Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children; some clinical trials have reported the effects of total glucosides of peony (TGP) in the treatment of JIA. However, no systematic review has yet been conducted. In this study, we assessed the efficacy and safety in patients with JIA enrolled in randomized controlled trials (RCTs) of TGP. We extracted data for studies searched from 8 electronic databases that were searched and also evaluated the methodological quality of the included studies. We assessed the following outcome measures: overall response rate, pain, tender joint count (TJC), swollen joint count (SJC), duration of morning stiffness (DMS), grip strength (GS), rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and adverse effects (AEs) in short term (4-8 weeks), intermediate term (9-26 weeks), and long term (>26 weeks). The final analysis showed that TGP acted as a unique nonbiologic disease-modifying antirheumatic drug (nonbiologic DMARD), and its therapeutic effects were safe and efficacious for the treatment of JIA with few AEs. However, more high-quality RCTs are needed to confirm these therapeutic effects.

Cardiovascular function depends on patent blood vessel formation by endothelial cells (ECs). However, the mechanisms underlying vascular "tubulogenesis" are only beginning to be unraveled. We show that endothelial tubulogenesis requires the Ras interacting protein 1, Rasip1, and its binding partner, the RhoGAP Arhgap29. Mice lacking Rasip1 fail to form patent lumens in all blood vessels, including the early endocardial tube. Rasipl null angioblasts fail to properly localize the polarity determinant Par3 and display defective cell polarity, resulting in mislocalized junctional complexes and loss of adhesion to extracellular matrix (ECM). Similarly, depletion of either Rasip1 or Arhgap29 in cultured ECs blocks in vitro lumen formation, fundamentally alters the cytoskeleton, and reduces integrin-dependent adhesion to ECM. These defects result from increased RhoA/ROCK/myosin II activity and blockade of Cdc42 and Rac1 signaling. This study identifies Rasip1 as a unique, endothelial-specific regulator of Rho GTPase signaling, which is essential for blood vessel morphogenesis.

The application of electron microscopy to hydrated biological samples has been limited by high-vacuum operating conditions. Traditional methods utilize harsh and laborious sample dehydration procedures, often leading to structural artefacts and creating difficulties for correlating results with high-resolution fluorescence microscopy. Here, we utilize graphene, a single-atom-thick carbon meshwork, as the thinnest possible impermeable and conductive membrane to protect animal cells from vacuum, thus enabling high-resolution electron microscopy of wet and untreated whole cells with exceptional ease. Our approach further allows for facile correlative super-resolution and electron microscopy of wet cells directly on the culturing substrate. In particular, individual cytoskeletal actin filaments are resolved in hydrated samples through electron microscopy and well correlated with super-resolution results.

Resting-state functional MRI (R-fMRI) studies have demonstrated widespread alterations in brain function in patients with major depressive disorder (MDD). However, a clear and consistent conclusion regarding a repeatable pattern of MDD-relevant alterations is still limited due to the scarcity of large-sample, multisite datasets. Here, we address this issue by including a large R-fMRI dataset with 1434 participants (709 patients with MDD and 725 healthy controls) from five centers in China. Individual functional activity maps that represent very local to long-range connections are computed using the amplitude of low-frequency fluctuations, regional homogeneity and distance-related functional connectivity strength. The reproducibility analyses involve different statistical strategies, global signal regression, across-center consistency, clinical variables, and sample size. We observed significant hypoactivity in the orbitofrontal, sensorimotor, and visual cortices and hyperactivity in the frontoparietal cortices in MDD patients compared to the controls. These alterations are not affected by different statistical analysis strategies, global signal regression and medication status and are generally reproducible across centers. However, these between-group differences are partially influenced by the episode status and the age of disease onset in patients, and the brain-clinical variable relationship exhibits poor cross-center reproducibility. Bootstrap analyses reveal that at least 400 subjects in each group are required to replicate significant alterations (an extent threshold of P < .05 and a height threshold of P < .001) at 50% reproducibility. Together, these results highlight reproducible patterns of functional alterations in MDD and relevant influencing factors, which provides crucial guidance for future neuroimaging studies of this disorder.

Alcohol consumption level and alcohol use disorder (AUD) diagnosis are moderately heritable traits. We conduct genome-wide association studies of these traits using longitudinal Alcohol Use Disorder Identification Test-Consumption (AUDIT-C) scores and AUD diagnoses in a multi-ancestry Million Veteran Program sample (N = 274,424). We identify 18 genome-wide significant loci: 5 associated with both traits, 8 associated with AUDIT-C only, and 5 associated with AUD diagnosis only. Polygenic Risk Scores (PRS) for both traits are associated with alcohol-related disorders in two independent samples. Although a significant genetic correlation reflects the overlap between the traits, genetic correlations for 188 non-alcohol-related traits differ significantly for the two traits, as do the phenotypes associated with the traits' PRS. Cell type group partitioning heritability enrichment analyses also differentiate the two traits. We conclude that, although heavy drinking is a key risk factor for AUD, it is not a sufficient cause of the disorder.

The basis for region-specific neuronal toxicity in Huntington disease is unknown. Here, we show that region-specific neuronal vulnerability is a substrate-driven response in astrocytes. Glucose is low in HdhQ(150/150) animals, and astrocytes in each brain region adapt by metabolically reprogramming their mitochondria to use endogenous, non-glycolytic metabolites as an alternative fuel. Each region is characterized by distinct metabolic pools, and astrocytes adapt accordingly. The vulnerable striatum is enriched in fatty acids, and mitochondria reprogram by oxidizing them as an energy source but at the cost of escalating reactive oxygen species (ROS)-induced damage. The cerebellum is replete with amino acids, which are precursors for glucose regeneration through the pentose phosphate shunt or gluconeogenesis pathways. ROS is not elevated, and this region sustains little damage. While mhtt expression imposes disease stress throughout the brain, sensitivity or resistance arises from an adaptive stress response, which is inherently region specific. Metabolic reprogramming may have relevance to other diseases.

Platelet glycoprotein Ibα (GPIbα) extracellular domain, which is part of the receptor complex GPIb-IX-V, plays an important role in tumor metastasis. However, the mechanism through which GPIbα participates in the metastatic process remains unclear. In addition, potential bleeding complication remains an obstacle for the clinical use of anti-platelet agents in cancer therapy.

Zinc finger SWIM-type containing 5 (ZSWIM5) is a newly discovered protein, which contains a novel zinc-chelating domain SWIM (CxCxnCxH), and is predicted to interact with DNA or proteins. Currently, the knowledge of functions of ZSWIM5 remains limited. In this study, we aimed to elucidate the biological functions of ZSWIM5 and their mechanisms.

Although decades of research have revealed numerous molecular abnormalities in the hippocampus associated with depression, the different mechanisms involved in the susceptibility and resilience of mice to chronic social defeat stress (CSDS)-induced depression remain poorly understand. Through the social defeat model, we can study the differences in molecular changes between the susceptible and resilient mice.

The CXCL12 rs1801157 polymorphism is putatively associated with the risk of malignancy. However, research results are inconsistent regarding particular cancers, especially colorectal cancer (CRC).

In this study, we investigated the role ofhistone deacetylase 4 (HDAC4) and MEG3/miR-125a-5p/interferonregulatoryfactor 1 (IRF1) on vascular smooth muscle cell (VSMCs)proliferation. Platelet derived growth factor (PDGF)-BB was used toinduce the proliferation and migration of VSMCs. The expressionsof MEG3, miR-125a-5p, HDAC4 and IRF1in VSMCs were detectedby qRT-PCR and western blot, respectively. ChIP assay was usedto determine the relationship between MEG3 and HDAC4. Doubleluciferase reporter assay was used to test the regulation betweenmiR-125-5p and IRF1. Results showed that PDGF-BB decreasedthe expression of MEG3 and IRF1, while increased the expressionof miR-125a-5p and HDAC4. In addition, HDAC4 knockdowninhibited the proliferation and migration of VSMCs via upregulatingMEG3 and downregulating miR-125a-5p. MiR-125a-5p inhibitorcould repress the proliferation and migration of VSMCs andalleviate intimal hyperplasia (IH) by directly upregulating IRF1expression. These results suggested that HDAC4 interferenceinhibited PDGF-BB-induced VSMCs proliferation via regulatingMEG3/miR-125a-5p/IRF1 axis, and then alleviated IH.

Changes in the characteristics, removal efficiency, and toxicity of pharmaceutical effluent organic matter (EfOM) after catalytic ozonation were investigated in this study. After a 90-min treatment with a catalytic ozonation process (COP) in the presence of MnO2 ceramsite, the total organic carbon (TOC), UV254, colority, protein, and humic acid removal rates were 13.24%, 60.83%, 85.42%, 29.36% and 74.19%, respectively. The polysaccharide content increased by 12.73 mg/L during the COP for reaction times between 0 and ~50 min and decreased by 6.97 mg/L between 50 and ~90 min. Furthermore, 64.44% of the total colority was detected in the hydrophobic organic matter (HOM) fraction, and after the COP, and 88.69% of the colority in the HOM was eliminated. Meanwhile, only 59.18% of the colority in the hydrophilic organic matter (HIM) fraction was removed. GC-MS analysis showed that 38 organic pollutant species were completely removed, 8 were partially removed, and 7 were generated. After 90 min of COP treatment, the pharmaceutical EfOM toxicity was effectively reduced based on the higher incubation and lower mortality rates.

During September 2010, an outbreak of acute hemorrhagic conjunctivitis reemerged in Jiangsu, three years after the nationwide epidemic in China in 2007. In total, 2409 cases were reported, 2118 of which were reported in September; 79.8% of those affected were students or teachers, with a median age of 16 years. To identify and demonstrate the genetic characteristics of the etiological agent, 52 conjunctival swabs were randomly collected from four different cities. After detection and isolation, 43 patients were positive for coxsackievirus A24 variant according to PCR and 20 according to culture isolation. Neither adenovirus nor EV70 was detected. A phylogenetic study of the complete 3Cpro and VP1 regions showed that the Jiangsu isolates clustered into a new lineage, GIV-C5, with two uniform amino-acid mutations that distinguished them from all previous strains. Another new cluster, GIV-C4, formed by Indian isolates from 2007 and Brazilian isolates from 2009, was also identified in this study. Interestingly, our isolates shared greatest homology with the GIV-C4 strains, not with the isolates that were responsible for the nationwide acute hemorrhagic conjunctivitis epidemic in China in 2007. Although all our isolates were closely related, they could be differentiated into two subclusters within GIV-C5. In conclusion, our study suggests that a new cluster of coxsackievirus A24 variant that had already evolved into diverse strains was associated with the acute hemorrhagic conjunctivitis outbreaks in Jiangsu in September 2010. These viruses might have originated from the virus isolated in India in 2007, rather than from the epidemic strains isolated in China in 2007.

X-linked retinoschisis is a retinal dystrophy caused by mutations in the RS1 gene in Xp22.1. These mutations lead to schisis (splitting) of the neural retina and subsequent reduction in visual acuity in affected men (OMIM # 312700). The aim of this study was to identify the RS1 gene mutations in a cohort of Chinese patients with X-linked retinoschisis, and to describe the associated phenotypes.

The objective of the current study was to determine the clinical significance of junctional adhesion molecule A (JAM-A) in patients with non-small cell lung cancer (NSCLC) and the biological function of JAM-A in NSCLC cell lines. We showed that JAM-A is predominantly expressed in cell membranes and high expression of JAM-A occurred in 37% of lung tumor specimens compared to corresponding normal tissues. High expression of JAM-A was significantly correlated with TNM stage (P = 0.021), lymph node metastasis (P = 0.007), and decreased overall survival (P = 0.02), In addition, we observed that silencing JAM-A by small interfering RNA inhibited tumor cell proliferation and induced cell cycle arrest at the G1/S boundary. Western blotting analysis revealed that knockdown of JAM-A decreased the protein levels of cyclin D1, CDK4, 6, and P-Rb. Thus, JAM-A plays an important role in NSCLC progression.

Our previous study found that thymosin β10 overexpressed in lung cancer and positively correlated with differentiation, lymph node metastasis and stage of lung cancer. In this reasearch we aim to study the effects and mechanism of exogenous human recombinant Tβ10 on the expression of VEGF-C on non-small cell lung cancer.

A single-nucleotide polymorphism at the LHPP gene (rs35936514) has been reported in genome-wide association studies to be associated with major depressive disorder (MDD). However, the neural system effects of rs35936514 that mediate the association are unknown. The present work explores whether the LHPP rs35936514 polymorphism moderates brain regional activity in MDD. A total of 160 subjects were studied: a CC group homozygous for the C allele (23 individuals with MDD and 57 controls) and a T-carrier group carrying the high risk T allele (CT/TT genotypes; 22 MDD and 58 controls). All participants underwent resting-state functional magnetic resonance imaging (rs-fMRI) scanning. Brain activity was assessed using the amplitudes of low-frequency fluctuations (ALFF). MDD patients showed a significant increased ALFF in the left middle temporal gyrus and occipital cortex. The T-carrier group showed increased ALFF in the left superior temporal gyrus. Significant diagnosis × genotype interaction was noted in the bilateral lingual gyri, bilateral dorsal lateral prefrontal cortex (dlPFC), and left medial prefrontal cortex (mPFC) (P < 0.05, corrected). Results demonstrated that MDD patients with LHPP rs35936514 CT/TT genotype may influence the regional brain activity. These findings implicate the effects of the rs35936514 variation on the neural system in MDD.

Multidrug resistance (MDR), mainly mediated by ABCB1 transporter, is a major cause for chemotherapy failure. Bufalin (BU), an active component of the traditional Chinese medicine chan'su, has been reported to have antitumor effects on various types of cancer cells. The purpose of this present study was to investigate the reversal effect of BU on ABCB1-mediated multidrug resistance in colorectal cancer. BU at safe concentration (5, 10, 20 nM) could reverse chemosensitivity of ABCB1-overexpression HCT8/ADR, LoVo/ADR and HCT8/ABCB1 nearly back to their parental cells level. In addition, results from the drug accumulation studies revealed that BU was able to enhance intracellular accumulation of doxorubicin (DOX) and Rhodamine 123 (Rho-123) in a dose-dependent manner. Furthermore, Western blot assays showed that BU significantly inhibited the expression level of ABCB1 protein. Meanwhile, BU stimulated the ATPase activity of ABCB1, which suggested that BU might be a substrate of ABCB1. More interestingly, docking analysis predicted that BU could be docked into the large hydrophobic drug-binding cavity of human ABCB1. Importantly, BU remarkable increased the effect of DOX against the ABCB1 resistant HCT8/ADR colorectal cell xenografts in nude mice, without inducing any obvious toxicity. Overall, we concluded that BU efficiently reversed ABCB1-mediated MDR through not only inhibited the efflux function of ABCB1, but also down-regulate its protein expression, which might represent a potential and superior ABCB1 modulator in colorectal cancer.

Liver transplantation has emerged as a vital therapy for end-stage liver diseases. Acute -phase inflammation play an important role in liver graft injury.Recent studies have revealed that inflammasome are responsible for initiating inflammation in early stage of acute organ rejection in liver transplantation, however the underlying mechanism remains unclear. Here we explored to block inflammasome activation to see whether it can alleviate early inflammation reaction during rejection of allgrafts in a rat model and gain further insights into the mechanism of inhibiting inflammation in allografts. By using Ac-YVAD-CMK, a highly selective caspase-1 inhibitor, to inhibit inflammation reaction involved in allograft rejection in a rat model. Our results showed that the rejection activity index (RAI) of Ac-YVAD-CMK-treated allografts is significantly diminished in similar magnitude to that of isografts. Compared with isografts, the expression of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and IL-1β in allograft group increased significantly with the development of rejection, exhibiting apparent correlation. Expression of IFN-γ mRNA in untreated allografts was maximal on day 3 while in Ac-YVAD-CMK-treated allografts and isografts, IFN-γ mRNA levels remained low over the duration of the time course. ELISA results revealed serum elevation of IL-1β by day 7 after othotopic liver transplantation (OLT) in comparison with isografts. There were no statistically significant differences between isografts and Ac-YVAD-CMK-treated allografts. For the first time, our data reveal that inhibition of the inflammasome activation pathway attenuates inflammation reaction of hepatic transplant rejection.

We previously reported that importin 13 (IPO13), a member of the importin-β family of nuclear import proteins, regulates nuclear import of the glucocorticoid receptor in airway epithelial cells, IPO13 serves as a potential marker for corneal epithelial progenitor cells, and IPO13 is associated with corneal cell proliferation. Here we investigated the role of IPO13 in the pathogenesis of pterygium and the underlying mechanism including interaction with other cell proliferation-related factors: keratin 17 (K17), a lesional protein and a member of the type I keratins, and c-Jun, a protein of the activator protein-1 complex.