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Xanthine oxidase (XO) is a key enzyme in the generation and development of hyperuricemia. Thiazolidine-2-thione, a typical heterocyclic compound, have been widely used in the field of drug synthesis. In this study, a series of novel thiazolidine-2-thione derivatives were synthesized as XO inhibitors, and the XO inhibitory potencies of obtained compounds were evaluated by in vitro enzyme catalysis. The result shown that compound 6k behaved the strongest XO inhibitory activity with an IC50 value of 3.56 μmol/L, which was approximately 2.5-fold more potent than allopurinol. The structure-activity relationship revealed that the phenyl-sulfonamide group was indispensable for thiazolidine-2-thione derivatives to produce XO inhibitory activity. The enzyme inhibition kinetics analyses confirmed that compound 6k exerted a mixed-type XO inhibition. Additionally, the molecular docking results suggested that the 4-fluorophenyl-sulfonyl moiety could interact with Gly260 and Ile264 in the innermost part of the active pocket through 2 hydrogen bonds, while the thiazolidinethione moiety could form two hydrogen bonds with Glu263 and Ser347 in hydrophobic pockets. In summary, the results described above suggested that compound 6k could be a valuable lead compound for the treatment of hyperuricemia as a novel XO inhibitor.

Sugarcane (Saccharum spp.) is an important economic crop, supplying up to 80% of the table sugar and ~60% of bio-ethanol worldwide. Due to population growth and dwindling fossil-fuel reserves, the demand for sugar and bio-ethanol requires significant improvement in sugarcane production. Breeding sugarcane cultivars with high-performance agronomic traits is undoubtedly the most efficient way to achieve this goal. Therefore, evaluating agronomic traits and dissecting underlying loci are critically important for this aim steps in providing genetic resources and molecular markers for selection. In this study, we assembled a diversity panel of 236 elite sugarcane germplasms originally collected from 12 countries. We evaluated 28 agronomic traits in the diversity panel with three replicates. The diversity panel was genotyped using amplified fragment length polymorphism markers, and a total of 1,359 markers were generated. Through the genome-wide association study, we identified three markers significantly associated with three traits evaluated at a stringent threshold (P < 0.05 after Bonferroni correction). The genotypes of the three associated markers grouped respective trait values into two distinct groups, supporting the reliability of these markers for breeding selection. Our study provides putative molecular markers linked to agronomic traits for breeding robust sugarcane cultivars. Additionally, this study emphasized the importance of sugarcane germplasm introduced from other countries and suggested that the use of these germplasms in breeding programs depends on local industrial needs.

Accumulated data suggests that cerebral microbleeds (CMBs) play an important role in the decline of cognitive function, but the results remain inconsistent. In the current study, we aimed to investigate the association between CMBs and cognitive function, as well as the various effects of CMBs on different domains of cognition.We searched through the databases of PubMed, Embase, Cochrane Library, and ScienceDirect. After a consistency test, the publication bias was evaluated and a sensitivity analysis was performed with combined odds ratios (OR) and standardized mean difference (SMD) of CMBs.A meta-analysis of 25 studies with 9343 participants total was conducted. Patients with CMBs had higher incidence of cognitive impairment (OR:3.5410; 95% confidence interval [CI] [2.2979, 5.4567], p

Hepatocellular carcinoma (HCC) is one of the most prevalent and life-threatening malignancies worldwide. There are few diagnostic and prognostic biomarkers and druggable targets for HCC. Aldehyde dehydrogenase 1 (ALDH1) is a marker of stem cells in a variety of cancers, but the mRNA levels and prognostic value of ALDH1 isoforms in HCC patients remain unknown. In the present study, gene ontology annotation of the ALDH1 family was performed using the Database for Annotation, Visualization and Integrated Discovery (DAVID), and the gene pathway analsis was performed using GeneMANIA software. The initial prognostic value of ALDH1 expression in 360 HCC patients was assessed using the OncoLnc database. The expression levels of ALDH1 isoforms in normal liver tissues and clinical specimens of cancer vs. normal control datasets were determined using the GTEx and Oncomine databases, respectively. We then analyzed the prognostic value of ALDH1 expression in 212 hepatitis B virus (HBV)-related HCC patients using the GEO database. We found that the ALDH1 isoform showed high aldehyde dehydrogenase activity. The ALDH1A1, ALDH1B1, and ALDH1L1 genes encoded for the ALDH1 enzyme. High ALDH1B1 expression had protective qualities in HCC patients. Moreover, HBV-related HCC patients who showed high ALDH1L1 gene expression had a better clinical outcomes. In addition, high ALDH1A1 expression was associated with a 57-month recurrence-free survival in HBV-related HCC patients. High ALDH1B1 expression was protective for HCCs with multiple nodules and high serum alpha-fetoprotein (AFP) level. Furthermore, high serum AFP levels contributed to lower ALDH1L1. ALDH1A1, ALDH1B1, and ALDH1L1, all of which were considered promising diagnostic and prognostic markers as well as potential drug targets.

The purpose of this study was to explore the neural mechanism in Chronic prostatitis/Chronic pelvic pain syndrome (CP/CPPS) using resting-state functional magnetic resonance imaging. The functional magnetic resonance imaging was performed on 31 male CP/CPPS-patients and 31 age and education matched male healthy controls on a 3-T magnetic resonance imaging unit. A two-sample t-test was adopted to reveal the regional homogeneity between the patients and healthy controls. The mean regional homogeneity values in the alerted brain regions of patients were correlated with the clinical measurements by using Pearson's correlation analyses. The CP/CPPS-patients had significantly decreased regional homogeneity in the bilateral anterior cingulate cortices, insular cortices and right medial prefrontal cortex, while significantly increased regional homogeneity in the brainstem and right thalamus compared with the healthy controls. In the CP/CPPS-patients, the mean regional homogeneity value in the left anterior cingulate cortex, bilateral insular cortices and brainstem were respectively correlated with the National Institutes of Health Chronic Prostatitis Symptom Index total score and pain subscale. These brain regions are important in the pain modulation process. Therefore, an impaired pain modulatory system, either by decreased descending pain inhibition or enhanced pain facilitation, may explain the pain symptoms in CP/CPPS.

Accurate and efficient detection of sleep spindles is a methodological challenge. The present study describes a method of using non-experts for manual detection of sleep spindles. We recruited five experts and 168 non-experts to manually identify spindles in stage N2 and stage N3 sleep data using a MATLAB interface. Scorers classified each spindle into definite and indefinite spindle (with weights of 1 and 0.5, respectively). First, a method of optimizing the thresholds of the expert/non-expert group consensus according to the results of experts and non-experts themselves is described. Using this method, we established expert and non-expert group standards from expert and non-expert scorers, respectively, and evaluated the performance of the non-expert group standards by compared with the expert group standard (termed EGS). The results indicated that the highest performance was the non-expert group standard when definite spindles were only considered (termed nEGS-1; F1 score = 0.78 for N2; 0.68 for N3). Second, four automatic spindle detection methods were compared with the EGS. We found that the performance of nEGS-1 versus EGS was higher than that of the four automated methods. Our results also showed positive correlation between the mean F1 score of individual expert in EGS and the F1 score of nEGS-1 versus EGS across 30 segments of stage N2 data (r = 0.61, P < 0.001). Further, we found that six and nine non-experts were needed to manually identify spindles in stages N2 and N3, respectively, while maintaining acceptable performance of nEGS-1 versus EGS (F1 score = 0.79 for N2; 0.64 for N3). In conclusion, this study establishes a detailed process for detection of sleep spindles by non-experts in a crowdsourcing scheme.

Enlarged perivascular spaces (EPVS) correlate with cognitive impairment and incident dementia. However, etiologies for severe basal ganglia EPVS (BG-EPVS) are still unclear. Our aim was to investigate the independent risk factors for severe BG-EPVS in patients with acute lacunar stroke.We prospectively identified patients with lacunar stroke (diameter on DWI ≤ 20mm) from Jan 2011 to May 2015. Patients with severe BG-EPVS were identified on T2 weighted MRI. Age (± 1 year) and sex matched controls were also recruited in the same population (two controls for one case). Vascular risk factors, clinical data, EPVS in centrum semiovale (rated 0 to 4), white matter hyperintensities (WMH) (by Fazekas scale), brain atrophy (rated 0 to 6) were compared between two groups. Logistic regression was performed to determine independent risk factors for severe BG-EPVS.During study period, 89 patients with severe BG-EPVS and 178 matched controls were included. Vascular risk factors did not differ between two groups. Patients with severe BG-EPVS had lower level of HbA1c and diastolic BP at admission, but presented with larger infarct size, more severe WMH (including total WMH, periventricular WMH and deep WMH) and brain atrophy. In logistic regression, brain atrophy (OR = 1.40; 95%CI 1.13, 1.73) and deep WMH (OR = 1.88; 95%CI 1.24, 2.83) were independent risk factors for severe BG-EPVS.Brain atrophy and deep WMH are independent risk factors for severe BG-EPVS, supporting the hypothesis that brain atrophy may be associated with the development of EPVS in basal ganglia.

Severe stroke patients have poor clinical outcome which may be associated with development of multiple organ dysfunction syndrome (MODS). Therefore, the aim of our study was to investigate independent risk factors for development of MODS in severe stroke patients.Ninety seven severe stroke patients were prospective recruited from Jan 2011 to Jun 2015. The development of MODS was identified by Sequential Organ Failure Assessment (SOFA) score (score ≥ 3, at least two organs), which was assessed on day 1, 4, 7, 10 and 14 after admission. Baseline characteristics, Acute Physiology and Chronic Health Evaluation (APACHE) II score, Glasgow coma score (GCS) and cerebral imaging parameters were collected at admission. Cox regression was performed to determine predictors for the development of MODS. Medical complications after admission and in-hospital mortality were also investigated.33 (34%) patients were in MODS group and 64 (66%) were in non-MODS group within 14 days after admission. Patients in MODS group had more smoker (51.5% vs 28.1%, p = 0.023), higher NIHSS score (23.48 ± 6.12 vs 19.81 ± 4.83, p = 0.004), higher APACHE II score (18.70 ± 5.18 vs 15.64 ± 4.36, p = 0.003) and lower GCS score (6.33 ± 2.48 vs 8.14 ± 2.73, p = 0.002). They also had higher rate of infarction in multi vascular territories (36.4% vs 10.9%, p = 0.003). The most common complication in all patients was pulmonary infection, while complication scores were comparable between two groups. Patients with MODS had higher in-hospital mortality (69.7% vs 9.4%, p = 0.000). In Cox regression, NIHSS score (RR = 1.084, 95% CI 1.019-1.153) and infarction in multi vascular territories (RR = 2.345 95% CI 1.105-4.978) were independent risk factors for development of MODS.In acute phase of stroke, NIHSS score and infarction in multi vascular territories predicted MODS in severe stroke patients. Moreover, patients with MODS had higher in-hospital mortality, suggesting that early identification of MODS is critical important.

The influence of the ventilation system on the abandoned gob weakens, so the gas seepage characteristics in the abandoned gob are significantly different from those in a normal mining gob. In connection with this, this study physically simulated the movement of overlying rock strata. A spatial distribution function for gob permeability was derived. A numerical model using FLUENT for abandoned gob methane drainage through surface wells was established, and the derived spatial distribution function for gob permeability was imported into the numerical model. The control range of surface wells, flow patterns and distribution rules for static pressure in the abandoned gob under different well locations were determined using the calculated results from the numerical model.

Evaluation of drug toxicity is necessary for drug safety, but in vivo drug absorption is varied; therefore, a rapid, sensitive and reliable method for measuring drugs is needed. Zebrafish are acceptable drug toxicity screening models; we used these animals with a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method in a multiple reaction monitoring mode to quantify drug uptake in zebrafish to better estimate drug toxicity. Analytes were recovered from zebrafish homogenate by collecting supernatant. Measurements were confirmed for drugs in the range of 10-1,000 ng/mL. Four antibiotics with different polarities were tested to explore any correlation of drug polarity, absorption, and toxicity. Zebrafish at 3 days post-fertilization (dpf) absorbed more drug than those at 6 h post-fertilization (hpf), and different developmental periods appeared to be differentially sensitive to the same compound. By observing abnormal embryos and LD50 values, zebrafish embryos at 6 hpf were considered to be suitable for evaluating embryotoxicity. Also, larvae at 3 dpf were adapted to measure acute drug toxicity in adult mammals. Thus, we can exploit zebrafish to study drug toxicity and can reliably quantify drug uptake with LC-MS/MS. This approach will be helpful for future studies of toxicology in zebrafish.

Precipitation is the only water supply and most important factor affecting vegetation growth on the slopes of semi-arid Loess Plateau of China. Based on precipitation data from 7 synoptic stations in the study area over the period 1957-2012, the trends of precipitation and standardized precipitation index (SPI) were analyzed by using linear regression, Mann-Kendall, and Spearman's Rho tests at the 5% significance level. The results show that (1) the precipitation fluctuation of monthly precipitation was intense (coefficients of variation> 100%), and the drier years were recorded as 1965 and 1995 at all stations. (2) The significant change trend of different stations varied on different time scales: the Changwu station had a significant decreasing trend in April (-0.488 mm/year) and November (-0.249 mm/year), while Luochuan station was in April (-0.457 mm/year); Changwu station displayed a significant increasing trends in winter (0.220 mm/year) and a significant decreasing trends in spring (-0.770 mm/year). The significant decreasing trends in annual precipitation were detected at the Suide (-2.034 mm/year) and Yan'an (-2.129 mm/year) stations. (3) The SPI-12 series analysis suggests that the drought degree of Yulin and Changwu was the lowest and that of Hengshan was the highest among the 7 synoptic stations.

BACKGROUND: Acupuncture has been commonly used for preventing migraine attacks and relieving pain during a migraine, although there is limited knowledge on the physiological mechanism behind this method. The objectives of this study were to compare the differences in brain activities evoked by active acupoints and inactive acupoints and to investigate the possible correlation between clinical variables and brain responses. METHODS AND RESULTS: A randomized controlled trial and resting-state functional magnetic resonance imaging (fMRI) were conducted. A total of eighty migraineurs without aura were enrolled to receive either active acupoint acupuncture or inactive acupoint acupuncture treatment for 8 weeks, and twenty patients in each group were randomly selected for the fMRI scan at the end of baseline and at the end of treatment. The neuroimaging data indicated that long-term active acupoint therapy elicited a more extensive and remarkable cerebral response compared with acupuncture at inactive acupoints. Most of the regions were involved in the pain matrix, lateral pain system, medial pain system, default mode network, and cognitive components of pain processing. Correlation analysis showed that the decrease in the visual analogue scale (VAS) was significantly related to the increased average Regional homogeneity (ReHo) values in the anterior cingulate cortex in the two groups. Moreover, the decrease in the VAS was associated with increased average ReHo values in the insula which could be detected in the active acupoint group. CONCLUSIONS: Long-term active acupoint therapy and inactive acupoint therapy have different brain activities. We postulate that acupuncture at the active acupoint might have the potential effect of regulating some disease-affected key regions and the pain circuitry for migraine, and promote establishing psychophysical pain homeostasis. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR-TRC-13003635.

Transgenic mouse models are powerful tools in exploring the mechanisms of AD. Most current transgenic models of AD mimic the memory impairment and the main pathologic features, among which the formation of beta-amyloid (Aβ) plaques is considered a dominant pathologic event. Recently, Aβ oligomers have been identified as more neurotoxic than Aβ plaques. However, no ideal transgenic mouse model directly support Aβ oligomers as a neurotoxic species due to the puzzling effects of amyloid plaques in the more widely-used models. Here, we constructed a single-mutant transgenic (Tg) model harboring the PS1V97L mutation and used Non-Tg littermates as a control group. Employing the Morris water maze, electrophysiology, immunohistochemistry, biochemistry, and electron microscopy, we investigated behavioral changes and pathology progression in our single-mutant transgenic model. We discovered the pathological alteration of intraneuronal accumulation of Aβ oligomers without Aβ plaques in the PS1V97L-Tg mouse model, which might be the result of PS1 gene mutation. Following Aβ oligomers, we detected synaptic alteration, tau hyperphosphorylation and glial activation. This model supports an initial role for Aβ oligomers in the onset of AD and suggests that Aβ plaques may not be the only prerequisite. This model provides a useful tool for studying the role of Aβ oligomers in AD pathogenesis.

Ribosome biogenesis is an important biological process for proper cellular function and development. Defects leading to improper ribosome biogenesis can cause diseases such as Diamond-Blackfan anemia and Shwachman-Bodian-Diamond syndrome. Nucleolar proteins are a large family of proteins and are involved in many cellular processes, including the regulation of ribosome biogenesis. Through a forward genetic screen and positional cloning, we identified and characterized a zebrafish line carrying mutation in nucleolar protein with MIF4G domain 1 (nom1), which encodes a conserved nulceolar protein with a role in pre-rRNA processing. Zebrafish nom1 mutants exhibit major defects in endoderm development, especially in exocrine pancreas. Further studies revealed that impaired proliferation of ptf1a-expressing pancreatic progenitor cells mainly contributed to the phenotype. RNA-seq and molecular analysis showed that ribosome biogenesis and pre-mRNA splicing were both affected in the mutant embryos. Several defects of ribosome assembly have been shown to have a p53-dependent mechanism. In the nom1 mutant, loss of p53 did not rescue the pancreatic defect, suggesting a p53-independent role. Further studies indicate that protein phosphatase 1 alpha, an interacting protein to Nom1, could partially rescue the pancreatic defect in nom1 morphants if a human nucleolar localization signal sequence was artificially added. This suggests that targeting Pp1α into the nucleolus by Nom1 is important for pancreatic proliferation. Altogether, our studies revealed a new mechanism involving Nom1 in controlling vertebrate exocrine pancreas formation.

Online gaming addiction, as the most popular subtype of Internet addiction, had gained more and more attention from the whole world. However, the structural differences in cortical thickness of the brain between adolescents with online gaming addiction and healthy controls are not well unknown; neither was its association with the impaired cognitive control ability. High-resolution magnetic resonance imaging scans from late adolescence with online gaming addiction (n = 18) and age-, education- and gender-matched controls (n = 18) were acquired. The cortical thickness measurement method was employed to investigate alterations of cortical thickness in individuals with online gaming addiction. The color-word Stroop task was employed to investigate the functional implications of the cortical thickness abnormalities. Imaging data revealed increased cortical thickness in the left precentral cortex, precuneus, middle frontal cortex, inferior temporal and middle temporal cortices in late adolescence with online gaming addiction; meanwhile, the cortical thicknesses of the left lateral orbitofrontal cortex (OFC), insula, lingual gyrus, the right postcentral gyrus, entorhinal cortex and inferior parietal cortex were decreased. Correlation analysis demonstrated that the cortical thicknesses of the left precentral cortex, precuneus and lingual gyrus correlated with duration of online gaming addiction and the cortical thickness of the OFC correlated with the impaired task performance during the color-word Stroop task in adolescents with online gaming addiction. The findings in the current study suggested that the cortical thickness abnormalities of these regions may be implicated in the underlying pathophysiology of online gaming addiction.

The majority of previous neuroimaging studies have demonstrated both structural and task-related functional abnormalities in adolescents with online gaming addiction (OGA). However, few functional magnetic resonance imaging (fMRI) studies focused on the regional intensity of spontaneous fluctuations in blood oxygen level-dependent (BOLD) during the resting state and fewer studies investigated the relationship between the abnormal resting-state properties and the impaired cognitive control ability. In the present study, we employed the amplitude of low frequency fluctuation (ALFF) method to explore the local features of spontaneous brain activity in adolescents with OGA and healthy controls during resting-state. Eighteen adolescents with OGA and 18 age-, education- and gender-matched healthy volunteers participated in this study. Compared with healthy controls, adolescents with OGA showed a significant increase in ALFF values in the left medial orbitofrontal cortex (OFC), the left precuneus, the left supplementary motor area (SMA), the right parahippocampal gyrus (PHG) and the bilateral middle cingulate cortex (MCC). The abnormalities of these regions were also detected in previous addiction studies. More importantly, we found that ALFF values of the left medial OFC and left precuneus were positively correlated with the duration of OGA in adolescents with OGA. The ALFF values of the left medial OFC were also correlated with the color-word Stroop test performance. Our results suggested that the abnormal spontaneous neuronal activity of these regions may be implicated in the underlying pathophysiology of OGA.

[This corrects the article DOI: 10.1371/journal.pone.0057864.].

BACKGROUND: Susceptibility weighted imaging (SWI) is a new MRI technique which has been proved very useful in the diagnosis of brain diseases, but few study was performed on its value in prostatic diseases. The aim of the present study was to investigate the value of SWI in distinguishing prostate cancer from benign prostatic hyperplasia and detecting prostatic calcification. METHODOLOGY/PRINCIPAL FINDINGS: 23 patients with prostate cancer and 53 patients with benign prostatic hyperplasia proved by prostate biopsy were scanned on a 3.0T MR and a 16-row CT scanner. High-resolution SWI, conventional MRI and CT were performed on all patients. The MRI and CT findings, especially SWI, were analyzed and compared. The analyses revealed that 19 out of 23 patients with prostate cancer presented hemorrhage within tumor area on SWI. However, in 53 patients with benign prostatic hyperplasia, hemorrhage was detected only in 1 patient in prostate by SWI. When comparing SWI, conventional MRI and CT in detecting prostate cancer hemorrhage, out of the 19 patients with prostate cancer who had prostatic hemorrhage detected by SWI, the prostatic hemorrhage was detected in only 7 patients by using conventional MRI, and none was detected by CT. In addition, CT demonstrated calcifications in 22 patients which were all detected by SWI whereas only 3 were detected by conventional MRI. Compared to CT, SWI showed 100% in the diagnostic sensitivity, specificity, accuracy, positive predictive value(PPV) and negative predictive value(NPV) in detecting calcifications in prostate but conventional MRI demonstrated 13.6% in sensitivity, 100% in specificity, 75% in accuracy, 100% in PPV and 74% in NPV. CONCLUSIONS: More apparent prostate hemorrhages were detected on SWI than on conventional MRI or CT. SWI may provide valuable information for the differential diagnosis between prostate cancer and prostatic hyperplasia. Filtered phase images can identify prostatic calcifications as well as CT.

BACKGROUND:Bidirectional relationship between migraine and depression suggests that there might be some etiological risk factors shared. However, few studies investigated resting state abnormalities affected by depressive symptoms in migraine patients without aura (MWoA). MATERIALS AND METHODS:According to their self-rating depression scale (SDS) score, MWoA were divided into twenty in the SDS (+) (SDS > 49) group and 20 in the SDS (-) (SDS ≤ 49) group. Regional homogeneity (ReHo) method were employed to assess local features of spontaneous brain activity between 1) all MWoA and healthy controls, 2) each subgroup and healthy controls, and 3) SDS (-) group and SDS (+) group. RESULTS:Compared with healthy controls, decreased ReHo in similar regions were shown in the MWoA group and subgroups. It is noteworthy that the caudate showed increased ReHo in the SDS (-) group compared with healthy controls and the SDS (+) group. Moreover, the average ReHo values of the caudate in SDS (-) group were significantly positively correlated with duration of migraine. CONCLUSIONS:Our results suggested that ReHo patterns in migraine patients may be affected by depressive symptoms and serve as a biomarker to reflect depression severity in MWoA.

The lack of small animal models for hepatitis C virus has impeded the discovery and development of anti-HCV drugs. HCV-IRES plays an important role in HCV gene expression, and is an attractive target for antiviral therapy. In this study, we report a zebrafish model with a biscistron expression construct that can co-transcribe GFP and HCV-core genes by human hepatic lipase promoter and zebrafish liver fatty acid binding protein enhancer. HCV core translation was designed mediated by HCV-IRES sequence and gfp was by a canonical cap-dependent mechanism. Results of fluorescence image and in situ hybridization indicate that expression of HCV core and GFP is liver-specific; RT-PCR and Western blotting show that both core and gfp expression are elevated in a time-dependent manner for both transcription and translation. It means that the HCV-IRES exerted its role in this zebrafish model. Furthermore, the liver-pathological impact associated with HCV-infection was detected by examination of gene markers and some of them were elevated, such as adiponectin receptor, heparanase, TGF-β, PDGF-α, etc. The model was used to evaluate three clinical drugs, ribavirin, IFNα-2b and vitamin B12. The results show that vitamin B12 inhibited core expression in mRNA and protein levels in dose-dependent manner, but failed to impact gfp expression. Also VB12 down-regulated some gene transcriptions involved in fat liver, liver fibrosis and HCV-associated pathological process in the larvae. It reveals that HCV-IRES responds to vitamin B12 sensitively in the zebrafish model. Ribavirin did not disturb core expression, hinting that HCV-IRES is not a target site of ribavirin. IFNα-2b was not active, which maybe resulted from its degradation in vivo for the long time. These findings demonstrate the feasibility of the zebrafish model for screening of anti-HCV drugs targeting to HCV-IRES. The zebrafish system provides a novel evidence of using zebrafish as a HCV model organism.

Increasing crop yield and water use efficiency (WUE) in dryland farming requires a quantitative understanding of relationships between crop yield and the water balance over many years. Here, we report on a long-term dryland monitoring site at the Loess Plateau, Shanxi, China, where winter wheat was grown for 30 consecutive years and soil water content (0-200 cm) was measured every 10 days. The monitoring data were used to calibrate the AquaCrop model and then to analyse the components of the water balance. There was a strong positive relationship between total available water and mean cereal yield. However, only one-third of the available water was actually used by the winter wheat for crop transpiration. The remaining two-thirds were lost by soil evaporation, of which 40 and 60% was lost during the growing and fallow seasons, respectively. Wheat yields ranged from 0.6 to 3.9 ton/ha and WUE from 0.3 to 0.9 kg/m(3). Results of model experiments suggest that minimizing soil evaporation via straw mulch or plastic film covers could potentially double wheat yields and WUE. We conclude that the relatively low wheat yields and low WUE were mainly related to (i) limited rainfall, (ii) low soil water storage during fallow season due to large soil evaporation, and (iii) poor synchronisation of the wheat growing season to the rain season. The model experiments suggest significant potential for increased yields and WUE.

Phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin inhibitor (mTOR) pathway is often constitutively activated in human tumor cells and thus has been considered as a promising drug target. To ascertain a therapeutical approach of nasopharyngeal carcinoma (NPC), we hypothesized NVP-BEZ235, a novel and potent imidazo[4,5-c] quinolone derivative, that dually inhibits both PI3K and mTOR kinases activities, had antitumor activity in NPC. Expectedly, we found that NVP-BEZ235 selectively inhibited proliferation of NPC cells rather than normal nasopharyngeal cells using MTT assay. In NPC cell lines, with the extended exposure, NVP-BEZ235 selectively inhibited proliferation of NPC cells harboring PIK3CA mutation, compared to cells with wild-type PIK3CA. Furthermore, exposure of NPC cells to NVP-BEZ235 resulted in G1 growth arrest by Propidium iodide uptake assay, reduction of cyclin D1and CDK4, and increased levels of P27 and P21 by Western blotting, but negligible apoptosis. Moreover, we found that cisplatin (CDDP) activated PI3K/AKT and mTORC1 pathways and NVP-BEZ235 alleviated the activation by CDDP through dually targeting PI3K and mTOR kinases. Also, NVP-BEZ235 combining with CDDP synergistically inhibited proliferation and induced apoptosis in NPC cells. In CNE2 and HONE1 nude mice xenograft models, orally NVP-BEZ235 efficiently attenuated tumor growth with no obvious toxicity. In combination with NVP-BEZ235 and CDDP, there was dramatic synergy in shrinking tumor volumes and inducing apoptosis through increasing Noxa, Bax and decreasing Mcl-1, Bcl-2. Based on the above results, NVP-BEZ235, which has entered phase I/II clinical trials in patients with advanced solid tumors, has a potential as a monotherapy or in combination with CDDP for NPC treatment.

BACKGROUND AND AIMS: Brain dysfunction in functional dyspepsia (FD) has been identified by multiple neuroimaging studies. This study aims to investigate the regional gray matter density (GMD) changes in meal-related FD patients and their correlations with clinical variables, and to explore the possible influence of the emotional state on FD patients's brain structures. METHODS: Fifty meal-related FD patients and forty healthy subjects (HS) were included and underwent a structural magnetic resonance imaging scan. Voxel-based morphometry analysis was employed to identify the cerebral structure alterations in meal-related FD patients. Regional GMD changes' correlations with the symptoms and their durations, respectively, have been analyzed. RESULTS: Compared to the HS, the meal-related FD patients showed a decreased GMD in the bilateral precentral gyrus, medial prefrontal cortex (MPFC), anterior cingulate cortex (ACC) and midcingulate cortex (MCC), left orbitofrontal cortex (OFC) and right insula (p50). After controlling for anxiety and depression, the meal-related FD patients showed a decreased GMD in the bilateral middle frontal gyrus, left MCC, right precentral gyrus and insula (p50). Before controlling psychological factors, the GMD decreases in the ACC were negatively associated with the symptom scores of the Nepean Dyspepsia Index (NDI) (r = -0.354, p = 0.048, Bonferroni correction) and the duration of FD (r = -0.398, p = 0.02, Bonferroni correction) respectively. CONCLUSIONS: The regional GMD of meal-related FD patients, especially in the regions of the homeostatic afferent processing network significantly differed from that of the HS, and the psychological factors might be one of the essential factors significantly affecting the regional brain structure of meal-related FD patients.

OBJECTIVES: This updated meta-analysis was conducted to assess the association between coffee consumption and breast cancer risk. METHODS: We conducted a systematic search updated July 2012 to identify observational studies providing quantitative estimates for breast cancer risk in relation to coffee consumption. Pooled relative risks (RRs) with 95% confidence intervals (CIs) were calculated using a random-effects model, and generalized least square trend estimation was used to assess dose-response relationships. RESULTS: A total of 26 studies (16 cohort and 10 case-control studies) on coffee intake with 49497 breast cancer cases were included in the meta-analysis. The pooled RR showed a borderline significant influence of highest coffee consumption (RR = 0.96; 95% CI 0.93-1.00), low-to moderate coffee consumption (RR = 0.99; 95% CI 0.95-1.04), or an increment of 2 cups/day of coffee consumption (RR = 0.98; 95% CI 0.97-1.00) on the risk of breast cancer. In stratified analysis, a significant inverse association was observed in ER-negative subgroup. However, no significant association was noted in the others. CONCLUSIONS: Our findings suggest that increased coffee intake is not associated with a significantly reduced risk of breast cancer, but we observe an inverse association in ER-negative subgroup analysis. More large studies are needed to determine subgroups to obtain more valuable data on coffee drinking and breast cancer risk.

Recent neuroimaging studies have shown local brain aberrations in functional dyspepsia (FD) patients, yet little attention has been paid to the whole-brain resting-state functional network abnormalities. The purpose of this study was to investigate whether FD disrupts the patterns of whole-brain networks and the abnormal functional connectivity could reflect the severity of the disease. The dysfunctional interactions between brain regions at rest were investigated in FD patients as compared with 40 age- and gender- matched healthy controls. Multivariate pattern analysis was used to evaluate the discriminative power of our results for classifying patients from controls. In our findings, the abnormal brain functional connections were mainly situated within or across the limbic/paralimbic system, the prefrontal cortex, the tempo-parietal areas and the visual cortex. About 96% of the subjects among the original dataset were correctly classified by a leave one-out cross-validation approach, and 88% accuracy was also validated in a replication dataset. The classification features were significantly associated with the patients' dyspepsia symptoms, the self-rating depression scale and self-rating anxiety scale, but it was not correlated with duration of FD patients (p>0.05). Our results may indicate the effectiveness of the altered brain functional connections reflecting the disease pathophysiology underling FD. These dysfunctional connections may be the epiphenomena or causative agents of FD, which may be affected by clinical severity and its related emotional dimension of the disease rather than the clinical course.

The natural flavone acacetin has been demonstrated to inhibit transient outward potassium current (Ito) in human atrial myocytes. However, the molecular determinants of acacetin for blocking Ito are unknown. The present study was designed to investigate the properties and molecular determinants of this compound for blocking hKv4.3 channels (coding Ito) stably expressed in HEK 293 cells using the approaches of whole-cell patch voltage-clamp technique and mutagenesis. It was found that acacetin inhibited hKv4.3 current by binding to both the closed and open channels, and decreased the recovery from inactivation. The blockade of hKv4.3 channels by acacetin was use- and frequency-dependent, and IC50s of acacetin for inhibiting hKv4.3 were 7.9, 6.1, 3.9, and 3.2 µM, respectively, at 0.2, 0.5, 1, and 3.3 Hz. The mutagenesis study revealed that the hKv4.3 mutants T366A and T367A in the P-loop helix, and V392A, I395A and V399A in the S6-segment had a reduced channel blocking efficacy of acacetin (IC50, 44.5 µM for T366A, 25.8 µM for T367A, 17.6 µM for V392A, 16.2 µM for I395A, and 19.1 µM for V399A). These results demonstrate the novel information that acacetin may inhibit the closed channels and block the open state of the channels by binding to their P-loop filter helix and S6 domain. The use- and rate-dependent blocking of hKv4.3 by acacetin is likely beneficial for managing atrial fibrillation.

BACKGROUND: Previous imaging studies on functional dyspepsia (FD) have focused on abnormal brain functions during special tasks, while few studies concentrated on the resting-state abnormalities of FD patients, which might be potentially valuable to provide us with direct information about the neural basis of FD. The main purpose of the current study was thereby to characterize the distinct patterns of resting-state function between FD patients and healthy controls (HCs). METHODOLOGY/PRINCIPAL FINDINGS: Thirty FD patients and thirty HCs were enrolled and experienced 5-mintue resting-state scanning. Based on the support vector machine (SVM), we applied multivariate pattern analysis (MVPA) to investigate the differences of resting-state function mapped by regional homogeneity (ReHo). A classifier was designed by using the principal component analysis and the linear SVM. Permutation test was then employed to identify the significant contribution to the final discrimination. The results displayed that the mean classifier accuracy was 86.67%, and highly discriminative brain regions mainly included the prefrontal cortex (PFC), orbitofrontal cortex (OFC), supplementary motor area (SMA), temporal pole (TP), insula, anterior/middle cingulate cortex (ACC/MCC), thalamus, hippocampus (HIPP)/parahippocamus (ParaHIPP) and cerebellum. Correlation analysis revealed significant correlations between ReHo values in certain regions of interest (ROI) and the FD symptom severity and/or duration, including the positive correlations between the dmPFC, pACC and the symptom severity; whereas, the positive correlations between the MCC, OFC, insula, TP and FD duration. CONCLUSIONS: These findings indicated that significantly distinct patterns existed between FD patients and HCs during the resting-state, which could expand our understanding of the neural basis of FD. Meanwhile, our results possibly showed potential feasibility of functional magnetic resonance imaging diagnostic assay for FD.

The research on brain plasticity has fascinated researchers for decades. Use/training serves as an instrumental factor to influence brain neuroplasticity. Parallel to acquisition of behavioral expertise, extensive use/training is concomitant with substantial changes of cortical structure. Acupuncturists, serving as a model par excellence to study tactile-motor and emotional regulation plasticity, receive intensive training in national medical schools following standardized training protocol. Moreover, their behavioral expertise is corroborated during long-term clinical practice. Although our previous study reported functional plastic brain changes in the acupuncturists, whether or not structural plastic changes occurred in acupuncturists is yet elusive.Cohorts of acupuncturists (N = 22) and non-acupuncturists (N = 22) were recruited. Behavioral tests were delivered to assess the acupuncturists' behavioral expertise. The results confirmed acupuncturists' tactile-motor skills and emotion regulation proficiency compared to non-acupuncturists. Using the voxel-based morphometry technique, we revealed larger grey matter volumes in acupuncturists in the hand representation of the contralateral primary somatosensory cortex (SI), the right lobule V/VI and the bilateral ventral anterior cingulate cortex/ventral medial prefrontal cortex. Grey matter volumes of the SI and Lobule V/VI positively correlated with the duration of acupuncture practice.To our best knowledge, this study provides first evidence for the anatomical alterations in acupuncturists, which would possibly be the neural correlates underlying acupuncturists' exceptional skills. On one hand, we suggest our findings may have ramifications for tactile-motor rehabilitation. On the other hand, our results in emotion regulation domain may serve as a target for our future studies, from which we can understand how modulations of aversive emotions elicited by empathic pain develop in the context of expertise. Future longitudinal study is necessary to establish the presence and direction of a causal link between practice/use and brain anatomy.

BackgroundDiffusion tensor imaging (DTI) study revealed reduced fractional anisotropy (FA) values in the corpus callosum (CC) in migraine patients without aura. Abnormalities in white matter integrity, particularly in the CC, may affect inter-hemispheric resting state functional connectivity (RSFC). Unfortunately, relatively little is known about the alterations in functional interactions between the cerebral hemispheres during resting state in migraine patients without aura, and even less about how the inter-hemispheric RSFC are affected by the abnormalities of the CC.Methods and findingsTwenty-one migraine patients without aura and 21 healthy controls participated in this study, age-, sex-, and education-matched. Tract-based spatial statistics (TBSS) was employed to investigate the white matter alterations of the CC. Meanwhile, voxel-mirrored homotopic connectivity (VMHC) was used to compare the inter-hemispheric RSFC differences between the patients and controls. TBSS analysis revealed reduced FA values in the genu and the splenium of CC in patient group. VMHC analysis showed decreased inter-hemispheric RSFC of anterior cingulate cortex (ACC) in migraine patients without aura relative to that of the controls. Furthermore, in migraine patients without aura, the reduced FA values of the genu of CC correlated with the decreased inter-hemispheric RSFC of the ACC.ConclusionsOur findings demonstrated that the migraine patients without aura showed reduced FA values of the genu of CC and decreased inter-hemispheric RSFC of the ACC. The correlation between the above structural and functional changes suggested that the reduced fractional anisotropy (FA) of CC modulates inter-hemispheric VMHC in migraine patients without aura. Our results demonstrated that the VMHC alterations of ACC can reflect the FA changes of the genu of CC in migraine patients without aura.

BackgroundPrevious studies have defined low-frequency, spatially consistent intrinsic connectivity networks (ICN) in resting functional magnetic resonance imaging (fMRI) data which reflect functional interactions among distinct brain areas. We sought to explore whether and how repeated migraine attacks influence intrinsic brain connectivity, as well as how activity in these networks correlates with clinical indicators of migraine.Methods/principal findingsResting-state fMRI data in twenty-three patients with migraines without aura (MwoA) and 23 age- and gender-matched healthy controls (HC) were analyzed using independent component analysis (ICA), in combination with a "dual-regression" technique to identify the group differences of three important pain-related networks [default mode network (DMN), bilateral central executive network (CEN), salience network (SN)] between the MwoA patients and HC. Compared with the HC, MwoA patients showed aberrant intrinsic connectivity within the bilateral CEN and SN, and greater connectivity between both the DMN and right CEN (rCEN) and the insula cortex - a critical region involving in pain processing. Furthermore, greater connectivity between both the DMN and rCEN and the insula correlated with duration of migraine.ConclusionsOur findings may provide new insights into the characterization of migraine as a condition affecting brain activity in intrinsic connectivity networks. Moreover, the abnormalities may be the consequence of a persistent central neural system dysfunction, reflecting cumulative brain insults due to frequent ongoing migraine attacks.

RATIONALE AND OBJECTIVE: Drug cues can induce craving for drugs of abuse. Dysfunctional regulation of emotion and motivation regarding rewarding objects appears to be an integral part of addiction. It has been found that cognitive strategies decreased the intensity of craving in addicts. Reappraisal strategy is a type of cognitive strategy that requires participants to reinterpret the meaning of an emotional situation. In addition, studies have found that activation of the dorsal anterior cingulate cortex (dACC) is associated with the selection and application of cognitive reappraisal. In present study, we sought to determine whether such cognitive regulation engages the dACC and improves inhibition of craving in smokers. METHODS: Sixteen smokers underwent functional magnetic resonance imaging (fMRI) during performance of a cigarette reward-conditioning procedure with cognitive reappraisal. We focused our analyses on the dACC as a key structure of cognitive control of craving. Cue induced craving under different conditions was obtained. Correlational analysis between the functional response in the dACC and the subjective craving was performed. RESULTS: We found that using a cognitive reappraisal was successful in decreasing the conditioned craving. Right dACC (BA 24/32) engaged in the cognitive reappraisal. In addition, the individual's subjective craving was negatively correlated with the right dACC activation. CONCLUSIONS: These findings suggest that the dACC are important substrates of Inhibition of cue induced craving in smokers. Cognitive regulation by cognitive reappraisal may help addicted individuals avoid the anticipated situations where they are exposed to conditioned cues.

Histone deacetylase (HDAC) inhibitors are emerging as a novel class of anti-tumor agents and have manifested the ability to decrease proliferation and increase apoptosis in different cancer cells. A significant number of genes have been identified as potential effectors responsible for the anti-tumor function of HDAC inhibitor. However, the molecular mechanisms of these HDAC inhibitors in this process remain largely undefined. In the current study, we searched for microRNAs (miRs) that were affected by HDAC inhibitor trichostatin (TSA) and investigated their effects in endometrial cancer (EMC) cells. Our data showed that TSA significantly inhibited the growth of EMC cells and induced their apoptosis. Among the miRNAs that altered in the presence of TSA, the miR-106b-93-25 cluster, together with its host gene MCM7, were obviously down-regulated in EMC cells. p21 and BIM, which were identified as target genes of miR-106b-93-25 cluster, increased in TSA treated tumor cells and were responsible for cell cycle arrest and apoptosis. We further identified MYC as a regulator of miR-106b-93-25 cluster and demonstrated its down-regulation in the presence of TSA resulted in the reduction of miR-106b-93-25 cluster and up-regulation of p21 and BIM. More important, we found miR-106b-93-25 cluster was up-regulated in clinical EMC samples in association with the overexpression of MCM7 and MYC and the down-regulation of p21 and BIM. Thus our studies strongly indicated TSA inhibited EMC cell growth and induced cell apoptosis and cell cycle arrest at least partially through the down-regulation of the miR-106b-93-25 cluster and up-regulation of it's target genes p21 and BIM via MYC.

BACKGROUND: Following voxel-based morphometry (VBM), brain-derived neurotrophic factor (BDNF) Val66Met polymorphism (rs6265) has been shown to affect human brain morphology in Caucasians. However, little is known about the specific role of the Met/Met genotype on brain structure. Moreover, the relationship between BDNF Val66Met polymorphism and Chinese brain morphology has not been studied. METHODOLOGY/PRINCIPAL FINDINGS: The present study investigated brain structural differences among three genotypes of BDNF (rs6265) for the first time in healthy young Chinese adults via cortical thickness analysis and VBM. Brain differences in Met carriers using another grouping method (combining Val/Met and Met/Met genotypes into a group of Met carriers as in most previous studies) were also investigated using VBM. Dual-approach analysis revealed less gray matter (GM) in the frontal, temporal, cingulate and insular cortices in the Met/Met group compared with the Val/Val group (corrected, P

BACKGROUND: Little is known about the changes of brain structural and functional connectivity networks underlying the pathophysiology in migraine. We aimed to investigate how the cortical network reorganization is altered by frequent cortical overstimulation associated with migraine. METHODOLOGY/PRINCIPAL FINDINGS: Gray matter volumes and resting-state functional magnetic resonance imaging signal correlations were employed to construct structural and functional networks between brain regions in 43 female patients with migraine (PM) and 43 gender-matched healthy controls (HC) by using graph theory-based approaches. Compared with the HC group, the patients showed abnormal global topology in both structural and functional networks, characterized by higher mean clustering coefficients without significant change in the shortest absolute path length, which indicated that the PM lost optimal topological organization in their cortical networks. Brain hubs related to pain-processing revealed abnormal nodal centrality in both structural and functional networks, including the precentral gyrus, orbital part of the inferior frontal gyrus, parahippocampal gyrus, anterior cingulate gyrus, thalamus, temporal pole of the middle temporal gyrus and the inferior parietal gyrus. Negative correlations were found between migraine duration and regions with abnormal centrality. Furthermore, the dysfunctional connections in patients' cortical networks formed into a connected component and three dysregulated modules were identified involving pain-related information processing and motion-processing visual networks. CONCLUSIONS: Our results may reflect brain alteration dynamics resulting from migraine and suggest that long-term and high-frequency headache attacks may cause both structural and functional connectivity network reorganization. The disrupted information exchange between brain areas in migraine may be reshaped into a hierarchical modular structure progressively.

INTRODUCTION: Abdominal compartment syndrome (ACS) and intra abdominal hypertension(IAH) are common clinical findings in patients with severe acute pancreatitis(SAP). It is thought that an increased intra abdominal pressure(IAP) is associated with poor prognosis in SAP patients. But the detailed effect of IAH/ACS on different organ system is not clear. The aim of this study was to assess the effect of SAP combined with IAH on hemodynamics, systemic oxygenation, and organ damage in a 12 h lasting porcine model. MEASUREMENTS AND METHODS: Following baseline registrations, a total of 30 animals were divided into 5 groups (6 animals in each group): SAP+IAP30 group, SAP+IAP20 group, SAP group, IAP30 group(sham-operated but without SAP) and sham-operated group. We used a N(2) pneumoperitoneum to induce different levels of IAH and retrograde intra-ductal infusion of sodium taurocholate to induce SAP. The investigation period was 12 h. Hemodynamic parameters (CO, HR, MAP, CVP), urine output, oxygenation parameters(e.g., S(v)O(2), PO(2), PaCO(2)), peak inspiratory pressure, as well as serum parameters (e.g., ALT, amylase, lactate, creatinine) were recorded. Histological examination of liver, intestine, pancreas, and lung was performed. MAIN RESULTS: Cardiac output significantly decreased in the SAP+IAH animals compared with other groups. Furthermore, AST, creatinine, SUN and lactate showed similar increasing tendency paralleled with profoundly decrease in S(v)O(2). The histopathological analyses also revealed higher grade injury of liver, intestine, pancreas and lung in the SAP+IAH groups. However, few differences were found between the two SAP+IAH groups with different levels of IAP. CONCLUSIONS: Our newly developed porcine SAP+IAH model demonstrated that there were remarkable effects on global hemodynamics, oxygenation and organ function in response to sustained IAH of 12 h combined with SAP. Moreover, our model should be helpful to study the mechanisms of IAH/ACS-induced exacerbation and to optimize the treatment strategies for counteracting the development of organ dysfunction.

BackgroundRecent studies suggest that internet addiction disorder (IAD) is associated with structural abnormalities in brain gray matter. However, few studies have investigated the effects of internet addiction on the microstructural integrity of major neuronal fiber pathways, and almost no studies have assessed the microstructural changes with the duration of internet addiction.Methodology/principal findingsWe investigated the morphology of the brain in adolescents with IAD (N = 18) using an optimized voxel-based morphometry (VBM) technique, and studied the white matter fractional anisotropy (FA) changes using the diffusion tensor imaging (DTI) method, linking these brain structural measures to the duration of IAD. We provided evidences demonstrating the multiple structural changes of the brain in IAD subjects. VBM results indicated the decreased gray matter volume in the bilateral dorsolateral prefrontal cortex (DLPFC), the supplementary motor area (SMA), the orbitofrontal cortex (OFC), the cerebellum and the left rostral ACC (rACC). DTI analysis revealed the enhanced FA value of the left posterior limb of the internal capsule (PLIC) and reduced FA value in the white matter within the right parahippocampal gyrus (PHG). Gray matter volumes of the DLPFC, rACC, SMA, and white matter FA changes of the PLIC were significantly correlated with the duration of internet addiction in the adolescents with IAD.ConclusionsOur results suggested that long-term internet addiction would result in brain structural alterations, which probably contributed to chronic dysfunction in subjects with IAD. The current study may shed further light on the potential brain effects of IAD.

BackgroundMigraine shows gender-specific incidence and has a higher prevalence in females. However, little is known about gender-related differences in dysfunctional brain organization, which may account for gender-specific vulnerability and characteristics of migraine. In this study, we considered gender-related differences in the topological property of resting functional networks.Methodology/principal findingsData was obtained from 38 migraine patients (18 males and 20 females) and 38 healthy subjects (18 males and 20 females). We used the graph theory analysis, which becomes a powerful tool in investigating complex brain networks on a whole brain scale and could describe functional interactions between brain regions. Using this approach, we compared the brain functional networks between these two groups, and several network properties were investigated, such as small-worldness, network resilience, nodal centrality, and interregional connections. In our findings, these network characters were all disrupted in patients suffering from chronic migraine. More importantly, these functional damages in the migraine-affected brain had a skewed balance between males and females. In female patients, brain functional networks showed worse resilience, more regions exhibited decreased nodal centrality, and more functional connections revealed abnormalities than in male patients.ConclusionsThese results indicated that migraine may have an additional influence on females and lead to more dysfunctional organization in their resting functional networks.

Approximately 10% of cancers use recombination-mediated Alternative Lengthening of Telomeres (ALT) instead of telomerase to prevent telomere shortening. A characteristic of cells that utilize ALT is the presence of ALT-associated PML nuclear bodies (APBs) containing (TTAGGG)n DNA, telomere binding proteins, DNA recombination proteins, and heterochromatin protein 1 (HP1). The function of APBs is unknown and it is possible that they are functionally heterogeneous. Most ALT cells lack functional p53, and restoration of the p53/p21 pathway in these cells results in growth arrest/senescence and a substantial increase in the number of large APBs that is dependent on two HP1 isoforms, HP1α and HP1γ. Here we investigated the mechanism of HP1-mediated APB formation, and found that histone chaperones, HIRA and ASF1a, are present in APBs following activation of the p53/p21 pathway in ALT cells. HIRA and ASF1a were also found to colocalize inside PML bodies in normal fibroblasts approaching senescence, providing evidence for the existence of a senescence-associated ASF1a/HIRA complex inside PML bodies, consistent with a role for these proteins in induction of senescence in both normal and ALT cells. Moreover, knockdown of HIRA but not ASF1a significantly reduced p53-mediated induction of large APBs, with a concomitant reduction of large HP1 foci. We conclude that HIRA, in addition to its physical and functional association with ASF1a, plays a unique, ASF1a-independent role, which is required for the localization of HP1 to PML bodies and thus for APB formation.

BACKGROUND: The majority of previous heroin cue-reactivity functional magnetic resonance imaging (fMRI) studies focused on local function impairments, such as inhibitory control, decision-making and stress regulation. Our previous studies have demonstrated that these brain circuits also presented dysfunctional connectivity during the resting state. Yet few studies considered the relevance of resting state dysfunctional connectivity to task-related neural activity in the same chronic heroin user (CHU). METHODOLOGY/PRINCIPAL FINDINGS: We employed the method of graph theory analysis, which detected the abnormality of brain regions and dysregulation of brain connections at rest between 16 male abstinent chronic heroin users (CHUs) and 16 non-drug users (NDUs). Using a cue-reactivity task, we assessed the relationship between drug-related cue-induced craving activity and the abnormal topological properties of the CHUs' resting networks. Comparing NDUs' brain activity to that of CHUs, the intensity of functional connectivity of the medial frontal gyrus (meFG) in patients' resting state networks was prominently greater and positively correlated with the same region's neural activity in the heroin-related task; decreased functional connectivity intensity of the anterior cingulate cortex (ACC) in CHUs at rest was associated with more drug-related cue-induced craving activities. CONCLUSIONS: These results may indicate that there exist two brain systems interacting simultaneously in the heroin-addicted brain with regards to a cue-reactivity task. The current study may shed further light on the neural architecture that supports craving responses in heroin dependence.

Renal angiomyolipoma are part of the PEComa family of neoplasms, and occur both in association with Tuberous Sclerosis Complex (TSC) and independent of that disorder. Previous studies on the molecular genetic alterations that occur in angiomyolipoma are very limited. We evaluated 9 angiomyolipoma for which frozen tissue was available from a consecutive surgical series. Seven of 8 samples subjected to RT-PCR-cDNA sequencing showed mutations in TSC2; none showed mutations in TSC1 or RHEB. Six of the seven mutations were deletions. We searched for 983 activating and inactivating mutations in 115 genes, and found none in these tumors. Similarly analysis for genomic regions of loss or gain, assessed by Affymetrix SNP6.0 analysis, showed no abnormalities. Loss of heterozygosity in the TSC2 region was commonly seen, except in patients with low frequency TSC2 mutations. We conclude that sporadic renal angiomyolipoma usually have mutations in TSC2, but not TSC1 or RHEB, and have no other common genomic events, among those we searched for. However, chromosomal translocations and gene fusion events were not assessed here. TSC2 inactivation by mutation is a consistent and likely necessary genetic event in the pathogenesis of most angiomyolipoma.