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The expression of programmed death ligand‐1 (PD‐L1) in tumor has been used as a biomarker to predict the anti‐PD‐L1 immunotherapy response. To develop a noninvasive imaging technique to monitor the dynamic changes in PD‐L1 expression in colorectal cancer (CRC), we labeled an anti‐PD‐L1 monoclonal antibody with near‐infrared (NIR) dye and tested the ability of the NIR‐PD‐L1‐mAb probe to monitor the PD‐L1 expression in CRC‐xenografted mice by performing optical imaging. Consistent with the expression levels of PD‐L1 protein in three CRC cell lines in vitro by flow cytometry and Western blot analyses, our in vivo imaging showed the highest fluorescence signal of the xenografted tumors in mice bearing SW620 CRC cells, followed by tumors derived from SW480 and HCT8 cell lines. We detected the highest fluorescent intensity of the tumor at 120 hours after injection of NIR‐PD‐L1‐mAb. The highest fluorescence intensity was seen in the tumor, followed by the spleen and the liver in SW620 xenografted mice. In SW480 and HCT8 xenografted mice, however, the highest fluorescent signals were detected in the spleen, followed by the liver and the tumor. Our findings indicate that SW620 cells express a higher level of PD‐L1, and the NIR‐PD‐L1‐mAb binding to PD‐L1 on the surface of CRC cells was specific. The technique was safe and could provide valuable information on PD‐L1 expression of the tumor for development of a therapeutic strategy of personized targeted immunotherapies as well as treatment response of patients with CRC.

This study aimed to design a highly sensitive electrochemical aptasensor based on the dual-signal amplification strategy for detecting neomycin (NEO) in milk samples. The electronic signal of multi-walled carbon nanotubes (MWCNTs) was greatly improved due to the existence of ferrocene (Fc), which had good electron transfer ability. The silica hybridized mesoporous ferroferric oxide nanoparticles (Fe3O4@SiO2) were prepared by hydrothermal and chemical activation treatments, which had a large specific pore volume and a large specific surface area, they could fix more RNA aptamers (Apts) and promote the electron transfer of nanoparticle labels. A composite sandwich was formed between the two Apts (Apt1 and Apt2) and the target. Also, Apt2 was modified by gold nanoparticles (AuNPs), enhancing the electrochemical signal. Cyclic voltammetry (CV) and differential pulse voltammetry (DPV) were used to characterize the performance of the aptasensor in detail. Under optimized conditions, the response current differences of the electrochemical aptasensor exhibited a linear relationship toward the positive logarithm of NEO concentrations ranging from 5 × 10−3 nM to 5 × 102 nM and a detection limit of 0.759 nM. The electrochemical aptasensor showed specificity and selectivity. In addition, the constructed aptasensor was successfully applied to the detection of NEO in milk. These results indicated that the aptasensor had potential applications in the actual monitoring of NEO.

The Pt decorated Ni/C nanocatalysts were prepared for hydrogen oxidation reaction (HOR) in fuel cell. By regulating the contents of Pt and Ni in the catalyst, both the composition and the structure affected the electrochemical catalytic characteristics of the Pt-Ni/C catalysts. When the Pt mass content was 3.1% percent and that of Ni was 13.9% percent, the Pt-Ni/C-3 catalyst exhibited a larger electrochemically active surface area and a higher exchange current density toward HOR than those of pure supported platinum sample. Our study demonstrates a feasible approach for designing the more efficient catalysts with lower content of noble metal for HOR in fuel cell.

Cytochrome c has been used as first-aid in the clinic for organs which are lacking oxygen. But recent report show cytochrome c injection destroys dendritic cells (DCs) which play a pivotal role in feto-maternal tolerance. However, it is not clear whether cytochrome c injection causes abortion. The cytochrome c was injected by tail vein of mice at the Day 5.5 of pregnancy (E5.5) after mating with male BALB/c mice. The total number of implantations and resorption sites was recorded at the E12.5 in pregnant mice. Expression of interferon-γ, tumor necrosis-α interleukin (IL)-4, IL-10, IL-12 and transforming growth factor-β in the mouse endometrium was measured by ELISA. Injection of cytochrome c via tail vein at the E5.5 induced fetal resorption at E12.5, and evoked an immune imbalance at the maternal-fetal interface. Notably, injection of mouse bone marrow-derived DCs (BM-DCs) rescued the cytochrome c-evoked embryo resorption. The present study suggests cytochrome c injection causes embryo resorption in mice, hinting caution regarding the use of cytochrome c in pregnant women. In addition, it may provide an easy and novel way to establish a mouse model of abortion.HighlightsCytochrome c injection induced fetal rejection.Cytochrome c injection leads to a T helper 1/T helper 2 imbalance at the maternal-fetal interface.A mouse model of abortion was established by injecting tail vein with cytochrome c.

Accumulating evidence has shown that preeclampsia (PE) was associated with an aberrant maternal-fetal inflammatory response. In the present study, we first found that in human PE placentas levels of toll-like receptor 4 (TLR4), phosphorylated p38 mitogen-activated protein kinase (p-p38 MAPK) and inflammatory cytokines IL-6 and MCP-1 were significantly upregulated. Next, we demonstrated a notable increase in systolic blood pressure (SBP) and proteinuria in lipopolysaccharide (LPS)-treated pregnant rats and concomitant high levels of TLR4 and p-p38 in these PE-like rat placentas, which led to aberrant overexpression of both IL-6 and MCP-1, as well as deficient trophoblast invasion and spiral artery (SA) remodeling, and these abnormalities were ameliorated by SB203580, a reported inhibitor of p38. In vitro we further confirmed that LPS triggered the activation of TLR4/p38 signaling pathway, which promoted trophoblast apoptosis and damaged trophoblastic invasion via downstream effectors IL-6 and MCP-1; these mutations were rectified by silencing this signaling pathway. These findings elaborated potential mechanisms that aberrant TLR4/p38 signaling might contribute to PE and LPS-induced PE-like symptom by damaging trophoblast invasion and SA remodeling via activating inflammatory cytokines including IL-6 and MCP-1.

Background Curcumin is a major active ingredient extracted from powdered dry rhizome of Curcuma longa. In Ayurveda and traditional Chinese medicine, it has been used as a hepatoprotective agent for centuries. However, the underlying mechanisms are not clear. Objective The present study is to investigate the hepatoprotective effects of curcumin in chronic alcohol-induced liver injury and explore its mechanism. Design Alcohol-exposed Balb/c mice were treated with curcumin (75 and 150 mg/kg) once per day for 8 weeks. Tissue from individual was fixed with formaldehyde for pathological examination. The activities of mitochondrial antioxidant enzymes, Na+/k+-ATPase, Ca2+-ATPase, and Ca2+Mg2+-ATPase, were determined. The level of mitochondrial membrane potential (MMP) and mitochondrial permeability transition pore (MPTP) opening was also determined. The expression of PGC-1α, NRF1, Mn-SOD, GRP78, PERK, IRE1α, nuclear NF-κB, and phosphorylated IκBα was quantified by western blot. The contents of TNF-α, IL-1β, and IL-6 in the liver were measured using the ELISA method. Results Curcumin significantly promoted hepatic mitochondrial function by reducing the opening of MPTP, thus increasing the MMP, promoting the activity of Na+/k+-ATPase, Ca2+-ATPase, and Ca2+/Mg2+-ATPase, and attenuating oxidative stress. Curcumin upregulated the expression of PGC-1α, NRF1, and Mn-SOD, and downregulated the expression of GRP78, PERK, and IRE1α in hepatic tissue. Curcumin also attenuated inflammation by inhibiting the IκBα-NF-κB pathway, which reduced the production of TNF, IL-1β, and IL-6. Conclusion Curcumin attenuates alcohol-induced liver injury via improving mitochondrial function and attenuating endoplasmic reticulum stress and inflammation. This study provides strong evidence for the beneficial effects of curcumin in the treatment of chronic alcohol-induced liver injury.

The internal temperature of the battery is important for the design of battery thermal management and battery safety; however, it is difficult to be tested and seldom studied. A method of embedding thermocouples inside a prismatic L i [ N i 1 / 3 C o 1 / 3 M n 1 / 3 ] O 2 (NCM) lithium-ion battery was developed to study the temperature inconsistency between the battery interior and the surface. Six thermocouples were embedded in the interior and six were attached to the surface of the battery. First, the feasibility of the embedding-thermocouples method was verified by comparing the capacity, resistance, temperature etc. between the batteries with and without embedded thermocouples. Then 1C and 2C charging and discharging experiments were carried out under the adiabatic condition in an Accelerating Rate Calorimeter (ARC). 1C−5C rates of charging and discharging experiments were executed under the natural convection condition. The temporal and spatial temperature varieties of battery interior and surface were analyzed. The experimental results show that under the adiabatic condition, the temperature difference (TD) between the interior and surface of the battery was small, only 1.7 °C at 1C discharge rate and 3.1 °C at 2C discharge rate. However, under the natural convection condition, the maximum TD reached 11.3 °C at 5C discharge rate. The TD among the six internal temperature measurement points was small for all cases, which means a good uniform temperature distribution inside the battery. In addition, through experiment-data analysis, a near linear relationship was found for the battery internal and external temperature. The effect of the current rates on the maximum temperature and the maximum temperature difference was also studied. The results showed that a good quadratic function relationship was observed for both the maximum temperature and the maximum TD.

Carbon dioxide (CO2) mineralization is an advantageous and effective way to reduce CO2 emissions. In previous work, our research group presented a CO2 mineralization cell that sued alkaline solid waste and CO2 as raw materials to produce both electricity and baking soda. Two generations of the cell have been developed. In this paper, we report a novel version of the CO2 mineralization cell in which a highly soluble, proton-coupled electron transfer (PCET), organic redox couple is used to facilitate CO2 mineralization and electricity generation without the need of a precious metal catalyst such as platinum. The cell presented a maximum power density of 96.75 W m−2 (much higher than that the previously reported mineralization cells without a PCET redox couple). This cell could generate 146 kWh per ton of CO2 mineralized. The reaction mechanism of the cell is based on PCET considerably improved power generation capacity towing to the excellent characteristics of the organic catalyst. This idea provides a new direction toward solving the problem of needing precious metal catalysts in fuel cells.

SummaryIn an attempt to identify novel therapeutics and mechanisms to differentially kill tumor cells using phenotypic screening, we identified N-benzyl indole carbinols (N-BICs), synthetic analogs of the natural product indole-3-carbinol (I3C). To understand the mode of action for the molecules we employed Cancer Cell Line Encyclopedia viability profiling and correlative informatics analysis to identify and ultimately confirm the phase II metabolic enzyme sulfotransferase 1A1 (SULT1A1) as the essential factor for compound selectivity. Further studies demonstrate that SULT1A1 activates the N-BICs by rendering the compounds strong electrophiles which can alkylate cellular proteins and thereby induce cell death. This study demonstrates that the selectivity profile for N-BICs is through conversion by SULT1A1 from an inactive prodrug to an active species that induces cell death and tumor suppression.

Aim To evaluate the efficacy of probiotics in the treatment of adult and childhood non-alcoholic fatty liver disease (NAFLD). Methods Randomized controlled trials on the efficacy of probiotics in the treatment of adult and childhood NAFLD published before July 2015 were searched in multiple databases, including Cochrane Library, PubMed/MEDLINE, EBSCO, OVID, SCI, CNKI, and VIP. Article identification and data extraction were carried out by two reviewers based on the inclusion and exclusion criteria. RevMan 5.3 software was used for the meta-analysis. Results Nine randomized controlled trials with a total of 535 cases of NAFLD were included. Statistical differences in homeostasis model assessment, total cholesterol, high density lipoprotein, triglyceride, and tumor necrosis factor-α were detected between the probiotics and control groups with variations in different patient populations. No significant differences in body mass index (BMI), glucose, or insulin were detected between the two groups. Statistical differences in low density lipoprotein, alanine aminotransferase, aspartate transaminase, and BMI were detected between the two childhood groups (P ≤ 0.05). Conclusion Probiotics provided improvements in the outcomes of homeostasis model assessment, total cholesterol, high density lipoprotein, and tumor necrosis factor-α in any NAFLD patients and triglyceride in Italian and Spanish patients, but no improvement in the outcomes of BMI, glucose, or insulin in adult NAFLD patients. The currently available data are not sufficient to compare the effects of probiotics between adult and childhood NAFLD patients.

11S REGs (PA28s) are multimeric rings that bind proteasomes and stimulate peptide hydrolysis. Whereas REGalpha activates proteasomal hydrolysis of peptides with hydrophobic, acidic or basic residues in the P1 position, REGgamma only activates cleavage after basic residues. We have isolated REGgamma mutants capable of activating the hydrolysis of fluorogenic peptides diagnostic for all three active proteasome beta subunits. The most robust REGgamma specificity mutants involve substitution of Glu or Asp for Lys188. REGgamma(K188E/D) variants are virtually identical to REGalpha in proteasome activation but assemble into less stable heptamers/hexamers. Based on the REGalpha crystal structure, Lys188 of REGgamma faces the aqueous channel through the heptamer, raising the possibility that REG channels function as substrate-selective gates. However, covalent modification of proteasome chymotrypsin-like subunits by 125I-YL3-VS demonstrates that REGgamma(K188E)'s activation of all three proteasome active sites is not due to relaxed gating. We propose that decreased stability of REGgamma(K188E) heptamers allows them to change conformation upon proteasome binding, thus relieving inhibition of the CT and PGPH sites normally imposed by the wild-type REGgamma molecule.

The polymorphism of vitamin D receptor (VDR) gene is demonstrated to affect the activity of its encoding protein and the subsequent downstream effects mediated by vitamin D. Mutations in VDR gene FokI have been suggested in the development of various cancers. Whether the polymorphism of the VDR gene FokI confers risk to ovarian cancer still remains controversial across the published studies in different ethnicity. The aim of this meta-analysis was to determine the role of VDR gene FokI variant in the susceptibility to ovarian cancer. Six publications with 14 individual case-control studies involving a total of 10,964 subjects were finally included into our study after a comprehensive literature search of the PubMed, Embase, Web of Science, and Wanfang databases. The strength of the association between the VDR gene FokI polymorphism and ovarian cancer risk was estimated under the allelic (T vs. C), homozygous (TT vs. CC), additive (CT vs. CC), recessive (TT vs. CC + CT), and dominant (CT + TT vs. CC) gene models. The overall odds ratios (ORs) for the contrast models of T vs. C, TT vs. CC, CT vs. CC, and CT + TT vs. CC indicated that the VDR gene FokI variant was related to an increased risk of ovarian cancer (OR(T vs. C) = 1.09, 95 % confidence interval (CI) 1.03-1.15, P(OR) = 0.004; OR(TT vs. CC) = 1.17, 95 % CI 1.04-1.32, P(OR) = 0.011; OR(CT vs. CC) = 1.10, 95 % CI 1.01-1.20, P(OR) = 0.027; OR(CT + TT vs. CC) = 1.12, 95 % CI 1.03-1.21, P(OR) = 0.007). The stratified analysis among the Caucasians also identified a significant association between the VDR gene FokI polymorphism and the susceptibility to ovarian cancer. The present meta-analysis with large available published data has revealed that the VDR gene FokI polymorphism confers susceptibility to ovarian cancer, particularly among the Caucasian population.

Sphingosine 1-phosphate (S1P), a product of sphingomyelin metabolism, is generated via phosphorylation of sphingosine by sphingosine kinases (SphK). It acts via a family of G protein-coupled receptors or as an intracellular second messenger for agonists acting through the S1P receptors (S1P1–5). In our study, the expression of SphK1 and S1P1 was identified by immunohistochemistry and immunoblot. The concentration of S1P was measured using ELISA. The spontaneous contraction of isolated fallopian tube strips was determined by tension recording. Our results showed that SphK1 and S1P1 were localized in the fallopian tube epithelial cells. In addition, smooth muscle cells also contained S1P1. Compared with the intrauterine pregnancy group, SPHK1 and S1P1 were overexpressed in ectopic pregnancy. However, the S1P concentration within the human oviduct from ectopic pregnancy subjects was largely reduced than that from normal pregnancy subject. The results from tension recording indicated that exogenous and intracellularly generated S1P can regulate the spontaneous contraction of oviduct isolated from rats and human. In conclusion, the sphingolipid metabolism signal pathway functionally existed in the human fallopian tube. Aberrant sphingolipid metabolism in the human fallopian tube may be involved in ectopic pregnancy.

The proteasome activation properties of recombinant REG gamma molecules depend on purification procedures. Prior to ammonium sulfate precipitation recombinant REG gamma activates the trypsin-like catalytic subunit of the proteasome; afterwards it activates all three catalytic subunits. The expanded activation specificity is accompanied by reduced stability of the REG gamma heptamer providing support for the idea that a "tight" REG gamma heptamer suppresses the proteasome's chymotrypsin-like and postglutamyl-preferring active sites. In an attempt to determine whether REG gamma synthesized in mammalian cells also exhibits restricted activation properties, extracts were prepared from several mammalian organs and cell lines. Surprisingly, endogenous REG gamma was found to be largely monomeric. In an alternate approach, COS7 cells were cotransfected with plasmids expressing FLAG-REG gamma and REG gamma. The expressed FLAG-REG gamma molecules were shown to form oligomers with untagged REG gamma subunits, and the mixed oligomers preferentially activated the proteasome's trypsin-like subunit. Thus, REG gamma molecules synthesized in mammalian cells also exhibit restricted activation properties.