Cohesin complex is a major player on the stage of leukemogenesis

: Spinal cord injury (SCI) and associated pain and inflammation caused by the trauma or infection is one of the serious health care issues world-wide. The various inflammatory, redox-sensitive and apoptotic events are contributing factor but altered neuronal function, axonal degeneration, activated microglia, endothelial cells, astrocytes, fibroblasts,pericytes, Schwann cells, meningeal cells are the major player in its pathogenesis. Further, monocytes and neutrophil infiltration get recruited and facilitate the release of chemokines, cytokines, and other mediators of inflammation. This event leads to the production of different amino acids, neuropeptides kinin, prostaglandins, prostacyclin, thromboxane, leukotrienes, bradykinin, histamine, matrix metal proteinases and serotonin that stimulate nerve endings and manifests the inflammation and pain processes, etc. Arachidonic acid (AA), NF-kB, NLRP3 inflammasome, and nitric oxide pathways along with P2X7 receptor and ion channel transient receptor potential (TRP) vanilloid are some of the recently explored targets for modulation of pain and inflammation in SCI. Till now, NSAIDs, opioids, antidepressants, anticonvulsants, NMDA antagonists, α2-adrenergic agonists, and GABA-receptor agonists are used for the management of these pathological conditions. However, these drugs are associated with various side effects. Additionally, the number of available animal models for SCI has enhanced the understanding of the complex pathological mechanisms involved in the generation of chronic inflammatory pain in SCI. These findings enable us to identify and validate several potent natural analgesic-anti-inflammatory drug candidates with minimal side effects. However, until now, these compounds have been studied in preclinical models and shown promising results but no clinical studies have been performed. Therefore, a detailed exploration of these natural compounds is important for bringing them from bench to bedside.

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Hyperactivated RAGE in Comorbidities as a Risk Factor for Severe COVID-19—The Role of RAGE-RAS Crosstalk

Biomolecules ◽

10.3390/biom11060876 ◽

2021 ◽

Vol 11 (6) ◽

pp. 876

Author(s):

Sara Chiappalupi ◽

Laura Salvadori ◽

Rosario Donato ◽

Francesca Riuzzi ◽

Guglielmo Sorci

Keyword(s):

Gene Polymorphisms ◽

Renin Angiotensin System ◽

Molecular Target ◽

Advanced Glycation ◽

Angiotensin System ◽

Major Player ◽

Glycation End Products ◽

End Products ◽

And Oxidative Stress

The receptor for advanced glycation-end products (RAGE) is a multiligand receptor with a role in inflammatory and pulmonary pathologies. Hyperactivation of RAGE by its ligands has been reported to sustain inflammation and oxidative stress in common comorbidities of severe COVID-19. RAGE is essential to the deleterious effects of the renin–angiotensin system (RAS), which participates in infection and multiorgan injury in COVID-19 patients. Thus, RAGE might be a major player in severe COVID-19, and appears to be a useful therapeutic molecular target in infections by SARS-CoV-2. The role of RAGE gene polymorphisms in predisposing patients to severe COVID-19 is discussed.

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How is China’s energy security affected by exogenous shocks? Evidence of China–US trade dispute and COVID-19 pandemic

Discover Energy ◽

10.1007/s43937-021-00002-6 ◽

2021 ◽

Vol 1 (1) ◽

Author(s):

Shi Qiang Liu ◽

Xin Huang ◽

Xiangong Li ◽

Mahmoud Masoud ◽

Sai-Ho Chung ◽

...

Keyword(s):

Energy Security ◽

Energy Supply ◽

Alternative Energy ◽

The United States ◽

Matrix Analysis ◽

Settlement Systems ◽

Exogenous Shocks ◽

Trade Dispute ◽

Major Player ◽

Energy Diplomacy

AbstractThe trade dispute between China and the United States (US) since 2018 and the global COVID-19 pandemic since 2020 has significantly impacted China’s economic development. As China’s energy sources heavily depend on imports, its economic viability is becoming more and more risky. This study proposes a novel conceptual framework, involving macroeconomic, industrial and geopolitical factors, to evaluate China’s energy security as a major player in the trade dispute. This study also provides a comprehensive strategy for policymakers to make better decisions on reforming renewable energy patterns to guarantee energy security and achieve geopolitical advantages. The PESTEL (political, economic, social, technical, environmental and legislative) and SWOT (strengths, weaknesses, opportunities and threats) analytical methods are applied to evaluate the factors and attributes of China’s energy development and energy security in the current background. The China-US bipartite game reciprocity model and the QSPM (Quantitative Strategic Planning Matrix) analysis are conducted to assess which energy security strategy and policy are more suitable to deal with China-US trade dispute. To enhance energy security, China should diversify its energy supply chain, develop new sources of energy supply, advance the shale gas technology, popularise cleaner power-generation plants, increase nuclear-energy safety, introduce energy-conservation measures, promote alternative-energy vehicles, engage in international energy diplomacy, and rebuild international energy transaction and settlement systems.

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601 Development of improved small molecule STING agonists suitable for systemic administration

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0601 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A636-A636

Author(s):

Maciej Rogacki ◽

Stefan Chmielewski ◽

Magdalena Zawadzka ◽

Jolanta Mazurek ◽

Katarzyna Wnuk-Lipińska ◽

...

Keyword(s):

Tumor Growth ◽

Small Molecule ◽

Immune Cells ◽

Systemic Administration ◽

Cytokine Release ◽

Major Player ◽

Human Immune ◽

New Generation ◽

Dose Dependent ◽

Complete Tumor

BackgroundStimulator of Interferon Genes (STING) is a major player in the activation of robust innate immune response leading to initiation and enhancement of tumor-specific adaptive immunity. Several clinical and pre-clinical programs have shown that activation of the STING pathway triggers immune-mediated antitumor response. Although vast majority of programs focus on development of analogues of the endogenous STING ligands, their chemical nature and stability often limit their use to local administration. Herein, we present recent results from the development of our selective non-nucleotide, non-macrocyclic, small molecule direct STING agonists, suitable for systemic administration, characterized by improved activity in human immune cells.MethodsBinding to recombinant STING protein was examined using FTS, MST, FP and crystallography studies. Phenotypic screen was performed in THP-1 Dual reporter cells. Mouse bone marrow-derived dendritic cells (BMDC) were obtained from C57BL/6 mice and differentiated with mIL-4 and mGM-CSF. STING agonists were administered into BALB/c mice and cytokine release was measured in plasma. Additionally, mice were inoculated with CT26 murine colon carcinoma or EMT6 murine breast carcinoma cells and the compound was administered, followed by the regular tumor growth and body weight monitoring.ResultsRyvu’s small-molecule agonists demonstrate strong binding affinity to recombinant STING proteins across all tested species. The compounds bind to all human STING protein variants and trigger pro-inflammatory cytokine release from human immune cells regardless of the STING haplotype. Moreover, new generation of developed agonists show significantly improved binding to human protein as well as in vitro activity on human cells. Systemic, intravenous in vivo administration leads to a dose-dependent upregulation of STING-dependent pro-inflammatory cytokines, which results in a dose-dependent antitumor efficacy observed in CT26 and EMT6 mouse cancer models, leading to complete tumor remissions in all treated animals. Furthermore, observed efficacy is accompanied by development of a lasting immunological response demonstrated by lack of tumor engraftment or a delayed tumor growth in cured animals challenged with repeated inoculation of cancer cells.ConclusionsNew generation Ryvu’s STING agonists are strong and selective activators of STING-dependent signaling in both mouse and human immune cells promoting anti-tumor immunity. Treatment with Ryvu’s small-molecule STING agonists leads to engagement of the immune system which results in a complete tumor remission and development of immunological memory of the cancer antigens. The compounds show good selectivity and ADME properties enabling development for systemic administration. In addition developed compounds maintain small functional handles amenable to linker attachment making the series suitable for versatile development as single agents, for combinations with immunotherapies or as targeted agents.

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Aging of Bone Marrow Mesenchymal Stromal Cells: Hematopoiesis Disturbances and Potential Role in the Development of Hematologic Cancers

Cancers ◽

10.3390/cancers13010068 ◽

2020 ◽

Vol 13 (1) ◽

pp. 68

Author(s):

Fulvio Massaro ◽

Florent Corrillon ◽

Basile Stamatopoulos ◽

Nathalie Meuleman ◽

Laurence Lagneaux ◽

...

Keyword(s):

Bone Marrow ◽

Tumor Progression ◽

Cancer Progression ◽

Mesenchymal Stromal Cells ◽

Stromal Cells ◽

Cell Communication ◽

Bone Marrow Niche ◽

Hematopoietic Stem ◽

Wide Range ◽

Major Player

Aging of bone marrow is a complex process that is involved in the development of many diseases, including hematologic cancers. The results obtained in this field of research, year after year, underline the important role of cross-talk between hematopoietic stem cells and their close environment. In bone marrow, mesenchymal stromal cells (MSCs) are a major player in cell-to-cell communication, presenting a wide range of functionalities, sometimes opposite, depending on the environmental conditions. Although these cells are actively studied for their therapeutic properties, their role in tumor progression remains unclear. One of the reasons for this is that the aging of MSCs has a direct impact on their behavior and on hematopoiesis. In addition, tumor progression is accompanied by dynamic remodeling of the bone marrow niche that may interfere with MSC functions. The present review presents the main features of MSC senescence in bone marrow and their implications in hematologic cancer progression.

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Tata Wiron: branding galvanized wires

Emerald Emerging Markets Case Studies ◽

10.1108/eemcs-11-2014-0273 ◽

2015 ◽

Vol 5 (7) ◽

pp. 1-8

Author(s):

Vijay Pundalik Bhangale ◽

Maithili Prashant Dhuri

Keyword(s):

Learning Outcomes ◽

Market Segmentation ◽

Value Chain ◽

Far East ◽

Commodity Market ◽

Content Type ◽

Steel Wires ◽

Wide Range ◽

Major Player ◽

Depth Analysis

Subject area Marketing. Study level/applicability MBA Marketing Class. Case overview The case describes the transition of a “Galvanized Wires Business of Tata Steel” into a unique identity, the'Tata Wiron' brand. It focuses on key stages in this journey, including “Understanding the Customers in Galvanized Wires Business”, “Value Chain”, “Challenges Faced”, “Need for Branding”, “Market Segmentation”, “Competition”, “Process of Branding”, “Differentiation”, “Distribution & Sales” and “Promotion”. Tata Steel Wires Business is a major player in the steel wire industry, servicing the discerning needs of its customers across global markets and the leading producer of steel wires in India. A wealth of experience and expertise in the wire industry coupled with latest technology incorporations has enabled Tata Steel Wires Division to constantly meet the most exacting specifications and requirements of its customers. It manufactures a wide range of wires catering to the needs of various industry segments, such as automobile, infrastructure, power and general engineering. The products are well established across the markets of Europe, the USA, Middle East Asia, Australasia, South Asia and Asia and the Far East. Expected learning outcomes The expected learning outcomes are as follows: understanding how in-depth analysis of the competition and value chain establishes the need for branding in a commodity market; understanding how consumer insights help in market segmentation and targeting; and building a brand in commodity market. Supplementary materials Teaching notes are available for educators only. Please contact your library to gain login details or email [email protected] to request teaching notes.

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p53 down-regulates SARS coronavirus replication and is targeted by the SARS-unique domain and PLprovia E3 ubiquitin ligase RCHY1

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1603435113 ◽

2016 ◽

Vol 113 (35) ◽

pp. E5192-E5201 ◽

Cited By ~ 55

Author(s):

Yue Ma-Lauer ◽

Javier Carbajo-Lozoya ◽

Marco Y. Hein ◽

Marcel A. Müller ◽

Wen Deng ◽

...

Keyword(s):

Ubiquitin Ligase ◽

Nonstructural Protein ◽

E3 Ubiquitin Ligase ◽

Ring Finger ◽

Immune Recognition ◽

Major Player ◽

Nonstructural Protein 3 ◽

Human Coronaviruses ◽

Unique Domain

Highly pathogenic severe acute respiratory syndrome coronavirus (SARS-CoV) has developed strategies to inhibit host immune recognition. We identify cellular E3 ubiquitin ligase ring-finger and CHY zinc-finger domain-containing 1 (RCHY1) as an interacting partner of the viral SARS-unique domain (SUD) and papain-like protease (PLpro), and, as a consequence, the involvement of cellular p53 as antagonist of coronaviral replication. Residues 95–144 of RCHY1 and 389–652 of SUD (SUD-NM) subdomains are crucial for interaction. Association with SUD increases the stability of RCHY1 and augments RCHY1-mediated ubiquitination as well as degradation of p53. The calcium/calmodulin-dependent protein kinase II delta (CAMK2D), which normally influences RCHY1 stability by phosphorylation, also binds to SUD. In vivo phosphorylation shows that SUD does not regulate phosphorylation of RCHY1 via CAMK2D. Similarly to SUD, the PLpros from SARS-CoV, MERS-CoV, and HCoV-NL63 physically interact with and stabilize RCHY1, and thus trigger degradation of endogenous p53. The SARS-CoV papain-like protease is encoded next to SUD within nonstructural protein 3. A SUD–PLprofusion interacts with RCHY1 more intensively and causes stronger p53 degradation than SARS-CoV PLproalone. We show that p53 inhibits replication of infectious SARS-CoV as well as of replicons and human coronavirus NL63. Hence, human coronaviruses antagonize the viral inhibitor p53 via stabilizing RCHY1 and promoting RCHY1-mediated p53 degradation. SUD functions as an enhancer to strengthen interaction between RCHY1 and nonstructural protein 3, leading to a further increase in in p53 degradation. The significance of these findings is that down-regulation of p53 as a major player in antiviral innate immunity provides a long-sought explanation for delayed activities of respective genes.

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