cancers and has been reported to affect the prognosis of patients with cancer. In this study, we examined the prognostic role of metabolic gene PSPH in gastric cancer based on the TCGA dataset and our hospital-based cohort cases. METHODS: We collected and analysed RNA-seq data of Pan-cancer and gastric cancer in the TCGA dataset and PSPH expression data obtained from immunohistochemical analysis of 243 patients with gastric cancer from Sun Yat-sen University cancer center. Further, Kaplan-Meier survival analysis and Cox analysis were used to assess the effect of PSPH on prognosis. The ESTIMATE and Cibersort algorithms were used to elucidate the relationship between PSPH and the abundance of immune cells using the TCGA dataset. RESULTS: We observed that PSPH expression displayed considerably high in gastric cancer and it was significantly associated with inferior prognosis (P = 0.043). Surprisingly, there was a significant relationship between lower immune scores and high expression of PSPH (P < 0.05). Furthermore, patients with a low amount of immune cells exhibited poor prognosis (P = 0.046). The expression of PSPH significantly increased in activated memory CD4 T cells, resting NK cells and M0 macrophages (P = 0.037, < 0.001, and 0.005, respectively). CONCLUSIONS: This study highlighted that PSPH influences the prognosis of patients with gastric cancer, and this is associated with the infiltration of tumour immune cells, indicating that PSPH may be a new immune-related target for treating gastric cancer.

Effect of a functional brace in combination with physical therapy for early correction of cubitus varus in young children.

BACKGROUND: This study aimed to assess the clinical and radiologic outcomes of a functional brace in combination with physical therapy (FBPT) for early correction of cubitus varus in young children. METHODS: Eighteen consecutive patients with cubitus varus secondary to supracondylar fractures were enrolled between July 2017 and March 2019. We used the FBPT technique to correct varus and sagittal plane deformity for early cubitus varus in young children. The clinical evaluation included measurement of varus angulation, sagittal plane, and range of motion at three, six, and twelve months post-intervention. The clinical and radiographic results were assessed according to the Bellemore criteria. RESULTS: Pre-treatment humerus-elbow-wrist (HEW) angle measured on the affected side (varus deformity) ranged between -38° and -12° (average, -23.2°) while the post-treatment HEW angle ranged between -10° and + 15° (average, 8.8°). Compared with the unaffected side, no statistically significant difference was found in the affected side post-intervention (P > 0.05). According to the Bellemore criteria, we got excellent results in fourteen patients (77.8%), good results in three patients (16.7%), and poor result in one patient (5.5%). All patients and their parents (except one patient with residual varus deformities) were satisfied with the functional and cosmetic outcomes. CONCLUSIONS: The FBPT is effective for the treatment of cubitus varus in children, especially for young children within 6 months of the injury.

NRSF deficiency leads to abnormal postnatal development of dentate gyrus and impairment of progenitors in subgranular zone of hippocampus.

Neuron-restrictive silencing factor (NRSF) is a zinc-finger transcription factor that regulates expression of a diverse set of genes. However, NRSF function in brain development still remains elusive. In the present study, we generated NRSF-conditional knockout (NRSF-cKO) mice by hGFAP-Cre/loxp system to study the effect of NRSF deficiency on brain development. Results showed that NRSF conditional knockout caused a smaller hippocampus and a thinner granule cell layer (GCL) in mice. Moreover, the reduction and disarrangement of GFAP+ cells in subgranular zone (SGZ) of NRSF-cKO mice was accompanied with the decreased number of premature neurons, neural stem cells (NSCs) and neural progenitor cells (NPCs), as well as compromising the majority of mitotically active cells. The analysis of postnatal development of hippocampus indicated the existence of an abnormality at postnatal day (P) 8, rather than at P1, in NRSF-cKO mice, although the densities of Ki67+ cells with mitotic ability in dentate gyrus were relatively unaffected at P1 and P8. Meanwhile, NRSF deficiency led to abnormal organization of SGZ at P8 during postnatal development. RNA-Seq analysis revealed 79 deregulated genes in hippocampus of NRSF-cKO mice at P8, which were involved in p53 signal transduction, neuron migration and negative regulation of cell proliferation, etc. The deregulation of p53 pathway in NRSF-cKO mice at P1 and P8 was evidenced, of which p21/Cdkn1a was accumulated in a portion of NSCs and NPCs in hippocampus during postnatal development. Together, these results, for the first time, revealed that NRSF could significantly influence the postnatal development of hippocampus, especially the formation of SGZ.

Plasma SGIP1 methylation in diagnosis and prognosis prediction in hepatocellular carcinoma.

Aberrant methylation of some genes can serve as promising biomarkers in hepatocellular carcinoma (HCC). This study aimed to investigate the diagnostic and prognostic value of plasma SGIP1 methylation in HCC. The study included a total of 269 subjects, of which 129 were with HCC, 45 with liver cirrhosis (LC), 45 with chronic hepatitis B (CHB), and 50 were healthy controls (HCs). The aberrant methylation was detected by quantitative methylation-specific polymerase chain reaction (qMSP). The area under the curve (AUC) was 0.872 in distinguishing HCC from HCs, with a sensitivity of 85.3% and a specificity of 88%. The AUC was 0.728, when it distinguished HCC from CHB, with a sensitivity of 43.4% and a specificity of 97.8%. The AUC was 0.728 in distinguishing HCC from LC, with a sensitivity of 43.4% and a specificity of 97.8%. Elevated levels of SGIP1 methylation in HCC patients showed poorer overall survival (OS), progression-free survival (PFS), and metastasis-free survival (MFS) than those with low levels (Kaplan-Meier method and the log-rank test, p<0.05). SGIP1 methylation in different study groups demonstrated different sensitivities. SGIP1 methylation detection in the plasma may serve as a non-invasive diagnostic and prognostic biomarker for HCC.

Diagnostic value of miR-637 in patients with atherosclerosis and its predictive significance for the future cardiovascular events.

OBJECTIVES: Atherosclerosis is a common vascular disease. MiR-637 has been demonstrated to be low-expressed in hypertensive patients, and atherosclerosis is closely related to hypertension. Therefore, this study speculated that miR-637 may play an important role in the development of atherosclerosis. In brief, this study examined the expression level of miR-637 in patients with atherosclerosis and further analyzed its clinical value in patients with atherosclerosis. METHODS: The expression level of miR-637 was detected in serum from 86 patients with atherosclerosis and 75 healthy controls by using quantitative reverse transcription-polymerase chain reaction. The receiver operating characteristic curve was used to assess the diagnostic value of miR-637 in atherosclerosis. Pearson's correlation analysis was performed to evaluate the relationship between serum miR-637 and different clinical parameters. The prognostic value of miR-637 in atherosclerosis was analyzed by the Kaplan-Meier survival curve and multivariate cox regression analysis. RESULTS: Compared with healthy individuals, miR-637 was downregulated in the serum of atherosclerosis patients. The receiver operating characteristic curve suggested the high diagnostic value of miR-637 for atherosclerosis, with the AUC of 0.853, specificity of 77.9%, and sensitivity of 80.0%. The expression level of miR-637 was negatively correlated with CIMT (r = -0.8101, P < 0.0001) and CRP (r = -0.6154, P < 0.0001), respectively. Survival analysis indicated that miR-637 was also found to be an independent prognostic factor for atherosclerosis. CONCLUSIONS: MiR-637 is a potential noninvasive diagnostic marker of atherosclerosis and has important predictive value for the occurrence of future cardiovascular events.

Two-Dimensional MOF and COF Nanosheets: Synthesis and Applications in Electrochemistry.

Metal-organic framework (MOF) and covalent organic framework (COF) nanosheets are a new type of two-dimensional (2D) materials with unique design principles and various synthesis methods. They are considered ideal electrochemical devices due to the ultrathin thickness, easily tunable molecular structure, large porosity and other unique properties. There are two common methods to synthesize 2D MOF/COF nanosheets: bottom-up and top-down. The top-down strategy mainly includes ultrasonic assisted exfoliation, electrochemical exfoliation and mechanical exfoliation. Another strategy mainly includes interface synthesis, modulation synthesis, surfactant-assisted synthesis. In this Review, the development of ultrathin 2D nanosheets in the field of electrochemistry (supercapacitors, batteries, oxygen reduction, and hydrogen evolution) is introduced, and their unique dimensional advantages are highlighted.

Exposing {001} Crystal Plane on Hexagonal Ni-MOF with Surface-Grown Cross-Linked Mesh-Structures for Electrochemical Energy Storage.

Hexagonal nickel-organic framework (Ni-MOF) [Ni(NO3 )2 ·6H2 O, 1,3,5-benzenetricarboxylic acid, 4-4'-bipyridine] is fabricated through a one-step solvothermal method. The {001} crystal plane is exposed to the largest hexagonal surface, which is an ideal structure for electron transport and ion diffusion. Compared with the surrounding rectangular crystal surface, the ion diffusion length through the {001} crystal plane is the shortest. In addition, the cross-linked porous mesh structures growing on the {001} crystal plane strengthen the mixing with conductive carbon, inducing preferable conductivity, as well as increasing the area of ion contact and the number of active sites. These advantages enable the hexagonal Ni-MOF to exhibit excellent electrochemical performance as supercapacitor electrode materials. In a three-electrode cell, specific capacitance of hexagonal Ni-MOF in the 3.0 m KOH electrolyte is 977.04 F g-1 and remains at the initial value of 92.34% after 5,000 cycles. When the hexagonal Ni-MOF and activated carbon are assembled into aqueous devices, the electrochemical performance remains effective.

The State of Research Regarding Ordered Mesoporous Materials in Batteries.

Ordered mesoporous materials, porous materials with a pore size of 2-50 nm which are prepared via the sol-gel process using surfactant molecular aggregates as a template to assemble channels through the interfacial action of organic and inorganic substances, have recently triggered a heated debate. In addition to applications in the catalytic cracking of heavy oils and residues, the manufacturing of graft materials, the purification of water, the conversion of automobile exhaust, biochips, and the treatment of environmental pollutants via photocatalysts, ordered mesoporous materials have drawn substantial attention in the field of electrochemical energy storage due to advantages such as large specific surface area, uniform and continuously adjustable pore size, and orderly arrangement. Here, a general summary and appraisal of the study of ordered mesoporous materials for batteries in recent years is given, including the synthesis methods, meso/nanostructural features, and electrochemical capabilities of such materials.

Involvement of RhoA/ROCK Signaling in Aß-Induced Chemotaxis, Cytotoxicity and Inflammatory Response of Microglial BV2 Cells.

Reactive microglia clustering around amyloid plaques in brain is a histopathological feature of Alzheimer's disease (AD) and reflects the contribution of neuroinflammation in AD pathogenesis. ß-Amyloid peptide (Aß) has been shown to induce a range of microglial responses including chemotaxis, cytotoxicity and inflammation, but the underlying mechanism is poorly understood. Considering the fundamental role of RhoA/ROCK signaling in cell migration and its broad implication in AD and neuroinflammation, we hypothesized that RhoA/ROCK signaling might be involved in Aß-induced microglial responses. From in vivo mouse models including APP/PS1 transgene and fibrillar Aß stereotactic injection, we observed the elevated expression level of RhoA in reactive microglia. Through a series in vitro cell migration, cytotoxicity and biochemistry assays, we found that RhoA/ROCK signaling plays an essential role in Aß-induced responses of microglial BV2 cells. Small molecular agents Fasudil and Y27632 showed prominent beneficial effects, which implies the therapeutic potential of RhoA/ROCK signaling inhibitors in AD treatment.

Pseudo-phosphorylation at AT8 epitopes regulates the tau truncation at aspartate 421.

Tau pathology in Alzheimer's disease (AD) includes hyperphosphorylation and truncation of tau. Phosphorylation at S422 is found to suppress truncation of tau at D421 that leading to the generation of ΔTau. However, the interrelation between hyperphosphorylation and generation of ΔTau in AD remains elusive. In current study, staurosporine (Stau) induced ΔTau generation by caspases in SH-SY5Y cells with tau overexpression was found to be accompanied by a dramatic dephosphorylation at S422 and the epitope of the diagnostic antibody AT8 (S199 + S202 + T205), but a moderate dephosphorylation of PHF1 (S396 + S404) epitope. Therefore, to explore the effect of AT8 epitope on tau truncation, the residues in AT8 epitope were mutated to produce "pseudo-phosphorylated" (AT8E) or "pseudo-unphosphorylated" (AT8A) tau constructs. With Stau treatment, the generation of ΔTau from tau-AT8E was significantly attenuated comparing with that from tau-AT8A, which was S422-independent in that addition of S422A mutation still preserved this effect. Interestingly, this modulatory effect was able to be reversed by addition of PHF1E mutation. Moreover, treating the crude tau extracts with recombinant caspase-3 in vitro, also showed that ΔTau level was suppressed by AT8E, and potentiated by AT8E + PHF1E. The results primarily revealed the modulating effects of phosphorylation on ΔTau generation which may have potential implications in tau pathological processes and therapeutic intervention.

Expression of Demethylase Genes, FTO and ALKBH1, Is Associated with Prognosis of Gastric Cancer.

BACKGROUND: Reversible N6-methyladenosine (m6A) modifications in messenger RNAs can be categorized under the field of "RNA epigenetics." However, the potential role of m6A-related genes in gastric cancer (GC) prognosis has not been systematically researched. AIMS: This study was aimed at providing insights into the prognostic role of m6A-related gene expression, at both mRNA and protein levels. METHODS: Kaplan-Meier (KM) plotter database and The Cancer Genome Atlas (TCGA) database were used to explore the prognostic significance of individual m6A-related genes in overall survival (OS) and progression-free survival at the mRNA level. For independent validation, the protein level of genes significantly associated with prognosis in both databases was further detected in 450 paired GC and corresponding adjacent non-tumor tissues using tissue microarray (TMA)-based immunohistochemistry (IHC). The relationship between the FTO and ALKBH1 expression and the clinicopathological characteristics was explored. RESULTS: Among nine m6A-related genes, aberrantly high mRNA expression of FTO and ALKBH1 was associated with poor OS in the KM and TCGA cohorts. However, the TMA-IHC indicated that protein expression of FTO and ALKBH1 was markedly downregulated in GC tissues. A lower protein level of ALKBH1 was closely correlated with larger tumor sizes (≥ 5 cm) and more advanced TNM stages, while lower FTO protein expression was associated with shorter OS in GC patients. CONCLUSIONS: Aberrant expression of demethylase genes, FTO and ALKBH1, has a distinct prognostic value in GC patients, indicating that FTO and ALKBH1 may play vital roles in GC progression and metastasis.

Memantine Differentially Regulates Tau Phosphorylation Induced by Chronic Restraint Stress of Varying Duration in Mice.

Exposure to chronic psychiatric stress has been linked to Alzheimer's disease-related tau hyperphosphorylation and abnormalities in glutamate neurotransmission. However, the pathological relationship between glutamatergic dysfunction and tau phosphorylation in the cerebral cortex under chronic psychiatric stress is not fully understood. The present study investigated the effects of memantine (MEM, 5 and 10 mg/kg), an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, on chronic restraint stress- (CRS-) induced tau phosphorylation in mice. CRS administered for 16 or 28 consecutive days (1 h daily) induced significant tau phosphorylation in the brain. MEM treatment suppressed the elevation of phosphorylated tau (P-tau) levels induced by 16-day CRS in a dose-dependent manner. P-tau reduction was accompanied by the attenuation of the upregulation of GSK3ß and CDK5 expression and the downregulation of PP2A activity induced by CRS. Additionally, MEM reduced CRS-induced upregulation of NMDA receptor subunit levels (GluN2A, GluN2B) in the frontal cortex. However, MEM markedly enhanced tau phosphorylation in the frontal cortex and other cerebral cortical regions following 28 days of CRS. The stimulatory effect of MEM on CRS-induced tau phosphorylation was correlated with increased activities of AKT, JNK, and GSK3ß, inactivation of PP2A, and downregulation of Pin1 and HSP70. Moreover, MEM did not effectively reverse the NMDA receptor upregulation induced by 28-day CRS and even increased GluN2B subunit levels. In contrast to the duration-dependent effects of MEM on P-tau levels, MEM produced an anxiolytic effect in both regimens as revealed by elevated plus maze testing. However, MEM did not affect the body weight reduction induced by CRS. Thus, MEM exerts distinctive effects on CRS-induced tau phosphorylation, which might be related to the expression of GluN2B. The differential effects of MEM on P-tau levels have crucial implications for its clinical application.

π-Conjugated Molecule Boosts Metal-Organic Frameworks as Efficient Oxygen Evolution Reaction Catalysts.

To improve the efficiency of water electrolysis, developing efficient oxygen evolution reaction (OER) electrocatalysis is extremely important due to its four-electron transfer dynamics. In this work, a π-conjugated molecule (2,3,6,7,10,11-hexahydroxytriphenylene, HHTP), which can accelerate the electron transfer, is coated directly on pristine ZIF-67, resulting in a composite named HHTP@ZIF-67, via a simple one-step solvothermal method. The obtained HHTP@ZIF-67 possesses a Brunauer-Emmett-Teller surface area of 2013.9 m2 g-1 and displays microporous behavior, which can provide enough active sites for OER. The double-layer capacitance of HHTP@ZIF-67 is also enhanced, corresponding to an enlarged electrochemical active surface area. HHTP@ZIF-67 presents a quite low overpotential of 238 mV at 10 mA cm-2 in 1.0 m KOH. This material synthesized via the simple coating strategy is promising in the application of energy conversion devices.

The Research Development of Quantum Dots in Electrochemical Energy Storage.

Quantum dots, which are made from semiconductor materials, possess tunable physical dimensions and outstanding optoelectronic characteristics, and they have aroused widespread interest in recent years. In addition to applications in biomolecular analysis, sensors, organic photovoltaic devices, fluorescence, solar cells, photochemical reagents, light-emitting diodes, and catalysis, quantum dots have attracted mounting attention in the field of electrochemical energy storage owing to their size confinement and anisotropic geometry. In this review, a comprehensive summary is given and the research progress of the study of quantum dots for batteries and electrochemical capacitors in recent years, including their synthesis methods, micro/nanostructural features, and electrochemical performance, is appraised.

MOF-Derived Metal Oxide Composites for Advanced Electrochemical Energy Storage.

Over the past two decades, metal-organic frameworks (MOFs), a type of porous material, have aroused great interest as precursors or templates for the derivation of metal oxides and composites for the next generation of electrochemical energy storage applications owing to their high specific surface areas, controllable structures, and adjustable pore sizes. The electrode materials, which affect the performance in practical applications, are pivotal components of batteries and supercapacitors. Metal oxide composites derived from metal-organic frameworks possessing high reversible capacity and superior rate and cycle performance are excellent electrode materials. In this Review, potential applications for MOF-derived metal oxide composites for lithium-ion batteries, sodium-ion batteries, lithium-oxygen batteries, and supercapacitors are studied and summarized. Finally, the challenges and opportunities for future research on MOF-derived metal oxide composites are proposed on the basis of academic knowledge from the reported literature as well as from experimental experience.

Recent Progress in Some Amorphous Materials for Supercapacitors.

A breakthrough in technologies having "green" and sustainable energy storage conversion is urgent, and supercapacitors play a crucial role in this area of research. Owing to their unique porous structure, amorphous materials are considered one of the best active materials for high-performance supercapacitors due to their high specific capacity, excellent cycling stability, and fast charging rate. This Review summarizes the synthesis of amorphous materials (transition metal oxides, carbon-based materials, transition metal sulfides, phosphates, hydroxides, and their complexes) to highlight their electrochemical performance in supercapacitors.

Infection of Common Marmosets with GB Virus B Chimeric Virus Encoding the Major Nonstructural Proteins NS2 to NS4A of Hepatitis C Virus.

UNLABELLED: A lack of immunocompetent-small-primate models has been an obstacle for developing hepatitis C virus (HCV) vaccines and affordable antiviral drugs. In this study, HCV/GB virus B (GBV-B) chimeric virus carrying the major nonstructural proteins NS2 to NS4A (HCV NS2 to -4A chimera) was produced and used to infect common marmosets, since HCV NS2 to NS4A proteins are critical proteases and major antigens. Seven marmosets were inoculated intrahepatically with HCV NS2 to -4A chimera RNA for primary infection or intravenously injected with chimera-containing serum for passage infection. Three animals used as controls were injected with phosphate-buffered saline (PBS) or GBV-B, respectively. Six of seven HCV NS2 to -4A chimera-infected marmosets exhibited consistent viremia and one showed transient viremia during the course of follow-up detection. All six infected animals with persistent circulating viremia presented characteristics typical of viral hepatitis, including viral RNA and proteins in hepatocytes and histopathological changes in liver tissue. Viremia was consistently detected for 5 to 54 weeks of follow-up. FK506 immunosuppression facilitated the establishment of persistent chimera infection in marmosets. An animal with chimera infection spontaneously cleared the virus in blood 7 weeks following the first inoculation, but viral-RNA persistence, low-level viral protein, and mild necroinflammation remained in liver tissue. The specific antibody and T-cell response to HCV NS3 in this viremia-resolved marmoset was boosted by rechallenging, but no viremia was detected during 57 weeks of follow-up. The chimera-infected marmosets described can be used as a suitable small-primate animal model for studying novel antiviral drugs and T-cell-based vaccines against HCV infection. IMPORTANCE: HCV infection causes approximately 70% of chronic hepatitis and is frequently associated with primary liver cancer globally. Chimpanzees have been used as a reliable primate model for HCV infection, but ethical considerations have restricted their utility in biomedical research. GB virus B (GBV-B) is a flavivirus related to HCV. It can infect common marmosets, a New World small primate, and induces viral hepatitis similar to HCV infection in humans. To minimize differences between GBV-B and HCV, we generated HCV NS2 to -4A/GBV-B chimeric viruses and established a chimera-infected marmoset model. HCV NS2 to -4A chimera-infected marmosets provide a small-animal model for evaluating novel antiviral drugs targeting HCV NS3-NS4A protease and T-cell-based HCV vaccines.

Effects of PTEN inhibition on the regulation of Tau phosphorylation in rat cortical neuronal injury after oxygen and glucose deprivation.

OBJECTIVE: This report investigated the involvement of the PTEN pathway in the regulation of Tau phosphorylation using an oxygen and glucose deprivation (OGD) model with rat cortical neurons. METHODS: Primary cortical neurons were used to establish the oxygen and glucose deprivation (OGD) model in vitro. These were randomly divided into control, OGD, bpV+OGD, As+OGD, Se+OGD and Mock treatment groups. The neuron viability was assessed by MTT, the cell apoptosis was detected using TUNEL staining. The expression of Phospho-PTEN/PTEN, Phospho-Tau/Tau, Phospho-Akt/Akt and Phospho-GSK-3ß/GSK-3ß were detected by Western blotting. RESULTS: OGD induced Tau phosphorylation through PTEN and glycogen synthase kinase-3ß (GSK-3ß) activation, together with a decrease in AKT activity. Pre-treatment with bpv, a potent PTEN inhibitor, and PTEN antisense nucleotides decreased PTEN and GSK-3ß activity and caused alterations in Tau phosphorylation. Neuronal apoptosis was also reduced. CONCLUSIONS: The PTEN/Akt/GSK-3ß/Tau pathway is involved in the regulation of neuronal injury, providing a novel route for protecting neurons following neonatal HI.