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  • 1
    Language: English
    In: Respiratory research, 2020-06-12, Vol.21 (1), p.149-149
    Description: Oral CXC chemokine receptor 2 (CXCR2) antagonists have been shown to inhibit neutrophil migration and activation in the lung in preclinical and human models of neutrophilic airway inflammation. A previous study with danirixin, a reversible CXCR2 antagonist, demonstrated a trend for improved respiratory symptoms and health status in patients with COPD. This 26-week, randomised, double-blind, placebo-controlled phase IIb study enrolled symptomatic patients with mild-to-moderate COPD at risk for exacerbations. Patients received danirixin 5, 10, 25, 35 or 50 mg twice daily or placebo in addition to standard of care. Primary end-points were the dose response of danirixin compared with placebo on the incidence and severity of respiratory symptoms (Evaluating Respiratory Symptoms in COPD [E-RS:COPD] scores) and safety. Secondary end-points included the incidence of moderate-severe exacerbations, health status (COPD Assessment test, CAT) and health-related quality of life HRQoL (St. George Respiratory Questionnaire-COPD, SGRQ-C). A total of 614 participants were randomized to treatment. There were no improvements in E-RS:COPD, CAT or SGRQ-C scores in participants treated with any dose of danirixin compared to placebo; a larger than expected placebo effect was observed. There was an increased incidence of exacerbation in the danirixin-treated groups and an increased number of pneumonias in participants treated with danirixin 50 mg. The robust placebo and study effects prohibited any conclusions on the efficacy of danirixin. However, the absence of a clear efficacy benefit and the observed increase in exacerbations in danirixin-treated groups suggests an unfavorable benefit-risk profile in patients with COPD. This study was registered with clinicaltrials.gov, NCT03034967.
    Subject(s): Follow-Up Studies ; Humans ; Middle Aged ; Male ; Pulmonary Disease, Chronic Obstructive - physiopathology ; Receptors, Interleukin-8B - antagonists & inhibitors ; Dose-Response Relationship, Drug ; Forced Expiratory Volume ; Young Adult ; Aged, 80 and over ; Adult ; Female ; Mucus - metabolism ; Surveys and Questionnaires ; Retrospective Studies ; Pulmonary Disease, Chronic Obstructive - metabolism ; Piperidines - administration & dosage ; Double-Blind Method ; Administration, Oral ; Lung - physiopathology ; Disease Progression ; Adolescent ; Aged ; Pulmonary Disease, Chronic Obstructive - drug therapy ; Sulfones - administration & dosage ; Clinical trial ; CXCR2 ; COPD ; Danirixin
    ISSN: 1465-993X
    E-ISSN: 1465-993X
    Source: BioMedCentral Open Access
    Source: Academic Search Ultimate
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 2
    Language: English
    In: Strategic management journal, 2021-04, Vol.42 (4), p.833-861
    Description: Research summary We examine how university entrepreneurship programs affect entrepreneurial activity using a unique entrepreneurship‐focused survey of Stanford alumni. OLS regressions find a positive relationship between program participation and entrepreneurship activities. However, endogeneity hinders causal interpretation. We utilize the fact that the entrepreneurship programs were implemented at the school level. Using the introduction of each school's program as an instrument for program participation, we find that the Business School program has a negative to zero impact on entrepreneurship rates. Participation in the Engineering School program has no impact on entrepreneurship rates. However, the Business School initiative decreases startup failure and increases firm revenue. University entrepreneurship programs may not increase entrepreneurship rates, but help students better identify their potential as entrepreneurs and improve the quality of entrepreneurship. Managerial summary Recently, many universities have developed programs to promote entrepreneurship. However, relatively little is known about the impacts of such university initiatives. In this article, we examine the two major initiatives that were established in the mid‐1990s—the Stanford Center for Entrepreneurial Studies at the Business School and the Stanford Technology Ventures Program at the Engineering School. We find that the Business School program had a negative to zero impact on entrepreneurship rates and participation in the Engineering School program had no impact on entrepreneurship rates. However, the Business School initiative decreased startup failure and increased firm revenue. University entrepreneurship programs may not increase entrepreneurship rates, but help students better identify their potential as entrepreneurs and improve the startup performance.
    Subject(s): alumni ; academic entrepreneurship ; ability ; universities ; self‐selection ; Businesspeople ; Engineering schools ; Business schools ; Entrepreneurship
    ISSN: 0143-2095
    E-ISSN: 1097-0266
    Source: Alma/SFX Local Collection
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  • 3
    Language: English
    In: Scientific reports, 2021-02-24, Vol.11 (1), p.4490-4490
    Description: With recent advances in biotechnology and sequencing technology, the microbial community has been intensively studied and discovered to be associated with many chronic as well as acute diseases. Even though a tremendous number of studies describing the association between microbes and diseases have been published, text mining methods that focus on such associations have been rarely studied. We propose a framework that combines machine learning and natural language processing methods to analyze the association between microbes and diseases. A hierarchical long short-term memory network was used to detect sentences that describe the association. For the sentences determined, two different parse tree-based search methods were combined to find the relation-describing word. The ensemble model of constituency parsing for structural pattern matching and dependency-based relation extraction improved the prediction accuracy. By combining deep learning and parse tree-based extractions, our proposed framework could extract the microbe-disease association with higher accuracy. The evaluation results showed that our system achieved an F-score of 0.8764 and 0.8524 in binary decisions and extracting relation words, respectively. As a case study, we performed a large-scale analysis of the association between microbes and diseases. Additionally, a set of common microbes shared by multiple diseases were also identified in this study. This study could provide valuable information for the major microbes that were studied for a specific disease. The code and data are available at https://github.com/DMnBI/mdi_predictor .
    Subject(s): Disease ; Short term memory ; Learning algorithms
    ISSN: 2045-2322
    E-ISSN: 2045-2322
    Source: Nature Open Access
    Source: Academic Search Ultimate
    Source: PubMed Central
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  • 4
    Language: English
    In: International journal of cancer, 2017-02-15, Vol.140 (4), p.798-806
    Description: Relationship on new statin use and the risk of hepatocellular carcinoma (HCC) in patients with incident type 2 diabetes mellitus (T2DM), who might be at the risk of developing HCC, is uncertained. A nationwide population–based nested case–control study was conducted within the National Health Insurance Service National Sample Cohort 2002–2013 in Korea. Newly prescribed statin after newly diagnosed T2DM was defined as statin use. Controls were matched to case patients on age, sex, follow–up time, and the date of diabetes diagnosis at a five–to–one ratio. Odds ratios (ORs) for associations of statin use with HCC were calculated using conditional logistic regression. After at least a 5‐year HCC–free period, there were 229 incident HCC cases and 1,145 matched controls from 47,738 patients with incident diabetes. Of these 229 incident HCC cases, 27 (11.8%) were statin users, whereas 378 (33.0%) were statin users among 1,145 controls. Statin use was associated with a reduced risk of HCC development (adjusted OR [AOR]= 0.36, 95% confidence interval [CI] 0.22–0.60) after adjustment for chronic viral hepatitis, liver cirrhosis, alcoholic liver disease, previous cancer, aspirin use, insulin use, sulfonylurea use, metformin use, thiazolidinedione use, history of chronic obstructive pulmonary disease, Charlson comorbidity score, household income level, and residential area. Risk reduction was accentuated with an increase of cumulative defined daily doses (cDDD) compared with non–users (AORs 0.53, 0.36, 0.32, and 0.26 in ≤60, 60–180, 181–365, and 〉365cDDD, respectively; P for trend 〈0.0001). The risk reduction was apparent in the presence of liver disease (AOR = 0.27, 95% CI 0.14–0.50), including heterogeneous groups of clinical diagnosis of liver disease, but not significant in the absence of liver disease (AOR = 0.64, 95% CI 0.32–1.29). Among patients with new onset T2DM, statin use before HCC diagnosis may have a beneficial inhibitory effect on HCC development in a dose–dependent manner, especially in individuals with liver disease. What's new? In a nationwide population‐based nested case‐control study, the association between statin use and the risk of hepatocellular carcinoma in patients with incident type 2 diabetes mellitus, who might be at the risk of developing hepatocellular carcinoma, was investigated. Initiation of statin in patients with newly diagnosed type 2 diabetes mellitus was associated with a beneficial inhibitory effect on hepatocellular carcinoma development in a dose‐dependent manner, especially in individuals with liver disease.
    Subject(s): cohort study ; statin ; liver disease ; diabetes ; hepatocellular carcinoma ; Carcinoma, Hepatocellular - epidemiology ; Follow-Up Studies ; Humans ; Middle Aged ; Male ; Risk ; Case-Control Studies ; Socioeconomic Factors ; Diabetes Mellitus, Type 2 - epidemiology ; Incidence ; Hepatitis, Viral, Human - epidemiology ; Liver Neoplasms - epidemiology ; Aged, 80 and over ; Adult ; Female ; Odds Ratio ; Republic of Korea - epidemiology ; Hypoglycemic Agents - therapeutic use ; Dyslipidemias - drug therapy ; Comorbidity ; Logistic Models ; Dyslipidemias - epidemiology ; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology ; Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use ; Aged ; Diabetes Mellitus, Type 2 - drug therapy ; Fatty Liver - epidemiology ; Virus diseases ; Type 2 diabetes ; Medical research ; Care and treatment ; Liver ; Medicine, Experimental ; Respiratory tract diseases ; Hepatoma ; Liver cirrhosis ; Statins ; Diabetes therapy
    ISSN: 0020-7136
    E-ISSN: 1097-0215
    Source: Alma/SFX Local Collection
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  • 5
    Language: English
    In: Frontiers in microbiology, 2016, Vol.7, p.218-218
    Description: A novel esterase, MtEst45, was isolated from a fosmid genomic library of Microbulbifer thermotolerans DAU221. The encoding gene is predicted to have a mass of 45,564 Da and encodes 495 amino acids, excluding a 21 amino acid signal peptide. MtEst45 showed a low amino acid identity (approximately 23-24%) compared with other lipolytic enzymes belonging to Family III, a closely related bacterial lipolytic enzyme family. MtEst45 also showed a conserved GXSXG motif, G131IS133YG135, which was reported as active site of known lipolytic enzymes, and the putative catalytic triad composed of D237 and H265. Because these mutants of MtEst45, which was S133A, D237N, and H265L, had no activity, these catalytic triad is deemed essential for the enzyme catalysis. MtEst45 was overexpressed in Escherichia coli BL21 (DE3) and purified via His-tag affinity chromatography. The optimal pH and temperature of MtEst45 were estimated to be 8.17 and 46.27°C by response surface methodology, respectively. Additionally, MtEst45 was also active between 1 and 15°C. The optimal hydrolysis substrate for MtEst45 among p-nitrophenyl esters (C2-C18) was p-nitrophenyl butyrate, and the K m and V max values were 0.0998 mM and 550 μmol/min/mg of protein, respectively. MtEst45 was strongly inhibited by Hg(2+), Zn(2+), and Cu(2+) ions; by phenylmethanesulfonyl fluoride; and by β-mercaptoethanol. Ca(2+) did not affect the enzyme's activity. These biochemical properties, sequence identity, and phylogenetic analysis suggest that MtEst45 represents a novel and valuable bacterial lipolytic enzyme family and is useful for biotechnological applications.
    Subject(s): esterase ; Microbulbifer thermotolerans ; Microbiology ; bacterial lipolytic enzyme ; cold-adapted enzyme ; DAU221 ; Cold-adapted enzyme ; Bacterial lipolytic enzyme
    ISSN: 1664-302X
    E-ISSN: 1664-302X
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 6
    Language: English
    In: Chromosome research, 2013-12, Vol.21 (6), p.685-693
    Description: Many eukaryotes, including plants, produce a large number of long noncoding RNAs (lncRNAs). Growing number of lncRNAs are being reported to have regulatory roles in various developmental processes. Emerging mechanisms underlying the function of lncRNAs indicate that lncRNAs are versatile regulatory molecules. They function as potent cis- and trans-regulators of gene expression, including the formation of modular scaffolds that recruit chromatin-modifying complexes to target chromatin. LncRNAs have also been reported in plants. Here, we describe our current understanding on potential roles of lncRNA in plants.
    Subject(s): Life Sciences ; Human Genetics ; Gene silencing ; RNA-seq ; Long noncoding RNA (lncRNA) ; Cell Biology ; Animal Genetics and Genomics ; Plant Genetics & Genomics ; Chromatin modification ; Gene activation ; Transcriptional Activation - genetics ; Plants - genetics ; Epigenesis, Genetic ; Gene Silencing ; Chromatin Assembly and Disassembly - genetics ; RNA, Long Noncoding - genetics ; Chromatin - genetics ; Antisense RNA ; Genetic engineering ; Plants ; Gene expression ; Laws, regulations and rules ; Genes
    ISSN: 0967-3849
    E-ISSN: 1573-6849
    Source: Alma/SFX Local Collection
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  • 7
    Language: English
    In: Molecular microbiology, 2014-01, Vol.91 (1), p.175-184
    Description: Summary The Salmonella flagellar motor consists of a rotor and about a dozen stator elements. Each stator element, consisting of MotA and MotB, acts as a proton channel to couple proton flow with torque generation. A highly conserved Asp33 residue of MotB is directly involved in the energy coupling mechanism, but it remains unknown how it carries out this function. Here, we show that the MotB(D33E) mutation dramatically alters motor performance in response to changes in external load. Rotation speeds of the MotA/B(D33E) and MotA(V35F)/B(D33E) motors were markedly slower than the wild‐type motor and fluctuated considerably at low load but not at high load, whereas the rotation rate of the wild‐type motor was stable at any load. At low load, pausing events were frequently observed in both mutant motors. The proton conductivities of these mutant stator channels in their ‘unplugged’ forms were only half of the conductivity of the wild‐type channel. These results suggest that the D33E mutation induces a load‐dependent inactivation of the MotA/B complex. We propose that the stator element is a load‐sensitive proton channel that efficiently couples proton translocation with torque generation and that Asp33 of MotB is critical for this co‐ordinated proton translocation.
    Subject(s): Protons ; Flagella - physiology ; Salmonella typhimurium - physiology ; Movement ; Salmonella typhimurium - genetics ; Bacterial Proteins - chemistry ; Bacterial Proteins - genetics ; Models, Molecular ; Asparagine - metabolism ; Bacterial Proteins - metabolism ; Flagella - genetics ; Mutation ; Amino Acid Substitution
    ISSN: 0950-382X
    E-ISSN: 1365-2958
    Source: Alma/SFX Local Collection
    Source: Wiley-Blackwell Full Collection 2014
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  • 8
    Language: English
    In: Molecular microbiology, 2014-03, Vol.91 (6), p.1214-1226
    Description: Summary The bacterial flagellar export apparatus is required for the construction of the bacterial flagella beyond the cytoplasmic membrane. The membrane‐embedded part of the export apparatus, which consists of FlhA, FlhB, FliO, FliP, FliQ and FliR, is located in the central pore of the MS ring formed by 26 copies of FliF. The C‐terminal cytoplasmic domain of FlhA is located in the centre of the cavity within the C ring made of FliG, FliM and FliN. FlhA interacts with FliF, but its assembly mechanism remains unclear. Here, we fused yellow fluorescent protein (YFP) and cyan fluorescent protein (CFP) to the C‐termini of FliF and FlhA and investigated their subcellular localization by fluorescence microscopy. The punctate pattern of FliF–YFP localization required FliG but neither FliM, FliN, FlhA, FlhB, FliO, FliP, FliQ nor FliR. In contrast, FlhA–CFP localization required FliF, FliG, FliO, FliP, FliQ and FliR. The number of FlhA–YFP molecules associated with the MS ring was estimated to be about nine. We suggest that FlhA assembles into the export gate along with other membrane components during the MS ring complex formation in a co‐ordinated manner.
    Subject(s): Green Fluorescent Proteins - analysis ; Bacterial Proteins - genetics ; Recombinant Fusion Proteins - analysis ; Green Fluorescent Proteins - genetics ; Bacterial Proteins - analysis ; Basal Bodies - metabolism ; Basal Bodies - chemistry ; Luminescent Proteins - analysis ; Salmonella - chemistry ; Protein Binding ; Recombinant Fusion Proteins - genetics ; Bacterial Proteins - metabolism ; Luminescent Proteins - genetics ; Membrane Proteins - metabolism ; Genes, Reporter ; Microscopy, Fluorescence ; Salmonella - metabolism ; Fluorescence
    ISSN: 0950-382X
    E-ISSN: 1365-2958
    Source: Alma/SFX Local Collection
    Source: Wiley-Blackwell Full Collection 2014
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  • 9
    Article
    Article
    2014
    ISSN: 2092-6413  ISSN: 1226-3613 
    Language: English
    In: Experimental & molecular medicine, 2014-03-14, Vol.46 (3), p.e85-e85
    Description: Vaccination is one of the most successful applications of immunology and for a long time has depended on parenteral administration protocols. However, recent studies have pointed to the promise of mucosal vaccination because of its ease, economy and efficiency in inducing an immune response not only systemically, but also in the mucosal compartment where many pathogenic infections are initiated. However, successful mucosal vaccination requires the help of an adjuvant for the efficient delivery of vaccine material into the mucosa and the breaking of the tolerogenic environment, especially in oral mucosal immunization. Given that M cells are the main gateway to take up luminal antigens and initiate antigen-specific immune responses, understanding the role and characteristics of M cells is crucial for the development of successful mucosal vaccines. Especially, particular interest has been focused on the regulation of the tolerogenic mucosal microenvironment and the introduction of the luminal antigen into the lymphoid organ by exploiting the molecules of M cells. Here, we review the characteristics of M cells and the immune regulatory factors in mucosa that can be exploited for mucosal vaccine delivery and mucosal immune regulation.
    Subject(s): Administration, Oral ; Humans ; Antigens, Bacterial - immunology ; Immunity, Mucosal ; Viral Vaccines - administration & dosage ; Intestinal Mucosa - cytology ; Antigens, Viral - immunology ; Peyer's Patches - cytology ; Animals ; Bacterial Vaccines - administration & dosage ; Bacterial Vaccines - immunology ; Intestinal Mucosa - immunology ; Peyer's Patches - immunology ; Viral Vaccines - immunology ; vaccine ; M cell ; Review ; immunity
    ISSN: 2092-6413
    ISSN: 1226-3613
    E-ISSN: 2092-6413
    Source: Nature Open Access
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 10
    Language: English
    In: Virology journal, 2018-08-08, Vol.15 (1), p.124-124
    Description: Antimicrobial peptides (AMPs) are primarily known for their innate immune defense against invading microorganisms, including viruses. In addition, recent research has suggested their modulatory activity in immune induction. Given that most subunit vaccines require an adjuvant to achieve effective immune induction through the activation of innate immunity, AMPs are plausible candidate molecules for stimulating not only innate immune but also adaptive immune responses. In this study, we investigated the ability of human β-defensin (HBD) 2 to promote antiviral immunity in vitro and in vivo using a receptor-binding domain (RBD) of Middle East respiratory syndrome-coronavirus (MERS-CoV) spike protein (S RBD) as a model antigen (Ag). When HBD 2-conjugated S RBD was used to treat THP-1 human monocytic cells, the expression levels of antiviral (IFN-β, IFN-γ, MxA, PKR, and RNaseL) and primary immune-inducing (NOD2, TNF-α, IL-1β, and IL-6) molecules were enhanced compared to those expressed after treatment with S RBD only. The expression of chemokines capable of recruiting leukocytes, including monocytes/macrophages, natural killer cells, granulocytes, T cells, and dendritic cells, was also increased following HBD 2-conjugated S RBD treatment. More important, immunization of mice with HBD 2-conjugated S RBD enhanced the immunogenicity of the S RBD and elicited a higher S RBD-specific neutralizing antibody response than S RBD alone. We conclude that HBD 2 activates the primary antiviral innate immune response and may also mediate the induction of an effective adaptive immune response against a conjugated Ag.
    Subject(s): Coronavirus Infections - prevention & control ; Adjuvants, Immunologic - administration & dosage ; Antiviral Agents - immunology ; Humans ; Cercopithecus aethiops ; Antibodies, Viral - blood ; Middle East Respiratory Syndrome Coronavirus - immunology ; Female ; Spike Glycoprotein, Coronavirus - immunology ; Adaptive Immunity - immunology ; Vero Cells ; Macrophages - immunology ; Mice, Inbred C57BL ; THP-1 Cells ; Antigens, Viral - chemistry ; Vaccines, Subunit - immunology ; Coronavirus Infections - immunology ; Middle East Respiratory Syndrome Coronavirus - chemistry ; beta-Defensins - chemistry ; Viral Vaccines - administration & dosage ; Antigens, Viral - immunology ; Immunity, Innate - immunology ; Animals ; Vaccines, Subunit - administration & dosage ; Cell Line, Tumor ; Mice ; Spike Glycoprotein, Coronavirus - chemistry ; Viral Vaccines - immunology ; Antibodies, Neutralizing - blood ; beta-Defensins - immunology ; Antigen ; Adjuvant ; MERS-CoV ; Research ; Antibody ; Human β-defensin
    ISSN: 1743-422X
    E-ISSN: 1743-422X
    Source: BioMedCentral Open Access
    Source: Academic Search Ultimate
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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