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  • 1
    Publication Date: 2018-07-20
    Description: Inactivation of the von Hippel-Lindau (VHL) E3 ubiquitin ligase protein is a hallmark of clear cell renal cell carcinoma (ccRCC). Identifying how pathways affected by VHL loss contribute to ccRCC remains challenging. We used a genome-wide in vitro expression strategy to identify proteins that bind VHL when hydroxylated. Zinc fingers and homeoboxes 2 (ZHX2) was found as a VHL target, and its hydroxylation allowed VHL to regulate its protein stability. Tumor cells from ccRCC patients with VHL loss-of-function mutations usually had increased abundance and nuclear localization of ZHX2. Functionally, depletion of ZHX2 inhibited VHL-deficient ccRCC cell growth in vitro and in vivo. Mechanistically, integrated chromatin immunoprecipitation sequencing and microarray analysis showed that ZHX2 promoted nuclear factor B activation. These studies reveal ZHX2 as a potential therapeutic target for ccRCC.
    Keywords: Cell Biology, Medicine, Diseases
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2018-03-29
    Description: Respiratory syncytial virus (RSV) is the main cause of acute lower respiratory tract infection (ALRI) in children worldwide. Virus-host interactions affect the progression and prognosis of the infection. Autophagy plays important roles in virus-host interactions. Respiratory epithelial cells serve as the front line of host defense during RSV infection, However, it is still unclear how they interact with RSV. In this study, we found that RSV induced autophagy that favored RSV replication and exacerbated lung pathology in vivo . Mechanistically, RSV induced complete autophagy flux through reactive oxygen species (ROS) generation and activation of the AMP-activated protein kinase/mammalian target of rapamycin (AMPK-MTOR) signaling pathway in HEp-2 cells. Furthermore, we evaluated the functions of autophagy in RSV replication and found that RSV replication was increased in HEp-2 cells treated with rapamycin but decreased remarkably in cells treated with 3-methylademine (3-MA) or wortmannin. Knockdown key molecules in the autophagy pathway with short hairpinp RNA (shRNA) against autophagy-related gene 5 ( ATG5 ), autophagy-related gene 7 ( ATG7 ), or BECN1/Beclin 1 or treatment with ROS scavenger N-acetyl- l -cysteine (NAC) and AMPK inhibitor (compound C) suppressed RSV replication. 3-MA or sh ATG5/BECN1 significantly decreased cell viability and increased cell apoptosis at 48 hours postinfection (hpi). Blocking apoptosis with Z-VAD-FMK partially restored virus replication at 48 hpi. Those results provide strong evidence that autophagy may function as a proviral mechanism in a cell-intrinsic manner during RSV infection. IMPORTANCE An understanding of the mechanisms that respiratory syncytial virus utilizes to interact with respiratory epithelial cells is critical to the development of novel antiviral strategies. In this study, we found that RSV induces autophagy through a ROS-AMPK signaling axis, which in turn promotes viral infection. Autophagy favors RSV replication through blocking cell apoptosis at 48 hpi. Mechanistically, RSV induces mitophagy, which maintains mitochondrial homeostasis and therefore decreases cytochrome c release and apoptosis induction. This study provides a novel insight into this virus-host interaction, which may help to exploit new antiviral treatments targeting autophagy processes.
    Print ISSN: 0022-538X
    Electronic ISSN: 1098-5514
    Topics: Medicine
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  • 3
    Publication Date: 2018-11-02
    Description: Purpose: The prognosis for patients with refractory soft-tissue sarcoma (STS) is dismal. Anlotinib has previously shown antitumor activity on STS in preclinical and phase I studies. Patients and Methods: Patients 18 years and older, progressing after anthracycline-based chemotherapy, naïve from angiogenesis inhibitors, with at least one measurable lesion according to RECIST 1.1, were enrolled. The main subtypes eligible were undifferentiated pleomorphic sarcoma (UPS), liposarcoma (LPS), leiomyosarcoma (LMS), synovial sarcoma (SS), fibrosarcoma (FS), alveolar soft-part sarcoma (ASPS), and clear cell sarcoma (CCS). Participants were treated with anlotinib. The primary endpoint was progression-free rate at 12 weeks (PFR 12 weeks ). Results: A total of 166 patients were included in the final analysis. Overall, the PFR 12 weeks was 68%, and objective response rate was 13% (95% confidence interval, 7.6%–18%). The median progression-free survival (PFS) and overall survival (OS) were 5.6 and 12 months, respectively. The PFR 12 weeks , median PFS and OS were: 58%, 4.1 and 11 months for UPS ( n = 19); 63%, 5.6 and 13 months for LPS ( n = 13); 75%, 11 and 15 months for LMS ( n = 26); 75%, 7.7 and 12 months for SS ( n = 47); 81%, 5.6 and 12 months for FS ( n = 18); 77%, 21 and not reached for ASPS ( n = 13); 54%, 11 and 16 months for CCS ( n = 7); and 44%, 2.8 and 8.8 months for other sarcoma ( n = 23), respectively. The most common clinically significant grade 3 or higher adverse events were hypertension (4.8%), triglyceride elevation (3.6%), and pneumothorax (2.4%). No treatment-related death occurred. Conclusions: Anlotinib showed antitumor activity in several STS entities. The toxicity was manageable. Clin Cancer Res; 24(21); 5233–8. ©2018 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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  • 4
    Publication Date: 2015-10-17
    Description: Neural stem cells show age-dependent developmental potentials, as evidenced by their production of distinct neuron types at different developmental times. Drosophila neuroblasts produce long, stereotyped lineages of neurons. We searched for factors that could regulate neural temporal fate by RNA-sequencing lineage-specific neuroblasts at various developmental times. We found that two RNA-binding proteins, IGF-II mRNA-binding protein (Imp) and Syncrip (Syp), display opposing high-to-low and low-to-high temporal gradients with lineage-specific temporal dynamics. Imp and Syp promote early and late fates, respectively, in both a slowly progressing and a rapidly changing lineage. Imp and Syp control neuronal fates in the mushroom body lineages by regulating the temporal transcription factor Chinmo translation. Together, the opposing Imp/Syp gradients encode stem cell age, specifying multiple cell fates within a lineage.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liu, Zhiyong -- Yang, Ching-Po -- Sugino, Ken -- Fu, Chi-Cheng -- Liu, Ling-Yu -- Yao, Xiaohao -- Lee, Luke P -- Lee, Tzumin -- R01-GM084947/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Oct 16;350(6258):317-20. doi: 10.1126/science.aad1886.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Janelia Research Campus, 19700 Helix Drive, Ashburn, VA, USA. ; Howard Hughes Medical Institute, Janelia Research Campus, 19700 Helix Drive, Ashburn, VA, USA. Departments of Bioengineering, Electrical Engineering, and Computer Science, and Biophysics Graduate Program, University of California Berkeley, 408C Stanley Hall, Berkeley, CA, USA. ; Departments of Bioengineering, Electrical Engineering, and Computer Science, and Biophysics Graduate Program, University of California Berkeley, 408C Stanley Hall, Berkeley, CA, USA. ; Howard Hughes Medical Institute, Janelia Research Campus, 19700 Helix Drive, Ashburn, VA, USA. leet@janelia.hhmi.org.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26472907" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Cell Lineage ; Drosophila Proteins/genetics/metabolism/*physiology ; Drosophila melanogaster/genetics/*growth & development ; Mushroom Bodies/cytology/growth & development ; Nerve Tissue Proteins/metabolism ; Neural Stem Cells/*cytology ; Neurogenesis/genetics/*physiology ; Neurons/*cytology ; RNA-Binding Proteins/genetics/*physiology ; Sequence Analysis, RNA
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 5
    Publication Date: 2018-08-09
    Description: Safety assessments are a crucial first step in preventing coal and gas outburst accidents. The main purpose of this study was to create a new accident prevention technique using a novel safety assessment method based on fault tree basic event importance, grey relational analysis and the bow tie model. The innovation of the proposed method lies in generating the composite importance of a basic event from the fundamental importance via grey relational analysis; bow tie analysis serves to reveal the most critical basic event. First, the minimal cut sets and minimal path sets of a coal and gas outburst accident are determined by fault tree analysis. The role of minimal cut and path sets is determined and the coal and gas outburst occurrence frequency is calculated accordingly. Second, the structure, probability, critical and Fussell–Vesely importance ranked basic events differently due to different aspects of the basic events as investigated. We establish a composite importance to represent single basic events and achieved new ranking results by grey relational analysis. Third, the critical basic event low permeability coefficient is analysed via bow tie model and safety measures are defined which prevent the dangerous consequences of a low permeability coefficient. An actual coal and gas outburst accident is used as a case study to test the feasibility and effectiveness of the proposed method.
    Keywords: power and energy systems, energy
    Electronic ISSN: 2054-5703
    Topics: Natural Sciences in General
    Published by Royal Society
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  • 6
    Publication Date: 2018-08-21
    Description: A fasting mimetic diet blunts inflammation, and intermittent fasting has shown ameliorative effects in obese asthmatics. To examine whether canonical inflammatory pathways linked with asthma are modulated by fasting, we designed a pilot study in mild asthmatic subjects to assess the effect of fasting on the NLRP3 inflammasome, Th2 cell activation, and airway epithelial cell cytokine production. Subjects with documented reversible airway obstruction and stable mild asthma were recruited into this study in which pulmonary function testing (PFT) and PBMCextraction was performed 24 h after fasting, with repeated PFT testing and blood draw 2.5 h after refeeding. PFTs were not changed by a prolonged fast. However, steroid-naive mild asthmatics showed fasting-dependent blunting of the NLRP3 inflammasome. Furthermore, PBMCs from these fasted asthmatics cocultured with human epithelial cells resulted in blunting of house dust mite–induced epithelial cell cytokine production and reduced CD4 + T cell Th2 activation compared with refed samples. This pilot study shows that prolonged fasting blunts the NLRP3 inflammasome and Th2 cell activation in steroid-naive asthmatics as well as diminishes airway epithelial cell cytokine production. This identifies a potential role for nutrient level–dependent regulation of inflammation in asthma. Our findings support the evaluation of this concept in a larger study as well as the potential development of caloric restriction interventions for the treatment of asthma.
    Print ISSN: 0022-1767
    Electronic ISSN: 1550-6606
    Topics: Medicine
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  • 7
    Publication Date: 2018-03-07
    Description: Commensal bacteria are critical for physiological functions in the gut, and dysbiosis in the gut may cause diseases. In this article, we report that mice deficient in cathelin-related antimicrobial peptide (CRAMP) were defective in the development of colon mucosa and highly sensitive to dextran sulfate sodium (DSS)-elicited colitis, as well as azoxymethane-mediated carcinogenesis. Pretreatment of CRAMP –/– mice with antibiotics markedly reduced the severity of DSS-induced colitis, suggesting CRAMP as a limiting factor on dysbiosis in the colon. This was supported by observations that wild-type (WT) mice cohoused with CRAMP –/– mice became highly sensitive to DSS-induced colitis, and the composition of fecal microbiota was skewed by CRAMP deficiency. In particular, several bacterial species that are typically found in oral microbiota, such as Mogibacterium neglectum , Desulfovibrio piger , and Desulfomicrobium orale , were increased in feces of CRAMP –/– mice and were transferred to WT mice during cohousing. When littermates of CRAMP +/– parents were examined, the composition of the fecal microbiota of WT pups and heterozygous parents was similar. In contrast, although the difference in fecal microbiota between CRAMP –/– and WT pups was small early on after weaning and single mouse housing, there was an increasing divergence with prolonged single housing. These results indicate that CRAMP is critical in maintaining colon microbiota balance and supports mucosal homeostasis, anti-inflammatory responses, and protection from carcinogenesis.
    Print ISSN: 0022-1767
    Electronic ISSN: 1550-6606
    Topics: Medicine
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  • 8
    Publication Date: 2018-02-16
    Description: Objectives To describe the clinical characteristics and management of patients hospitalised with community-acquired pneumonia (CAP) in China. Design This was a multicentre, retrospective, observational study. Setting 13 teaching hospitals in northern, central and southern China from 1 January 2014 to 31 December 2014 Participants Information on hospitalised patients aged ≥14 years with radiographically confirmed pneumonia with illness onset in the community was collected using standard case report forms. Primary and secondary outcome measures Resource use for CAP management. Results Of 14 793 patients screened, 5828 with radiographically confirmed CAP were included in the final analysis. Low mortality risk patients with a CURB-65 score 0–1 and Pneumonia Severity Index risk class I–II accounted for 81.2% (4434/5594) and 56.4% (2034/3609) patients, respectively. 21.7% (1111/5130) patients had already achieved clinical stability on admission. A definite or probable pathogen was identified only in 12.7% (738/5828) patients. 40.9% (1575/3852) patients without pseudomonal infection risk factors received antimicrobial overtreatment regimens. The median duration between clinical stability to discharge was 5.0 days with 30-day mortality of 4.2%. Conclusions These data demonstrated the overuse of health resources in CAP management, indicating that there is potential for improvement and substantial savings to healthcare systems in China. Trial registration number NCT02489578 ; Results.
    Keywords: Open access, Infectious diseases
    Electronic ISSN: 2044-6055
    Topics: Medicine
    Published by BMJ Publishing
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  • 9
    Publication Date: 2018-01-06
    Description: The origin of the pseudogap region below a temperature T * is at the heart of the mysteries of cuprate high-temperature superconductors. Unusual properties of the pseudogap phase, such as broken time-reversal and inversion symmetry are observed in several symmetry-sensitive experiments: polarized neutron diffraction, optical birefringence, dichroic angle-resolved photoemission spectroscopy, second harmonic generation, and polar Kerr effect. These properties suggest that the pseudogap region is a genuine thermodynamic phase and are predicted by theories invoking ordered loop currents or other forms of intra-unit-cell (IUC) magnetic order. However, muon spin rotation (μSR) and nuclear magnetic resonance (NMR) experiments do not see the static local fields expected for magnetic order, leaving room for skepticism. The magnetic resonance probes have much longer time scales, however, over which local fields could be averaged by fluctuations. The observable effect of the fluctuations in magnetic resonance is then dynamic relaxation. We have measured dynamic muon spin relaxation rates in single crystals of YBa 2 Cu 3 O y (6.72 〈 y 〈 6.95) and have discovered "slow" fluctuating magnetic fields with magnitudes and fluctuation rates of the expected orders of magnitude that set in consistently at temperatures T mag T *. The absence of any static field (to which μSR would be linearly sensitive) is consistent with the finite correlation length from neutron diffraction. Equally important, these fluctuations exhibit the critical slowing down at T mag expected near a time-reversal symmetry breaking transition. Our results explain the absence of static magnetism and provide support for the existence of IUC magnetic order in the pseudogap phase.
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
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  • 10
    Publication Date: 2018-07-19
    Description: Safe production is the foundation of the normal operations of petrochemical enterprises, and it helps maintain social stability. The main purpose of this study is to prevent petrochemical enterprise accidents by proposing a composite safety assessment approach based on the cloud model, preliminary hazard analysis–layer of protection analysis (PHA–LOPA) and the bow-tie model. First, the petrochemical enterprise and its relevant indicators were evaluated based on the cloud model. Second, the quantitative effect of the uncertainty transformation on the evaluation result of the cloud model was further analysed. This mainly includes the error analysis of the numerical characteristics under the conditions of few samples and small values. Third, the critical indicators such as shock and noise can be weakened and prevented by corresponding safety measures based on PHA–LOPA and the bow-tie model. After adopting two independent protection layers, the risk levels of shock and noise decrease from 3 to 2. Then, shock and noise were analysed in depth with the bow-tie model, and the causes and consequences were identified. Moreover, corresponding safety measures were taken to prevent accidents. The case study validated the validity and feasibility of the composite safety assessment approach proposed here.
    Keywords: energy
    Electronic ISSN: 2054-5703
    Topics: Natural Sciences in General
    Published by Royal Society
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