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In the present article, we report a novel colorimetric probe (TNT@MB) for the detection of the phosphate ion, which is based on the strong binding affinity between the phosphate ion and titanium dioxide nanotubes (TNTs). TNTs were synthesized from TiO2 nanoparticles by hydrothermal treatment. The obtained TNTs had an average length of 200 ± 50 nm and an average width of 12 ± 5 nm. TNT@MB was prepared by adsorbing methyl blue onto TNTs in acidic condition. The optimal synthesis conditions for TNT@MB consisted in having 0.05 g of TNTs react with 1 μmole of methyl blue at pH 2 for 90 min. TNTs and TNT@MB were characterized by UV–vis diffuse reflection spectroscopy, TEM, FTIR, and XPS. The phosphate-ion sensing behavior of TNT@MB was investigated by UV–visible spectroscopy. The phosphate-ion concentration linear range and detection limit of this method based on TNT@MB were 1–40 μM and 0.59 μM, respectively. A sample of lake water was used as a real sample, and analyte recovery rates were measured in the 102.5–103.6% range, with relative standard deviations below 5.6% (n = 3). We also found that this probe could be reused after regeneration in alkaline solution. These results indicate that as a colorimetric probe, TNT@MB has the advantages of being environmentally friendly, inexpensive, and simple to use, as well as giving rise to an easily observable color change.

Pulmonary tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is a global public health concern. Although inflammasome and the toll-like receptor 2 (TLR2) genes play an important role in host defense against Mtb, the associations of polymorphisms in these genes with TB risk are incompletely understood. A total of 230 TB patients and 213 individuals without TB were enrolled in this study. A significant difference in the frequencies of different AIM2 rs2276405 genotypes between the non-TB and TB groups was detected. When the patients were stratified by gender or age, significant differences in genotype frequencies at NLRP3 rs34298354 in men and in non-aged (≤65-year-old) subjects and at IFI16 rs1772408 in women were found. OR analysis showed that the TC rs34298354 genotype in NLRP3 was associated with reduced risk of TB. In women, the AG rs1772408 genotype in IFI16 was associated with decreased TB risk. Haplotype analysis showed that, in comparison with the most common haplotype (T-T) of rs3804099-rs3804100 in the TLR2 gene, the C-T haplotype was associated with an increased risk for TB. Our study indicates that rs34298354 in NLRP3 and rs1772408 in IFI16 protect individuals from TB, and that the less common TLR2 haplotype is associated with increased TB susceptibility.

Currently, many strains of influenza A virus have developed resistance against anti-influenza drugs, and it is essential to find new chemicals to combat this virus. The influenza polymerase with three proteins, PA, PB1 and PB2, is a crucial component of the viral ribonucleoprotein (RNP) complex. Here, we report the identification of a hit compound 221 by surface plasmon resonance (SPR) direct binding screening on the C-terminal of PA (PAC). Compound 221 can subdue influenza RNP activities and attenuate influenza virus replication. Its analogs were subsequently investigated and twelve of them could attenuate RNP activities. One of the analogs, compound 312, impeded influenza A virus replication in Madin-Darby canine kidney cells with IC50 of 27.0 ± 16.8 μM. In vitro interaction assays showed that compound 312 bound directly to PAC with Kd of about 40 μM. Overall, the identification of novel PAC-targeting compounds provides new ground for drug design against influenza virus in the future.

Increased p66Shc expression has been associated with diabetic nephropathy (DN). However, whether p66Shc can serve as a potential biomarker for tubular oxidative injury in DN is unknown. We measured the expression of p66Shc in peripheral blood monocytes (PBMs) and renal biopsy tissues from DN patients and then analysed the relationship between p66Shc expression and the clinical characteristics of patients with DN. Patients were divided into 4 groups (class IIa, class IIb, class III and the control group). qPCR, Western blotting and immunohistochemistry were performed. The results showed that both p66Shc and p-p66Shc expression significantly increased in PBMs and kidney tissues of DN patients. Moreover, Spearman's correlation and multiple regression analyses were carried out. A positive relationship between the p66Shc expression and oxidative stress was found. p66Shc and oxidative stress were significant predictors of the degree of tubular damage. In addition, p66Shc expression was positively correlated with the concentrations of β-NAG, UACR and 8-OHdG, low-density lipoprotein and blood glucose levels, and duration of diabetes in patients with DN from class IIa to class III. These data indicated that increased expression of p66Shc may serve as a therapeutic target and a novel biomarker of DN.

Liver receptor homologue-1 (LRH-1) plays a critical role in hepatic metabolism and disease. Here we show that LRH-1 protein stability is regulated by the cullin 4 (CUL4) E3 ubiquitin ligase complex. We found that DNA damage-binding protein 2 (DDB2) directly interacts with LRH-1 and functions as a substrate recognition component of CUL4-DDB1 to promote LRH-1 ubiquitination and proteasomal degradation. In human hepatoma (HepG2) cells, we observed that protein levels of endogenous LRH-1 are increased by insulin without a change in mRNA levels of LRH-1. However, overexpression of DDB2 impaired the insulin-stimulated increase in LRH-1 levels. In addition, DDB2 overexpression decreased LRH-1 transcriptional activation and expression of target genes, such as glucokinase, whereas knockdown of DDB2 increased the expression of glucokinase. Finally, we demonstrated that DDB2 knockdown increases glucose uptake and intracellular levels of glucose-6-phosphate in HepG2 cells. Our study reveals a novel regulatory mechanism of LRH-1 activity and suggests a role for DDB2 in hepatic glucose metabolism.

The purpose of this study was to investigate the neuroprotective effects of low-intensity pulsed ultrasound (LIPUS) on behavioral and histological outcomes in a mouse model of traumatic brain injury (TBI). Mice subjected to controlled cortical impact injury were treated with LIPUS in the injured region daily for a period of 4 weeks. The effects of LIPUS on edema were observed by MR imaging in the mouse brain at 1 and 4 days following TBI. Brain water content, blood-brain barrier permeability, histology analysis, and behavioral studies were performed to assess the effects of LIPUS. Two-way analysis of variance and Student t test were used for statistical analyses, with a significant level of 0.05. Treatment with LIPUS significantly attenuated brain edema, blood-brain barrier permeability, and neuronal degeneration beginning at day 1. Compared with the TBI group, LIPUS also significantly improved functional recovery and reduced contusion volumes up to post-injury day 28. Post-injury LIPUS treatment reduced brain edema and improved behavioral and histological outcomes following TBI. The neuroprotective effects of LIPUS may be a promising new technique for treating TBI.

We sought to investigate the impact of hormone receptor (HR) status and distant recurrence-free interval (DRFI) on the degree of overall survival (OS) benefit from palliative trastuzumab-containing treatment in HER2-positive metastatic breast cancer (MBC). Here, we retrospectively identified 588 eligible HER2-positive patients with postoperative distant recurrence. DRFI of HR+HER2+ MBC patients (median: 30.7 months, IQR: 18.5–45.9, P 24 months is an independent favourable prognostic factor for both HR−HER2+ patients (Hazard Ratio (HzR) = 0.55, 95% CI: 0.39–0.76, P P < 0.001). Upon further analysis of the interaction between trastuzumab and DRFI, the degree of trastuzumab benefits in HR−HER2+ MBC patients remained basically unchanged regardless of DRFI length. Unlikely, the degree in HR+HER2+ MBC patients decreased gradually along with DRFI extending, indicating that trastuzumab failed to translate into an OS benefit for late recurrent (DRFI > 5years) HR+HER2+ MBC patients.

Demand for rapid and massive-scale exfoliation of bulky graphite remains high in graphene commercialization and property manipulation. We report a procedure utilizing “preformed acidic oxidizing medium (PAOM)” as a modified version of the Hummers’ method for fast and reliable synthesis of graphene oxide. Pre-mixing of KMnO4 and concentrated H2SO4 prior to the addition of graphite flakes enables the formation of effectively and efficiently oxidized graphene oxide (EEGO) featured by its high yields and suspension homogeneity. PAOM expedites diffusion of the Mn-oxidants into the graphite galleries, resulting in the rapid graphite oxidation, capable of oxidizing bulky graphite flakes (~0.8 mm in diameter) that can not be realized by the Hummers’ method. In the scale-up tests, ten-time amount of graphite can be completely exfoliated by PAOM without need of extended reaction time. The remarkable suspension homogeneity of EEGO can be exploited to deposit ultra-flat coating for wafer-scale nanopatterning. We successfully fabricated GO optical gratings with well-defined periodicity (300 nm) and uniform thickness (variation

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A general solvent-dependent protocol directly influencing the oxygen reduction reaction (ORR) in metal oxide/graphene nanohybrids has been demonstrated. We conducted the two-step synthesis of cobalt oxide/N-doped graphene nanohybrids (CNG) with solvents of water, ethanol, and dimethylformamide (DMF), representing tree typical categories of aqueous, polar organic, and organic N-containing solvents commonly adopted for graphene nanocomposites preparation. The superior ORR performance of the DMF-hybrids can be attributed to the high nitrogen-doping, aggregation-free hybridization, and unique graphene porous structures. As DMF is the more effective N-source, the spectroscopic results support a catalytic nitrogenation potentially mediated by cobalt-DMF coordination complexes. The wide-distribution of porosity (covering micro-, meso-, to macro-pore) and micron-void assembly of graphene may further enhance the diffusion kinetics for ORR. As the results, CNG by DMF-synthesis exhibits the high ORR activities close to Pt/C (i.e. only 8 mV difference of half-wave potential with electron transfer number of 3.96) with the better durability in the alkaline condition. Additional graphene hybrids comprised of iron and manganese oxides also show the superior ORR activities by DMF-synthesis, confirming the general solvent-dependent protocol to achieve enhanced ORR activities.

Whether red cell distribution width (RDW) can be a potential indicator for diabetic nephropathy (DN) is unknown. A total of 809 type 2 diabetes mellitus (T2D) patients were divided into 4 groups according to the quartiles (Q) of the RDW (%): Q1 ≤ 12.4 (n = 229), 12.4 2+ (OR = 0.178) were negatively associated with Q4. This data suggest that high level of RDW in T2D patients indicates a higher risk and a poor prognosis for DN.

Increased p66Shc expression has been associated with diabetic nephropathy (DN). However, whether p66Shc can serve as a potential biomarker for tubular oxidative injury in DN is unknown. We measured the expression of p66Shc in peripheral blood monocytes (PBMs) and renal biopsy tissues from DN patients and then analysed the relationship between p66Shc expression and the clinical characteristics of patients with DN. Patients were divided into 4 groups (class IIa, class IIb, class III and the control group). qPCR, Western blotting and immunohistochemistry were performed. The results showed that both p66Shc and p-p66Shc expression significantly increased in PBMs and kidney tissues of DN patients. Moreover, Spearman’s correlation and multiple regression analyses were carried out. A positive relationship between the p66Shc expression and oxidative stress was found. p66Shc and oxidative stress were significant predictors of the degree of tubular damage. In addition, p66Shc expression was positively correlated with the concentrations of β-NAG, UACR and 8-OHdG, low-density lipoprotein and blood glucose levels, and duration of diabetes in patients with DN from class IIa to class III. These data indicated that increased expression of p66Shc may serve as a therapeutic target and a novel biomarker of DN.

Polycyclic aromatic hydrocarbons (PAHs) and nitro-PAHs are ubiquitous in the environment. Some of them are probable carcinogens and some are source markers. This work presents an ultra-high performance liquid chromatography-atmospheric pressure photoionization-tandem mass spectrometry (UHPLC-APPI-MS/MS) method for simultaneous analysis of 20 PAHs and nine nitro-PAHs. These compounds are separated in 15 minutes in the positive mode and 11 minutes in the negative mode, one half of GC/MS analysis time. Two pairs of precursor/product ions are offered, which is essential for confirmation. This method separates and quantifies benzo[a]pyrene (the most toxic PAHs) and non-priority benzo[e]pyrene (isomers, little toxicity) to avoid overestimation of toxin levels, demonstrating its importance for health-related researches. With 0.5% 2,4-difluoroanisole in chlorobenzene as the dopant, limits of detection of PAHs except acenaphthylene and those of nitro-PAHs except 2-nitrofluoranthene are below 10 pg and 3 pg, respectively, mostly lower than or comparable to those reported using LC-related systems. The responses were linear over two orders of magnitude with fairly good accuracy and precision. Certified reference materials and real aerosol samples were analyzed to demonstrate its applicability. This fast, sensitive and reliable method is the first UHPLC-APPI-MS/MS method capable of simultaneously analyzing 29 environmentally and toxicologically important PAHs and nitro-PAHs.

Voltage-gated CLC-1 chloride channels play a critical role in controlling the membrane excitability of skeletal muscles. Mutations in human CLC-1 channels have been linked to the hereditary muscle disorder myotonia congenita. We have previously demonstrated that disease-associated CLC-1 A531V mutant protein may fail to pass the endoplasmic reticulum quality control system and display enhanced protein degradation as well as defective membrane trafficking. Currently the molecular basis of protein degradation for CLC-1 channels is virtually unknown. Here we aim to identify the E3 ubiquitin ligase of CLC-1 channels. The protein abundance of CLC-1 was notably enhanced in the presence of MLN4924, a specific inhibitor of cullin-RING E3 ligases. Subsequent investigation with dominant-negative constructs against specific subtypes of cullin-RING E3 ligases suggested that CLC-1 seemed to serve as the substrate for cullin 4A (CUL4A) and 4B (CUL4B). Biochemical examinations further indicated that CUL4A/B, damage-specific DNA binding protein 1 (DDB1) and cereblon (CRBN) appeared to co-exist in the same protein complex with CLC-1. Moreover, suppression of CUL4A/B E3 ligase activity significantly enhanced the functional expression of the A531V mutant. Our data are consistent with the idea that the CUL4A/B-DDB1-CRBN complex catalyses the polyubiquitination and thus controls the degradation of CLC-1 channels.