MAP kinases transduce signals that are involved in a multitude of cellular pathways and functions in response to a variety of ligands and cell stimuli. Aberrant or inappropriate functions of MAPKs have now been identi...MAP kinases transduce signals that are involved in a multitude of cellular pathways and functions in response to a variety of ligands and cell stimuli. Aberrant or inappropriate functions of MAPKs have now been identified in diseases ranging from cancer to inflammatory disease to obesity and diabetes. In many cell types, the MAPKs ERK1/2 are linked to cell proliferation. ERK1/2 are thought to play a role in some cancers, because mutations in Ras and B-Raf, which can activate the ERK1/2 cascade, are found in many human tumors. Abnormal ERK1/2 signaling has also been found in polycystic kidney disease, and serious developmental disorders such as cardio-facio-cutaneous syndrome arise from mutations in components of the ERK1/2 cascade. ERK1/2 are essential in well-differentiated cells and have been linked to long-term potentiation in neurons and in maintenance of epithelial polarity. Additionally, ERK1/2 are important for insulin gene transcription in pancreatic beta cells, which produce insulin in response to increases in circulating glucose to permit efficient glucose utilization and storage in the organism. Nutrients and hormones that induce or repress insulin secretion activate and/or inhibit ERK1/2 in a manner that reflects the secretory demand on beta cells. Disturbances in this and other regulatory pathways may result in the contribution of ERK1/2 to the etiology of certain human disorders.展开更多
The Keap1–Nrf2–ARE pathway is an important antioxidant defense mechanism that protects cells from oxidative stress and the Keap1–Nrf2 protein–protein interaction(PPI) has become an important drug target to upregul...The Keap1–Nrf2–ARE pathway is an important antioxidant defense mechanism that protects cells from oxidative stress and the Keap1–Nrf2 protein–protein interaction(PPI) has become an important drug target to upregulate the expression of ARE-controlled cytoprotective oxidative stress response enzymes in the development of therapeutic and preventive agents for a number of diseases and conditions. However, most known Nrf2 activators/ARE inducers are indirect inhibitors of Keap1–Nrf2PPI and they are electrophilic species that act by modifying the sulfhydryl groups of Keap1's cysteine residues. The electrophilicity of these indirect inhibitors may cause "off-target" side effects by reacting with cysteine residues of other important cellular proteins. Efforts have recently been focused on the development of direct inhibitors of Keap1–Nrf2 PPI. This article reviews these recent research efforts including the development of high throughput screening assays, the discovery of peptide and small molecule direct inhibitors, and the biophysical characterization of the binding of these inhibitors to the target Keap1 Kelch domain protein. These non-covalent direct inhibitors of Keap1–Nrf2 PPI could potentially be developed into effective therapeutic or preventive agents for a variety of diseases and conditions.展开更多
The FAIR principles have been widely cited,endorsed and adopted by a broad range of stakeholders since their publication in 2016.By intention,the 15 FAIR guiding principles do not dictate specific technological implem...The FAIR principles have been widely cited,endorsed and adopted by a broad range of stakeholders since their publication in 2016.By intention,the 15 FAIR guiding principles do not dictate specific technological implementations,but provide guidance for improving Findability,Accessibility,Interoperability and Reusability of digital resources.This has likely contributed to the broad adoption of the FAIR principles,because individual stakeholder communities can implement their own FAIR solutions.However,it has also resulted in inconsistent interpretations that carry the risk of leading to incompatible implementations.Thus,while the FAIR principles are formulated on a high level and may be interpreted and implemented in different ways,for true interoperability we need to support convergence in implementation choices that are widely accessible and(re)-usable.We introduce the concept of FAIR implementation considerations to assist accelerated global participation and convergence towards accessible,robust,widespread and consistent FAIR implementations.Any self-identified stakeholder community may either choose to reuse solutions from existing implementations,or when they spot a gap,accept the challenge to create the needed solution,which,ideally,can be used again by other communities in the future.Here,we provide interpretations and implementation considerations(choices and challenges)for each FAIR principle.展开更多
AIMTo evaluate the effect of sitagliptin vs placebo on histologic and non-histologic parameters of non-alcoholic steatohepatitis (NASH).METHODSTwelve patients with biopsy-proven NASH were randomized to sitagliptin (10...AIMTo evaluate the effect of sitagliptin vs placebo on histologic and non-histologic parameters of non-alcoholic steatohepatitis (NASH).METHODSTwelve patients with biopsy-proven NASH were randomized to sitagliptin (100 mg daily) (n = 6) or placebo (n = 6) for 24 wk. The primary outcome was improvement in liver fibrosis after 24 wk. Secondary outcomes included evaluation of changes in NAFLD activity score (NAS), individual components of NAS (hepatocyte ballooning, lobular inflammation, and steatosis), glycemic control and insulin resistance [including measurements of glycated hemoglobin (HbA1C) and adipocytokines], lipid profile including free fatty acids, adipose distribution measured using magnetic resonance imaging (MRI), and thrombosis markers (platelet aggregation and plasminogen activator inhibitor 1 levels). We also sought to determine the correlation between changes in hepatic fat fraction (%) [as measured using the Iterative Decomposition of water and fat with Echo Asymmetry and Least-squares estimation (IDEAL) MRI technique] and changes in hepatic steatosis on liver biopsy.RESULTSSitagliptin was not significantly better than placebo at reducing liver fibrosis score as measured on liver biopsy (mean difference between sitagliptin and placebo arms, 0.40, P = 0.82). There were no significant improvements evident with the use of sitagliptin vs placebo for the secondary histologic outcomes of NAS total score as well as for the individual components of NAS. Compared to baseline, those patients who received sitagliptin demonstrated improved HbA1C (6.7% ± 0.4% vs 7.9% ± 1.0%, P = 0.02), and trended towards improved adiponectin levels (4.7 ± 3.5 μg/mL vs 3.9 ± 2.7 μg/mL, P = 0.06) and triglyceride levels (1.26 ± 0.43 mmol/L vs 2.80 ± 1.64 mmol/L, P = 0.08). However, when compared with placebo, sitagliptin did not cause a statistically significant improvement in HbA1C (mean difference, -0.7%, P = 0.19) nor triglyceride levels (mean difference -1.10 mm展开更多
Ethylene insensitive 2 （EIN2）, an integral membrane protein of the ER network, has been identified as the central regulator of the ethylene signaling pathway. Still, the mechanism by which the ethylene signal is tra...Ethylene insensitive 2 （EIN2）, an integral membrane protein of the ER network, has been identified as the central regulator of the ethylene signaling pathway. Still, the mechanism by which the ethylene signal is transferred from the receptors to EIN2 has not been solved yet. Here, we show that protein phosphorylation is a key mechanism to control the interaction of EIN2 and the receptors. In vivo and in vitro fluorescence studies reveal that the kinase domain of the receptors is essential for the interaction. Cyanide, an ethylene agonist, which is known to reduce auto-phosphorylation of the ethylene receptor ethylene resistant 1 （ETR1） or a mutation in the kinase domain of ETR1 that prevents autophosphorylation （H353A）, increases the affinity of the receptors for EIN2. On the other hand, mimicking permanent auto-phosphorylation of ETR1 as in the mutant H353E releases the EiN2-ETR1 interaction from the control by the plant hormone. Based on our data, we propose a novel model on the integration of EIN2 in the ethylene signaling cascade.展开更多
Classical interferon-alpha has been shown to be correlated with the development of a variety of autoimmune disorders. A 38 year-old female patient developed simultaneously diabetic ketoacidosis and hyperthyroidism 5 m...Classical interferon-alpha has been shown to be correlated with the development of a variety of autoimmune disorders. A 38 year-old female patient developed simultaneously diabetic ketoacidosis and hyperthyroidism 5 mo following initiation of treatment with pegylated interferon-α and ribavirin for chronic hepatitis C. High titers of glutamic acid decarboxylase, antinuclear and thyroid (thyroid peroxidase and thyroglobulin) antibodies were detected. Antiviral treatment was withdrawn and the patient was treated with insulin for insulin-dependent diabetes mellitus and propranolol for hyperthyroidism. Twelve months after cessation of pegylated interferon-α therapy the patient was euthyroid without any medication but remained insulin-dependent.展开更多
Traditional Chinese herbal drugs have been used for thousands of years in Chinese pharmacopoeia. The bark of Magnolia officinalis Rehder ＆ E. Wilson, known under the pinyin name ＂Houpo＂, has been traditionally used...Traditional Chinese herbal drugs have been used for thousands of years in Chinese pharmacopoeia. The bark of Magnolia officinalis Rehder ＆ E. Wilson, known under the pinyin name ＂Houpo＂, has been traditionally used in Chinese and Japanese medicines for the treatment of anxiety, asthma, depression, gastrointestinal disorders, headache, and more. Moreover, Magnolia bark extract is a major constituent of currently marketed dietary supplements and cosmetic products. Much pharmacological activity has been reported for this herb and its major compounds notably antioxidant, anti-inflammatory, antibiotic and antispasmodic effects. However, the mechanisms underlying this have not been elucidated and only a very few clinical trials have been published. In vitro and in vivo toxicity studies have also been published and indicate some intriguing features. The present review aims to summarize the literature on M. officinalis bark composition, utilisation, pharmacology, and safety.展开更多
Improved seed composition in soybean [Glycine max (L.) Merr.] for protein and oil quality is one of the major goals of soybean breeders. A group of genes that act as quantitative traits with their effects can alter pr...Improved seed composition in soybean [Glycine max (L.) Merr.] for protein and oil quality is one of the major goals of soybean breeders. A group of genes that act as quantitative traits with their effects can alter protein, oil, palmitic, stearic, oleic, linoleic, and linolenic acids percentage in soybean seeds. The objective of this study was to identify Quantitative Trait Loci (QTL) controlling protein, oil, and fatty acids content in a set of F5:8 RILs derived from a cross between lines, ‘MD 96-5722’ and ‘Spencer’ using 5376 Single Nucleotide Polymorphism (SNP) markers from the Illumina Infinium SoySNP6K BeadChip array. QTL analysis used WinQTL Cart 2.5 software for composite interval mapping (CIM). Identified, were;one protein content QTL on linkage group (LG-) B2 or chromosome (Chr_) 14;11 QTL associated with oil content on six linkage groups LG-N (Chr_3), LG-A1 (Chr_5), LG-K (Chr_9), LG-F (Chr_13), LG-B2 (Chr_14), and LG-J (Chr_16);and sixteen QTL for five major fatty acids (palmitic, stearic, oleic, linoleic, and linolenic acids) on LG-N (Chr_3), LG-F (Chr_13), LG-B2 (Chr_14), LG-E (Chr_15), LG-J (Chr_16), and LG-G (Chr_18). The SNP markers closely linked to the QTL reported here will be useful for development of cultivars with altered oil and fatty acid compositions in soybean breeding programs.展开更多
Transforming growth factor-β(TGF-β)and bone morphogenetic protein(BMP)play important roles in bone metabolism.Smad ubiquitination regulatory factors(Smurfs)regulate TGF-β/BMP signaling via ubiquitination,resulting ...Transforming growth factor-β(TGF-β)and bone morphogenetic protein(BMP)play important roles in bone metabolism.Smad ubiquitination regulatory factors(Smurfs)regulate TGF-β/BMP signaling via ubiquitination,resulting in degradation of signaling molecules to prevent excessive activation of TGF-β/BMP signaling.Though Smurf2 has been shown to negatively regulate TGF-β/Smad signaling,its involvement in BMP/Smad signaling in bone metabolism has not been thoroughly investigated.In the present study,we sought to evaluate the role of Smurf2 in BMP/Smad signaling in bone metabolism.Absorbable collagen sponges containing 3μg of recombinant human BMP2(rhBMP2)were implanted in the dorsal muscle pouches of wild type(WT)and Smurf2−/−mice.The rhBMP2-induced ectopic bone in Smurf2−/−mice showed greater bone mass,higher mineral apposition and bone formation rates,and greater osteoblast numbers than the ectopic bone in WT mice.In WT mice,the ectopic bone consisted of a thin discontinuous outer cortical shell and scant inner trabecular bone.In contrast,in Smurf2−/−mice,the induced bone consisted of a thick,continuous outer cortical shell and abundant inner trabecular bone.Additionally,rhBMP2-stimulated bone marrow stromal cells(BMSCs)from Smurf2−/−mice showed increased osteogenic differentiation.Smurf2 induced the ubiquitination of Smad1/5.BMP/Smad signaling was enhanced in Smurf2−/−BMSCs stimulated with rhBMP2,and the inhibition of BMP/Smad signaling suppressed osteogenic differentiation of these BMSCs.These findings demonstrate that Smurf2 negatively regulates BMP/Smad signaling,thereby identifying a new regulatory mechanism in bone metabolism.展开更多
This article draws on a rich empirical literature on comparative corruption and rich theoretical literatures on the related topics ofinstitutions and credible commitment to analyze China’s newestanticorruption campai...This article draws on a rich empirical literature on comparative corruption and rich theoretical literatures on the related topics ofinstitutions and credible commitment to analyze China’s newestanticorruption campaign, ongoing today. It argues that the campaign differs notably from previous efforts. In addition to its mostobvious features of longer duration and higher reach, the campaign has significantly changed the structure of Party and government incentives so as to reduce bureaucratic opportunities forcorruption and structural obstacles to anticorruption enforcement.These features constitute important steps toward anticorruptioninstitutionalisation and credible commitment to good governance.The article concludes by proposing some strategic policy choicesto promote and protect anticorruption gains.展开更多
Objective This study aims to assess the status of successful aging （SA） in longevity areas in China and explore multiple factors associated with SA among the young-old and oldest-old. Methods A total of 2296 elderly...Objective This study aims to assess the status of successful aging （SA） in longevity areas in China and explore multiple factors associated with SA among the young-old and oldest-old. Methods A total of 2296 elderly people aged 65 and older were interviewed in the longevity areas sub-sample of the Chinese Longitudinal Healthy Longevity Survey （CLHLS） in 2012. Baseline assessments included a researcher-administered questionnaire, physical examination, and laboratory testing. A logistic regression model was used to identify factors associated with SA. Results The prevalence of SA was 38.81% in the CLHLS in 2012. There were significant differences between ages groups, with SA compromising 56.85% among _〉65 years group and 20.31% among 〉100 years group （X2trend=126.73, P〈O.01）. The prevalence of SA among females was 33.59%, which was significantly lower than that among males （45.58%） （X2gender=33.65, P〈0.05）. In the regression analysis, having anemia ~OR=0.744, 95% CI： 0.609-0.910）, poor lifestyle （OR=0.697, 95% CI： 0.568-0.854）, poor sleep quality （OR=0.558, 95% CI： 0.456-0.682）, and central obesity （OR=0.684, 95% CI： 0.556-0.841） were the main factors associated with SA. The promoting SA rate decreased as age increased, and the group of 65-79 years had higher odds than the other age group. Conclusion Preventing central obesity, improving sleep quality and promoting healthy lifestyle may contribute to achieve SA among the elderly.展开更多
Carotenoids are pigments required for photosynthesis, photoprotection and the production of carotenoid- derived hormones such as ABA and strigolactones. The carotenoid biosynthetic pathway bifurcates after lycopene to...Carotenoids are pigments required for photosynthesis, photoprotection and the production of carotenoid- derived hormones such as ABA and strigolactones. The carotenoid biosynthetic pathway bifurcates after lycopene to produce epsilon- and beta-carotenoids and this branch is critical for determining carotenoid composition. Here, we show how the branch point can be regulated by the chromatin-modifying histone methyltransferase, Set Domain Group 8 （SDG8） targeting the carotenoid isomerase （CRTISO）. SDG8 is required to maintain permissive expression of CRTISO during seedling development, in leaves, shoot apex, and some floral organs. The CRTISO and SDG8 promoters show overlapping tissue-specific patterns of reporter gene activity. Interestingly, CRTISO showed atypical reporter gene expression in terms of greater variability between different lines compared to the Cauliflower Mosaic Virus 35S promoter （CaMV35s） and ~LCY promoters, potentially due to chromosomal position effects. Regulation of the CRTISO promoter was dependent in part upon the presence or absence of SDG8. Knockouts of SDG8 （carotenoid and chloroplast regulation （ccrl）） and CRTISO （ccr2） result in altered carotenoid composition and this could be restored in ccr2 using the CaMV35s or CRTISO promoters. In contrast, varying degrees of GUS expression and carotenoid complementation by CRTISO overexpression using CaMV35S or CRTISO promoters in the ccrl background demonstrated that both the CRTISO promoter and open reading frame are necessary for SDG8-mediated expression of CRTISO.展开更多
Background: Acute lung injury(ALI) is a major component of multiple organ dysfunction syndrome(MODS) following pulmonary and systemic infection. Alveolar macrophages(AMφ) are at the center of ALI pathogenesis. Emergi...Background: Acute lung injury(ALI) is a major component of multiple organ dysfunction syndrome(MODS) following pulmonary and systemic infection. Alveolar macrophages(AMφ) are at the center of ALI pathogenesis. Emerging evidence has shown that cell-cell interactions in the lungs play an important regulatory role in the development of acute lung inflammation. However, the underneath mechanisms remain poorly addressed. In this study, we explore a novel function of lung epithelial cells(LEPCs) in regulating the release of exosomes from AMφ following LPS stimulation.Methods: For the in vivo experiments, C57 BL/6 wildtype(WT) mice were treated with lipopolysaccharide(LPS)(2 mg/kg) in 0.2 ml of saline via intratracheal aerosol administration. Bronchoalveolar lavage fluid was collected at 0–24 h after LPS treatment, and exosomes derived from AMφ were measured. For the in vitro studies, LEPCs and bone marrowderived Mφ(BMDM) were isolated from WT or TLR4-/-mice and were then cocultured in the Transwell? system. After coculture for 0–24 h, the BMDM and supernatant were harvested for the measurement of exosomes and cytokines.Results: We demonstrate that LPS induces macrophages(Mφ) to release exosomes, which are then internalized by neighboring Mφ to promote TNF-α expression. The secreted interleukin(IL)-25 from LEPCs downregulates Rab27 a and Rab27 b expression in Mφ, resulting in suppressed exosome release and thereby attenuating exosome-induced TNF-α expression and secretion.Conclusion: These findings reveal a previously unidentified crosstalk pathway between LEPCs and Mφ that negatively regulates the inflammatory responses of Mφ to LPS. Modulating IL-25 signaling and targeting exosome release may present a new therapeutic strategy for the treatment of ALI.展开更多
Medial tibial stress syndrome(MTSS) is a debilitating overuse injury of the tibia sustained by individuals whoperform recurrent impact exercise such as athletes and military recruits. Characterised by diffuse tibial a...Medial tibial stress syndrome(MTSS) is a debilitating overuse injury of the tibia sustained by individuals whoperform recurrent impact exercise such as athletes and military recruits. Characterised by diffuse tibial anteromedial or posteromedial surface subcutaneous periostitis, in most cases it is also an injury involving underlying cortical bone microtrauma, although it is not clear if the soft tissue or cortical bone reaction occurs first. Nuclear bone scans and magnetic resonance imaging(MRI) can both be used for the diagnosis of MTSS, but the patient's history and clinical symptoms need to be considered in conjunction with the imaging findings for a correct interpretation of the results, as both imaging modalities have demonstrated positive findings in the absence of injury. However, MRI is rapidly becoming the preferred imaging modality for the diagnosis of bone stress injuries. It can also be used for the early diagnosis of MTSS, as the developing periosteal oedema can be identified. Retrospective studies have demonstrated that MTSS patients have lower bone mineral density(BMD) at the injury site than exercising controls, and preliminary data indicates the BMD is lower in MTSS subjects than tibial stress fracture(TSF) subjects. The values of a number of tibial geometric parameters such as cross-sectional area and section modulus are also lower in MTSS subjects than exercising controls, but not as low as the values in TSF subjects. Thus, the balance between BMD and cortical bone geometry may predict an individual's likelihood of developing MTSS. However, prospective longitudinal studies are needed to determine how these factors alter during the development of the injury and to find the detailed structural cause, which is still unknown. Finite element analysis has recently been used to examine the mechanisms involved in tibial stress injuries and offer a promising future tool to understand the mechanisms involved in MTSS. Contemporary accurate diagnosis of either MTSS or a TSF includes a thorough clinical ex展开更多
文摘MAP kinases transduce signals that are involved in a multitude of cellular pathways and functions in response to a variety of ligands and cell stimuli. Aberrant or inappropriate functions of MAPKs have now been identified in diseases ranging from cancer to inflammatory disease to obesity and diabetes. In many cell types, the MAPKs ERK1/2 are linked to cell proliferation. ERK1/2 are thought to play a role in some cancers, because mutations in Ras and B-Raf, which can activate the ERK1/2 cascade, are found in many human tumors. Abnormal ERK1/2 signaling has also been found in polycystic kidney disease, and serious developmental disorders such as cardio-facio-cutaneous syndrome arise from mutations in components of the ERK1/2 cascade. ERK1/2 are essential in well-differentiated cells and have been linked to long-term potentiation in neurons and in maintenance of epithelial polarity. Additionally, ERK1/2 are important for insulin gene transcription in pancreatic beta cells, which produce insulin in response to increases in circulating glucose to permit efficient glucose utilization and storage in the organism. Nutrients and hormones that induce or repress insulin secretion activate and/or inhibit ERK1/2 in a manner that reflects the secretory demand on beta cells. Disturbances in this and other regulatory pathways may result in the contribution of ERK1/2 to the etiology of certain human disorders.
基金the financial support of Grants CA133791, CA125868, and MH093197 from the National Institutes of Health, United States
文摘The Keap1–Nrf2–ARE pathway is an important antioxidant defense mechanism that protects cells from oxidative stress and the Keap1–Nrf2 protein–protein interaction(PPI) has become an important drug target to upregulate the expression of ARE-controlled cytoprotective oxidative stress response enzymes in the development of therapeutic and preventive agents for a number of diseases and conditions. However, most known Nrf2 activators/ARE inducers are indirect inhibitors of Keap1–Nrf2PPI and they are electrophilic species that act by modifying the sulfhydryl groups of Keap1's cysteine residues. The electrophilicity of these indirect inhibitors may cause "off-target" side effects by reacting with cysteine residues of other important cellular proteins. Efforts have recently been focused on the development of direct inhibitors of Keap1–Nrf2 PPI. This article reviews these recent research efforts including the development of high throughput screening assays, the discovery of peptide and small molecule direct inhibitors, and the biophysical characterization of the binding of these inhibitors to the target Keap1 Kelch domain protein. These non-covalent direct inhibitors of Keap1–Nrf2 PPI could potentially be developed into effective therapeutic or preventive agents for a variety of diseases and conditions.
基金The work of A.Jacobsen,C.Evelo,M.Thompson,R.Cornet,R.Kaliyaperuma and M.Roos is supported by funding from the European Union’s Horizon 2020 research and innovation program under the EJP RD COFUND-EJP N°825575.The work of A.Jacobsen,C.Evelo,C.Goble,M.Thompson,N.Juty,R.Hooft,M.Roos,S-A.Sansone,P.McQuilton,P.Rocca-Serra and D.Batista is supported by funding from ELIXIR EXCELERATE,H2020 grant agreement number 676559.R.Hooft was further funded by NL NWO NRGWI.obrug.2018.009.N.Juty and C.Goble were funded by CORBEL(H2020 grant agreement 654248)N.Juty,C.Goble,S-A.Sansone,P.McQuilton,P.Rocca-Serra and D.Batista were funded by FAIRplus(IMI grant agreement 802750)+12 种基金N.Juty,C.Goble,M.Thompson,M.Roos,S-A.Sansone,P.McQuilton,P.Rocca-Serra and D.Batista were funded by EOSClife H2020-EU(grant agreement number 824087)C.Goble was funded by DMMCore(BBSRC BB/M013189/)M.Thompson,M.Roos received funding from NWO(VWData 400.17.605)S-A.Sansone,P.McQuilton,P.Rocca-Serra and D.Batista have been funded by grants awarded to S-A.Sansone from the UK BBSRC and Research Councils(BB/L024101/1,BB/L005069/1)EU(H2020-EU 634107H2020-EU 654241,IMI(IMPRiND 116060)NIH Data Common Fund,and from the Wellcome Trust(ISA-InterMine 212930/Z/18/ZFAIRsharing 208381/A/17/Z)The work of A.Waagmeester has been funded by grant award number GM089820 from the National Institutes of Health.M.Kersloot was funded by the European Regional Development Fund(KVW-00163).The work of N.Meyers was funded by the National Science Foundation(OAC 1839030)The work of M.D.Wilkinson is funded by Isaac Peral/Marie Curie cofund with the Universidad Politecnica de Madrid and the Ministerio de Economia y Competitividad grant number TIN2014-55993-RMThe work of B.Magagna,E.Schultes,L.da Silva Santos and K.Jeffery is funded by the H2020-EU 824068The work of B.Magagna,E.Schultes and L.da Silva Santos is funded by the GO FAIR ISCO grant of the Dutch Ministry of Science and CultureThe work of G.Guizzardi is supported by the OCEAN Project(FUB).M.Courtot received funding from the I
文摘The FAIR principles have been widely cited,endorsed and adopted by a broad range of stakeholders since their publication in 2016.By intention,the 15 FAIR guiding principles do not dictate specific technological implementations,but provide guidance for improving Findability,Accessibility,Interoperability and Reusability of digital resources.This has likely contributed to the broad adoption of the FAIR principles,because individual stakeholder communities can implement their own FAIR solutions.However,it has also resulted in inconsistent interpretations that carry the risk of leading to incompatible implementations.Thus,while the FAIR principles are formulated on a high level and may be interpreted and implemented in different ways,for true interoperability we need to support convergence in implementation choices that are widely accessible and(re)-usable.We introduce the concept of FAIR implementation considerations to assist accelerated global participation and convergence towards accessible,robust,widespread and consistent FAIR implementations.Any self-identified stakeholder community may either choose to reuse solutions from existing implementations,or when they spot a gap,accept the challenge to create the needed solution,which,ideally,can be used again by other communities in the future.Here,we provide interpretations and implementation considerations(choices and challenges)for each FAIR principle.
基金the Physicians’Services Incorporated Foundation 10q2083(Joy TR and Beaton MD)Academic Medical Organization of Southwestern Ontario,No.F10-002(Beaton MD)+1 种基金partly funded through academic research funds from the Program of Experimental Medicine(Joy TR)Department of Medicine Academic Funds(Joy TR)from Western University,London,Ontario,Canada
文摘AIMTo evaluate the effect of sitagliptin vs placebo on histologic and non-histologic parameters of non-alcoholic steatohepatitis (NASH).METHODSTwelve patients with biopsy-proven NASH were randomized to sitagliptin (100 mg daily) (n = 6) or placebo (n = 6) for 24 wk. The primary outcome was improvement in liver fibrosis after 24 wk. Secondary outcomes included evaluation of changes in NAFLD activity score (NAS), individual components of NAS (hepatocyte ballooning, lobular inflammation, and steatosis), glycemic control and insulin resistance [including measurements of glycated hemoglobin (HbA1C) and adipocytokines], lipid profile including free fatty acids, adipose distribution measured using magnetic resonance imaging (MRI), and thrombosis markers (platelet aggregation and plasminogen activator inhibitor 1 levels). We also sought to determine the correlation between changes in hepatic fat fraction (%) [as measured using the Iterative Decomposition of water and fat with Echo Asymmetry and Least-squares estimation (IDEAL) MRI technique] and changes in hepatic steatosis on liver biopsy.RESULTSSitagliptin was not significantly better than placebo at reducing liver fibrosis score as measured on liver biopsy (mean difference between sitagliptin and placebo arms, 0.40, P = 0.82). There were no significant improvements evident with the use of sitagliptin vs placebo for the secondary histologic outcomes of NAS total score as well as for the individual components of NAS. Compared to baseline, those patients who received sitagliptin demonstrated improved HbA1C (6.7% ± 0.4% vs 7.9% ± 1.0%, P = 0.02), and trended towards improved adiponectin levels (4.7 ± 3.5 μg/mL vs 3.9 ± 2.7 μg/mL, P = 0.06) and triglyceride levels (1.26 ± 0.43 mmol/L vs 2.80 ± 1.64 mmol/L, P = 0.08). However, when compared with placebo, sitagliptin did not cause a statistically significant improvement in HbA1C (mean difference, -0.7%, P = 0.19) nor triglyceride levels (mean difference -1.10 mm
文摘Ethylene insensitive 2 （EIN2）, an integral membrane protein of the ER network, has been identified as the central regulator of the ethylene signaling pathway. Still, the mechanism by which the ethylene signal is transferred from the receptors to EIN2 has not been solved yet. Here, we show that protein phosphorylation is a key mechanism to control the interaction of EIN2 and the receptors. In vivo and in vitro fluorescence studies reveal that the kinase domain of the receptors is essential for the interaction. Cyanide, an ethylene agonist, which is known to reduce auto-phosphorylation of the ethylene receptor ethylene resistant 1 （ETR1） or a mutation in the kinase domain of ETR1 that prevents autophosphorylation （H353A）, increases the affinity of the receptors for EIN2. On the other hand, mimicking permanent auto-phosphorylation of ETR1 as in the mutant H353E releases the EiN2-ETR1 interaction from the control by the plant hormone. Based on our data, we propose a novel model on the integration of EIN2 in the ethylene signaling cascade.
文摘Classical interferon-alpha has been shown to be correlated with the development of a variety of autoimmune disorders. A 38 year-old female patient developed simultaneously diabetic ketoacidosis and hyperthyroidism 5 mo following initiation of treatment with pegylated interferon-α and ribavirin for chronic hepatitis C. High titers of glutamic acid decarboxylase, antinuclear and thyroid (thyroid peroxidase and thyroglobulin) antibodies were detected. Antiviral treatment was withdrawn and the patient was treated with insulin for insulin-dependent diabetes mellitus and propranolol for hyperthyroidism. Twelve months after cessation of pegylated interferon-α therapy the patient was euthyroid without any medication but remained insulin-dependent.
文摘Traditional Chinese herbal drugs have been used for thousands of years in Chinese pharmacopoeia. The bark of Magnolia officinalis Rehder ＆ E. Wilson, known under the pinyin name ＂Houpo＂, has been traditionally used in Chinese and Japanese medicines for the treatment of anxiety, asthma, depression, gastrointestinal disorders, headache, and more. Moreover, Magnolia bark extract is a major constituent of currently marketed dietary supplements and cosmetic products. Much pharmacological activity has been reported for this herb and its major compounds notably antioxidant, anti-inflammatory, antibiotic and antispasmodic effects. However, the mechanisms underlying this have not been elucidated and only a very few clinical trials have been published. In vitro and in vivo toxicity studies have also been published and indicate some intriguing features. The present review aims to summarize the literature on M. officinalis bark composition, utilisation, pharmacology, and safety.
文摘Improved seed composition in soybean [Glycine max (L.) Merr.] for protein and oil quality is one of the major goals of soybean breeders. A group of genes that act as quantitative traits with their effects can alter protein, oil, palmitic, stearic, oleic, linoleic, and linolenic acids percentage in soybean seeds. The objective of this study was to identify Quantitative Trait Loci (QTL) controlling protein, oil, and fatty acids content in a set of F5:8 RILs derived from a cross between lines, ‘MD 96-5722’ and ‘Spencer’ using 5376 Single Nucleotide Polymorphism (SNP) markers from the Illumina Infinium SoySNP6K BeadChip array. QTL analysis used WinQTL Cart 2.5 software for composite interval mapping (CIM). Identified, were;one protein content QTL on linkage group (LG-) B2 or chromosome (Chr_) 14;11 QTL associated with oil content on six linkage groups LG-N (Chr_3), LG-A1 (Chr_5), LG-K (Chr_9), LG-F (Chr_13), LG-B2 (Chr_14), and LG-J (Chr_16);and sixteen QTL for five major fatty acids (palmitic, stearic, oleic, linoleic, and linolenic acids) on LG-N (Chr_3), LG-F (Chr_13), LG-B2 (Chr_14), LG-E (Chr_15), LG-J (Chr_16), and LG-G (Chr_18). The SNP markers closely linked to the QTL reported here will be useful for development of cultivars with altered oil and fatty acid compositions in soybean breeding programs.
基金the JSPS Grant-in-Aid(C)grant number 17K11005the JSPS bilateral Joint Research Project grant number 1007397 to T.K.,MEXT/JSPS grant number JP19K12218 to T.S.,MEXT/JSPS grant number JP15H05952(“Resonance Bio”)to T.S.and T.I.,and MEXT/JSPS KAKENHI grant number JP16H06280(“Advanced Bioimaging Support”)。
文摘Transforming growth factor-β(TGF-β)and bone morphogenetic protein(BMP)play important roles in bone metabolism.Smad ubiquitination regulatory factors(Smurfs)regulate TGF-β/BMP signaling via ubiquitination,resulting in degradation of signaling molecules to prevent excessive activation of TGF-β/BMP signaling.Though Smurf2 has been shown to negatively regulate TGF-β/Smad signaling,its involvement in BMP/Smad signaling in bone metabolism has not been thoroughly investigated.In the present study,we sought to evaluate the role of Smurf2 in BMP/Smad signaling in bone metabolism.Absorbable collagen sponges containing 3μg of recombinant human BMP2(rhBMP2)were implanted in the dorsal muscle pouches of wild type(WT)and Smurf2−/−mice.The rhBMP2-induced ectopic bone in Smurf2−/−mice showed greater bone mass,higher mineral apposition and bone formation rates,and greater osteoblast numbers than the ectopic bone in WT mice.In WT mice,the ectopic bone consisted of a thin discontinuous outer cortical shell and scant inner trabecular bone.In contrast,in Smurf2−/−mice,the induced bone consisted of a thick,continuous outer cortical shell and abundant inner trabecular bone.Additionally,rhBMP2-stimulated bone marrow stromal cells(BMSCs)from Smurf2−/−mice showed increased osteogenic differentiation.Smurf2 induced the ubiquitination of Smad1/5.BMP/Smad signaling was enhanced in Smurf2−/−BMSCs stimulated with rhBMP2,and the inhibition of BMP/Smad signaling suppressed osteogenic differentiation of these BMSCs.These findings demonstrate that Smurf2 negatively regulates BMP/Smad signaling,thereby identifying a new regulatory mechanism in bone metabolism.
文摘This article draws on a rich empirical literature on comparative corruption and rich theoretical literatures on the related topics ofinstitutions and credible commitment to analyze China’s newestanticorruption campaign, ongoing today. It argues that the campaign differs notably from previous efforts. In addition to its mostobvious features of longer duration and higher reach, the campaign has significantly changed the structure of Party and government incentives so as to reduce bureaucratic opportunities forcorruption and structural obstacles to anticorruption enforcement.These features constitute important steps toward anticorruptioninstitutionalisation and credible commitment to good governance.The article concludes by proposing some strategic policy choicesto promote and protect anticorruption gains.
基金supported by National Natural Science Foundation of China[81273160,71233001,71110107025]United Nations Population Fund and the United States National Institutes of Health[R01AG23627]
文摘Objective This study aims to assess the status of successful aging （SA） in longevity areas in China and explore multiple factors associated with SA among the young-old and oldest-old. Methods A total of 2296 elderly people aged 65 and older were interviewed in the longevity areas sub-sample of the Chinese Longitudinal Healthy Longevity Survey （CLHLS） in 2012. Baseline assessments included a researcher-administered questionnaire, physical examination, and laboratory testing. A logistic regression model was used to identify factors associated with SA. Results The prevalence of SA was 38.81% in the CLHLS in 2012. There were significant differences between ages groups, with SA compromising 56.85% among _〉65 years group and 20.31% among 〉100 years group （X2trend=126.73, P〈O.01）. The prevalence of SA among females was 33.59%, which was significantly lower than that among males （45.58%） （X2gender=33.65, P〈0.05）. In the regression analysis, having anemia ~OR=0.744, 95% CI： 0.609-0.910）, poor lifestyle （OR=0.697, 95% CI： 0.568-0.854）, poor sleep quality （OR=0.558, 95% CI： 0.456-0.682）, and central obesity （OR=0.684, 95% CI： 0.556-0.841） were the main factors associated with SA. The promoting SA rate decreased as age increased, and the group of 65-79 years had higher odds than the other age group. Conclusion Preventing central obesity, improving sleep quality and promoting healthy lifestyle may contribute to achieve SA among the elderly.
文摘Carotenoids are pigments required for photosynthesis, photoprotection and the production of carotenoid- derived hormones such as ABA and strigolactones. The carotenoid biosynthetic pathway bifurcates after lycopene to produce epsilon- and beta-carotenoids and this branch is critical for determining carotenoid composition. Here, we show how the branch point can be regulated by the chromatin-modifying histone methyltransferase, Set Domain Group 8 （SDG8） targeting the carotenoid isomerase （CRTISO）. SDG8 is required to maintain permissive expression of CRTISO during seedling development, in leaves, shoot apex, and some floral organs. The CRTISO and SDG8 promoters show overlapping tissue-specific patterns of reporter gene activity. Interestingly, CRTISO showed atypical reporter gene expression in terms of greater variability between different lines compared to the Cauliflower Mosaic Virus 35S promoter （CaMV35s） and ~LCY promoters, potentially due to chromosomal position effects. Regulation of the CRTISO promoter was dependent in part upon the presence or absence of SDG8. Knockouts of SDG8 （carotenoid and chloroplast regulation （ccrl）） and CRTISO （ccr2） result in altered carotenoid composition and this could be restored in ccr2 using the CaMV35s or CRTISO promoters. In contrast, varying degrees of GUS expression and carotenoid complementation by CRTISO overexpression using CaMV35S or CRTISO promoters in the ccrl background demonstrated that both the CRTISO promoter and open reading frame are necessary for SDG8-mediated expression of CRTISO.
基金supported by the National Institute of Health Grant(R01-HL-079669 by JF and MAW)the National Institute of Health Grant(R56-HL-123882 by JF)+3 种基金the National Institute of Health Grant(R01HL076179–09 by PW and JF)the VA Merit Award(1I01BX002729 by JF)the National Natural Science Foundation of China(81470262 by JF)the National Institute of Health Grant(R01GM102146 by MJS)
文摘Background: Acute lung injury(ALI) is a major component of multiple organ dysfunction syndrome(MODS) following pulmonary and systemic infection. Alveolar macrophages(AMφ) are at the center of ALI pathogenesis. Emerging evidence has shown that cell-cell interactions in the lungs play an important regulatory role in the development of acute lung inflammation. However, the underneath mechanisms remain poorly addressed. In this study, we explore a novel function of lung epithelial cells(LEPCs) in regulating the release of exosomes from AMφ following LPS stimulation.Methods: For the in vivo experiments, C57 BL/6 wildtype(WT) mice were treated with lipopolysaccharide(LPS)(2 mg/kg) in 0.2 ml of saline via intratracheal aerosol administration. Bronchoalveolar lavage fluid was collected at 0–24 h after LPS treatment, and exosomes derived from AMφ were measured. For the in vitro studies, LEPCs and bone marrowderived Mφ(BMDM) were isolated from WT or TLR4-/-mice and were then cocultured in the Transwell? system. After coculture for 0–24 h, the BMDM and supernatant were harvested for the measurement of exosomes and cytokines.Results: We demonstrate that LPS induces macrophages(Mφ) to release exosomes, which are then internalized by neighboring Mφ to promote TNF-α expression. The secreted interleukin(IL)-25 from LEPCs downregulates Rab27 a and Rab27 b expression in Mφ, resulting in suppressed exosome release and thereby attenuating exosome-induced TNF-α expression and secretion.Conclusion: These findings reveal a previously unidentified crosstalk pathway between LEPCs and Mφ that negatively regulates the inflammatory responses of Mφ to LPS. Modulating IL-25 signaling and targeting exosome release may present a new therapeutic strategy for the treatment of ALI.
文摘Medial tibial stress syndrome(MTSS) is a debilitating overuse injury of the tibia sustained by individuals whoperform recurrent impact exercise such as athletes and military recruits. Characterised by diffuse tibial anteromedial or posteromedial surface subcutaneous periostitis, in most cases it is also an injury involving underlying cortical bone microtrauma, although it is not clear if the soft tissue or cortical bone reaction occurs first. Nuclear bone scans and magnetic resonance imaging(MRI) can both be used for the diagnosis of MTSS, but the patient's history and clinical symptoms need to be considered in conjunction with the imaging findings for a correct interpretation of the results, as both imaging modalities have demonstrated positive findings in the absence of injury. However, MRI is rapidly becoming the preferred imaging modality for the diagnosis of bone stress injuries. It can also be used for the early diagnosis of MTSS, as the developing periosteal oedema can be identified. Retrospective studies have demonstrated that MTSS patients have lower bone mineral density(BMD) at the injury site than exercising controls, and preliminary data indicates the BMD is lower in MTSS subjects than tibial stress fracture(TSF) subjects. The values of a number of tibial geometric parameters such as cross-sectional area and section modulus are also lower in MTSS subjects than exercising controls, but not as low as the values in TSF subjects. Thus, the balance between BMD and cortical bone geometry may predict an individual's likelihood of developing MTSS. However, prospective longitudinal studies are needed to determine how these factors alter during the development of the injury and to find the detailed structural cause, which is still unknown. Finite element analysis has recently been used to examine the mechanisms involved in tibial stress injuries and offer a promising future tool to understand the mechanisms involved in MTSS. Contemporary accurate diagnosis of either MTSS or a TSF includes a thorough clinical ex
