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  • 1
    Publication Date: 2018-05-30
    Description: As a prevalent agent in cats, feline herpesvirus 1 (FHV-1) infection contributes to feline respiratory disease and acute and chronic conjunctivitis. FHV-1 can successfully evade the host innate immune response and persist for the lifetime of the cat. Several mechanisms of immune evasion by human herpesviruses have been elucidated, but the mechanism of immune evasion by FHV-1 remains unknown. In this study, we screened for FHV-1 open reading frames (ORFs) responsible for inhibiting the type I interferon (IFN) pathway with an IFN-β promoter reporter and analysis of IFN-β mRNA levels in HEK 293T cells and the Crandell-Reese feline kidney (CRFK) cell line, and we identified the Ser/Thr kinase US3 as the most powerful inhibitor. Furthermore, we found that the anti-IFN activity of US3 depended on its N terminus (amino acids 1 to 75) and was independent of its kinase activity. Mechanistically, the ectopic expression of US3 selectively inhibited IFN regulatory factor 3 (IRF3) promoter activation. Furthermore, US3 bound to the IRF association domain (IAD) of IRF3 and prevented IRF3 dimerization. Finally, US3-deleted recombinant FHV-1 and US3-repaired recombinant FHV-1 (rFHV-dUS3 and rFHV-rUS3, respectively) were constructed. Compared with wild-type FHV-1 and rFHV-rUS3, infection with rFHV-dUS3 induced large amounts of IFN-β in vitro and in vivo . More importantly, US3 deletion significantly attenuated virulence, reduced virus shedding, and blocked the invasion of trigeminal ganglia. These results indicate that FHV-1 US3 efficiently inhibits IFN induction by using a novel immune evasion mechanism and that FHV-1 US3 is a potential regulator of neurovirulence. IMPORTANCE Despite widespread vaccination, the prevalence of FHV-1 remains high, suggesting that it can successfully evade the host innate immune response and infect cats. In this study, we screened viral proteins for inhibiting the IFN pathway and identified the Ser/Thr kinase US3 as the most powerful inhibitor. In contrast to other members of the alphaherpesviruses, FHV-1 US3 blocked the host type I IFN pathway in a kinase-independent manner and via binding to the IRF3 IAD and preventing IRF3 dimerization. More importantly, the depletion of US3 attenuated the anti-IFN activity of FHV-1 and prevented efficient viral replication in vitro and in vivo . Also, US3 deletion significantly attenuated virulence and blocked the invasion of trigeminal ganglia. We believe that these findings not only will help us to better understand the mechanism of how FHV-1 manipulates the host IFN response but also highlight the potential role of US3 in the establishment of latent infection in vivo .
    Print ISSN: 0022-538X
    Electronic ISSN: 1098-5514
    Topics: Medicine
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  • 2
    Publication Date: 2018-11-09
    Description: The maintenance of autoreactive B cells in a quiescent state is crucial for preventing autoimmunity. Here we identify a variant of human immunoglobulin G1 (IgG1) with a Gly 396 -〉Arg substitution (hIgG1-G396R), which positively correlates with systemic lupus erythematosus. In induced lupus models, murine homolog Gly 390 -〉Arg (G390R) knockin mice generate excessive numbers of plasma cells, leading to a burst of broad-spectrum autoantibodies. This enhanced production of antibodies is also observed in hapten-immunized G390R mice, as well as in influenza-vaccinated human G396R homozygous carriers. This variant potentiates the phosphorylation of the IgG1 immunoglobulin tail tyrosine (ITT) motif. This, in turn, alters the availability of phospho-ITT to trigger longer adaptor protein Grb2 dwell times in immunological synapses, leading to hyper–Grb2–Bruton’s tyrosine kinase (Btk) signaling upon antigen binding. Thus, the hIgG1-G396R variant is important for both lupus pathogenesis and antibody responses after vaccination.
    Keywords: Immunology, 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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  • 3
    Publication Date: 2018-05-18
    Description: Introduction Frozen-thawed embryo transfer (FET) has become an increasingly important part of in-vitro fertilisation (IVF) treatment. Currently, there is still no good scientific evidence to support when to perform FET following a stimulated IVF cycle. Since all published studies are retrospective and the findings are contradictory, a randomised controlled study is needed to provide Level 1 evidence to guide the clinical practice. Methods/analysis This is a randomised controlled trial. A total of 724 women undergoing the first FET following ovarian stimulation in IVF will be enrolled and randomised according to a computer-generated randomisation list to either (1) the immediate group in which FET will be performed in the first cycle following the stimulated IVF cycle or (2) the delayed group in which FET will be performed at least in the second cycle following the stimulated IVF cycle. The primary outcome is the ongoing pregnancy defined as a viable pregnancy beyond 12 weeks’ gestation. Ethics and dissemination Ethical approval has been granted by the Ethics Committee of Assisted Reproductive Medicine in Shanghai JiAi Genetics & IVF Institute (JIAI E2017-12) and from the Institutional Review Board of the University of Hong Kong Hospital Authority Hong Kong West Cluster (UW 17–371). A written informed consent will be obtained from each woman before any study procedure is performed, according to good clinical practice. The results of this trial will be disseminated in a peer-reviewed journal. Trial registration number NCT03201783 ;Pre-results.
    Keywords: Open access, Reproductive medicine
    Electronic ISSN: 2044-6055
    Topics: Medicine
    Published by BMJ Publishing
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  • 4
    Publication Date: 2018-06-02
    Description: Objective Willingness to receive eldercare is an important factor affecting the reasonable allocation of resources and appropriate development of eldercare services. This study aimed to investigate the differences in willingness to receive eldercare and the influencing factors in urban and rural areas. Design Cross-sectional survey. Setting Research was conducted in the urban and rural areas of three cities (Harbin, Qiqihar and Jiamusi) in Heilongjiang province, China. Participants A total of 1003 elderly were selected through multistage sampling in Heilongjiang province, including 581 in urban areas and 422 in rural areas. Main outcome measures Descriptive statistics were reported for socioeconomic and demographic status, physical health, life satisfaction and social support in urban and rural areas. Mean differences were examined using t-tests, and categorical variable differences were examined using 2 tests. The factors influencing willingness to receive eldercare in urban and rural areas were analysed using logistic regression. Results The results showed that 51.6% of urban elderly and 59.0% of rural elderly preferred family eldercare. Factors that influenced willingness to receive eldercare for urban elderly were age (OR 2.791, 95% CI 1.644 to 4.737), house property (OR 0.494, 95% CI 0.329 to 0.740) and objective support (OR 0.764, 95% CI 0.681 to 0.858). For rural elderly, the factors were having children (OR 0.368, 95% CI 0.146 to 0.930), house property (OR 0.371, 95% CI 0.231 to 0.596) and living arrangement (OR 3.361, 95% CI 1.436 to 7.866). Conclusion More attention should be paid to improving the functioning of family eldercare and promoting the development of varied eldercare services. Investments and targeted policies should be undertaken for different subgroups of urban and rural elderly.
    Keywords: Open access, Public health
    Electronic ISSN: 2044-6055
    Topics: Medicine
    Published by BMJ Publishing
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  • 5
    Publication Date: 2018-06-20
    Description: Zika virus infection stimulates a type I interferon (IFN) response in host cells, which suppresses viral replication. Type I IFNs exert antiviral effects by inducing the expression of hundreds of IFN-stimulated genes (ISGs). To screen for antiviral ISGs that restricted Zika virus replication, we individually knocked out 21 ISGs in A549 lung cancer cells and identified PARP12 as a strong inhibitor of Zika virus replication. Our findings suggest that PARP12 mediated the ADP-ribosylation of NS1 and NS3, nonstructural viral proteins that are involved in viral replication and modulating host defense responses. This modification of NS1 and NS3 triggered their proteasome-mediated degradation. These data increase our understanding of the antiviral activity of PARP12 and suggest a molecular basis for the potential development of therapeutics against Zika virus.
    Print ISSN: 1945-0877
    Topics: Medicine
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  • 6
    Publication Date: 2018-06-28
    Description: This study demonstrated rapid degradation of malachite green (MG) by a microwave (MW)-induced enhanced catalytic process with CoFe 2 O 4 –SiC foam. The catalyst was synthesized from CoFe 2 O 4 particles and SiC foam by the hydrothermal method. X-ray diffraction and scanning electron microscopy techniques were used to confirm that CoFe 2 O 4 particles were settled on the surface of SiC foam. In this experiment, a novel fixed-bed reactor was set up with this catalyst for a continuous flow process in a MW oven. The different parameters that affect the MW-induced degradation rate of MG were explored. The MW irradiation leads to the effective catalytic degradation of MG, achieving 95.01% degradation within 5 min at pH 8.5. At the same time, the good stability and applicability of CoFe 2 O 4 –SiC foam for the degradation process were also discussed, as well as the underlying mechanism. In brief, these findings make the CoFe 2 O 4 –SiC foam an excellent catalyst that could be used in practical rapid degradation of MG.
    Keywords: environmental chemistry, environmental engineering, environmental science
    Electronic ISSN: 2054-5703
    Topics: Natural Sciences in General
    Published by Royal Society
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  • 7
    Publication Date: 2018-11-30
    Description: We report a 3.5-angstrom-resolution cryo–electron microscopy structure of a respiratory supercomplex isolated from Mycobacterium smegmatis. It comprises a complex III dimer flanked on either side by individual complex IV subunits. Complex III and IV associate so that electrons can be transferred from quinol in complex III to the oxygen reduction center in complex IV by way of a bridging cytochrome subunit. We observed a superoxide dismutase-like subunit at the periplasmic face, which may be responsible for detoxification of superoxide formed by complex III. The structure reveals features of an established drug target and provides a foundation for the development of treatments for human tuberculosis.
    Keywords: Biochemistry, Online Only
    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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  • 8
    Publication Date: 2012-10-02
    Description: Assessment and characterization of gut microbiota has become a major research area in human disease, including type 2 diabetes, the most prevalent endocrine disease worldwide. To carry out analysis on gut microbial content in patients with type 2 diabetes, we developed a protocol for a metagenome-wide association study (MGWAS) and undertook a two-stage MGWAS based on deep shotgun sequencing of the gut microbial DNA from 345 Chinese individuals. We identified and validated approximately 60,000 type-2-diabetes-associated markers and established the concept of a metagenomic linkage group, enabling taxonomic species-level analyses. MGWAS analysis showed that patients with type 2 diabetes were characterized by a moderate degree of gut microbial dysbiosis, a decrease in the abundance of some universal butyrate-producing bacteria and an increase in various opportunistic pathogens, as well as an enrichment of other microbial functions conferring sulphate reduction and oxidative stress resistance. An analysis of 23 additional individuals demonstrated that these gut microbial markers might be useful for classifying type 2 diabetes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Qin, Junjie -- Li, Yingrui -- Cai, Zhiming -- Li, Shenghui -- Zhu, Jianfeng -- Zhang, Fan -- Liang, Suisha -- Zhang, Wenwei -- Guan, Yuanlin -- Shen, Dongqian -- Peng, Yangqing -- Zhang, Dongya -- Jie, Zhuye -- Wu, Wenxian -- Qin, Youwen -- Xue, Wenbin -- Li, Junhua -- Han, Lingchuan -- Lu, Donghui -- Wu, Peixian -- Dai, Yali -- Sun, Xiaojuan -- Li, Zesong -- Tang, Aifa -- Zhong, Shilong -- Li, Xiaoping -- Chen, Weineng -- Xu, Ran -- Wang, Mingbang -- Feng, Qiang -- Gong, Meihua -- Yu, Jing -- Zhang, Yanyan -- Zhang, Ming -- Hansen, Torben -- Sanchez, Gaston -- Raes, Jeroen -- Falony, Gwen -- Okuda, Shujiro -- Almeida, Mathieu -- LeChatelier, Emmanuelle -- Renault, Pierre -- Pons, Nicolas -- Batto, Jean-Michel -- Zhang, Zhaoxi -- Chen, Hua -- Yang, Ruifu -- Zheng, Weimou -- Li, Songgang -- Yang, Huanming -- Wang, Jian -- Ehrlich, S Dusko -- Nielsen, Rasmus -- Pedersen, Oluf -- Kristiansen, Karsten -- Wang, Jun -- England -- Nature. 2012 Oct 4;490(7418):55-60. doi: 10.1038/nature11450. Epub 2012 Sep 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉BGI-Shenzhen, Shenzhen 518083, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23023125" target="_blank"〉PubMed〈/a〉
    Keywords: Asian Continental Ancestry Group ; Butyrates/metabolism ; China/ethnology ; Cohort Studies ; Diabetes Mellitus, Type ; 2/classification/complications/*microbiology/physiopathology ; Feces/microbiology ; Genetic Linkage/genetics ; Genetic Markers ; Genome-Wide Association Study/*methods ; High-Throughput Nucleotide Sequencing ; Humans ; Intestines/*microbiology ; Metabolic Networks and Pathways/genetics ; Metagenome/*genetics ; Metagenomics/*methods ; Opportunistic Infections/complications/microbiology ; Reference Standards ; Sulfates/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 9
    Publication Date: 2013-07-12
    Description: On 29 March 2013, the Chinese Center for Disease Control and Prevention confirmed the first reported case of human infection with an avian influenza A(H7N9) virus. The recent human infections with H7N9 virus, totalling over 130 cases with 39 fatalities to date, have been characterized by severe pulmonary disease and acute respiratory distress syndrome (ARDS). This is concerning because H7 viruses have typically been associated with ocular disease in humans, rather than severe respiratory disease. This recent outbreak underscores the need to better understand the pathogenesis and transmission of these viruses in mammals. Here we assess the ability of A/Anhui/1/2013 and A/Shanghai/1/2013 (H7N9) viruses, isolated from fatal human cases, to cause disease in mice and ferrets and to transmit to naive animals. Both H7N9 viruses replicated to higher titre in human airway epithelial cells and in the respiratory tract of ferrets compared to a seasonal H3N2 virus. Moreover, the H7N9 viruses showed greater infectivity and lethality in mice compared to genetically related H7N9 and H9N2 viruses. The H7N9 viruses were readily transmitted to naive ferrets through direct contact but, unlike the seasonal H3N2 virus, did not transmit readily by respiratory droplets. The lack of efficient respiratory droplet transmission was corroborated by low receptor-binding specificity for human-like alpha2,6-linked sialosides. Our results indicate that H7N9 viruses have the capacity for efficient replication in mammals and human airway cells and highlight the need for continued public health surveillance of this emerging virus.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Belser, Jessica A -- Gustin, Kortney M -- Pearce, Melissa B -- Maines, Taronna R -- Zeng, Hui -- Pappas, Claudia -- Sun, Xiangjie -- Carney, Paul J -- Villanueva, Julie M -- Stevens, James -- Katz, Jacqueline M -- Tumpey, Terrence M -- GM62116/GM/NIGMS NIH HHS/ -- England -- Nature. 2013 Sep 26;501(7468):556-9. doi: 10.1038/nature12391. Epub 2013 Jul 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia 30333, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23842497" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Cell Polarity ; Disease Models, Animal ; Epithelial Cells/virology ; Female ; Ferrets/*virology ; Humans ; Influenza A Virus, H3N2 Subtype/growth & development/pathogenicity ; Influenza A Virus, H9N2 Subtype/growth & development/pathogenicity ; Influenza A virus/growth & development/isolation & ; purification/metabolism/*pathogenicity ; Influenza, Human/virology ; Madin Darby Canine Kidney Cells ; Male ; Mice/*virology ; Mice, Inbred BALB C ; Orthomyxoviridae Infections/*transmission/*virology ; Polysaccharides/chemistry/metabolism ; Receptors, Virus/chemistry/metabolism ; Respiratory System/cytology ; Substrate Specificity ; Virus Replication/physiology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 10
    Publication Date: 2014-11-11
    Description: Lysosomal degradation of cytoplasmic components by autophagy is essential for cellular survival and homeostasis under nutrient-deprived conditions. Acute regulation of autophagy by nutrient-sensing kinases is well defined, but longer-term transcriptional regulation is relatively unknown. Here we show that the fed-state sensing nuclear receptor farnesoid X receptor (FXR) and the fasting transcriptional activator cAMP response element-binding protein (CREB) coordinately regulate the hepatic autophagy gene network. Pharmacological activation of FXR repressed many autophagy genes and inhibited autophagy even in fasted mice, and feeding-mediated inhibition of macroautophagy was attenuated in FXR-knockout mice. From mouse liver chromatin immunoprecipitation and high-throughput sequencing data, FXR and CREB binding peaks were detected at 178 and 112 genes, respectively, out of 230 autophagy-related genes, and 78 genes showed shared binding, mostly in their promoter regions. CREB promoted autophagic degradation of lipids, or lipophagy, under nutrient-deprived conditions, and FXR inhibited this response. Mechanistically, CREB upregulated autophagy genes, including Atg7, Ulk1 and Tfeb, by recruiting the coactivator CRTC2. After feeding or pharmacological activation, FXR trans-repressed these genes by disrupting the functional CREB-CRTC2 complex. This study identifies the new FXR-CREB axis as a key physiological switch regulating autophagy, resulting in sustained nutrient regulation of autophagy during feeding/fasting cycles.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4257899/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4257899/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Seok, Sunmi -- Fu, Ting -- Choi, Sung-E -- Li, Yang -- Zhu, Rong -- Kumar, Subodh -- Sun, Xiaoxiao -- Yoon, Gyesoon -- Kang, Yup -- Zhong, Wenxuan -- Ma, Jian -- Kemper, Byron -- Kemper, Jongsook Kim -- DK62777/DK/NIDDK NIH HHS/ -- DK95842/DK/NIDDK NIH HHS/ -- R01 DK062777/DK/NIDDK NIH HHS/ -- R01 DK095842/DK/NIDDK NIH HHS/ -- England -- Nature. 2014 Dec 4;516(7529):108-11. doi: 10.1038/nature13949. Epub 2014 Nov 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA. ; 1] Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA [2] Institute for Medical Science, Ajou University School of Medicine, Suwon 442-749, Korea. ; Department of Bioengineering and the Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA. ; Department of Statistics, University of Georgia, Athens, Gerogia 30602, USA. ; Institute for Medical Science, Ajou University School of Medicine, Suwon 442-749, Korea.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25383523" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Autophagy/*genetics ; Cyclic AMP Response Element-Binding Protein/*metabolism ; Fasting/physiology ; *Gene Expression Regulation/drug effects ; Isoxazoles/pharmacology ; Liver/cytology/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Protein Binding ; Receptors, Cytoplasmic and Nuclear/agonists/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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