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  1. AU="Besnik Bajrami"
  2. AU=Mazza Mario Gennaro
  3. AU="Kwong, A S K"
  4. AU="Hadian, Marziye"
  5. AU="Chen, Yaying"
  6. AU="Ortega, Francisco B"
  7. AU=Cobb Samuel N
  8. AU="Abdelmohssin El Mokaddem"
  9. AU="Iwao Ojima"
  10. AU="Abazi, Sokol"
  11. AU="Cook, Rebecca"
  12. AU=Martin Flavius
  13. AU="Cipriani, Raffaela"
  14. AU="Levin, Michael E."
  15. AU="Yang, Dayu"

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  1. Artikel ; Online: The Role of Albanian Personalities in the Ottoman Empire

    Rudina Mita / Besnik Bajrami

    Mediterranean Journal of Social Sciences, Vol 6, Iss 2 S

    2015  Band 2

    Abstract: Albania was one of those countries whose physical and geographical position was tempting and favorable in the Western Balkans as well as South-Eastern Europe. Its position attracted many conquerors and empires through centuries who established their ... ...

    Abstract Albania was one of those countries whose physical and geographical position was tempting and favorable in the Western Balkans as well as South-Eastern Europe. Its position attracted many conquerors and empires through centuries who established their territorial and political hegemony. One of these was also the Ottoman Empire. The Ottoman Empire, not only a political and economic power of that time, but also with the purpose of following the policy of territorial expansion, it intensified its efforts not only in the Balkans but also in other regions. The conquering policy was mainly focused on the linguistic, educational, cultural and religious unification including even the income, economy, taxes, the assets of this place, going even further aiming the use of the political elite as well as Albanian and Balkan leaders, who were soon under the subjugation and in the service of the Empire. DOI:10.5901/mjss.2015.v6n2s2p189
    Schlagwörter Social Sciences ; H
    Thema/Rubrik (Code) 900
    Sprache Englisch
    Erscheinungsdatum 2015-03-01T00:00:00Z
    Verlag richtmann publishing
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  2. Artikel ; Online: BI 456906

    Tina Zimmermann / Leo Thomas / Tamara Baader-Pagler / Peter Haebel / Eric Simon / Wolfgang Reindl / Besnik Bajrami / Wolfgang Rist / Ingo Uphues / Daniel J. Drucker / Holger Klein / Rakesh Santhanam / Dieter Hamprecht / Heike Neubauer / Robert Augustin

    Molecular Metabolism, Vol 66, Iss , Pp 101633- (2022)

    Discovery and preclinical pharmacology of a novel GCGR/GLP-1R dual agonist with robust anti-obesity efficacy

    2022  

    Abstract: Objective: Obesity and its associated comorbidities represent a global health challenge with a need for well-tolerated, effective, and mechanistically diverse pharmaceutical interventions. Oxyntomodulin is a gut peptide that activates the glucagon ... ...

    Abstract Objective: Obesity and its associated comorbidities represent a global health challenge with a need for well-tolerated, effective, and mechanistically diverse pharmaceutical interventions. Oxyntomodulin is a gut peptide that activates the glucagon receptor (GCGR) and glucagon-like peptide-1 receptor (GLP-1R) and reduces bodyweight by increasing energy expenditure and reducing energy intake in humans. Here we describe the pharmacological profile of the novel glucagon receptor (GCGR)/GLP-1 receptor (GLP-1R) dual agonist BI 456906. Methods: BI 456906 was characterized using cell-based in vitro assays to determine functional agonism. In vivo pharmacological studies were performed using acute and subchronic dosing regimens to demonstrate target engagement for the GCGR and GLP-1R, and weight lowering efficacy. Results: BI 456906 is a potent, acylated peptide containing a C18 fatty acid as a half-life extending principle to support once-weekly dosing in humans. Pharmacological doses of BI 456906 provided greater bodyweight reductions in mice compared with maximally effective doses of the GLP-1R agonist semaglutide. BI 456906’s superior efficacy is the consequence of increased energy expenditure and reduced food intake. Engagement of both receptors in vivo was demonstrated via glucose tolerance, food intake, and gastric emptying tests for the GLP-1R, and liver nicotinamide N-methyltransferase mRNA expression and circulating biomarkers (amino acids, fibroblast growth factor-21) for the GCGR. The dual activity of BI 456906 at the GLP-1R and GCGR was supported using GLP-1R knockout and transgenic reporter mice, and an ex vivo bioactivity assay. Conclusions: BI 456906 is a potent GCGR/GLP-1R dual agonist with robust anti-obesity efficacy achieved by increasing energy expenditure and decreasing food intake.
    Schlagwörter Glucagon ; Glucagon-like peptide-1 ; Obesity ; G protein coupled receptor ; Peptide ; Internal medicine ; RC31-1245
    Thema/Rubrik (Code) 571
    Sprache Englisch
    Erscheinungsdatum 2022-12-01T00:00:00Z
    Verlag Elsevier
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  3. Artikel ; Online: Gasdermin D Exerts Anti-inflammatory Effects by Promoting Neutrophil Death

    Hiroto Kambara / Fei Liu / Xiaoyu Zhang / Peng Liu / Besnik Bajrami / Yan Teng / Li Zhao / Shiyi Zhou / Hongbo Yu / Weidong Zhou / Leslie E. Silberstein / Tao Cheng / Mingzhe Han / Yuanfu Xu / Hongbo R. Luo

    Cell Reports, Vol 22, Iss 11, Pp 2924-

    2018  Band 2936

    Abstract: Summary: Gasdermin D (GSDMD) is considered a proinflammatory factor that mediates pyroptosis in macrophages to protect hosts from intracellular bacteria. Here, we reveal that GSDMD deficiency paradoxically augmented host responses to extracellular ... ...

    Abstract Summary: Gasdermin D (GSDMD) is considered a proinflammatory factor that mediates pyroptosis in macrophages to protect hosts from intracellular bacteria. Here, we reveal that GSDMD deficiency paradoxically augmented host responses to extracellular Escherichia coli, mainly by delaying neutrophil death, which established GSDMD as a negative regulator of innate immunity. In contrast to its activation in macrophages, in which activated inflammatory caspases cleave GSDMD to produce an N-terminal fragment (GSDMD-cNT) to trigger pyroptosis, GSDMD cleavage and activation in neutrophils was caspase independent. It was mediated by a neutrophil-specific serine protease, neutrophil elastase (ELANE), released from cytoplasmic granules into the cytosol in aging neutrophils. ELANE-mediated GSDMD cleavage was upstream of the caspase cleavage site and produced a fully active ELANE-derived NT fragment (GSDMD-eNT) that induced lytic cell death as efficiently as GSDMD-cNT. Thus, GSDMD is pleiotropic, exerting both pro- and anti-inflammatory effects that make it a potential target for antibacterial and anti-inflammatory therapies. : Kambara et al. find that GSDMD deficiency augments host responses to extracellular Escherichia coli, mainly by delaying neutrophil death, establishing GSDMD as a negative regulator of innate immunity. GSDMD cleavage and activation in neutrophils is mediated by ELANE, released from cytoplasmic granules into the cytosol in aging neutrophils. Keywords: GSDMD, neutrophil death, neutrophil elastase, innate immunity, host defense
    Schlagwörter Biology (General) ; QH301-705.5
    Thema/Rubrik (Code) 572
    Sprache Englisch
    Erscheinungsdatum 2018-03-01T00:00:00Z
    Verlag Elsevier
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  4. Artikel ; Online: Allosteric inhibition of PPM1D serine/threonine phosphatase via an altered conformational state

    Peter G. Miller / Murugappan Sathappa / Jamie A. Moroco / Wei Jiang / Yue Qian / Sumaiya Iqbal / Qi Guo / Andrew O. Giacomelli / Subrata Shaw / Camille Vernier / Besnik Bajrami / Xiaoping Yang / Cerise Raffier / Adam S. Sperling / Christopher J. Gibson / Josephine Kahn / Cyrus Jin / Matthew Ranaghan / Alisha Caliman /
    Merissa Brousseau / Eric S. Fischer / Robert Lintner / Federica Piccioni / Arthur J. Campbell / David E. Root / Colin W. Garvie / Benjamin L. Ebert

    Nature Communications, Vol 13, Iss 1, Pp 1-

    2022  Band 16

    Abstract: In this work, the authors report a sophisticated combination of genetic, biophysical, and biochemical analyses to identifies the cycling conformational states of PPM1D. The findings reveal how an allosteric inhibitor locks the protein into a ... ...

    Abstract In this work, the authors report a sophisticated combination of genetic, biophysical, and biochemical analyses to identifies the cycling conformational states of PPM1D. The findings reveal how an allosteric inhibitor locks the protein into a conformationally inactive state, and explain the distribution of PPM1D activating mutations in cancer.
    Schlagwörter Science ; Q
    Sprache Englisch
    Erscheinungsdatum 2022-06-01T00:00:00Z
    Verlag Nature Portfolio
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  5. Artikel ; Online: Conservation of the structure and function of bacterial tryptophan synthases

    Karolina Michalska / Jennifer Gale / Grazyna Joachimiak / Changsoo Chang / Catherine Hatzos-Skintges / Boguslaw Nocek / Stephen E. Johnston / Lance Bigelow / Besnik Bajrami / Robert P. Jedrzejczak / Samantha Wellington / Deborah T. Hung / Partha P. Nag / Stewart L. Fisher / Michael Endres / Andrzej Joachimiak

    IUCrJ, Vol 6, Iss 4, Pp 649-

    2019  Band 664

    Abstract: Tryptophan biosynthesis is one of the most characterized processes in bacteria, in which the enzymes from Salmonella typhimurium and Escherichia coli serve as model systems. Tryptophan synthase (TrpAB) catalyzes the final two steps of tryptophan ... ...

    Abstract Tryptophan biosynthesis is one of the most characterized processes in bacteria, in which the enzymes from Salmonella typhimurium and Escherichia coli serve as model systems. Tryptophan synthase (TrpAB) catalyzes the final two steps of tryptophan biosynthesis in plants, fungi and bacteria. This pyridoxal 5′-phosphate (PLP)-dependent enzyme consists of two protein chains, α (TrpA) and β (TrpB), functioning as a linear αββα heterotetrameric complex containing two TrpAB units. The reaction has a complicated, multistep mechanism resulting in the β-replacement of the hydroxyl group of l-serine with an indole moiety. Recent studies have shown that functional TrpAB is required for the survival of pathogenic bacteria in macrophages and for evading host defense. Therefore, TrpAB is a promising target for drug discovery, as its orthologs include enzymes from the important human pathogens Streptococcus pneumoniae, Legionella pneumophila and Francisella tularensis, the causative agents of pneumonia, legionnaires' disease and tularemia, respectively. However, specific biochemical and structural properties of the TrpABs from these organisms have not been investigated. To fill the important phylogenetic gaps in the understanding of TrpABs and to uncover unique features of TrpAB orthologs to spearhead future drug-discovery efforts, the TrpABs from L. pneumophila, F. tularensis and S. pneumoniae have been characterized. In addition to kinetic properties and inhibitor-sensitivity data, structural information gathered using X-ray crystallography is presented. The enzymes show remarkable structural conservation, but at the same time display local differences in both their catalytic and allosteric sites that may be responsible for the observed differences in catalysis and inhibitor binding. This functional dissimilarity may be exploited in the design of species-specific enzyme inhibitors.
    Schlagwörter allosteric regulation ; crystal structure ; enzyme inhibitors ; tryptophan ; catalysis ; structure determination ; protein structure ; molecular recognition ; X-ray crystallography ; enzyme mechanisms ; drug discovery ; tryptophan synthase ; Streptococcus pneumoniae ; Legionella pneumophila ; Francisella tularensis ; Science ; Q
    Thema/Rubrik (Code) 572
    Sprache Englisch
    Erscheinungsdatum 2019-07-01T00:00:00Z
    Verlag International Union of Crystallography
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  6. Artikel ; Online: Positive Regulation of Interleukin-1β Bioactivity by Physiological ROS-Mediated Cysteine S-Glutathionylation

    Xue Zhang / Peng Liu / Christie Zhang / Direkrit Chiewchengchol / Fan Zhao / Hongbo Yu / Jingyu Li / Hiroto Kambara / Kate Y. Luo / Arvind Venkataraman / Ziling Zhou / Weidong Zhou / Haiyan Zhu / Li Zhao / Jiro Sakai / Yuanyuan Chen / Ye-Shih Ho / Besnik Bajrami / Bing Xu /
    Leslie E. Silberstein / Tao Cheng / Yuanfu Xu / Yuehai Ke / Hongbo R. Luo

    Cell Reports, Vol 20, Iss 1, Pp 224-

    2017  Band 235

    Abstract: Reactive oxygen species (ROS)-induced cysteine S-glutathionylation is an important posttranslational modification (PTM) that controls a wide range of intracellular protein activities. However, whether physiological ROS can modulate the function of ... ...

    Abstract Reactive oxygen species (ROS)-induced cysteine S-glutathionylation is an important posttranslational modification (PTM) that controls a wide range of intracellular protein activities. However, whether physiological ROS can modulate the function of extracellular components via S-glutathionylation is unknown. Using a screening approach, we identified ROS-mediated cysteine S-glutathionylation on several extracellular cytokines. Glutathionylation of the highly conserved Cys-188 in IL-1β positively regulates its bioactivity by preventing its ROS-induced irreversible oxidation, including sulfinic acid and sulfonic acid formation. We show this mechanism protects IL-1β from deactivation by ROS in an in vivo system of irradiation-induced bone marrow (BM) injury. Glutaredoxin 1 (Grx1), an enzyme that catalyzes deglutathionylation, was present and active in the extracellular space in serum and the BM, physiologically regulating IL-1β glutathionylation and bioactivity. Collectively, we identify cysteine S-glutathionylation as a cytokine regulatory mechanism that could be a therapeutic target in the treatment of various infectious and inflammatory diseases.
    Schlagwörter cytokines ; interleukin-1 ; oxidation ; infection and inflammation ; reactive oxygen species ; posttranslational modification ; cysteine S-glutathionylation ; Biology (General) ; QH301-705.5
    Thema/Rubrik (Code) 572
    Sprache Englisch
    Erscheinungsdatum 2017-07-01T00:00:00Z
    Verlag Elsevier
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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