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All-inorganic perovskite cesium lead iodide/bromide (CsPbI 2 Br) is considered as a robust absorber for perovskite solar cells (PSCs) because of its excellent thermal stability that guarantees its long-term operation stability. Efficient CsPbI 2 Br PSCs are available when obtaining low energy loss, which needs efficient charge generation, less charge recombination, and balanced charge extraction. However, numerous traps in perovskites hinder the photon-electron conversion process. Herein, hierarchical manipulation of charge recombination is proposed for CsPbI 2 Br PSCs featuring low energy loss. Nonselective trap reduction and selective halogen vacancy passivation are performed using 2,2'-(ethylenedioxy)diethylamine and phenylbutylammonium iodide for the bottom and top contacts, respectively. Because of all-around suppressed charge recombination, balanced charge extraction and suppressed hysteresis are realized. The champion PSC achieves an open-circuit voltage of 1.30 eV, a fill factor of 80.2%, and a power conversion efficiency of 16.6% that is 28.6% higher than that of the reference device. Moreover, the thermostability of PSCs is simultaneously enhanced because of the limited defect-assisted degradation.

Electrochemical nitrogen fixation techniques have emerged as a promisingly sustainable approach to face the challenge associated with nitrogen activation of ammonia synthesis by the Haber-Bosch process under ambient conditions. Herein, the performance of electrocatalytic nitrogen reduction for the production of α-Fe 2 O 3 nanospindles coated with mesoporous TiO 2 with different crystallinity [denoted as α-Fe 2 O 3 @mTiO 2 -X (X=300, 400, and 500 °C)] were investigated. The as-prepared α-Fe 2 O 3 @mTiO 2 -400 composite exhibits a large NH 3 yield (27.2 μg h -1  mg cat. -1 ) at -0. 5 V vs. the reversible hydrogen electrode and a high Faradaic efficiency (13.3 %) in 0.1 m Na 2 SO 4 , with excellent electrochemical durability. This work presents a novel avenue for the rational design of efficient unique hetero-phase nanocatalysts toward sustainable electrocatalytic N 2 fixation., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Postretrieval extinction procedures are effective nonpharmacological interventions for disrupting drug-associated memories. Nonetheless, the conditioned stimulus (CS) memory retrieval-extinction procedure is ineffective in inhibiting drug craving and relapse after prolonged withdrawal, which significantly undermines its therapeutic potential. In the present study, we showed that, unlike the CS memory retrieval-extinction procedure, noncontingent heroin injections (unconditioned stimulus [UCS]) 1 hour before the extinction sessions decreased the heroin-priming-induced reinstatement, renewal, and spontaneous recovery of heroin seeking after 28 days of withdrawal (ie, remote heroin-associated memories) in rats. The UCS retrieval manipulation induced reactivation of the basolateral amygdala (BLA) after prolonged withdrawal, and this reactivation was absent with the CS retrieval manipulation. Chemogenetic inactivation of the BLA abolished the inhibitory effect of the UCS memory retrieval-extinction procedure on heroin-priming-induced reinstatement after prolonged withdrawal. Furthermore, the combination of chemogenetic reactivation of BLA and CS retrieval-extinction procedure resembled the inhibitory effect of UCS retrieval-extinction procedure on heroin seeking after prolonged withdrawal. We also observed that the inhibitory effect of the UCS retrieval-extinction procedure is mediated by regulation of AMPA receptor endocytosis in the BLA. Our results demonstrate critical engagement of the BLA in reconsolidation updating of heroin-associated memory after prolonged withdrawal, extending our knowledge of the boundary conditions of the reconsolidation of drug-associated memories., (© 2019 Society for the Study of Addiction.)

Electrochemical conversion of N 2 to NH 3 under ambient conditions is a promising and environmentally friendly route compared with the CO 2 -emitting and energy-intensive Haber-Bosch process. Nevertheless, due to ultrahigh stability of N 2 , it is urgent to explore efficient catalysts to weaken and activate the N≡N bond. Here, we report the Mo-doped iron phosphide (Mo-FeP) nanosphere as a valid transition-metal-based catalyst for electrochemical N 2 -to-NH 3 fixation under ambient conditions. This catalyst exhibits excellent catalytic performance with a NH 4 + yield rate (13.1 μg h -1 mg -1 ) and Faradaic efficiency (7.49%) at -0.3 and -0.2 V vs reversible hydrogen electrode (RHE), respectively. However, the FeP catalyst without doped Mo species displays weak catalytic performance. We found that the better catalytic performance of Mo-FeP might be due to the doping of Mo species, which is favorable for the polarization of adsorbed N 2 molecules, making the N≡N bond more viable to dissociate.

Deposition of H2A.Z in chromatin is known to be mediated by a conserved SWR1 chromatin-remodeling complex in eukaryotes. However, little is known about whether and how the SWR1 complex cooperates with other chromatin regulators. Using immunoprecipitation followed by mass spectrometry, we found all known components of the Arabidopsis thaliana SWR1 complex and additionally identified the following three classes of previously uncharacterized plant-specific SWR1 components: MBD9, a methyl-CpG-binding domain-containing protein; CHR11 and CHR17 (CHR11/17), ISWI chromatin remodelers responsible for nucleosome sliding; and TRA1a and TRA1b, accessory subunits of the conserved NuA4 histone acetyltransferase complex. MBD9 directly interacts with CHR11/17 and the SWR1 catalytic subunit PIE1, and is responsible for the association of CHR11/17 with the SWR1 complex. MBD9, TRA1a, and TRA1b function as canonical components of the SWR1 complex to mediate H2A.Z deposition. CHR11/17 are not only responsible for nucleosome sliding but also involved in H2A.Z deposition. These results indicate that the association of the SWR1 complex with CHR11/17 may facilitate the coupling of H2A.Z deposition with nucleosome sliding, thereby co-regulating gene expression, development, and flowering time., (© 2020 The Authors.)

This paper reports a case with alveolar echinococcosis metastatic to the brain. This case underwent 10-year antiechinococcosis treatment and operations of the liver, right kidney and brain. Following multiple operations and oral administration of albendazole, the case still had recurrence and distant metastasis of hepatic echinococcosis. It is suggested that early prevention, early diagnosis, early regular treatment and surgical radical treatment are critical to the treatment of alveolar echinococcosis.

Level structures in the neutron-rich ^{144}Ba nucleus have been reinvestigated by measuring prompt γ rays in the spontaneous fission of ^{252}Cf. The previous s=+1 octupole band structure with reflection asymmetric shape has been expanded, and a side quadrupole band structure based on a 3^{+} state with reflection symmetric shape is identified. Thus, the results show the coexistence of reflection asymmetric and symmetric shapes in ^{144}Ba. This is a first identification of such a shape coexistence structure in a nuclear structure. The other structural characteristics are discussed.

Previously, we identified that sortilin related VPS10 domain containing receptor 1 (SorCS1) was hypermethylated in colorectal cancer (CRC) tissues. Here, we aimed to investigate the association between CRC and SorCS1. DNA methylation was determined by methylation-specific polymerase chain reaction (MSP) or quantitative real-time methylation analysis (MethyLight). Colorectal cancer tissue specimens from 239 patients that had undergone surgical treatment were evaluated using immunohistochemistry (IHC) analysis for the expression of SorCS1 and correlated with clinicopathological variables and prognosis. We found that SorCS1 was hypermethylated in CRC cell lines and 67.5% (27/40) CRC tumor tissues. The loss of SorCS1 mRNA (p<0.001) and protein expression (p=0.033) were highly correlated with promoter methylation. In addition, SorCS1 expression was significantly increased in younger patients (p=0.006), low CEA level (p<0.001) and pT1-2 stage (p=0.005). Survival analysis revealed that decreased expression of SorCS1 was an independent factor for predicting the increased risk of recurrence (p=0.024) and poor overall survival (p=0.006). Subgroup analysis for CEA level, pT and pN classifications showed that SorCS1 retained its stratified significance only in patients with low CEA level, pT3-4 tumors and pN1-2 lymph node status. Our findings suggest that SorCS1 is epigenetically inactivated in a substantial fraction of CRC, and its expression may be a promising prognostic factor in CRC patients.

The authors describe an electrochemical and an optical method for the determination of As(V) by using iron oxyhydroxide (FeOOH) nanorods that display peroxidase-mimicking activity. The nanorods catalyze the oxidation of substrate ABTS by H 2 O 2 to form a green product with an absorption maximum at 418 nm. If, however, As(V) is electrostatically adsorbed on the nanorods, the oxidation is gradually inhibited. A colorimetric assay was worked out based on these findings. Response is linear in the 0 to 8 ppb and 8 to 200 ppb As(V) concentration range, and the detection limit is 0.1 ppb. Even higher sensitivity is achieved in an electrochemical method which is based on the excellent electrical conductivity of FeOOH nanorods. Electrochemical analysis of As(V) was achieved by first adsorbing As(V) on the nanorods. This inhibits the ABTS reduction current signal, best measured at a potential of 150 mV (vs. Ag/AgCl). The linear range extends from 0.04 to 200 ppb, and the detection limit is as low as 12 ppt. Graphical abstract Schematic representation of FeOOH nanorod-based colorimetric and electrochemical assays for arsenate (As(V)). As(V) adsorbed on FeOOH nanorods inhibits the peroxidase-mimicking activity of nanorods, and a colorimetric and electrochemical dual-signal assay was constructed to achieve sensitive determination of As(V).

Inorganic mixed-halide CsPbX 3 -based perovskite solar cells (PeSCs) are emerging as one of the most promising types of PeSCs on account of their thermostability compared to organic-inorganic hybrid counterparts. However, dissatisfactory device performance and high processing temperature impede their development for viable applications. Herein, a facile route is presented for tuning the energy levels and electrical properties of sol-gel-derived ZnO electron transport material (ETM) via the doping of a classical alkali metal carbonate Cs 2 CO 3 . Compared to bare ZnO, Cs 2 CO 3 -doped ZnO possesses more favorable interface energetics in contact with the CsPbI 2 Br perovskite layer, which can reduce the ohmic loss to a negligible level. The optimized PeSCs achieve an improved open-circuit voltage of 1.28 V, together with an increase in fill factor and short-circuit current. The optimized power conversion efficiencies of 16.42% and 14.82% are realized on rigid glass substrate and flexible plastic substrate, respectively. A high thermostability can be simultaneously obtained via defect passivation at the Cs 2 CO 3 -doped ZnO/CsPbI 2 Br interface, and 81% of the initial efficiency is retained after aging for 200 h at 85 °C., Competing Interests: The authors declare no conflict of interest., (© 2019 The Authors. Published by WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Carcinoembryonic antigen (CEA) is a commonly used biomarker in colorectal cancer. However, controversy exists regarding the insufficient prognostic value of preoperative serum CEA alone in rectal cancer. Here, we combined preoperative serum CEA and the maximum tumor diameter to correct the CEA level, which may better reflect the malignancy of rectal cancer., Aim: To assess the prognostic impact of preoperative CEA/tumor size in rectal cancer., Methods: We retrospectively reviewed 696 stage I to III rectal cancer patients who underwent curative tumor resection from 2007 to 2012. These patients were randomly divided into two cohorts for cross-validation: training cohort and validation cohort. The training cohort was used to generate an optimal cutoff point and the validation cohort was used to further validate the model. Maximally selected rank statistics were used to identify the optimum cutoff for CEA/tumor size. The Kaplan-Meier method and log-rank test were used to plot the survival curve and to compare the survival data. Univariate and multivariate Cox regression analyses were used to determine the prognostic value of CEA/tumor size. The primary and secondary outcomes were overall survival (OS) and disease-free survival (DFS), respectively., Results: In all, 556 patients who satisfied both the inclusion and exclusion criteria were included and randomly divided into the training cohort (2/3 of 556, n = 371) and the validation cohort (1/3 of 556, n = 185). The cutoff was 2.429 ng/mL per cm. Comparison of the baseline data showed that high CEA/tumor size was correlated with older age, high TNM stage, the presence of perineural invasion, high CEA, and high carbohydrate antigen 19-9 (CA 19-9). Kaplan-Meier curves showed a manifest reduction in 5-year OS (training cohort: 56.7% vs 81.1%, P < 0.001; validation cohort: 58.8% vs 85.6%, P < 0.001) and DFS (training cohort: 52.5% vs 71.9%, P = 0.02; validation cohort: 50.3% vs 79.3%, P = 0.002) in the high CEA/tumor size group compared with the low CEA/tumor size group. Univariate and multivariate analyses identified CEA/tumor size as an independent prognostic factor for OS (training cohort: hazard ratio (HR) = 2.18, 95% confidence interval (CI): 1.28-3.73, P = 0.004; validation cohort: HR = 4.83, 95%CI: 2.21-10.52, P < 0.001) as well as DFS (training cohort: HR = 1.47, 95%CI: 0.93-2.33, P = 0.096; validation cohort: HR = 2.61, 95%CI: 1.38-4.95, P = 0.003)., Conclusion: Preoperative CEA/tumor size is an independent prognostic factor for patients with stage I-III rectal cancer. Higher CEA/tumor size is associated with worse OS and DFS., Competing Interests: Conflict-of-interest statement: The authors declare that they have no conflict of interest.

Objective: To establish SNaPShot-fluorescence capillary analysis (SNaPShot-FCA) assay for rapid detection of the genotype of aldehyde dehydrogenase 2 gene ( ALDH 2) rs671 locus., Methods: The genomic DNA was extracted from peripheral blood cells. Using R6G-ddATP and cy5-ddGTP as fluorescent substrates, the ALDH 2 gene was amplified by SNaPShot to generate DNA products with different fluorescent dyes at the 3' end. FCA was used to detect the products separated by agarose gel electrophoresis and recovered by gel recovery kit, and the genetype of ALDH 2 polymorphism was analyzed by fluorescence spectrum. The samples were tested three times repeatedly and compared with the results of DNA sequencing., Results: The optimal concentrations of R6G-ddATP and cy5-ddGTP were 1.4 μ mol/L and 8.0 μ mol/L, respectively. 106 samples were tested for ALDH 2 genotype by SNaPShot-FCA under optimal conditions, including 67 of wild type (GG), 38 of hybrid type (AG), and 1 of mutant type (AA), which were consistent with the sequencing results., Conclusion: This study successfully established the SNaPShot-FCA for the micro-detection of ALDH 2 genotype for the rapid screening and identification of ALDH 2 gene., (Copyright© by Editorial Board of Journal of Sichuan University (Medical Science Edition).)

Objective: To analyze the status of domestic surgical treatment of synchronous peritoneal carcinomatosis from colorectal cancer in China. Methods: Clinicopathological data of patients who underwent surgery from October 2003 to October 2018 in 16 domestic medical centers was retrospectively analyzed. Excel database was created which covered 77 fields of 7 parts: baseline information of patients, laboratory tests, imaging tests, chemoradiotherapy information, intra-operative findings, postoperative pathology and follow-up data. The Wilcoxon rank-sum test was used for comparison of the measurement data between groups. The χ(2) test was used for comparison of the categorical data between groups. The survival curve was calculated by the Kaplan-Meier method. Results: Of the 1 003 patients, there were 575 male and 428 female patients with the age of (58.5±14.1) years (range: 18 to 92 years). In a total of 920 patients, the carcinoma of sigmoid colon was performed in 292 cases (31.8%) with the highest ratio. The proportion of patients with liver metastasis and lung metastasis were 27.9% (219/784) and 8.3% (64/769). Preoperative detection of carcino-embryonic antigen level was the most common method in China (87.74%, 880/1 003), and the positive rate was 64.5% (568/880). The correct rate of preoperative imaging tests was 40.7% (280/688). The ratio of peritoneal carcinomatosis index (PCI) scores between 0 and 10 was the highest (59.6%, 170/285). Two hundred and sixty-two (27.0%) patients were performed by totally laparoscopic operation in 971 patients. The resection of primary tumor was performed in 588 of the 817 patients (72.0%). In a total of 457 cases, 253 (55.4%) patients were performed cytoreduction which group scored completeness of cytoreduction (CCR) 0. The postoperative hyperthermic intraperitoneal chemotherapy was implemented in 70 of the 334 cases (21.0%). Among 1 003 cases, 562 cases (56.03%) had complete follow-up data and the median overall survival was 15 months. The primary tumor resection and the CCR scores were affected by the PCI scores. The patients underwent primary tumor resection (187/205 vs . 26/80, χ(2)=105.085, P= 0.000) and the patients were performed cytoreduction which scored CCR 0 or CCR 1 (162/204 vs . 8/78, Z= -10.465, P= 0.000) had significant difference between the groups of PCI<20 and ≥20. There was a close correlation between the surgical method and the CCR scores ( Z= -3.246, P= 0.001).When the maximum degree of tumor reduction was planned, most surgeons would choose laparotomy. The overall survival time was longer in patients with primary tumor resection ( P= 0.000). The median survival time was 18.6 months in the group of primary tumor resection. Conclusions: It is difficult to diagnose the synchronous peritoneal carcinomatosis from colorectal cancer before the operation. Primary tumor resection has an obvious effect to prolong the survival time. It is necessary to standardize the treatment of peritoneal metastasis.

Aims: TL1A was reported to contribute to the susceptibility to ulcerative colitis (UC). However, the molecular mechanisms of TL1A in UC development are poorly understood. We aimed to investigate the role of TL1A in colitis, and reveal the regulatory mechanism of TL1A in chronic colitis development., Main Methods: Wild-type mice and transgenic mice with overexpressing TL1A in lymphocytes were used to construct chronic DSS colitis models. To investigate the molecular mechanism in vitro, CD4 + T cells were sorted from spleens and mesenteric lymph node cells to induce Th9 cells. Biopsy specimens from ulcerative colitis patients were collected for in vivo validation., Key Findings: The elevated TL1A expression in chronic DSS colitis models exacerbated intestinal inflammation. The differentiation of Th9 cells, IL-9 secretion and production of TGF-β, IL-4 and PU.1 was significantly enhanced in transgenic mice with TL1A overexpression. In vitro results showed that TL1A enhanced the Th9 cells, IL-9 and PU.1 production, while TL1A antibodies inhibited their production. In human translational studies, patients with ulcerative colitis with elevated TL1A expression also exhibited more serious inflammation with higher levels of Th9 cells, IL-9 and PU.1 expression., Significance: We presented a possible mechanism of TL1A in UC development that TL1A may promote the differentiation of Th9 cells and enhanced IL-9 secretion by up-regulating the expression of TGF-β, IL-4 and PU.1, which provided a novel perspective to study the UC pathogenesis, and indicated that targeting of TL1A signal pathway may by a likely strategy for the treatment of chronic colitis., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Men and women were reported to be different in brain structure and sleep patterns. Here we analyzed the region, sleep stage and frequency band-specific EEG synchronization intensity of whole night sleep recording of 14 male and 14 age-matched female subjects by calculating weighted phase lag indexes. Moreover, resting wakeful stage EEG was also analyzed and compared. The synchronization intensities showed significant gender differences in all stages and bands: higher in women in non-rapid eye movement (NREM) sleep, and higher in men in α and β bands in wakeful stage and rapid eye movement (REM) sleep. However, Except for α band, the similar changing trends in characteristics of EEG synchronization during different stages were found in both male and female subjects. These results suggest that there may be some differences in the mechanisms of sleep regulation between men and women. Moreover, the synchronous intensity of different sleep stages in different frequency bands of male and female groups was not consistent with the influence of age, which may be related to the gender differences in aging patterns.

In situ-derived boron-doped graphene quantum dots can significantly improve the activity of boron carbide nanosheets for artificial N2 fixation and reduction with superior electrocatalytic activity (NH3 yield: 28.6 μg h-1 mgcat.-1 at -0.45 V vs. RHE; faradaic efficiency: 16.7%), high electrochemical stability, and high selectivity in 0.1 M HCl under ambient conditions.

Background: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor type in the gastrointestinal system. Presently, various classification systems to prognosticate GISTs have been proposed., Aim: To evaluate the application value of four different risk stratification systems for GISTs., Methods: Patients who were diagnosed with GISTs and underwent surgical resection at four hospitals from 1998 to 2015 were identified from a database. Risk of recurrence was stratified by the modified National Institute of Health (NIH) criteria, the Armed Forces Institute of Pathology (AFIP) criteria, the Memorial Sloan Kettering Cancer Center (MSKCC) prognostic nomogram, and the contour maps. Receiver operating characteristic (ROC) curves were established to compare the four abovementioned risk stratification systems based on the area under the curve (AUC)., Results: A total of 1303 patients were included in the study. The mean age of the patients was 55.77 ± 13.70 yr; 52.3% of the patients were male. The mean follow-up period was 64.91 ± 35.79 mo. Approximately 67.0% the tumors were located in the stomach, and 59.5% were smaller than 5 cm; 67.3% of the patients had a mitotic count ≤ 5/50 high-power fields (HPFs). Thirty-four tumors ruptured before and during surgery. Univariate analysis demonstrated that tumor size > 5 cm ( P < 0.05), mitotic count > 5/50 HPFs ( P < 0.05), non-gastric location ( P < 0.05), and tumor rupture ( P < 0.05) were significantly associated with increased recurrence rates. According to the ROC curve, the AFIP criteria showed the largest AUC (0.754)., Conclusion: According to our data, the AFIP criteria were associated with a larger AUC than the NIH modified criteria, the MSKCC nomogram, and the contour maps, which might indicate that the AFIP criteria have better accuracy to support therapeutic decision-making for patients with GISTs., Competing Interests: Conflict-of-interest statement: All authors have no conflict of interest related to the manuscript.

This study aims to elucidate the effects of soil particle composition and fractal dimension on soil physical and chemical properties following sand-binding revegetation within straw checkerboard in south-eastern Tengger Desert. Three afforested plantations in the year of 2016 (i.e., 1 year), 2013 (i.e., 4 years) and 1987 (i.e., 30 years) were selected as study sites, with the adjacent mobile sand land as control (CK). We measured soil particle composition, soil fractal dimension, and the changes of soil physical and chemical properties. The relationship between soil particle composition, soil fractal dimension, and soil properties was analyzed. The results showed that contents of soil particle with the size of both 100-250 μm and 250-500 μm were greater than that of 50-100 μm, ranging from 42.5% to 80.1% and from 12.5% to 42.2% relative to that ranging from 0.2% to 20.8%. Contents of soil particle with the size of <2 μm and 2-50 μm were remarka-bly lower than that of 100-250 μm, 250-500 μm and 50-100 μm, ranging from 0 to 1.3% and from 0 to 22.7%, respectively. However, contents of soil particle at the size of 500-1000 μm was the lowest occupying <0.3% of soil particle composition. Soil particle with the size of <2 μm and 2-50 μm were found in the 30-year sites only. Soil particle distribution at the size of 50-100 μm, 100-250 μm, and 250-500 μm followed the order of 30 a>1 a>4 a＞CK, 4 a>1 a>CK>30 a, and CK>1 a>4 a> 30a, respectively. Soil particle with the size of 500-1000 μm occupied little of soil particle composition, with no significant difference between each site. The fractal dimension of soil particles ranged from 0.54 to 2.59. There was significantly greater soil fractal dimension in 30 a in comparison to 4 a, 1 a and CK, with the intermediate values in 4 a and 1 a, and the lowest values in CK. There was a significantly positive correlation of fractal dimension of soil particles with soil particle content of clay, silt, very fine sand, and a significantly negative correlation of fractal dimension of soil particles with soil particle content of medium sand. Fractal dimension of soil particles was positively correlated with soil electrical conductivity, organic carbon, total nitrogen, and carbon-nitrogen ratio, but with no correlation with soil pH and soil water content. Soil particle content at the size of <2 μm, 2-50 μm, and 50-100 μm had a significant positive correlation with soil electrical conductivity, organic carbon, total nitrogen, and carbon-nitrogen ratio, whereas soil particle content at the size of 250-500 μm had a negative correlation with the former four soil indices and soil water content. In addition, there was a significant negative correlation of soil particle content at the size of 500-1000 μm with soil water content. It was concluded that the sand-binding reve-getation within straw checkerboard in Tengger Desert could facilitate the fine soil particles by ameli-orating stressful soil conditions. Long-term succession of revegetation on mobile sand land could enhance soil clay and silt content as well as soil fractal dimension, thus be beneficial for the improvement of soil physical and chemical properties and desertification control.

Background: In recent decades, neoadjuvant therapy (NT) has been the standardized treatment for locally advanced rectal cancer (LARC). Approximately 8%-35% of patients with LARC who received NT were reported to have achieved a complete pathological response (pCR). If the pathological response (PR) can be accurately predicted, these patients may not need surgery. In addition, no response after NT implies that the tumor is destructive, resistant to both chemotherapy and radiotherapy, and prone to having a high metastatic potential. Therefore, developing accurate models to predict PR has great clinical significance and can help achieve individualized treatment in LARC patients., Aim: To establish nomograms for predicting PR to different NT regimens based on pretreatment parameters for patients with LARC., Methods: Rectal cancer patients were identified from the database of The Sixth Affiliated Hospital, Sun Yat-sen University from January 2012 to December 2016. Logistic regression and nomograms were developed to predict the probability of pCR and good downstaging to ypT0-2N0M0 (ypTNM 0-I), respectively, based on pretreatment parameters for all LARC patients. Nomograms were also developed for three NT regimens (capecitabine/deGramont-RT, mFOLFOX6, and mFOLFOX6-RT) to predict pCR probability., Results: Four hundred and three patients were included in this study; 72 (17.9%) had pCR at the final pathology report, and 177 (43.9%) achieved good downstaging to ypT0-2N0M0 (ypTNM 0-I). The nomogram for predicting pCR probability showed that NT regimens, tumor differentiation, mesorectal fascia (MRF) status, and tumor length significantly influenced pCR probability. When predicting the probability of good downstaging, tumor differentiation, MRF status, and clinical T stage were the significant factors. Nomograms were developed based on NT regimens. For the capecitabine/de Gramont-RT group, the multivariate analysis showed that the neutrophil-lymphocyte ratio (NLR) was the only significant factor, thus we could not develop a nomogram for this regimen. For the mFOLFOX6-RT group, the analysis showed that the significant factors were tumor length and MRF status; and for the mFOLFOX6 group, the significant factors were tumor length and tumor differentiation., Conclusion: We established accurate nomograms for predicting the PR to preoperative NT regimens based on pretreatment parameters for LARC patients., Competing Interests: Conflict-of-interest statement: We have no financial relationships to disclose.

The study is aimed to assess whether the addition of contourlet-based hippocampal magnetic resonance imaging (MRI) texture features to multivariant models improves the classification of Alzheimer's disease (AD) and the prediction of mild cognitive impairment (MCI) conversion, and to evaluate whether Gaussian process (GP) and partial least squares (PLS) are feasible in developing multivariant models in this context. Clinical and MRI data of 58 patients with probable AD, 147 with MCI, and 94 normal controls (NCs) were collected. Baseline contourlet-based hippocampal MRI texture features, medical histories, symptoms, neuropsychological tests, volume-based morphometric (VBM) parameters based on MRI, and regional CMgl measurement based on fluorine-18 fluorodeoxyglucose-positron emission tomography were included to develop GP and PLS models to classify different groups of subjects. GPR1 model, which incorporated MRI texture features and was based on GPG, performed better in classifying different groups of subjects than GPR2 model, which used the same algorithm and had the same data as GPR1 except that MRI texture features were excluded. PLS model, which included the same variables as GPR1 but was based on the PLS algorithm, performed best among the three models. GPR1 accurately predicted 82.2% (51/62) of MCI convertors confirmed during the 2-year follow-up period, while this figure was 53 (85.5%) for PLS model. GPR1 and PLS models accurately predicted 58 (79.5%) vs. 61 (83.6%) of 73 patients with stable MCI, respectively. For seven patients with MCI who converted to NCs, PLS model accurately predicted all cases (100%), while GPR1 predicted six (85.7%) cases. The addition of contourlet-based MRI texture features to multivariant models can effectively improve the classification of AD and the prediction of MCI conversion to AD. Both GPR and LPS models performed well in the classification and predictive process, with the latter having significantly higher classification and predictive accuracies. Advances in knowledge: We combined contourlet-based hippocampal MRI texture features, medical histories, symptoms, neuropsychological tests, volume-based morphometric (VBM) parameters, and regional CMgl measurement to develop models using GP and PLS algorithms to classify AD patients.

Background: X-linked thrombocytopenia (XLT) is a milder form of Wiskott-Aldrich syndrome (WAS), characterized predominantly by thrombocytopenia with small-sized platelets. Mutations in the WAS gene are responsible for the disease. We herein detected a new mutation in the WAS gene responsible for XLT in a 3-generation Chinese pedigree., Methods: Peripheral blood samples were collected from 7 members in the family. WAS gene was amplified from genomic DNA isolated from leucocytes, and then direct sequencing was performed., Results: Three male members of this family (the proband, his younger brother and maternal uncle) had thrombocytopenia and decreased mean platelet volume. A homozygous mutation (T>C) was found at nucleotide position 319 in exon 3, causing the amino acid Tyr (T) to be abnormally changed to His (H) at position 107. Two female members (the proband's mother and grandmother) were carriers of the mutation., Conclusions: XLT is easy to misdiagnose as immune thrombocytopenic purpura (ITP). The diagnosis of XLT should be considered in any male with congenital microthrombocytopenia or early onset of microthrombocytope-nia (< 7 fL). This article adds to the growing number of known mutations associated with XLT.

Liver injury remains a significant global health problem and has a variety of causes, including oxidative stress (OS), inflammation, and apoptosis of liver cells. There is currently no curative therapy for this disorder. Sanwei Ganjiang Prescription (SWGJP), derived from traditional Chinese medicine (TCM), has shown its effectiveness in long-term liver damage therapy, although the underlying molecular mechanisms are still not fully understood. To explore the underlining mechanisms of action for SWGJP in liver injury from a holistic view, in the present study, a systems pharmacology approach was developed, which involved drug target identification and multilevel data integration analysis. Using a comprehensive systems approach, we identified 43 candidate compounds in SWGJP and 408 corresponding potential targets. We further deciphered the mechanisms of SWGJP in treating liver injury, including compound-target network analysis, target-function network analysis, and integrated pathways analysis. We deduced that SWGJP may protect hepatocytes through several functional modules involved in liver injury integrated-pathway, such as Nrf2-dependent anti-oxidative stress module. Notably, systems pharmacology provides an alternative way to investigate the complex action mode of TCM., (Copyright © 2018 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.)

Objective: To investigate the effect of insulin-like growth factor (IGF)-1 on regulating the occurrence of retinal neovascularization and the expression mechanism of Angiotensin II (Ang II) and vascular endothelial factor (VEGF)., Materials and Methods: A total of 40 C57BL/6J healthy mice of either gender were selected, and randomly divided into 4 groups: control group, model group, IGF-1 overexpression carrier intervention group and IGF-1 siRNA intervention group (10 in each group). Mice in control group were fed in the air without any further processing. The mice in other 3 groups were used to build high oxygen-induced retinal neovascularization model. The vitreous cavity of mice in the model group was injected with the equal amount of normal saline, while the mice in the IGF-1 overexpression carrier intervention group were injected with 1 μl IGF-1 liposomes mixture. At the same time, IGF-1 siRNA intervention group mice were continuously injected with 1 μl IGF-1 siRNA liposomes mixture for 3d. Stretched preparation of retina was used to observe the neovascularization form; HE staining tissue section were prepared to observe the amount of vascular endothelial nuclei out of the retina boundary; IGF-1, Ang II and VEGF expression levels of retinal tissue were detected by RT-PCR and Western blot., Results: A large area of non-perfusion and tortuous expansion form of the blood vessel was found in the optic nerve surroundings of retinal serial sections in model group, while neovascularization plexus and fluorescence leakage were observed between perfusion and non-perfusion area. Non-perfusion and neovascularization have experienced a decrease in IGF-1 overexpression group but an increase in IGF-1 siRNA group. The number of neovascularization endothelial nuclei out of the internal limiting membrane in model group was remarkably higher than that in control group. This number in IGF-1 over-expression group decreases while in IGF-1 siRNA group it increases, with a significant statistical difference (p < 0.05). Histone IGF-1 expression level in the model group was lower than that in the control group, but Ang II and VEGF expression level were higher. IGF-1 in over-expression group was higher but with a lower expression level of Ang II and VEGF; however, the results in siRNA group were opposite. The difference was statistically significant (p < 0.05)., Conclusions: The occurrence of retinal neovascularization is related to the reduction of IGF-1 expression and the increase of Ang II and VEGF.

Neuronal atrophy and alterations of synaptic structure and function in the medial prefrontal cortex (mPFC) have been implicated in the pathogenesis of depression, but the underlying molecular mechanisms are largely unknown. The protein kinase Mζ (PKMζ), a brain-specific atypical protein kinase C isoform, is important for maintaining long-term potentiation and storing memory. In the present study, we explored the role of PKMζ in mPFC in two rat models of depression, chronic unpredictable stress (CUS) and learned helplessness. The involvement of PKMζ in the antidepressant effects of conventional antidepressants and ketamine were also investigated. We found that chronic stress decreased the expression of PKMζ in the mPFC and hippocampus but not in the orbitofrontal cortex. Overexpression of PKMζ in mPFC prevented the depressive-like and anxiety-like behaviors induced by CUS, and reversed helplessness behaviors. Inhibition of PKMζ in mPFC by expressing a PKMζ dominant-negative mutant induced depressive-like behaviors after subthreshold unpredictable stress and increased learned helplessness behavior. Furthermore, stress-induced deficits in synaptic proteins and decreases in dendritic density and the frequency of miniature excitatory postsynaptic currents in the mPFC were prevented by PKMζ overexpression and potentiated by PKMζ inhibition in subthreshold stress rats. The antidepressants fluoxetine, desipramine and ketamine increased PKMζ expression in mPFC and PKMζ mediated the antidepressant effects of ketamine. These findings identify PKMζ in mPFC as a critical mediator of depressive-like behavior and antidepressant response, providing a potential therapeutic target in developing novel antidepressants.

Objective: To explore the effects of macrophages with high expression of TL1A on the activation and proliferation of HSCs in vitro. Methods: The Bone marrow-derived macrophages (BMMs) and peritoneal macrophages (PMs) from wild type (WT) and myeloid-overexpressed TL1A transgenic mice were isolated, differentiated and activated. HSCs were harvested from activated macrophages culture supernatant (CM). HSCs were detected by immunofluorescence and real-time Q-PCR. And the proliferation was detected by CCK-8 and BrdU assay kit. The levels of IL-1β and PDGF-BB in macrophage culture supernatants were determined by enzyme-linked immunosorbent assay (ELISA). Results: BMMs-derived CM-intervention HSCs were used to detect the expression of α-smooth muscle actin (α-SMA) on the 2nd, 4th and 6th day respectively by immunofluorescence method. There was no significant difference between the two groups on the 2 nd and the 6th day, P > 0.05; On day 4, the CM/Tg group was significantly higher than that of CM/WT group, P < 0.01; the results of CMs derived from PMs were consistent with the above trend. The expression of α-SMA mRNA on the 2nd, 4th and 6th day was detected by real-time Q-PCR method using BM-derived CMs. No significant difference was found between the groups on the 2nd day ( P > 0.05).α-SMA mRNA increased further on the 4th and 6th day, and the level of CM/Tg in CM/Tg group was significantly higher than that in CM/WT group ( P < 0.05). The detection results of CMs derived from PMs were consistent with the above trend. The results of CCK-8 assay and BrdU assay showed that the proliferation rate of HSCs in CM Tg group was significantly higher than that in CM/WT group ( P < 0.01). The CMs derived from PMs were used to interfere with HSCs. And the results were consistent with the above trend. For BMMs, the levels of IL-1β and PDGF-BB in the lipopolysaccharide (LPS) + IFNγ/Tg culture supernatant were significantly higher than those in the LPS+IFNγ/WT group ( P < 0.01). For the culture supernatants of PMs Liquid test results consistent with the above trend. Conclusion: Macrophages with high expression of TL1A could enhance the activation and proliferation of HSCs by increasing the secretion of IL-1β and PDGF-BB.

Herein, a fluorescent capillary biosensor was developed for quantifying micro-volume intracellular pyruvate (PA), in which AuNPs and lactate dehydrogenase (LDH) were modified on the inner surface of an amination capillary (20 μL) via a self-assembly technique. The PA concentration was quantified by the change in the value of the fluorescence of NADH after sucking a mixed solution of the sample and NADH into the biosensor. This study investigated factors including the degree of protonation of the amino groups on the surface of the capillary, the AuNP concentration and time for self-assembly, the activity concentration and time for the LDH self-assembly, the flow rate and acidity for LDH immobilization, pH, temperature, and reaction time for the NADH/PA/LDH reaction system. Under the optimized conditions, the linear response range of the biosensor towards PA was 2.5-120 μmol L -1 , in which the determination limit and detection limit were 2.5 and 0.75 μmol L -1 , respectively. The biosensor could be reused more than 41 times when its relative standard deviation (RSD) was controlled at less than 1.5%. At room temperature (approximately 25 °C), the intracellular PA in the erythrocyte of a healthy person was measured using the biosensor, and the PA content was observed to be 241.76 ± 68.05 μmol L -1 (n = 8). The standard addition recovery was 95-106%. Employment of the AuNPs in the PA biosensor not only improved the affinity of the immobilized LDH towards PA and its stability, but also significantly enhanced the service life of the PA biosensor.

The SU(VAR)-3-9-related protein family member SUVR2 has been previously identified to be involved in transcriptional gene silencing both in RNA-dependent and -independent pathways. It interacts with the chromatin-remodeling proteins CHR19, CHR27, and CHR28 (CHR19/27/28), which are also involved in transcriptional gene silencing. Here our study demonstrated that SUVR2 is almost fully mono-sumoylated in vivo. We successfully identified the exact SUVR2 sumoylation site by combining in vitro mass spectrometric analysis and in vivo immunoblotting confirmation. The luminescence imaging assay and quantitative RT-PCR results demonstrated that SUVR2 sumoylation is involved in transcriptional gene silencing. Furthermore, we found that SUVR2 sumoylation is required for the interaction of SUVR2 with CHR19/27/28, which is consistent with the fact that SUMO proteins are necessary for transcriptional gene silencing. These results suggest that SUVR2 sumoylation contributes to transcriptional gene silencing by facilitating the interaction of SUVR2 with the chromatin-remodeling proteins CHR19/27/28.

RNA-binding proteins (RBPs) regulate the expression of thousands of transcripts, and some are reported to be involved in human tumorigenesis. However, little is known about the dysregulation of RBPs at the genomic level in human cancers. Here, we conducted comprehensive analyses for expression, somatic copy number alteration (SCNA), and mutation profiles of 1,542 RBPs in ∼7,000 clinical specimens across 15 cancer types. We identified markedly dysregulated RBPs and found that downregulation was a predominant pattern in cancer. Combined with recurrent SCNA data, we identified 76 RBPs as potential drivers. We also discovered a set of 139 RBPs that were significantly mutated in cancers. We confirmed the oncogenic property of six RBPs in colorectal and liver cancer cell lines by using in vitro functional experiments. Our study highlights the potential roles of RBPs in carcinogenesis and lays the groundwork to better understand the functions and mechanisms of RBPs in cancer., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Nicotine craving and relapse often occurs after reactivation of nicotine reward memories. We recently developed a memory retrieval-reconsolidation interference procedure in which reactivating nicotine reward memories by acute exposure to nicotine (the unconditioned stimulus [UCS]) and then pharmacologically interfering with memory reconsolidation decreased relapse to nicotine seeking in rats and nicotine craving in smokers. Here, we investigated underlying mechanisms., Methods: In the first series of experiments, we trained rats for nicotine-induced conditioned place preference (CPP) or nicotine self-administration and ventricularly microinjected them with the protein synthesis inhibitor anisomycin immediately after UCS-induced memory retrieval. In the second series of experiments, we used tyramide-amplified immunohistochemistry-fluorescence in situ hybridization to examine neural ensembles in the basolateral amygdala (BLA) reactivated by nicotine conditioned stimulus- or UCS-induced memory retrieval. We then used the Daun02 chemogenetic inactivation procedure to selectively inhibit the nicotine UCS-reactivated BLA neuronal ensembles., Results: Ventricular injections of the anisomycin immediately after nicotine UCS memory retrieval inhibited subsequent nicotine CPP and relapse to operant nicotine seeking after short or prolonged abstinence. More important, within BLA, distinct neuronal ensembles encoded pavlovian CPP and operant self-administration reward memories and nicotine (the UCS) injections in the home cage reactivated both neuronal ensembles. Daun02 chemogenetic inactivation of the nicotine-reactivated ensembles inhibited both nicotine CPP and relapse to nicotine seeking., Conclusions: Results demonstrate that the nicotine UCS-induced memory retrieval manipulation reactivates multiple nicotine reward memories that are encoded by distinct BLA neuronal ensembles that play a role in nicotine preference and relapse., (Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: To understand the antiretroviral treatment (ART) discontinuation rate and its influencing factors among HIV infected patients who initiated ART between 2012 and 2015 in Wenshan prefecture, Yunnan province. Methods: Demographic characteristics, baseline informations of ART, initial treatment regimens and follow-up status of a total of 4 354 patients who initiated ART from 2012 to 2015 in Wenshan prefecture were collected. A historical cohort study was used to describe the discontinuation incidence rate of ART. Life table was used to estimate cumulative retention rate and Cox proportional hazard model was used to determine the influencing factors of ART discontinuation. Results: The percentage and incidence rate of discontinuation were 25.1% (1 092/4 354) and 14.53 per 100 person-years among patients who initiated ART from 2012 to 2015 in Wenshan prefecture. ART retention rates were 88%, 83%, 78%, 74% at 6(th) month, 12(th) month, 18(th) month, 24(th) month, respectively. The multivariate Cox proportional hazard regression model showed that male patients were at a higher risk of discontinuation ( HR =1.24, 95% CI: 1.09-1.41) than female patients, patients aged ≥50 years were at a higher risk of discontinuation ( HR =1.27, 95% CI: 1.06-1.53) than patients aged<30 years, discontinuation hazard among patients who were unmarried or divorced or widowed was 1.30 times ( HR :1.30, 95% CI: 1.14-1.48) as patients who were married or cohabitation, discontinuation hazard among patients infected with HIV through injection drug use (IDU) was 1.49 times ( HR :1.49, 95% CI: 1.23-1.82) as those infected through heterosexual transmission, patients with a baseline CD4 cell count < 350/μl ( HR =1.34, 95% CI: 1.13-1.58) or ≥500/μl ( HR =1.36, 95% CI: 1.09-1.71) were at a higher risk of discontinuation than those with a baseline CD4 cell count from 350/μl to 500/μl, patients initiating ART in 2014 ( HR =1.25, 95% CI: 1.04-1.50) or in 2015 ( HR =1.26, 95% CI: 1.02-1.55) were at a higher risk of discontinuation than those initiating ART in 2012. Conclusion: There is an uptrend for ART discontinuation rate in Wenshan prefecture. Male, 50 years or older, unmarried or divorced or widowed, transmission route as IDU, baseline CD4 count < 350/μl or ≥500/μl are risk factors of ART discontinuation.

The risk of incident prediabetes with gain in waist circumference (WC) has not been addressed among Chinese adults. A total of 7951 participants who underwent health check-ups at the Beijing Physical Examination Center and Beijing Xiaotangshan hospital were recruited in 2009 and followed up in 2016. Participants were classified into four groups according to categories of percent WC gain: ≤-2.5%, -2.5-2.5%, 2.5-5%, and >5%. The effect of WC gain on prediabetes was evaluated using modified Poisson regression models. Over seven years of follow-up, we identified 1034 prediabetes cases (413 women). Compared with a WC gain of ≤-2.5%, participants with a WC gain of >5% have a higher risk of prediabetes, be they male (non-abdominal obesity at baseline group: RR = 1.57, 95% CI: 1.10-2.24, abdominal obesity at baseline group: RR = 1.66, 95% CI: 1.20-2.30) or female (non-abdominal obesity at baseline group: RR = 1.74, 95% CI: 1.14-2.64, abdominal obesity at baseline group: RR = 2.47, 95% CI: 1.43-4.28). In conclusion, the risk of prediabetes increased significantly with increasing WC for both genders in the Chinese population. Lifestyle interventions aiming at preventing abdominal obesity are urgently needed to reduce the increasing burden of prediabetes, diabetes, and its complications., Competing Interests: The authors declare no conflict of interest.

Bullous pemphigoid is a common autoimmune blistering disease of the elderly associated with autoantibody-mediated complement activation, and complement dysregulation is critical for its pathogenesis. As a crucial regulator of the complement system, CD55 has been widely studied in autoimmune diseases. Here, we investigated the involvement of CD55 in bullous pemphigoid, as little is known regarding its role in this disease. We found that CD55 levels were significantly lower in the lesions of patients with bullous pemphigoid (n = 8) compared to those in skin samples from healthy controls (n = 6). Interestingly, CD55 depletion in HaCaT human keratinocytes enhanced autoantibody-mediated complement activation. Moreover, complement activation was blocked by exogenous recombinant CD55 protein in both skin sections and keratinocytes exposed to pathogenic antibodies from patients with bullous pemphigoid. Notably, a significant increase in the expression of TNF-α and IFN-γ, administration of which downregulated CD55 levels in HaCaT cells, was observed in the sera of patients with bullous pemphigoid (n = 38) compared to that in healthy controls (n = 19). We found that ERK1/2 is involved in both TNF-α- and IFN-γ-induced CD55 downregulation. Thus, CD55 deficiency is a crucial factor in bullous pemphigoid pathogenesis, suggesting that increasing CD55 levels may exert a therapeutic effect., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

Exposure to drug-paired cues causes drug memories to be in a destabilized state and interfering with memory reconsolidation can inhibit relapse. Calpain, a calcium-dependent neutral cysteine protease, is involved in synaptic plasticity and the formation of long-term fear memory. However, the role of calpain in the reconsolidation of drug reward memory is still unknown. In the present study, using a conditioned place preference (CPP) model, we found that exposure to drug-paired contextual stimuli induced the activation of calpain and decreased the expression of glutamate receptor interacting protein 1 (GRIP1) in the nucleus accumbens (NAc) core, but not shell, of male rats. Infusions of calpain inhibitors in the NAc core immediately after retrieval disrupted the reconsolidation of cocaine/morphine cue memory and blocked retrieval-induced calpain activation and GRIP1 degradation. The suppressive effect of calpain inhibitors on the expression of drug-induced CPP lasted for at least 14 d. The inhibition of calpain without retrieval 6 h after retrieval or after exposure to an unpaired context had no effects on the expression of reward memory. Calpain inhibition after retrieval also decreased cocaine seeking in a self-administration model and this effect did not recover spontaneously after 28 d. Moreover, the knock-down of GRIP1 expression in the NAc core by lentivirus-mediated short-hairpin RNA blocked disruption of the reconsolidation of drug cue memories that was induced by calpain inhibitor treatment. These results suggest that calpain activity in the NAc core is crucial for the reconsolidation of drug reward memory via the regulation of GRIP1 expression. SIGNIFICANCE STATEMENT Calpain plays an important role in synaptic plasticity and long-term memory consolidation, however, its role in the reconsolidation of drug cue memory remains unknown. Using conditioned place preference and self-administration procedures, we found that exposure to drug-paired cues induced the activation of calpain and decreased glutamate receptor interacting protein 1 (GRIP1) expression in the nucleus accumbens (NAc) core. The inhibition of calpain activity in the NAc core immediately after retrieval disrupted the reconsolidation of cocaine/morphine cue memory that was blocked by prior GRIP1 knock-down. Our findings indicate that calpain-GRIP signaling is essential for the restabilization process that is associated with drug cue memory and the inhibition of calpain activity may be a novel strategy for the prevention of drug relapse., (Copyright © 2017 the authors 0270-6474/17/378938-14$15.00/0.)

The inability to successfully adapt to stress produces pathological changes that can lead to depression. Molecular hydrogen has anti-oxidative and anti-inflammatory activities and neuroprotective effects. However, the potential role of molecular hydrogen in stress-related disorders is still poorly understood. The present study aims to investigate the effects of hydrogen gas on resilience to stress in mice. The results showed that repeated inhalation of hydrogen-oxygen mixed gas [67%:33% (V/V)] significantly decreased both the acute and chronic stress-induced depressive- and anxiety-like behaviors of mice, assessed by tail suspension test (TST), forced swimming test (FST), novelty suppressed feeding (NSF) test, and open field test (OFT). ELISA analyses showed that inhalation of hydrogen-oxygen mixed gas blocked CMS-induced increase in the serum levels of corticosterone, adrenocorticotropic hormone, interleukin-6, and tumor necrosis factor-α in mice exposed to chronic mild stress. Finally, inhalation of hydrogen gas in adolescence significantly increased the resilience to acute stress in early adulthood, which illustrates the long-lasting effects of hydrogen on stress resilience in mice. This was likely mediated by inhibiting the hypothalamic-pituitary-adrenal axis and inflammatory responses to stress. These results warrant further exploration for developing molecular hydrogen as a novel strategy to prevent the occurrence of stress-related disorders.

Aims: Oxidative stress contributes to the development of cardiac hypertrophy and heart failure. One of the mitochondrial sirtuins, Sirt4, is highly expressed in the heart, but its function remains unknown. The aim of the present study was to investigate the role of Sirt4 in the pathogenesis of pathological cardiac hypertrophy and the molecular mechanism by which Sirt4 regulates mitochondrial oxidative stress., Methods and Results: Male C57BL/6 Sirt4 knockout mice, transgenic (Tg) mice exhibiting cardiac-specific overexpression of Sirt4 (Sirt4-Tg) and their respective controls were treated with angiotensin II (Ang II, 1.1 mg/kg/day). At 4 weeks, hypertrophic growth of cardiomyocytes, fibrosis and cardiac function were analysed. Sirt4 deficiency conferred resistance to Ang II infusion by significantly suppressing hypertrophic growth, and the deposition of fibrosis. In Sirt4-Tg mice, aggravated hypertrophy and reduced cardiac function were observed compared with non-Tg mice following Ang II treatment. Mechanistically, Sirt4 inhibited the binding of manganese superoxide dismutase (MnSOD) to Sirt3, another member of the mitochondrial sirtuins, and increased MnSOD acetylation levels to reduce its activity, resulting in elevated reactive oxygen species (ROS) accumulation upon Ang II stimulation. Furthermore, inhibition of ROS with manganese 5, 10, 15, 20-tetrakis-(4-benzoic acid) porphyrin, a mimetic of SOD, blocked the Sirt4-mediated aggravation of the hypertrophic response in Ang II-treated Sirt4-Tg mice., Conclusions: Sirt4 promotes hypertrophic growth, the generation of fibrosis and cardiac dysfunction by increasing ROS levels upon pathological stimulation. These findings reveal a role of Sirt4 in pathological cardiac hypertrophy, providing a new potential therapeutic strategy for this disease., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Objectives: To determine the value of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in diagnosing lung or mediastinal lymph node cancer and tuberculosis., Methods: Clinical and pathological data of 553 patients who underwent EBUS-TBNA from January 2013 to September 2016 in West China Hospital of Sichuan University were reviewed. The sensitivity, specificity and accuracy of EBUS-TBNA for diagnosing lymph node tumor and tuberculosis of hilar and mediastinal lymph nodes were calculated., Results: The sensitivity, specificity and accuracy of EBUS-TBNA in diagnosing hilar and mediastinal lymph node cancer were 89.2% (263/295), 100% (247/247) and 94.1% (510/542), respectively, compared with 70% (76/117), 97.2% (385/396) and 89.9% (461/513), respectively, for diagnosing tuberculosis identified though granulomatous biopsy. In the 102 cases with acid fast staining and TB-PCR, 63.7% accuracy (58/91), 90.9% (10/11) sensitivity and 66.7% (68/102) specificity were found for any positive findings from acid fast bacilli or TB-DNA., Conclusions: EBUS-TBNA has high sensitivity and specificity for diagnosing hilar and mediastinal tumor, which can be used in combination with acid fast staining and TB-PCR for diagnosing tuberculosis.

Relapse to drug seeking can be caused by exposure to drug-associated cues, provoking drug craving even after prolonged abstinence. Recent studies demonstrated that AMP-activated protein kinase (AMPK) regulates neuronal morphology and membrane excitability in neurons. Here, we investigated the role of AMPK activity in the nucleus accumbens (NAc) in relapse to cocaine seeking. We found that exposure to drug-related cues reinstated cocaine-seeking behavior and increased AMPK and p70s6k phosphorylation in the NAc core but not shell. Augmenting AMPK activity by intra-NAc core infusions of the AMPK activator 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide (AICAR) or adenovirus expressing constitutively active subunits of AMPK decreased cue-induced reinstatement of cocaine seeking and inhibited the mammalian target of rapamycin complex 1 (mTORC1) and extracellular signal-regulated kinase 1/2 (ERK1/2) pathways. In contrast, inhibition of AMPK activity by intra-NAc core infusions of the AMPK inhibitor compound C or adenovirus expressing dominant-negative subunits of AMPK increased cue-induced reinstatement of cocaine seeking and enhanced mTORC1 and ERK1/2 activity. The regulation of AMPK activity in the NAc shell had no effect on cue-induced cocaine seeking. Altogether, these results indicate that AMPK activity in the NAc core is critical for the cue-induced reinstatement of cocaine seeking, which may be mediated by mTORC1 and ERK1/2 signaling.

Objective: To clarify the role of cytochrome P450 in nonalcoholic fatty liver disease (NAFLD) by RNA-Seq and bioinformatics analysis. Methods: A total of 20 male C57BL/6 mice were used. Ten mice were fed with high-fat diet (D12492, 60% kcal fat) for 16 weeks to establish a mouse model of NAFLD, and the other 10 mice were fed with low-fat diet (D12450B, 10% kcal fat) as control group. At the end of the experiment, the body weight, liver weight, and hepatic triglyceride (TG) content were measured. Meanwhile, HE staining and RNA-Seq analysis were performed for the liver tissues. The differentially expressed genes were screened out and subjected to bioinformatics analysis, including KEGG and GO BP enrichment analyses and interaction network analysis. Comparison of means between the two groups was made using t-test. Results: Compared with the control group, the mice in the model group were obviously obese, with significantly increased body weight (41.41 ± 6.01 g vs 28.78 ± 1.79 g, t = 6.04, P < 0.01) and liver weight (1.38 ± 0.30 g vs 1.08 ± 0.10 g, t = 2.89, P < 0.01). The mice in the model group showed obvious steatosis, accompanied by a small amount of inflammatory cell infiltration, but with no obvious fibrosis, according to the results of HE staining. In addition, the hepatic TG content in the model group was significantly increased compared with that in the control group (0.64 ± 0.01 mg/mg vs 0.29 ± 0.06 mg/mg, t = 10.11, P = 0.04). Compared with the control group, a total of 367 differentially expressed genes, including 211 down-regulated and 156 up-regulated ones, were identified in the model group according to the RNA-seq results. Meanwhile, 19 CYP450 subtypes, accounting for 5% of the differentially expressed genes, were identified, and CYP2E1, CYP2C70, CYP3A11, CYP3A25, CYP2D26, CYP4A10, CYP17A1, CYP2B10, and CYP2C38 were involved in oxidative stress, steroid hormone metabolism, fatty acid metabolism, arachidonic acid metabolism, and the PPAR signaling pathway. An interaction network was constructed with 30 nodes, and CYP2E1 and CYP2C70 were identified as key nodes. RT-PCR validation results showed that the expression changes of CYP450 subtypes and lipid metabolism-related genes were consistent with the findings of sequencing. Conclusion: The CYP450 family plays a vital role in the pathogenesis of fatty liver by regulating lipid metabolism-related pathways, including oxidative stress, arachidonic acid metabolism, steroid hormone metabolism , and fatty acid metabolism.

To provide scientific basis for reasonable application of nitrogen and create varieties with high N use-efficiency, an experiment was carried out to study the effects of nitrogen fertilizer application rate on grain yield, N use rate and quality of different rice varieties. Four different genotypic rice varieties, Nipponbare, N70, N178 and OM052 were used as tested material and three levels of nitrogen application rate (0, 120, 270 kg·hm -2 ) were conducted. Urea as nitrogen source was applied as basal (70%) and panicle (30%) fertilizer. The results showed that nitrogen fertilizer could raise yield mainly because of the increased effective panicles and filled grains per panicle. When the N application rate was 120 and 270 kg·hm -2 , OM052 had the largest grain yield among four varieties, being 41.1% and 76.8% higher, respectively compared with control. Difference in grain yield among four varieties was due to the difference of nitrogen use efficiency. Under 120 and 270 kg·hm -2 nitrogen levels, Nipponbare had the lowest grain yield and N agronomic efficiency (NAE, 40.90 g·g -1 and 18.56 g·g -1 ), which was a variety with low N use-efficiency. On the contrary, OM052 had the highest grain yield and NAE (145.9 g·g -1 and 81.24 g·g -1 ), was a variety with high N use-efficiency. N fertilizer application increased the amylose content and protein content, lengthened gel consistency, reduced chalky kernel, chalkiness, and alkali digestion value. With the increase of N fertilizer application, hot paste viscosity, peak viscosity, consistence viscosity and breakdown viscosity were decreased gradually, and setback viscosity was increased. Correlation analysis showed that the yield and yield components had more significant correlations with appearance quality, cooking and eating quality under low N level. This study confirmed that OM052 was a double high variety with extremely high N agronomic efficiency and yield. Reasonable application of nitrogen fertilizer could significantly increase effective panicles and filled grains per panicle, improve rice quality, and ensure high yield and superior quality simultaneously.

Importance: A relapse into nicotine addiction during abstinence often occurs after the reactivation of nicotine reward memories, either by acute exposure to nicotine (a smoking episode) or by smoking-associated conditioned stimuli (CS). Preclinical studies suggest that drug reward memories can undergo memory reconsolidation after being reactivated, during which they can be weakened or erased by pharmacological or behavioral manipulations. However, translational clinical studies using CS-induced memory retrieval-reconsolidation procedures to decrease drug craving reported inconsistent results., Objective: To develop and test an unconditioned stimulus (UCS)-induced retrieval-reconsolidation procedure to decrease nicotine craving among people who smoke., Design, Setting, and Participants: A translational rat study and human study in an academic outpatient medical center among 96 male smokers (aged 18- 45 years) to determine the association of propranolol administration within the time window of memory reconsolidation (after retrieval of the nicotine-associated memories by nicotine UCS exposure) with relapse to nicotine-conditioned place preference (CPP) and operant nicotine seeking in rats, and measures of preference to nicotine-associated CS and nicotine craving among people who smoke., Intervention: The study rats were injected noncontingently with the UCS (nicotine 0.15 mg/kg, subcutaneous) in their home cage, and the human study participants administered a dose of propranolol (40 mg, per os; Zhongnuo Pharma)., Main Outcomes and Measures: Nicotine CPP and operant nicotine seeking in rats, and preference and craving ratings for newly learned and preexisting real-life nicotine-associated CS among people who smoke., Results: Sixty-nine male smokers completed the experiment and were included for statistical analysis: 24 in the group that received placebo plus 1 hour plus UCS, 23 who received propranolol plus 1 hour plus UCS, and 22 who received UCS plus 6 hours plus propranolol. In rat relapse models, propranolol injections administered immediately after nicotine UCS-induced memory retrieval inhibited subsequent nicotine CPP and operant nicotine seeking after short (CPP, d = 1.72, 95% CI, 0.63-2.77; operant seeking, d = 1.61, 95% CI, 0.59-2.60) or prolonged abstinence (CPP, d = 1.46, 95% CI, 0.42-2.47; operant seeking: d = 1.69, 95% CI, 0.66-2.69), as well as nicotine priming-induced reinstatement of nicotine CPP (d = 1.28, 95% CI, 0.27-2.26) and operant nicotine seeking (d = 1.61, 95% CI, 0.59-2.60) after extinction. Among the smokers, oral propranolol administered prior to nicotine UCS-induced memory retrieval decreased subsequent nicotine preference induced by newly learned nicotine CS (CS1, Cohen d = 0.61, 95% CI, 0.02-1.19 and CS2, d = 0.69, 95% CI, 0.10-1.28, respectively), preexisting nicotine CS (d = 0.57, 95% CI, -0.02 to 1.15), and nicotine priming (CS1, d = 0.82, 95% CI, 0.22-1.41 and CS2, d = 0.78, 95% CI, 0.18-1.37, respectively; preexisting nicotine CS, d = 0.92, 95% CI, 0.31-1.52), as well as nicotine craving induced by the preexisting nicotine CS (d = 0.64, 95% CI, 0.05-1.22), and nicotine priming (d = 1.15, 95% CI, 0.52-1.76)., Conclusions and Relevance: In rat-to-human translational study, a novel UCS-induced memory retrieval-reconsolidation interference procedure inhibited nicotine craving induced by exposure to diverse nicotine-associated CS and nicotine itself. This procedure should be studied further in clinical trials.

Objective: To explore the relationship between variation of hemoglobin saturation and related respiratory events in patients with obstructive sleep apnea and hypopnea syndrome (OSAHS). Method: According to the SaO₂, the respiratory events were divided into two groups, followed or not followed the second events (SRE and N-SRE). Four features were extracted from SaO₂ and compared within groups under SRE versus N-SRE, and comparisons were also developed between moderate patients and severe patients. Result: ΔSaO₂, max, the duration and Dvmax was significantly higher in SRE than N-SRE ( P < 0.01), while Nadir was significantly lower in SRE than N-SRE ( P < 0.01). There was also significant difference in the blood oxygen index between moderate and severe patients. The change of SaO₂ is correlated with the ventilation restoration. The results also suggest that the severity of the patient's condition will affect the change of SaO₂ related indicators. Conclusion: This study provides information on the further study of ventilation restoration. Moreover, this study may provide a possible solution for the treatment of OSAHS., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Editorial Department of Journal of Clinical Otorhinolaryngology Head and Neck Surgery.)

Neuropeptides play important roles in modulating the rewarding value of abused drugs. Trefoil factor 3 (TFF3) was recently reported to modulate withdrawal syndrome of morphine, but the effects of TFF3 on the cocaine-induced behavioral changes are still elusive. In the present study, cocaine-induced hyperlocomotion and conditioned place preference (CPP) rat paradigms were provided to investigate the role of TFF3 in the reward response to cocaine. High-performance liquid chromatography (HPLC) analysis was used to analyse the dopamine concentration. The results showed that systemic TFF3 administration (0.1 mg/kg i.p.) significantly augmented cocaine- induced hyperlocomotion and CPP formation, without any effects on locomotor activity and aversive or rewarding effects per se. TFF3 significantly augmented the increment of the dopamine concentration in the NAc and the activity of the mTOR signalling pathway induced by acute cocaine exposure (10 mg/kg, i.p.) in the NAc shell, but not the core. The Intra-NAc shell infusion of rapamycin blocked TFF3-induced hyperactivity in cocaine-treatment rats. These findings indicated that TFF3 could potentiate behavioural response to cocaine, which may be associated with regulating dopamine concentration. Furthermore, the findings indicated that mTOR signalling pathway in the NAc shell is important for TFF3-induced enhancement on the cocaine-induced behavioral changes.

Background: Longitudinal associations between triglycerides (TG) and other metabolic syndrome (MetS) components have rarely been reported. The purpose was to investigate the longitudinal association between TG and other MetS components with time., Methods: The longitudinal study was established in 2007 on individuals who attended health check-ups at Beijing Tongren Hospital and Beijing Xiaotangshan Hospital. Data used in this study was based on 7489 participants who had at least three health check-ups over a period of 5-year follow up. Joint model was used to explore longitudinal associations between TG and other MetS components after adjusted for age., Results: There were positive correlations between TG and other MetS components except for high density lipoprotein (HDL), and the correlations increased with time. A negative correlation was displayed between TG and HDL, and the correlation also increased with time. Among all five pairs of TG and other MetS components, the marginal correlation between TG and body mass index (BMI) was the largest for both men and women. The marginal correlation between TG and fasting plasma glucose was the smallest for men, while the marginal correlation between TG and diastolic blood pressure was the smallest for women., Conclusions: The longitudinal association between TG and other MetS components increased with time. Among five pairs of TG and other MetS components, the longitudinal correlation between TG and BMI was the largest. It is important to closely monitor subjects with high levels of TG and BMI in health check-up population especially for women, because these two components are closely associated with development of hypertension, diabetes, cardiovascular disease and other metabolic diseases.

Background: Currently, the majority cases of the novel down-to-up transanal total mesorectal excision (TaTME) were performed in a hybrid approach with conventional laparoscopic assistance because of less operative difficulty. However, although cases are limited, the successes of TaTME in a pure approach (without laparoscopic assistance) indicate that the costly and less mini-invasive hybrid TaTME could be potentially avoided., Methods: In the present single institutional, prospective study, we attempted to demonstrate the safety and feasibility of this approach in rectal cancer by evaluating the short-term results of our first 20 TaTME cases. For the majority of cases, we adopted a strategy that laparoscopic assistance was not introduced unless it was required during the planned pure TaTME procedure., Results: A total of 20 patients (12 males and 8 females) were analyzed in this study, including 11 cases (55 %) of pure TaTME and 9 cases (45 %) of hybrid TaTME. Overall, the median operative time was 200 min (range 70-420), along with a median estimated blood loss of 50 ml (range 20-800). Morbidity rate was 20 % (one urethral injury, two urinary retentions, one anastomotic hemorrhage and one mild anastomotic leak). The median number of harvested lymph nodes was 12 (range 1-20). All specimens were intact in mesorectum without positive distal and circumferential resection margins. Among the 15 patients who were preoperatively scheduled to undertake pure TaTME, four patients (26.7 %) required converting to laparoscopic assistance. Moreover, among these 15 patients, the results of the comparative analysis between female and male subgroups favor the former, suggesting easier operation in them., Conclusion: This preliminary study demonstrates that TaTME in rectal cancer is safe and feasible. The strategy of not introducing laparoscopic assistance unless it is required while performing the planned pTaTME should be cautiously explored. Further studies with larger sample size and longer follow-up are warranted.

The mechanism by which MORPHEUS' MOLECULE1 (MOM1) contributes to transcriptional gene silencing has remained elusive since the gene was first identified and characterized. Here, we report that two Arabidopsis thaliana PIAS (PROTEIN INHIBITOR OF ACTIVATED STAT)-type SUMO E3 ligase-like proteins, PIAL1 and PIAL2, function redundantly to mediate transcriptional silencing at MOM1 target loci. PIAL1 and PIAL2 physically interact with each other and with MOM1 to form a high molecular mass complex. In the absence of either PIAL2 or MOM1, the formation of the high molecular mass complex is disrupted. We identified a previously uncharacterized IND (interacting domain) in PIAL1 and PIAL2 and demonstrated that IND directly interacts with MOM1. The CMM2 (conserved MOM1 motif 2) domain of MOM1 was previously shown to be required for the dimerization of MOM1. We demonstrated that the CMM2 domain is also required for the interaction of MOM1 with PIAL1 and PIAL2. We found that although PIAL2 has SUMO E3 ligase activity, the activity is dispensable for PIAL2's function in transcriptional silencing. This study suggests that PIAL1 and PIAl2 act as components of the MOM1-containing complex to mediate transcriptional silencing at heterochromatin regions., (© 2016 American Society of Plant Biologists. All rights reserved.)

The axon guidance factor netrin-1 promotes tumorigenesis in multiple types of cancers, particularly at their advanced stages. Here, we investigate whether netrin-1 is involved in the in vivo growth of pancreatic adenocarcinoma. We show that netrin-1 is significantly under-expressed in stage-I/II pancreatic ductal adenocarcinoma (PDAC). Netrin-1 over-expression effectively arrests the growth of xenografted PDAC cells without decreasing cell proliferation or increasing apoptosis in two-dimensional cultures in vitro. Integrin-beta4 (ITGB4) expression is significantly reduced, and ITGB4-knockdown mimics the tumor-suppressive effect of netrin-1, implying that ITGB4 is a main target of netrin-1 in constraining PDAC. We further show that netrin-1 signals to UNC5B/FAK to stimulate nitric oxide production, which promotes PP2A-mediated inhibition of the MEK/ERK pathway and decreases phosphorylated-c-Jun recruitment to the ITGB4 promoter. Our findings suggest that netrin-1 can suppress the growth of PDAC and provide a mechanistic insight into this suppression., Competing Interests: The authors declare that they have no conflicts of interest.

Background: Several studies suggested that hypertension is positively related to cancer incidence and mortality. In this study, we investigated the association between perioperative blood pressure (BP) and long-term survival outcomes in patients with rectal cancer., Methods: This study included a cohort of 358 patients with stages I-III rectal cancer who underwent a curative resection between June 2007 and June 2011. Both pre- and postoperative BPs were measured, by which patients were grouped (low BP: <120/80 mmHg; high BP: ≥120/80 mmHg). The survival outcomes were compared between these two groups. The primary endpoints were disease-free survival (DFS) and cancer-specific survival (CSS)., Results: Univariate analysis showed that patients with high preoperative systolic BP had lower 3-year DFS (67.2% vs. 82.1%, P = 0.041) and CSS rates (81.9% vs. 94.8%, P = 0.003) than patients with low preoperative systolic BP, and the associations remained significant in the Cox multivariate analysis, with the adjusted hazard ratios equal to 1.97 [95% confidence interval (CI) = 1.08-3.60, P = 0.028] and 2.85 (95% CI = 1.00-8.25, P = 0.050), respectively. Similarly, in postoperative evaluation, patients with high systolic BP had significantly lower 3-year CSS rates than those with low systolic BP (78.3% vs. 88.9%, P = 0.032) in univariate analysis. Moreover, high pre- and/or postoperative systolic BP presented as risk factors for CSS in the subgroups of patients who did not have a history of hypertension, with and/or without perioperative administration of antihypertensive drugs., Conclusions: High preoperative systolic BP was an independent risk factor for both CSS and DFS rates, and high postoperative systolic BP was significantly associated with a low CSS rate in rectal cancer patients. Additionally, our results suggest that rectal cancer patients may get survival benefit from BP control in perioperative care. However, further studies should be conducted to determine the association between BP and CSS and targets of BP control.