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1
Lushpa, Vladislav A., Marina V. Goncharuk, Irina A. Talyzina, Alexander S. Arseniev, Eduard V. Bocharov, Konstantin S. Mineev, and Sergey A. Goncharuk. "TIR domains of TLR family-from the cell culture to the protein sample for structural studies." PLOS ONE 19, no. 7 (July 5, 2024): e0304997. http://dx.doi.org/10.1371/journal.pone.0304997.
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Toll-like receptors (TLRs) are key players in the innate immune system. Despite the great efforts in TLR structural biology, today we know the spatial structures of only four human TLR intracellular TIR domains. All of them belong to one of five subfamilies of receptors. One of the main bottlenecks is the high-level production of correctly folded proteins in soluble form. Here we used a rational approach to find the optimal parameters to produce TIR domains of all ten human TLR family members in soluble form in E. coli cells. We showed that dozens of milligrams of soluble His-tagged TLR2/3/6/7TIR and MBP-tagged TLR3/5/7/8TIR can be produced. We also developed the purification protocols and demonstrated by CD and NMR spectroscopy that purified TLR2/3/7TIR demonstrate a structural organization inherent to TIR domains. This illustrates the correct folding of produced proteins and their suitability for further structural and functional investigations.
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Thon, Jonathan N., Christopher G. Peters, Kellie R. Machlus, Rukhsana Aslam, Jesse Rowley, Hannah Macleod, Matthew T. Devine, et al. "T granules in human platelets function in TLR9 organization and signaling." Journal of Cell Biology 198, no. 4 (August 20, 2012): 561–74. http://dx.doi.org/10.1083/jcb.201111136.
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Human and murine platelets (PLTs) variably express toll-like receptors (TLRs), which link the innate and adaptive immune responses during infectious inflammation and atherosclerotic vascular disease. In this paper, we show that the TLR9 transcript is specifically up-regulated during pro-PLT production and is distributed to a novel electron-dense tubular system-related compartment we have named the T granule. TLR9 colocalizes with protein disulfide isomerase and is associated with either VAMP 7 or VAMP 8, which regulates its distribution in PLTs on contact activation (spreading). Preincubation of PLTs with type IV collagen specifically increased TLR9 and CD62P surface expression and augmented oligodeoxynucleotide (ODN) sequestration and PLT clumping upon addition of bacterial/viral ODNs. Collectively, this paper (a) tracks TLR9 to a new intracellular compartment in PLTs and (b) describes a novel mechanism of TLR9 organization and signaling in human PLTs.
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Gupta, Neetu, Debasis Pore, Ken Matsui, and Neetha Parameswaran. "Ezrin regulates inflammation by limiting B cell interleukin-10 production." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 198.2. http://dx.doi.org/10.4049/jimmunol.196.supp.198.2.
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Abstract In addition to their essential role in antibody production, B cells regulate immune responses by secreting effector cytokines. Interleukin 10 (IL-10) produced by B cells is important for controlling inflammation and autoimmunity, underscoring the importance of identifying mechanisms regulating B cell IL-10 production. We have previously demonstrated that the membrane-cytoskeleton linker protein ezrin regulates B cell antigen receptor organization and signaling. Further, we have shown that ezrin undergoes rapid dephosphorylation in naïve B cells treated with LPS, suggesting that it may regulate TLR4-mediated IL-10 production. In the present study, we demonstrate that conditional deletion of ezrin in B cells increases IL-10 production induced by TLR4, but not TLR2 or TLR9, ligation. The MyD88-independent TRIF-TBK1-IRF3 pathway is required for ezrin-deficient B cells to produce higher IL-10 upon LPS stimulation. Treatment of B cells with a novel small molecule inhibitor of ezrin induces its dephosphorylation, and increases LPS-induced NF-κB and IRF3 activation and IL-10 secretion, indicating a role for Thr567 phosphorylation of ezrin in limiting IL-10. Loss of ezrin in B cells results in dampened pro-inflammatory response to a sub-lethal dose of LPS in vivo, which is dependent on increased IL-10 production. Taken together, our data yield new insights into molecular and membrane-cytoskeletal regulation of B cell IL-10 production, and reveal ezrin as a potential therapeutic target in inflammatory diseases.
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Bakaros, Evangelos, Ioanna Voulgaridi, Vassiliki Paliatsa, Nikolaos Gatselis, Georgios Germanidis, Evangelia Asvestopoulou, Stamatia Alexiou, et al. "Innate Immune Gene Polymorphisms and COVID-19 Prognosis." Viruses 15, no. 9 (August 22, 2023): 1784. http://dx.doi.org/10.3390/v15091784.
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COVID-19 is characterized by a heterogeneous clinical presentation and prognosis. Risk factors contributing to the development of severe disease include old age and the presence of comorbidities. However, the genetic background of the host has also been recognized as an important determinant of disease prognosis. Considering the pivotal role of innate immunity in the control of SARS-CoV-2 infection, we analyzed the possible contribution of several innate immune gene polymorphisms (including TLR2-rs5743708, TLR4-rs4986790, TLR4-rs4986791, CD14-rs2569190, CARD8-rs1834481, IL18-rs2043211, and CD40-rs1883832) in disease severity and prognosis. A total of 249 individuals were enrolled and further divided into five (5) groups, according to the clinical progression scale provided by the World Health Organization (WHO) (asymptomatic, mild, moderate, severe, and critical). We identified that elderly patients with obesity and/or diabetes mellitus were more susceptible to developing pneumonia and respiratory distress syndrome after SARS-CoV-2 infection, while the IL18-rs1834481 polymorphism was an independent risk factor for developing pneumonia. Moreover, individuals carrying either the TLR2-rs5743708 or the TLR4-rs4986791 polymorphisms exhibited a 3.6- and 2.5-fold increased probability for developing pneumonia and a more severe disease, respectively. Our data support the notion that the host’s genetic background can significantly affect COVID-19 clinical phenotype, also suggesting that the IL18-rs1834481, TLR2-rs5743708, and TLR4-rs4986791 polymorphisms may be used as molecular predictors of COVID-19 clinical phenotype.
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Opsal, Monica Aa, Dag Inge Våge, Ben Hayes, Ingunn Berget, and Sigbjørn Lien. "Genomic organization and transcript profiling of the bovine toll-like receptor gene cluster TLR6-TLR1-TLR10." Gene 384 (December 2006): 45–50. http://dx.doi.org/10.1016/j.gene.2006.06.027.
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Westphal, Andreas, Weijia Cheng, Jinbo Yu, Guntram Grassl, Martina Krautkrämer, Otto Holst, Niko Föger, and Kyeong-Hee Lee. "Lysosomal trafficking regulator Lyst links membrane trafficking to toll-like receptor–mediated inflammatory responses." Journal of Experimental Medicine 214, no. 1 (November 23, 2016): 227–44. http://dx.doi.org/10.1084/jem.20141461.
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Subcellular compartmentalization of receptor signaling is an emerging principle in innate immunity. However, the functional integration of receptor signaling pathways into membrane trafficking routes and its physiological relevance for immune responses is still largely unclear. In this study, using Lyst-mutant beige mice, we show that lysosomal trafficking regulator Lyst links endolysosomal organization to the selective control of toll-like receptor 3 (TLR3)– and TLR4-mediated proinflammatory responses. Consequently, Lyst-mutant mice showed increased susceptibility to bacterial infection and were largely resistant to endotoxin-induced septic shock. Mechanistic analysis revealed that Lyst specifically controls TLR3- and TLR4-induced endosomal TRIF (TIR domain–containing adapter-inducing interferon β) signaling pathways. Loss of functional Lyst leads to dysregulated phagosomal maturation, resulting in a failure to form an activation-induced Rab7+ endosomal/phagosomal compartment. This specific Rab7+ compartment was further demonstrated to serve as a major site for active TRIF signaling events, thus linking phagosomal maturation to specific TLR signaling pathways. The immunoregulatory role of Lyst on TLR signaling pathways was confirmed in human cells by CRISPR/Cas9-mediated gene inactivation. As mutations in LYST cause human Chédiak-Higashi syndrome, a severe immunodeficiency, our findings also contribute to a better understanding of human disease mechanisms.
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Shah, Syed Zawar, Basit Jabbar, Muhammad Usman Mirza, Muhammad Waqas, Shahkaar Aziz, Sobia Ahsan Halim, Amjad Ali, et al. "An Immunoinformatics Approach to Design a Potent Multi-Epitope Vaccine against Asia-1 Genotype of Crimean–Congo Haemorrhagic Fever Virus Using the Structural Glycoproteins as a Target." Vaccines 11, no. 1 (December 27, 2022): 61. http://dx.doi.org/10.3390/vaccines11010061.
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Crimean–Congo haemorrhagic fever (CCHF), caused by Crimean–Congo haemorrhagic fever virus (CCHFV), is a disease of worldwide importance (endemic yet not limited to Asia, Middle East, and Africa) and has triggered several outbreaks amounting to a case fatality rate of 10–40% as per the World Health Organization. Genetic diversity and phylogenetic data revealed that the Asia-1 genotype of CCHFV remained dominant in Pakistan, where 688 confirmed cases were reported between the 2012–2022 period. Currently, no approved vaccine is available to tackle the viral infection. Epitope-based vaccine design has gained significant attention in recent years due to its safety, timeliness, and cost efficiency compared to conventional vaccines. In the present study, we employed a robust immunoinformatics-based approach targeting the structural glycoproteins G1 and G2 of CCHFV (Asia-1 genotype) to design a multi-epitope vaccine construct. Five B-cells and six cytotoxic T-lymphocytes (CTL) epitopes were mapped and finalized from G1 and G2 and were fused with suitable linkers (EAAAK, GGGS, AAY, and GPGPG), a PADRE sequence (13 aa), and an adjuvant (50S ribosomal protein L7/L12) to formulate a chimeric vaccine construct. The selected CTL epitopes showed high affinity and stable binding with the binding groove of common human HLA class I molecules (HLA-A*02:01 and HLA-B*44:02) and mouse major histocompatibility complex class I molecules. The chimeric vaccine was predicted to be an antigenic, non-allergenic, and soluble molecule with a suitable physicochemical profile. Molecular docking and molecular dynamics simulation indicated a stable and energetically favourable interaction between the constructed antigen and Toll-like receptors (TLR2, TLR3, and TLR4). Our results demonstrated that innate, adaptive, and humoral immune responses could be elicited upon administration of such a potent muti-epitope vaccine construct. These results could be helpful for an experimental vaccinologist to develop an effective vaccine against the Asia-1 genotype of CCHFV.
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Rahman, M. Shaminur, M. Nazmul Hoque, M. Rafiul Islam, Salma Akter, ASM Rubayet-Ul-Alam, Mohammad Anwar Siddique, Otun Saha, et al. "Epitope-based chimeric peptide vaccine design against S, M and E proteins of SARS-CoV-2 etiologic agent of global pandemic COVID-19: an in silico approach." PeerJ 8 (July 27, 2020): e9572. http://dx.doi.org/10.7717/peerj.9572.
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiologic agent of the ongoing pandemic of coronavirus disease 2019 (COVID-19), a public health emergency of international concerns declared by the World Health Organization (WHO). An immuno-informatics approach along with comparative genomics was applied to design a multi-epitope-based peptide vaccine against SARS-CoV-2 combining the antigenic epitopes of the S, M, and E proteins. The tertiary structure was predicted, refined and validated using advanced bioinformatics tools. The candidate vaccine showed an average of ≥90.0% world population coverage for different ethnic groups. Molecular docking and dynamics simulation of the chimeric vaccine with the immune receptors (TLR3 and TLR4) predicted efficient binding. Immune simulation predicted significant primary immune response with increased IgM and secondary immune response with high levels of both IgG1 and IgG2. It also increased the proliferation of T-helper cells and cytotoxic T-cells along with the increased IFN-γ and IL-2 cytokines. The codon optimization and mRNA secondary structure prediction revealed that the chimera is suitable for high-level expression and cloning. Overall, the constructed recombinant chimeric vaccine candidate demonstrated significant potential and can be considered for clinical validation to fight against this global threat, COVID-19.
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McBride, Amanda B., and Padmini Salgame. "Toll-like receptor 2: An important regulator of the Mycobacterium tuberculosis granuloma (45.23)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 45.23. http://dx.doi.org/10.4049/jimmunol.182.supp.45.23.
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Abstract Tubercle granulomas are highly organized immune structures that protect the host against Mycobacterium tuberculosis (Mtb) infection. The organization of immune cells around infected macrophages serves to sequester Mtb and enhance macrophage microbicidal responses. In addition, the granuloma localizes inflammation, thereby preventing damage to surrounding lung tissue. Although there is controversy regarding the involvement of Toll-like receptor 2 (TLR2) in host defense against Mtb, our findings indicate that TLR2 may be playing a key role in regulating these two opposing functions of the Mtb granuloma. Comparative studies between wild type and TLR2 gene-deficient mice demonstrated that the absence of TLR2 did not affect the magnitude of the Th1 effector response generated following aerosol infection with Mtb or the induction of recall Th1 memory immunity in response to Mtb challenge. However, the consequence of TLR2 absence was manifested at the level of the granuloma. Analysis of lungs from chronically-infected TLR−/− mice revealed increased bacterial burden and loss of granuloma integrity in comparison with infected WT mice. The infected lungs of TLR2−/− mice also exhibited enhanced inflammation and reduced Foxp3+ regulatory T cells. Together, these findings provide insights into how TLR2 might regulate the tubercle granuloma.
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ÖZBİLÜM, Nil, Burcu BAYYURT, Serdal ARSLAN, Sevgi BALTACI, and Mehmet BAKIR. "Toll-like Receptor 3 c.1377C/T and -7C/A Polymorphisms Associated with COVID-19 and COVID-19 Severity." Cumhuriyet Science Journal 44, no. 1 (March 26, 2023): 46–52. http://dx.doi.org/10.17776/csj.1167703.
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Chinese officials have reported the novel coronavirus to the world health organization, which is called the SARS-CoV-2. Toll-like receptor 3 (TLR3) induces antiviral immune responses via the production of type I interferons and inflammatory cytokines. In this study, we aimed to examine TLR3 c.1377C/T and -7C/A polymorphisms in COVID-19 and the association between some clinical parameters. We investigated the frequencies of TLR3 (c.1377C/T and -7C/A) polymorphisms in 150 patients with COVID-19 and 171 healthy individuals as controls. We performed polymerase chain reaction (PCR) based on restriction fragment length polymorphism (RFLP). We also investigated whether TLR3 c.1377C/T and-7C/A were associated with the severity of COVID-19. In addition, CHAID tree-based classification algorithm was created to investigate the severity of the patients in our study. TLR3 c.1377C/T TT genotype frequencies were statistically significant between cases and controls (p= 0.02). For TLR3 -7C/A polymorphism, the findings showed a statistically significant difference in A allele frequencies (p= 0.03). There was a statistically significant difference in the distribution of TLR3 -7C/A CA genotype frequency (p= 0.04). Our findings suggest that TLR3 c.1377C/T and -7C/A polymorphisms may be important on susceptibility or clinical course of COVID-19.
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Ingrao, Fiona, Victoria Duchatel, Isabel Fernandez Rodil, Mieke Steensels, Eveline Verleysen, Jan Mast, and Bénédicte Lambrecht. "The Expression of Hemagglutinin by a Recombinant Newcastle Disease Virus Causes Structural Changes and Alters Innate Immune Sensing." Vaccines 9, no. 7 (July 7, 2021): 758. http://dx.doi.org/10.3390/vaccines9070758.
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Recombinant Newcastle disease viruses (rNDV) have been used as bivalent vectors for vaccination against multiple economically important avian pathogens. NDV-vectored vaccines expressing the immunogenic H5 hemagglutinin (rNDV-H5) are considered attractive candidates to protect poultry from both highly pathogenic avian influenza (HPAI) and Newcastle disease (ND). However, the impact of the insertion of a recombinant protein, such as H5, on the biological characteristics of the parental NDV strain has been little investigated to date. The present study compared a rNDV-H5 vaccine and its parental NDV LaSota strain in terms of their structural and functional characteristics, as well as their recognition by the innate immune sensors. Structural analysis of the rNDV-H5 demonstrated a decreased number of fusion (F) and a higher number of hemagglutinin-neuraminidase (HN) glycoproteins compared to NDV LaSota. These structural differences were accompanied by increased hemagglutinating and neuraminidase activities of rNDV-H5. During in vitro rNDV-H5 infection, increased mRNA expression of TLR3, TLR7, MDA5, and LGP2 was observed, suggesting that the recombinant virus is recognized differently by sensors of innate immunity when compared with the parental NDV LaSota. Given the growing interest in using NDV as a vector against human and animal diseases, these data highlight the importance of thoroughly understanding the recombinant vaccines’ structural organization, functional characteristics, and elicited immune responses.
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Döring, Christin, Tommy Regen, Ulla Gertig, Denise van Rossum, Anne Winkler, Nasrin Saiepour, Wolfgang Brück, Uwe-Karsten Hanisch, and Hana Janova. "A presumed antagonistic LPS identifies distinct functional organization of TLR4 in mouse microglia." Glia 65, no. 7 (May 4, 2017): 1176–85. http://dx.doi.org/10.1002/glia.23151.
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Ramos Aguila, Luis Carlos, Hafiza Javaira Ashraf, Jessica Paola Sánchez Moreano, Komivi Senyo Akutse, Bamisope Steve Bamisile, Liuyang Lu, Xiaofang Li, Jingyi Lin, Qing Wu, and Liande Wang. "Genome-Wide Identification and Characterization of Toll-like Receptors (TLRs) in Diaphorina citri and Their Expression Patterns Induced by the Endophyte Beauveria bassiana." Journal of Fungi 8, no. 8 (August 22, 2022): 888. http://dx.doi.org/10.3390/jof8080888.
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Toll-like receptors (TLRs) are pathogen recognition receptors (PRRs), which play key roles in helping the host immune system fight pathogen invasions. Systematic information on TLRs at the genome-wide level and expression profiling in response to endophytic colonization is very important to understand their functions but is currently lacking in this field. Here, a total of two TLR genes were identified and characterized in Diaphorina citri. The TLR genes of D. citri were clustered into five families according to the phylogenetic analysis of different species’ TLRs. The domain organization analyses suggested that the TLRs were constituted of three important parts: a leucine-rich repeat (LRR) domain, a transmembrane region (TR) and a Toll/interleukin-1 receptor (TIR) domain. The mRNA expression levels of the two TLR genes (DcTOLL and DcTLR7) were highly regulated in both nymphs and adults of D. citri. These results elucidated the potentiated TLR gene expression in response to endophytically colonized plants. Furthermore, the 3D structures of the TIR domain were highly conserved during evolution. Collectively, these findings elucidate the crucial roles of TLRs in the immune response of D. citri to entomopathogens systematically established as endophytes, and provide fundamental knowledge for further understanding of the innate immunity of D. citri.
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Guo, Shengtao, Mengsha Zeng, Wenxue Gao, Fan Li, Xiuying Wei, Qiong Shi, Zhengyong Wen, and Zhaobin Song. "Toll-like Receptor 3 in the Hybrid Yellow Catfish (Pelteobagrus fulvidraco ♀ × P. vachelli ♂): Protein Structure, Evolution and Immune Response to Exogenous Aeromonas hydrophila and Poly (I:C) Stimuli." Animals 13, no. 2 (January 14, 2023): 288. http://dx.doi.org/10.3390/ani13020288.
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As a major mediator of cellular response to viral infection in mammals, Toll-like receptor 3 (TLR3) was proved to respond to double-stranded RNA (dsRNA). However, the molecular mechanism by which TLR3 functions in the viral infection response in teleosts remains to be investigated. In this study, the Toll-like receptor 3 gene of the hybrid yellow catfish was identified and characterized by comparative genomics. Furthermore, multiple sequence alignment, genomic synteny and phylogenetic analysis suggested that the homologous TLR3 genes were unique to teleosts. Gene structure analysis showed that five exons and four introns were common components of TLR3s in the 12 examined species, and interestingly the third exon in teleosts was the same length of 194 bp. Genomic synteny analysis indicated that TLR3s were highly conserved in various teleosts, with similar organizations of gene arrangement. De novo predictions showed that TLR3s were horseshoe-shaped in multiple taxa except for avian (with a round-shaped structure). Phylogenetic topology showed that the evolution of TLR3 was consistent with the evolution of the studied species. Selection analysis showed that the evolution rates of TLR3 proteins were usually higher than those of TLR3-TIR domains, indicating that the latter were more conserved. Tissue distribution analysis showed that TLR3s were widely distributed in the 12 tested tissues, with the highest transcriptions in liver and intestine. In addition, the transcription levels of TLR3 were significantly increased in immune-related tissues after infection of exogenous Aeromonas hydrophila and poly (I:C). Molecular docking showed that TLR3 in teleosts forms a complex with poly (I:C). In summary, our present results suggest that TLR3 is a pattern recognition receptor (PRR) gene in the immune response to pathogen infections in hybrid yellow catfish.
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Triantafilou, Martha, Philipp M. Lepper, Robin Olden, Ivo de Seabra Rodrigues Dias, and Kathy Triantafilou. "Location, Location, Location: Is Membrane Partitioning Everything When It Comes to Innate Immune Activation?" Mediators of Inflammation 2011 (2011): 1–10. http://dx.doi.org/10.1155/2011/186093.
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In the last twenty years, the general view of the plasma membrane has changed from a homogeneous arrangement of lipids to a mosaic of microdomains. It is currently thought that islands of highly ordered saturated lipids and cholesterol, which are laterally mobile, exist in the plane of the plasma membrane. Lipid rafts are thought to provide a means to explain the spatial segregation of certain signalling pathways emanating from the cell surface. They seem to provide the necessary microenvironment in order for certain specialised signalling events to take place, such as the innate immune recognition. The innate immune system seems to employ germ-lined encoded receptors, called pattern recognition receptors (PRRs), in order to detect pathogens. One family of such receptors are the Toll-like receptors (TLRs), which are the central “sensing” apparatus of the innate immune system. In recent years, it has become apparent that TLRs are recruited into membrane microdomains in response to ligands. These nanoscale assemblies of sphingolipid, cholesterol, and TLRs stabilize and coalesce, forming signalling platforms, which transduce signals that lead to innate immune activation. In the current paper, we will investigate all past and current literature concerning recruitment of extracellular and intracellular TLRs into lipid rafts and how this membrane organization modulates innate immune responses.
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Hajishengallis, George, Min Wang, Evlambia Harokopakis, Martha Triantafilou, and Kathy Triantafilou. "Porphyromonas gingivalis Fimbriae Proactively Modulate β2 Integrin Adhesive Activity and Promote Binding to and Internalization by Macrophages." Infection and Immunity 74, no. 10 (October 2006): 5658–66. http://dx.doi.org/10.1128/iai.00784-06.
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ABSTRACT In monocytes, the fimbriae of the oral pathogen Porphyromonas gingivalis activate cross talk signaling from Toll-like receptor 2 (TLR2) to the β2 integrin CD11b/CD18, leading to the induction of the high-affinity state of the latter receptor. CD14 plays an important role in this “inside-out” proadhesive pathway by binding fimbriae and facilitating the activation of TLR2 and phosphatidylinositol 3-kinase signaling. In its high-affinity state, CD11b/CD18 mediates monocyte adhesion to endothelial cells and transmigration to sites of infection. We have now shown that P. gingivalis fimbriae function as both an activator and a ligand of CD11b/CD18; thus, fimbriae proactively promote their own binding to monocytes. Indeed, treatments that interfered with fimbria-induced activation of CD11b/CD18 (i.e., blockade of CD14, TLR2, or phosphatidylinositol 3-kinase signaling) also suppressed the cell binding activity of fimbriae, which was largely inducible and CD11b/CD18 dependent. Development of a recombinant inside-out signaling system in Chinese hamster ovary cells confirmed the ability of fimbriae to activate CD14/TLR2 signaling and induce their own CD11b/CD18-dependent binding. Induction of this proadhesive pathway by P. gingivalis fimbriae appeared to take place in lipid rafts. Indeed, methyl-β-cyclodextrin, a cholesterol-sequestering agent that disrupts lipid raft organization, was found to inhibit the fimbria-induced assembly of CD14/TLR2 signaling complexes and the activation of the high-affinity state of CD11b/CD18. Experiments using macrophages from mice deficient in various pattern recognition receptors indicated that the receptors involved in the inside-out proadhesive pathway (CD14, TLR2, and CD11b/CD18) are important for mediating P. gingivalis internalization within macrophages. It therefore appears that P. gingivalis proactively modulates β2 integrin adhesive activity for intracellular uptake.
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Whitacre, Margaret, Janine Ward, Konner Jackson, Laura Bess, Rachel Jayah, Cherrokee Sands, Hathaipat Arayangkul, et al. "Pre-treatment with a novel synthetic TLR4 agonist prior to challenge with mouse-adapted H1N1 and H2N3 influenza strains reduced morbidity and mortality in BALB/c mice." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 64.04. http://dx.doi.org/10.4049/jimmunol.208.supp.64.04.
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Abstract According to the World Health Organization, influenza causes 3–5 million cases of severe illness and 250,000 – 500,000 deaths annually despite the availability of a seasonal vaccine. As an alternative therapy for use in high-risk groups and environments, we evaluated the efficacy of prophylactic treatment with a novel synthetic TLR4 agonist in BALB/c mice. Animals were anesthetized and treated with a TLR4 agonist intranasally (IN) 0 to 28 days prior to a lethal challenge with either H1N1 or H3N2 mouse-adapted human influenza. Animals were monitored daily for weight loss, decreased body temperature, body score, and mortality. Initial dose-response experiments demonstrated that mice treated with 50 μg or 10 μg of our novel TLR4 agonist in an aqueous formulation were similarly protected from H3N2 influenza challenge with respect to weight loss and survival. However, initial weight loss data demonstrated that 50 μg was not as well tolerated as 10 μg. The 10 μg dose was therefore selected as the lead dose in subsequent experiments. In a series of formulation comparison experiments, the lead formulation resulted in marked improvement in both percent weight loss and survival compared to initial TLR4 agonist formulations. Animals treated with all formulations of our novel synthetic TLR4 agonist 0, 7, or 14 days prior to infection resulted in 80–90% survival. The lead formulation also resulted 80–90% survival when given prophylactically 21 or 28 days prior to infection compared to 0–20% survival in untreated mice. Overall, our results show that pre-treatment with our novel synthetic TLR4 agonist prior to exposure to mouse-adapted H1N1 and H2N3 influenza strains reduced morbidity and mortality in infected mice for up to 28 days after treatment. This work was supported by NIH grant 5R44AI136081-03
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Maeda, Shin. "NF-κB, JNK, and TLR Signaling Pathways in Hepatocarcinogenesis." Gastroenterology Research and Practice 2010 (2010): 1–10. http://dx.doi.org/10.1155/2010/367694.
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Hepatocellular carcinoma (HCC) is the third largest cause of cancer deaths worldwide. The role of molecular changes in HCC have been used to identify prognostic markers and chemopreventive or therapeutic targets. It seems that toll-like receptors (TLRs) as well as the nuclear factor (NF)-κB, and JNK pathways are critical regulators for the production of the cytokines associated with tumor promotion. The cross-talk between an inflammatory cell and a neoplastic cell, which is instigated by the activation of NF-κB and JNKs, is critical for tumor organization. JNKs also regulate cell proliferation and act as oncogenes, making them the main tumor-promoting protein kinases. TLRs play roles in cytokine and hepatomitogen expression mainly in myeloid cells and may promote liver tumorigenesis. A better understanding of these signaling pathways in the liver will help us understand the mechanism of hepatocarcinogenesis and provide a new therapeutic target for HCC.
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Islam, Md Rashed-Ul, Laboni Begum, and Afroza Hossain. "An Investigation Approach for Assessing Challenges to Sustainable Consumption and Production Practices in the Leather Goods Industry." Textile & Leather Review 5 (February 24, 2022): 85–102. http://dx.doi.org/10.31881/tlr.2021.37.
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Sustainable consumption and production (SCP) practices in the leather goods industry is a new trend in the developing and developed countries and it is becoming more popular by the day. It is essential to introduce SCP practices for the production in the sub-sector of leather products in Bangladesh. The relevance of SCP activities to the leather goods industry is emphasized in this article. The previous work emphasised other industrial fields. Results reveal that the lack of technological up-gradation, lack of customer attitude and behaviour towards SCP, lack of incentives for/motivation of business organizations, lack of top management commitment, support, dedication and involvement, and customers who are attracted towards cheap products come under causal group challenges, which can help the decision makers formulate a policy for a successful implementation of SCP practices that will help achieve sustainable development goals.
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Liao, Zhiwei, Quanyuan Wan, Hang Su, Changsong Wu, and Jianguo Su. "Pattern recognition receptors in grass carp Ctenopharyngodon idella: I. Organization and expression analysis of TLRs and RLRs." Developmental & Comparative Immunology 76 (November 2017): 93–104. http://dx.doi.org/10.1016/j.dci.2017.05.019.
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Ganther, Sean, Allan Radaic, Erin Malone, Pachiyappan Kamarajan, Nai-Yuan Nicholas Chang, Christian Tafolla, Ling Zhan, J. Christopher Fenno, and Yvonne L. Kapila. "Treponema denticola dentilisin triggered TLR2/MyD88 activation upregulates a tissue destructive program involving MMPs via Sp1 in human oral cells." PLOS Pathogens 17, no. 7 (July 13, 2021): e1009311. http://dx.doi.org/10.1371/journal.ppat.1009311.
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Periodontal disease is driven by dysbiosis in the oral microbiome, resulting in over-representation of species that induce the release of pro-inflammatory cytokines, chemokines, and tissue-remodeling matrix metalloproteinases (MMPs) in the periodontium. These chronic tissue-destructive inflammatory responses result in gradual loss of tooth-supporting alveolar bone. The oral spirochete Treponema denticola, is consistently found at significantly elevated levels in periodontal lesions. Host-expressed Toll-Like Receptor 2 (TLR2) senses a variety of bacterial ligands, including acylated lipopolysaccharides and lipoproteins. T. denticola dentilisin, a surface-expressed protease complex comprised of three lipoproteins has been implicated as a virulence factor in periodontal disease, primarily due to its proteolytic activity. While the role of acylated bacterial components in induction of inflammation is well-studied, little attention has been given to the potential role of the acylated nature of dentilisin. The purpose of this study was to test the hypothesis that T. denticola dentilisin activates a TLR2-dependent mechanism, leading to upregulation of tissue-destructive genes in periodontal tissue. RNA-sequencing of periodontal ligament cells challenged with T. denticola bacteria revealed significant upregulation of genes associated with extracellular matrix organization and degradation including potentially tissue-specific inducible MMPs that may play novel roles in modulating host immune responses that have yet to be characterized within the context of oral disease. The Gram-negative oral commensal, Veillonella parvula, failed to upregulate these same MMPs. Dentilisin-induced upregulation of MMPs was mediated via TLR2 and MyD88 activation, since knockdown of expression of either abrogated these effects. Challenge with purified dentilisin upregulated the same MMPs while a dentilisin-deficient T. denticola mutant had no effect. Finally, T. denticola-mediated activation of TLR2/MyD88 lead to the nuclear translocation of the transcription factor Sp1, which was shown to be a critical regulator of all T. denticola-dependent MMP expression. Taken together, these data suggest that T. denticola dentilisin stimulates tissue-destructive cellular processes in a TLR2/MyD88/Sp1-dependent fashion.
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Paul, Tripti, and Sandeep Mondal. "A strategic analysis of tea leaves supply chain before manufacturing – a case in Assam." Benchmarking: An International Journal 26, no. 1 (February 4, 2019): 246–70. http://dx.doi.org/10.1108/bij-01-2018-0007.
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PurposeThere exists insufficient literature on classification and taxonomy of tea leaves supply chain (TLSC), so the purpose of this paper is to study the existing TLSCs and classify them accordingly. Apart from this, the paper also focuses on identification of key decisions issues in the supply chains (SC) and developing a TLSC decision framework for the state of Assam in India.Design/methodology/approachThe paper is based on a two-year detailed study on TLSC in Assam which encompasses 22 Tea Estates, 41 Small Tea Gardens (STGs) and a Research Institute (Tocklai Tea Research Institute). Secondary data were collected from relevant websites of various government organizations of India, company’s websites, annual reports, official statements from the companies, tea market reports, annual reports of the Indian Tea Association, the Tea Board of India, Tea Research Institute and published reports, etc.FindingsThe “point of origin” of TLSC is a tea garden, “point of consumption” is considered as a tea factory and green tea leaves (GTLs) forms the basic raw material. This SC includes mainly three players: Tea leaves growers, manufacturers of made tea and tea leaves agents. This study identifies the three types of TLSCs existing in Assam: TLSC1, TLSC2 and TLSC3. Among them, only TLSC1 is both responsive as well as an efficient chain, while the rest are only responsive chains. Later two SCs can be made efficient with the proposed TLSC4.Research limitations/implicationsThere is an insufficient literature on classification and taxonomy of TLSC, therefore the study (considerably the classification and taxonomy of TLSC) was developed from the primary data which were collected from the 22 Tea Estates and 41 STGs of four districts of Assam, because of limited time (two years). The study should have involved more tea estates and small tea gardens for better classification and taxonomy.Practical implicationsThe proposed model suggests that small tea growers may create a co-operative whereby smaller tea gardens (STGs) (members of the co-operative) unite to act as a single large garden, set up their own co-operative factory and recruit permanent tea plucking laborers. This up-gradation of TLSC2 and TLSC3 to TLSC4 may enable a group of STGs to work in a manner similar to a Tea Estate.Originality/valueTo the best of authors’ knowledge this is one of the first studies to classify the TLSC in Assam.
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Kim, Sangyoon. "Duplicity in possessive merger: evidence from Spanish alienable possessive constructions." Linguistic Review 35, no. 3 (September 25, 2018): 371–412. http://dx.doi.org/10.1515/tlr-2018-0001.
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Abstract In this paper, I argue that Spanish prenominal and postnominal possessives target different external merge positions focusing on alienable possessive constructions. The analysis is developed alongside a proposal on the organization of DPs, according to which articles are merged as a DP-internal category between the domains assigned to direct and indirect modifiers. Prenominal possessives are determiners reanalyzed from direct modification adjectives whereas postnominal possessives are indirect modification adjectives that arise as predicates of reduced relative clauses. This analysis provides a principled explanation on the behavior of Spanish possessives that is lacking in the generalized idea that they are pronouns with a unique merge position. Arguments are also presented showing that syntax-driven phonological restrictions condition the derivation of DPs. The account successfully derives the core properties of word order variation and related issues within possessive constructions.
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Pargai, Deepti, and Shahnaz Jahan. "The Functionalization of Cotton Fabric Using Urtica dioica Microcapsules to Develop UV Protective Textiles." Textile & Leather Review 7 (May 14, 2024): 720–37. http://dx.doi.org/10.31881/tlr.2024.023.
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The World Health Organization (WHO) and the United Nations Environment Programme (UNEP) have highlighted the increased risk of skin cancer due to exposure to UV radiation. This emphasizes the importance of safeguarding the skin. Although sunscreens are commonly used for protection their high cost, the need for frequent reapplication, and pollution in coastal areas necessitate alternative solutions. Clothing also offers protection but requires additional application of dyes and finishes for prolonged effectiveness. The application of synthetic or natural dyes can enhance the UV protection properties of the fabric but Synthetic dyes contribute to pollution, while natural dyes lack durability. Addressing these challenges, this study focuses on providing a durable and sustainable solution for enhancing the UV protective properties of cotton fabric using Urtica dioica microcapsules based on RSM design. Urtica dioica plant extract serves as the core material for the microcapsules. Design Expert software 10 has been used for the study. It was observed through software that at 4.116% concentration of microcapsules, 3% concentration of binder and a curing temperature of 113.258 °C an optimum UPF with sufficient fabric properties can be achieved. On conducting the experiments on these optimum conditions UPF, tensile strength and bending length value were found to be 277.60, 14.89 N/cm2 and 2.00 cm respectively. Results indicate that cotton fabric demonstrates excellent UV protection properties even after the 20th wash cycle. This research contributes to the ongoing quest for fabric with UV protection, emphasizing both efficacy and sustainability compared to current synthetic alternatives available in the market.
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Li, Wenqian, Jun Yan, and Yan Yu. "Geometrical reorganization of Dectin-1 and TLR2 on single phagosomes alters their synergistic immune signaling." Proceedings of the National Academy of Sciences 116, no. 50 (November 21, 2019): 25106–14. http://dx.doi.org/10.1073/pnas.1909870116.
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Receptors of innate immune cells function synergistically to detect pathogens and elicit appropriate immune responses. Many receptor pairs also appear “colocalized” on the membranes of phagosomes, the intracellular compartments for pathogen ingestion. However, the nature of the seemingly receptor colocalization and the role it plays in immune regulation are unclear, due to the inaccessibility of intracellular phagocytic receptors. Here, we report a geometric manipulation technique to directly probe the role of phagocytic receptor “colocalization” in innate immune regulation. Using particles with spatially patterned ligands as phagocytic targets, we can decouple the receptor pair, Dectin-1 and Toll-like receptor (TLR)2, to opposite sides on a single phagosome or bring them into nanoscale proximity without changing the overall membrane composition. We show that Dectin-1 enhances immune responses triggered predominantly by TLR2 when their centroid-to-centroid proximity is <500 nm, but this signaling synergy diminishes upon receptor segregation beyond this threshold distance. Our results demonstrate that nanoscale proximity, not necessarily colocalization, between Dectin-1 and TLR2 is required for their synergistic regulation of macrophage immune responses. This study elucidates the relationship between the spatial organization of phagocytic receptors and innate immune responses. It showcases a technique that allows spatial manipulation of receptors and their signal cross-talk on phagosomes inside living cells.
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García-Carnero, Laura C., Iván Martínez-Duncker, Manuela Gómez-Gaviria, and Héctor M. Mora-Montes. "Differential Recognition of Clinically Relevant Sporothrix Species by Human Mononuclear Cells." Journal of Fungi 9, no. 4 (April 6, 2023): 448. http://dx.doi.org/10.3390/jof9040448.
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Sporotrichosis is a human and animal fungal infection distributed worldwide that is caused by the thermodimorphic species of the Sporothrix pathogenic clade, which includes Sporothrix brasiliensis, Sporothrix schenckii, and Sporothrix globosa. The cell wall composition and the immune response against the Sporothrix species have been studied mainly in S. brasiliensis and S. schenckii, whilst little is known about the S. globosa cell wall and the immune response that its components trigger. Therefore, in this study, we aimed to analyze the cell wall composition of S. globosa in three morphologies (germlings, conidia, and yeast-like cells) and the differences in cytokine production when human peripheral blood mononuclear cells (PBMCs) interact with these morphotypes, using S. schenckii and S. brasiliensis as a comparison. We found that S. globosa conidia and yeast-like cells have a higher cell wall chitin content, while all three morphologies have a higher β-1,3-glucan content, which was found most exposed at the cell surface when compared to S. schenckii and S. brasiliensis. In addition, S. globosa has lower levels of mannose- and rhamnose-based glycoconjugates, as well as of N- and O-linked glycans, indicating that this fungal cell wall has species-specific proportions and organization of its components. When interacting with PBMCs, S. brasiliensis and S. globosa showed a similar cytokine stimulation profile, but with a higher stimulation of IL-10 by S. globosa. Additionally, when the inner cell wall components of S. globosa were exposed at the surface or N- and O-glycans were removed, the cytokine production profile of this species in its three morphotypes did not significantly change, contrasting with the S. schenckii and S. brasiliensis species that showed different cytokine profiles depending on the treatment applied to the walls. In addition, it was found that the anti-inflammatory response stimulated by S. globosa was dependent on the activation of dectin-1, mannose receptor, and TLR2, but not TLR4. All of these results indicate that the cell wall composition and structure of the three Sporothrix species in the three morphologies are different, affecting their interaction with human PBMCs and generating species-specific cytokine profiles.
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Damschroder, Laura J., Caitlin M. Reardon, Nina Sperber, Claire H. Robinson, Jacqueline J. Fickel, and Eugene Z. Oddone. "Implementation evaluation of the Telephone Lifestyle Coaching (TLC) program: organizational factors associated with successful implementation." Translational Behavioral Medicine 7, no. 2 (September 29, 2016): 233–41. http://dx.doi.org/10.1007/s13142-016-0424-6.
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Xu, Hao, Nancy J. Wandersee, YiHe H. Guo, Deron W. Jones, Sandra L. Holzhauer, Madelyn S. Hanson, Neil Hogg, et al. "HMGB1 Release and TLR4-Mediated Inflammation In Sickle Cell Disease At Baseline and During Acute Vaso-Occlusive Crisis." Blood 122, no. 21 (November 15, 2013): 181. http://dx.doi.org/10.1182/blood.v122.21.181.181.
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Abstract High Mobility Group Box 1 (HMGB1) is a nuclear protein that aids in regulating gene expression and the organization of DNA structure. However, upon cellular activation or injury, HMGB1 can be secreted from activated immune cells through non-classical ‘leaderless’ pathways or released from tissues through necrosis. Once released, HMGB1 acts as a Damaged-Associated Molecular Pattern (DAMP) that binds with other DAMPs and cytokines to activate Toll-Like Receptor 4 (TLR4), resulting in pro-inflammatory signaling and impaired endothelial cell function. It is well established that sickle cell disease (SCD) increases neutrophil count and activation. In addition, tissue injury and inflammation is further exacerbated by the ischemia/reperfusion that occurs during acute vaso-occlusion in SCD. Very little is known concerning HMGB1 release in SCD and its role in the pathology of SCD. We hypothesize that SCD increases HMGB1 release and that SCD-dependent increases in HMGB1 and oxidative stress act in concert to impair endothelial cell (EC) function and increase vascular congestion and tissue injury. To explore this hypothesis, we assessed plasma levels of HMGB1 in SCD as compared to normal controls. In humans, we found that individuals with SCD have ∼4-fold increased plasma HMGB1 levels compared to plasma levels in control individuals (p=0.02). Similarly, the Berkeley mouse model of SCD has ∼2-fold higher levels of plasma HMGB1 compared to control animals (p<0.01). Next, we measured plasma HMGB1 levels in SCD and control mice after exposure to hypoxia (3 hrs 10% FIO2) to induce acute sickling followed by reoxygenation (2 hrs room air, H/R) as an experimental model of acute vaso-occlusion. Importantly, hypoxia/reoxygenation (H/R) increased HMGB1 levels in SS mice more than 3-fold, while having little effect on the plasma levels of HMGB1 in control mice (p<0.03). This indicates that H/R induces immune cell activation and/or tissue injury, which increases the release of HMGB1 into the plasma. Since H/R induced such high plasma concentrations of HMGB1 in SCD mice, we examined if HMGB1 alone was sufficient to induce vascular congestion. Mice were injected with recombinant HMGB1 to deliver levels similar to that found in SCD mice post H/R; after 3 hrs mice were euthanized and lungs harvested. Histologic examination of lung sections showed that HMGB1 directly increased vascular congestion in SCD but not control mice. These data indicate that, even in the absence of acute sickling, SCD mice are more susceptible than control mice to HMGB1-induced lung vascular injury. Finally, to begin to understand how SCD induces chronic states of inflammation, we determined the effects of human and mouse plasma on TLR4 receptor activity. To assess TLR4 receptor activity we used TLR4 “reporter cells” that secrete alkaline phosphatase upon binding and activation of TLR4. We found that plasma from individuals with SCD induced ∼4-fold greater increases in TLR4 reporter activity compared to plasma from healthy race-matched individuals (p<0.025). Likewise, after H/R treatment, plasma from SCD mice induced ∼2-fold greater increase in TLR4 reporter activity compared to plasma from control mice (p<0.05). The “gold standard” for determining if HMGB1 plays a role in inflammation is the use of neutralizing antibodies. Interestingly, anti-HMGB1 antibody treatment of H/R-exposed SCD mice markedly diminished the plasma-induced TLR4 receptor activity to levels similar to that observed from control mice (p<0.05), suggesting that much of the increase in TLR4 receptor activity induced by plasma from SS-H/R mice is HMGB1-dependent. Taken together, these data indicate that SCD increases the release of HMGB1 and suggests that HMGB1 plays an important role in the mechanisms by which SCD impairs vascular function and increases vascular congestion. Disclosures: Wandersee: Bayer: Consultancy. Guo:Bayer: Consultancy. Hillery:Bayer: Consultancy; Biogen Idec: Consultancy.
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Bolevich, Sergey Brankovich, Peter Frantzevich Litvitsky, Sergei Vitalievich Grachev, Sergey Ivanovich Vorobyev, Alexandra Sergeevna Orlova, Marina Anatolievna Fokina, Alexei Alekseevich Novikov, et al. "Fundamental Basis of COVID-19 Pathogenesis." Serbian Journal of Experimental and Clinical Research 21, no. 2 (June 1, 2020): 93–111. http://dx.doi.org/10.2478/sjecr-2020-0029.
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AbstractAt the end of 2019, a new coronavirus infection occurred in the People’s Republic of China with an epicentre in the city of Wuhan. On February 11th, 2020, the World Health Organization assigned the official name of the infection caused by the new coronavirus – COVID-19. COVID-19 has affected people from all over the world given that the infection was noted in 200 countries resulting in annunciation of the pandemic situation. Human corona viruses cause mild to moderate respiratory infections. At the end of 2002, a new coronavirus appeared (SARS-CoV), the causal agent of atypical pneumonia, which caused acute respiratory distress syndrome (ARDS). The initial stage of COVID-19 infection is the penetration of SARS-CoV-2 into target cells that have angiotensin converting enzyme type II receptors. The virus enters the body through the respiratory tract and interacts primarily with toll-like receptors (TLRs). The events in SARS-Cov-2 induced infection follow the next scenario: epithelial cells via TLRs recognize and identify SARS-Cov-2, and after that the information is transmitted to the transcriptional NF-κB, which causes expression of the corresponding genes. Activated in this way, the epithelial cells begin to synthesize various biologically active molecules. The results obtained on preclinical material indicate that ROS generation increases and the antioxidant protection decreases, which plays a major role in the pathogenesis of SARS-CoV, as well as in the progression and severity of this respiratory disease.
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Wu, Yun Na, Chao Liu, and Hu Xu. "Applied-Information Technology in Project Portfolio Risk Management System Based on Hall's Three-Dimensional Structure." Advanced Materials Research 1046 (October 2014): 538–44. http://dx.doi.org/10.4028/www.scientific.net/amr.1046.538.
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Project portfolio management involves multiple projects, of which risk regulation is different from the risk regulation of single projects especially in information technology application. In addition to considering each project's own risk, it must consider risk of project portfolio from a broader perspective. Issues of risk regulation are more complex, therefore its risk regulation requires new management approaches. This paper draws on Hall's three-dimensional management structure, respectively, from the four aspects: project portfolio management process, project portfolio risk regulation process, project portfolio risk regulation approach and project portfolio risk regulation organization, to establish a project portfolio risk regulation four-dimensional system (tlkc system) by applied-information technology. It provides a theoretical guidance for current risk regulation of project portfolio management, contributes project-oriented enterprises to establish suitable project portfolio risk regulation measures with their own circumstances, which is a necessary complement for project portfolio theory.
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Hansson, Elisabeth, and Eva Skiöldebrand. "Coupled cell networks of astrocytes and chondrocytes are target cells of inflammation." Scandinavian Journal of Pain 12, no. 1 (July 1, 2016): 120–21. http://dx.doi.org/10.1016/j.sjpain.2016.05.013.
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AbstractAimsSystemic low-grade inflammation can be initiated in vivo after traumatic injury or in chronic diseases as neurodegenerative, metabolic and autoimmune diseases. Coupled cell networks are target cells leading to the spread of inflammation and changes in biochemical cellular parameters. Do astrocytes and chondrocytes behave in a similar way in an inflammatory reactive state with respect to Ca2+ signaling, actin filaments rearrangement, receptor properties, pro-inflammatory cytokine release etc?MethodsPrimary cultures of astrocytes and chondrocytes, respectively, were incubated with lipopolysaccharide (LPS) (10 ng/ml, 24h) or interleukin-1β (IL-1β) (5ng/ml, 24 h) to induce inflammatory reactivity. Ca2+ signaling, Na+/K+-ATPase-, connexin 43 (Cx43)-, and Toll-like receptor 4 (TLR4)- expressions, actin filament organization, and IL-1β release were analyzed.ResultsStimulation with IL-1β or LPS altered the Ca2+ signaling from single peaks to oscillating waves and increased the expression of Cx43 and TLR4, and decreased expression of Na+/K+-ATPase. A disruption of the actin filaments with more pronounced ring-formed structures was found in inflammatory induced astrocytes and chondrocytes which in turn affects Ca2+ oscillations. Additionally a release of active matrix metallopeptidase-13 was found in media from IL-1β stimulated chondrocytes.ConclusionsOur data show that cellular mechanisms of healthy chondrocytes as well as inflamed, resemble the coupled cell networks of astrocytes. Chronic, low-grade inflammation can influence coupled cell networks in one or several organs, leading to co-morbidity. It is crucial that inflammatory affected cells in various organs are restored back to a physiological non-inflammatory homeostasis in order to prevent tissue degradation and pain.
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Oliveira, João Pedro Paz Pinho, Sarah Ângelo Diniz Melo, Bianca Mickaela Santos Chaves, and Bárbara Verônica Cardoso de Souza. "Curcumina nanoencapsulada no tratamento da COVID-19: uma revisão de patentes." Peer Review 6, no. 7 (March 30, 2024): 185–98. http://dx.doi.org/10.53660/prw-2049-3731.
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A síndrome respiratória aguda grave coronavírus 2 (SARS-CoV-2), responsável pelo surto da doença coronavírus (COVID-19), não apenas ativa respostas imunes antivirais, mas também pode causar respostas inflamatórias. Esse trabalho teve como objetivo realizar uma revisão de patentes sobre a ação da curcumina nanoencapsulada no tratamento da COVID-19. As patentes foram pesquisadas nas bases World Intellectual Property Organization (WIPO), European Patent Office (Espacenet), United States Patent and Trademark Office (USPTO) e Instituto Nacional de Propriedade Intelectual (INPI), utilizando os descritores: Curcumin, Curcuma longa, Curcumin nanocapsules, Nanoencapsulated curcumin, Curcuma longa AND COVID-19, Curcumin nanocapsules AND COVID 19. Das patentes encontradas apenas quatro tratavam sobre a aplicação da curcumina nanoencapsulada no tratamento da COVID-19, mostrando efeitos inibitórios sobre sinalizações inflamatórias e oxidantes, inibindo expressões do citocromo P-450 e TLR7. Esses resultados representam uma perspectiva nas pesquisas e aplicações da curcumina nanoencapsulada, no tratamento da COVID-19, sendo a nanotecnologia uma técnica que aumenta a sua eficácia terapêutica.
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Colladon, Andrea Fronzetti, Maurizio Naldi, and Massimiliano M. Schiraldi. "Quality Management in the Design of TLC Call Centres." International Journal of Engineering Business Management 5 (January 1, 2013): 48. http://dx.doi.org/10.5772/56921.
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Call centres rely heavily on the self-service paradigm through the use of an automated IVR (Interactive Voice Response) system. The service time delivered by the IVR is a major component of the overall QoS (Quality of Service) delivered by the call centre. We analyse the structure and service times of IVR systems through a case study of five call centres in the telecommunications sector. The service trees of the call centres under survey are reconstructed by complete exploration and analysed through a set of metrics. The present design of service trees leads to service times typically larger than those spent waiting for a human agent and to excessively long announcements, with a negative impact on the overall QoS. Imbalances in the popularity of the services offered by the IVR can be exploited to reduce remarkably the average service time, by properly matching the most popular services with the shortest service times.
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Rokiman Letsara, Rigobert Andrianantenaina, Gédéon Ngiala Bongo, Colette Masengo Ashande, Mahendra Ilmi S Matondang, Koto-te-Nyiwa Ngbolua, and Baholy Robijaona Rahelivololoniaina. "TLC Profiling of Leaves Extracts of Some Aloe Threatened Species Endemic to Madagascar for Their Antioxidant Activity." Britain International of Exact Sciences (BIoEx) Journal 2, no. 3 (September 15, 2020): 653–62. http://dx.doi.org/10.33258/bioex.v2i3.304.
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The World Health Organization reported that at least 80% of populations rely on traditional medicine and medicinal plants for their primary health care. Due to their phytochemical compounds, the plants of the Aloe genus are reported to have high potential antiCovid-19 (and antioxidant properties. The aim of this study is to evaluate the in vitro antioxidant activity of some Malagasy endangered species of Aloe genus. The ethanolic extract of few Aloe of Madagascar leaf extracts was fractionated by liquid-liquid partition using hexane. In total 18 different fractions from 9 species have been used to determine their antioxidant activity through in vitro model by using 2,2-Diphenyl-1-picrylhydrazyl (DPPH) assay. Both hexanic extract and aqueous extract displayed antioxidant activities in four species. The most evident antioxidant activity was expressed by A. helenae.
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Tang, Da, Yunhang Gao, Rixin Wang, Yuena Sun, and Tianjun Xu. "Characterization, genomic organization, and expression profiles of MyD88, a key adaptor molecule in the TLR signaling pathways in miiuy croaker (Miichthys miiuy)." Fish Physiology and Biochemistry 38, no. 6 (December 2012): 1667–77. http://dx.doi.org/10.1007/s10695-012-9663-8.
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Thönes, Nadja, Anna Herreiner, Lysann Schädlich, Konrad Piuko, and Martin Müller. "A Direct Comparison of Human Papillomavirus Type 16 L1 Particles Reveals a Lower Immunogenicity of Capsomeres than Viruslike Particles with Respect to the Induced Antibody Response." Journal of Virology 82, no. 11 (April 2, 2008): 5472–85. http://dx.doi.org/10.1128/jvi.02482-07.
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ABSTRACT Capsomeres are considered to be an alternative to viruslike particle (VLP)-based vaccines as they can be produced in prokaryotic expression systems. So far, no detailed side-by-side comparison of VLPs and capsomeres has been performed. In the present study, we immunized mice with insect cell-derived human papillomavirus type 16 VLPs and capsomeres. VLPs induced consistently higher antibody titers than capsomeres but the two forms induced similar CD8 T-cell responses after subcutaneous, intranasal, and oral immunization, and at least 20 to 40 times more L1 in the form of capsomeres than in the form of VLPs was needed to achieve comparable antibody responses. These results were confirmed by DNA immunization. The lower immunogenicity of capsomeres was independent of the isotype switch, as it was also observed for the early immunoglobulin M responses. Although there were differences in the display of surface epitopes between the L1 particles, these did not contribute significantly to the differences in the immune responses. capsomeres were less immunogenic than VLPs in Toll-like receptor 4 (TLR4)-deficient mice, suggesting that the lower immunogenicity is not due to a failure of capsomeres to trigger TLR4. We observed better correlation between antibody results from enzyme-linked immunosorbent assays and neutralization assays for sera from VLP-immunized mice than for sera from capsomere-immunized mice, suggesting qualitative differences between VLPs and capsomeres. We also showed that the lower immunogenicity of capsomeres could be compensated by the use of an adjuvant system containing MPL. Taken together, these results suggest that, presumably because of the lower degree of complexity of the antigen organization, capsomeres are significantly less immunogenic than VLPs with respect to the humoral immune response and that this characteristic should be considered in the design of putative capsomere-based prophylactic vaccines.
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Dai, Peifang, Hang Wang, Xin Mu, Zhen Ren, Genli Liu, and Longying Gao. "Exploring Key Genes and Molecular Mechanisms Related to Myocardial Hypertrophy Based on Bioinformatics." Science of Advanced Materials 15, no. 6 (June 1, 2023): 824–31. http://dx.doi.org/10.1166/sam.2023.4488.
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This study aimed to identify key genes and molecular mechanisms associated with cardiac hypertrophy using bioinformatics analysis. Datasets from the Gene Expression Omnibus (GEO) database were analyzed using the GEO2R tool to identify differentially expressed genes (DEGs) related to cardiac hypertrophy. The top 10 DEGs from two datasets (GSE18801 and GSE47420) were used to generate heatmaps and a volcano plot. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed using the DAVID website. The protein interaction data for DEGs were visualized using Cytoscape software. A total of 767 DEGs were identified in GSE18801 and 447 DEGs in GSE47420, with 48 common differential genes named co-DEGs. GO enrichment analysis suggested these co-DEGs were mostly related to extracellular matrix organization, muscle system process, and tissue remodeling. KEGG pathway analysis demonstrated co-DEGs were related to malaria, estrogen signaling pathway, ECM-receptor interaction, and apelin signaling pathway. Eight hub genes were identified, including Fn1, Fbn1, Dcn, Ctgf, Timp1, Lox, Tlr4, and Lcn2. These hub genes might serve as therapeutic potential biomarkers of cardiac hypertrophy.
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Berezkin, Victor, and G. Nekhoroshev. "Use of an electroosmotic pump for organization of forced-flow TLC on a plate with an adsorbent layer closed with a polymer film." Journal of Planar Chromatography – Modern TLC 19, no. 108 (April 2006): 109–14. http://dx.doi.org/10.1556/jpc.19.2006.2.4.
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Khouly, Ismael, Rosalie Salus Braun, Michelle Ordway, Iya Ghassib, Lena Larsson, and Farah Asa’ad. "The Role of Epigenetics in Periodontal and Systemic Diseases and Smoking: A Systematic Review." Applied Sciences 11, no. 11 (June 6, 2021): 5269. http://dx.doi.org/10.3390/app11115269.
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The aims of this systematic review were to identify and synthesize the evidence for an association in DNA methylation/histone modifications between periodontal diseases and systemic diseases/smoking. Electronic database searches using relevant search terms in PubMed, Embase, MEDLINE, CINAHL, Web of Science, Scopus, and SciELO, and manual searches, were independently conducted to identify articles meeting the inclusion criteria. Nine studies of 1482 participants were included. Periodontitis was compared to metabolic disorders, rheumatoid arthritis (RA), cancer, and smokers, as well as healthy controls. Substantial variation regarding the reporting of sample sizes and patient characteristics, statistical analyses, and methodology was found. IL6 and TNF were modified similarly in RA and periodontitis. While TIMP-3 and GSTP-1 were significantly lower in periodontitis patients and controls than in cancer, SOCS-1, RMI2, CDH1, and COX2 were modified similarly in both cancer and periodontitis. While TLR4 in and CXCL8 were affected in periodontitis independent of smoking habit, smoking might change the transcription and methylation states of ECM organization-related genes, which exacerbated the periodontal condition. There was some evidence, albeit inconsistent, for an association between DNA methylation and periodontal diseases and systemic diseases or smokers compared to healthy patients or non-smokers.
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Mujawar, Shama, Gayatri Patil, Srushti Suthar, Tanuja Shendkar, and Vaishnavi Gangadhar. "COVID-19 progression towards ARDS: a genome wide study reveals host factors underlying critical COVID-19." Genomics & Informatics 21, no. 2 (June 30, 2023): e16. http://dx.doi.org/10.5808/gi.22080.
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Coronavirus disease 2019 (COVID-19) is a viral infection produced by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus epidemic, which was declared a global pandemic in March 2020. The World Health Organization has recorded around 43.3 billion cases and 59.4 million casualties to date, posing a severe threat to global health. Severe COVID-19 indicates viral pneumonia caused by the SARS-CoV-2 infections, which can induce fatal consequences, including acute respiratory distress syndrome (ARDS). The purpose of this research is to better understand the COVID-19 and ARDS pathways, as well as to find targeted single nucleotide polymorphism. To accomplish this, we retrieved over 100 patients’ samples from the Sequence Read Archive, National Center for Biotechnology Information. These sequences were processed through the Galaxy server next generation sequencing pipeline for variant analysis and then visualized in the Integrative Genomics Viewer, and performed statistical analysis using t-tests and Bonferroni correction, where six major genes were identified as DNAH7, CLUAP1, PPA2, PAPSS1, TLR4, and IFITM3. Furthermore, a complete understanding of the genomes of COVID-19-related ARDS will aid in the early identification and treatment of target proteins. Finally, the discovery of novel therapeutics based on discovered proteins can assist to slow the progression of ARDS and lower fatality rates.
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Burhan, Hira, Askari Syed Hasan, Syed Mansur-ul-Haque, Ghazanfar Zaidi, Taha Shaikh, and Aisha Zia. "Association between blood group and susceptibility to malaria and its effects on platelets, TLC, and Hb." Journal of Infection in Developing Countries 10, no. 10 (October 31, 2016): 1124–28. http://dx.doi.org/10.3855/jidc.6828.
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Introduction: According to the World Health Organization, the estimated number of malaria cases in Pakistan is about 1.5 million. Hematological variables like platelets, total leukocyte count (TLC), and hemoglobin (Hb) need to be evaluated to diagnose malaria in suspects. This study aimed to investigate the association between blood group and susceptibility to malaria and effects on platelets, TLC, and Hb. Methodology: This was a case-control study with a sample size of 446, of which 224 were malarial cases and 222 were controls. A designated questionnaire was developed to know age, gender, malarial strain, Hb, TLC, platelets, and blood group. Results: Of 224 malarial cases, 213 were P. vivax, and 11 were P. falciparum. There were 58 patients with blood group A, 72 with group B, 69 were O and 23 were AB. There was no significant difference in the blood group of controls compared to malarial patients (p > 0.05). Mean Hb level was 11.5mg/dL in malaria patients and 12.5mg/dL in controls. There was significant difference (p<0.01) in the mean platelet count in malarial (11,7000/μL) and control (24,5000/μL) patients. All blood groups showed similar falls in Hb and platelet levels, showing no significant difference among blood groups (p = 0.79 and p = 0.52, respectively). TLC was not significant between malarial and control groups (p = 0.072). Males were two times susceptible to malaria. Conclusions: There was no significant association between the type of blood group and susceptibility to malaria or developing anemia or thrombocytopenia.
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Brandenburg, Klaus, Raquel Ferrer-Espada, Guillermo Martinez-de-Tejada, Christian Nehls, Satoshi Fukuoka, Karl Mauss, Günther Weindl, and Patrick Garidel. "A Comparison between SARS-CoV-2 and Gram-Negative Bacteria-Induced Hyperinflammation and Sepsis." International Journal of Molecular Sciences 24, no. 20 (October 14, 2023): 15169. http://dx.doi.org/10.3390/ijms242015169.
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Sepsis is a life-threatening condition caused by the body’s overwhelming response to an infection, such as pneumonia or urinary tract infection. It occurs when the immune system releases cytokines into the bloodstream, triggering widespread inflammation. If not treated, it can lead to organ failure and death. Unfortunately, sepsis has a high mortality rate, with studies reporting rates ranging from 20% to over 50%, depending on the severity and promptness of treatment. According to the World Health Organization (WHO), the annual death toll in the world is about 11 million. One of the main toxins responsible for inflammation induction are lipopolysaccharides (LPS, endotoxin) from Gram-negative bacteria, which rank among the most potent immunostimulants found in nature. Antibiotics are consistently prescribed as a part of anti-sepsis-therapy. However, antibiotic therapy (i) is increasingly ineffective due to resistance development and (ii) most antibiotics are unable to bind and neutralize LPS, a prerequisite to inhibit the interaction of endotoxin with its cellular receptor complex, namely Toll-like receptor 4 (TLR4)/MD-2, responsible for the intracellular cascade leading to pro-inflammatory cytokine secretion. The pandemic virus SARS-CoV-2 has infected hundreds of millions of humans worldwide since its emergence in 2019. The COVID-19 (Coronavirus disease-19) caused by this virus is associated with high lethality, particularly for elderly and immunocompromised people. As of August 2023, nearly 7 million deaths were reported worldwide due to this disease. According to some reported studies, upregulation of TLR4 and the subsequent inflammatory signaling detected in COVID-19 patients “mimics bacterial sepsis”. Furthermore, the immune response to SARS-CoV-2 was described by others as “mirror image of sepsis”. Similarly, the cytokine profile in sera from severe COVID-19 patients was very similar to those suffering from the acute respiratory distress syndrome (ARDS) and sepsis. Finally, the severe COVID-19 infection is frequently accompanied by bacterial co-infections, as well as by the presence of significant LPS concentrations. In the present review, we will analyze similarities and differences between COVID-19 and sepsis at the pathophysiological, epidemiological, and molecular levels.
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Khan, Taimoor, Abbas Khan, Jawad Khaliq Ansari, Muzammil Hasan Najmi, Dong-Qing Wei, Khalid Muhammad, and Yasir Waheed. "Potential Immunogenic Activity of Computationally Designed mRNA- and Peptide-Based Prophylactic Vaccines against MERS, SARS-CoV, and SARS-CoV-2: A Reverse Vaccinology Approach." Molecules 27, no. 7 (April 6, 2022): 2375. http://dx.doi.org/10.3390/molecules27072375.
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The continued emergence of human coronaviruses (hCoVs) in the last few decades has posed an alarming situation and requires advanced cross-protective strategies against these pandemic viruses. Among these, Middle East Respiratory Syndrome coronavirus (MERS-CoV), Severe Acute Respiratory Syndrome coronavirus (SARS-CoV), and Severe Acute Respiratory Syndrome coronavirus-2 (SARS-CoV-2) have been highly associated with lethality in humans. Despite the challenges posed by these viruses, it is imperative to develop effective antiviral therapeutics and vaccines for these human-infecting viruses. The proteomic similarity between the receptor-binding domains (RBDs) among the three viral species offers a potential target for advanced cross-protective vaccine designs. In this study, putative immunogenic epitopes including Cytotoxic T Lymphocytes (CTLs), Helper T Lymphocytes (HTLs), and Beta-cells (B-cells) were predicted for each RBD-containing region of the three highly pathogenic hCoVs. This was followed by the structural organization of peptide- and mRNA-based prophylactic vaccine designs. The validated 3D structures of these epitope-based vaccine designs were subjected to molecular docking with human TLR4. Furthermore, the CTL and HTL epitopes were processed for binding with respective human Lymphocytes Antigens (HLAs). In silico cloning designs were obtained for the prophylactic vaccine designs and may be useful in further experimental designs. Additionally, the epitope-based vaccine designs were evaluated for immunogenic activity through immune simulation. Further studies may clarify the safety and efficacy of these prophylactic vaccine designs through experimental testing against these human-pathogenic coronaviruses.
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Rehman, Hafiz Muzzammel, Muhammad Usman Mirza, Mian Azhar Ahmad, Mahjabeen Saleem, Matheus Froeyen, Sarfraz Ahmad, Roquyya Gul, et al. "A Putative Prophylactic Solution for COVID-19: Development of Novel Multiepitope Vaccine Candidate against SARS-COV-2 by Comprehensive Immunoinformatic and Molecular Modelling Approach." Biology 9, no. 9 (September 18, 2020): 296. http://dx.doi.org/10.3390/biology9090296.
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The outbreak of 2019-novel coronavirus (SARS-CoV-2) that causes severe respiratory infection (COVID-19) has spread in China, and the World Health Organization has declared it a pandemic. However, no approved drug or vaccines are available, and treatment is mainly supportive and through a few repurposed drugs. The urgency of the situation requires the development of SARS-CoV-2-based vaccines. Immunoinformatic and molecular modelling are time-efficient methods that are generally used to accelerate the discovery and design of the candidate peptides for vaccine development. In recent years, the use of multiepitope vaccines has proved to be a promising immunization strategy against viruses and pathogens, thus inducing more comprehensive protective immunity. The current study demonstrated a comprehensive in silico strategy to design stable multiepitope vaccine construct (MVC) from B-cell and T-cell epitopes of essential SARS-CoV-2 proteins with the help of adjuvants and linkers. The integrated molecular dynamics simulations analysis revealed the stability of MVC and its interaction with human Toll-like receptors (TLRs), which trigger an innate and adaptive immune response. Later, the in silico cloning in a known pET28a vector system also estimated the possibility of MVC expression in Escherichia coli. Despite that this study lacks validation of this vaccine construct in terms of its efficacy, the current integrated strategy encompasses the initial multiple epitope vaccine design concepts. After validation, this MVC can be present as a better prophylactic solution against COVID-19.
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Hailesilase, Gebretekle Gebremichael, Yarra Rajeshwar, Gebremedhin Solomon Hailu, Gereziher Gebremedhin Sibhat, and Helen Bitew. "In Vivo Antimalarial Evaluation of Crude Extract, Solvent Fractions, and TLC-Isolated Compounds from Olea europaea Linn subsp. cuspidata (Oleaceae)." Evidence-Based Complementary and Alternative Medicine 2020 (May 14, 2020): 1–12. http://dx.doi.org/10.1155/2020/6731485.
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Malaria is a major global public health problem caused by Plasmodium parasites. Drug resistance is becoming a great challenge. New drugs with novel mechanism of action are urgently required. In malarious countries, medicinal plants are commonly used for malaria treatment. Olea europaea is traditionally used against malaria in Ethiopia. The aim of this study was to isolate and evaluate antimalarial activity of chemical constituents extracted from Olea europaea against chloroquine-sensitive Plasmodium berghei-infected mice. Stem bark of Olea europaea was extracted with 80% methanol and fractionated with three solvents. The butanol fraction was subjected to isolation with preparative thin-layer chromatography (PTLC). Acute oral toxicity studies were conducted in mice as per the Organization for Economic Co-operation and Development (OECD) guideline 425. Antimalarial activities of the test substances were evaluated using Peter’s 4-day suppressive test. The crude extract showed significant (p<0.01) antiplasmodial activity at all doses with a chemosuppression value of 52.40% at a dose of 600 mg/kg. All fractions also suppressed parasitaemia significantly (p<0.05), the highest suppression (45.42%) being with butanol fraction. In the phytochemical analysis, two compounds were isolated. Both compounds showed significant (p<0.05) antimalarial activities. Compound C inhibited parasitaemia up to 38.19% at a dose of 200 mg/kg. The crude extract, butanol fraction, and isolated compounds also prolonged survival time of mice. No sign of toxicity and mortality was seen in the test substances at up to a single dose of 2 g/kg. Findings of the current study may confirm the traditional antimalarial claim of Olea europaea and its relative safety as well as the potentiality of compound C for further investigations.
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Toka, Felix N., Zuzanna Biernacka, Justyna Struzik, Malgorzata Gierynska, and Lidia Szulc-Dabrowska. "Podosome dissolution and focal adhesion assembly drive the enhanced migratory capacity of dendritic cells infected by ectromelia virus." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 11.19. http://dx.doi.org/10.4049/jimmunol.206.supp.11.19.
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Abstract Podosomes and focal adhesions (FAs) are both adhesive cytoskeletal structures engaged in cell-matrix adhesion of many different cell types, including dendritic cells (DCs). Despite sharing almost, the same proteins, e.g. vinculin, paxillin, talin and Src family proteins, podosomes and FAs show differences in their architecture, dynamics and function. While highly dynamic podosomes are organized in an actin-rich core surrounded by a ring of adhesive molecules with a perpendicular orientation to the extracellular matrix (ECM), more stable FAs have elongated structure and exhibit tangential orientation to the substrate surface. A switch from podosomes to FAs is often observed during TLR4-mediated DC maturation and is associated with an increased motility of these cells. Ectromelia virus (ECTV) is an orthopoxvirus that can control several different aspects of the cytoskeleton organization and dynamics in DCs and, thus, provides a useful model to study virus-cytoskeleton interactions and cell motility in these specialized immune cells, in which ECTV can productively replicate. Our results show that DCs infected with ECTV completely lose podosomes during early stages of infection, within the viral factory formation phase in the cytoplasm (4 hpi). Instead of podosomes, ECTV-infected DCs develop FAs, which are larger but less numerous than in uninfected control cells. FAs are predominantly observed within long-branched cellular projections formed extensively during later stages of infection (18–24 hpi). Loss of podosomes is associated with enhanced migration of infected DCs in vitro, suggesting that ECTV may potentially exploit DC migration to facilitate dissemination of the virus in vivo.
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López-Ramírez, Luz A., Iván Martínez-Duncker, Anayeli Márquez-Márquez, Ana P. Vargas-Macías, and Héctor M. Mora-Montes. "Silencing of ROT2, the Encoding Gene of the Endoplasmic Reticulum Glucosidase II, Affects the Cell Wall and the Sporothrix schenckii–Host Interaction." Journal of Fungi 8, no. 11 (November 18, 2022): 1220. http://dx.doi.org/10.3390/jof8111220.
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Sporothrix schenckii is a member of the Sporothrix pathogenic clade and one of the most common etiological agents of sporotrichosis, a subcutaneous fungal infection that affects both animal and human beings. Like other fungal pathogens, the Sporothrix cell wall is composed of structural polysaccharides and glycoproteins that are covalently modified with both N-linked and O-linked glycans. Thus far, little is known about the N-linked glycosylation pathway in this organism or its contribution to cell wall composition and interaction with the host. Here, we silenced ROT2, which encodes the catalytic subunit of the endoplasmic reticulum α-glucosidase II, a processing enzyme key for the N-linked glycan core processing. Silencing of ROT2 led to the accumulation of the Glc2Man9GlcNAC2 glycan core at the cell wall and a reduction in the total content of N-linked glycans found in the wall. However, the highly silenced mutants showed a compensatory mechanism with increased content of cell wall O-linked glycans. The phenotype of mutants with intermediate levels of ROT2 silencing was more informative, as they showed changes in the cell wall composition and exposure of β-1.3-glucans and chitin at the cell surface. Furthermore, the ability to stimulate cytokine production by human mononuclear cells was affected, along with the phagocytosis by human monocyte-derived macrophages, in a mannose receptor-, complement receptor 3-, and TLR4-dependent stimulation. In an insect model of experimental sporotrichosis, these mutant cells showed virulence attenuation. In conclusion, S. schenckii ROT2 is required for proper N-linked glycosylation, cell wall organization and composition, and interaction with the host.
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Maddali, Pranav, Anthony Ambesi, and Paula J. McKeown-Longo. "Induction of pro-inflammatory genes by fibronectin DAMPs in three fibroblast cell lines: Role of TAK1 and MAP kinases." PLOS ONE 18, no. 5 (May 25, 2023): e0286390. http://dx.doi.org/10.1371/journal.pone.0286390.
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Changes in the organization and structure of the fibronectin matrix are believed to contribute to dysregulated wound healing and subsequent tissue inflammation and tissue fibrosis. These changes include an increase in the EDA isoform of fibronectin as well as the mechanical unfolding of fibronectin type III domains. In previous studies using embryonic foreskin fibroblasts, we have shown that fibronectin’s EDA domain (FnEDA) and the partially unfolded first Type III domain (FnIII-1c) function as Damage Associated Molecular Pattern (DAMP) molecules to stimulate the induction of inflammatory cytokines by serving as agonists for Toll-Like Receptor-4 (TLR4). However, the role of signaling molecules downstream of TLR-4 such as TGF-β Activated Kinase 1 (TAK1) and Mitogen activated protein kinases (MAPK) in regulating the expression of fibronectin DAMP induced inflammatory genes in specific cell types is not known. In the current study, we evaluate the molecular steps regulating the fibronectin driven induction of inflammatory genes in three human fibroblast cell lines: embryonic foreskin, adult dermal, and adult kidney. The fibronectin derived DAMPs each induce the phosphorylation and activation of TAK1 which results in the activation of two downstream signaling arms, IKK/NF-κB and MAPK. Using the specific inhibitor 5Z-(7)-Oxozeanol as well as siRNA, we show TAK1 to be a crucial signaling mediator in the release of cytokines in response to fibronectin DAMPs in all three cell types. Finally, we show that FnEDA and FnIII-1c induce several pro-inflammatory cytokines whose expression is dependent on both TAK1 and JNK MAPK and highlight cell-type specific differences in the gene-expression profiles of the fibroblast cell-lines.
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Dukić, Marija, Tijana Radonjić, Igor Jovanović, Marija Zdravković, Zoran Todorović, Nemanja Kraišnik, Bojana Aranđelović, et al. "Alcohol, Inflammation, and Microbiota in Alcoholic Liver Disease." International Journal of Molecular Sciences 24, no. 4 (February 13, 2023): 3735. http://dx.doi.org/10.3390/ijms24043735.
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Alcoholic liver disease (ALD) is a consequence of excessive alcohol use. According to many studies, alcohol represents a significant socioeconomic and health risk factor in today’s population. According to data from the World Health Organization, there are about 75 million people who have alcohol disorders, and it is well known that its use leads to serious health problems. ALD is a multimodality spectrum that includes alcoholic fatty liver disease (AFL) and alcoholic steatohepatitis (ASH), consequently leading to liver fibrosis and cirrhosis. In addition, the rapid progression of alcoholic liver disease can lead to alcoholic hepatitis (AH). Alcohol metabolism produces toxic metabolites that lead to tissue and organ damage through an inflammatory cascade that includes numerous cytokines, chemokines, and reactive oxygen species (ROS). In the process of inflammation, mediators are cells of the immune system, but also resident cells of the liver, such as hepatocytes, hepatic stellate cells, and Kupffer cells. These cells are activated by exogenous and endogenous antigens, which are called pathogen and damage-associated molecular patterns (PAMPs, DAMPs). Both are recognized by Toll-like receptors (TLRs), which activation triggers the inflammatory pathways. It has been proven that intestinal dysbiosis and disturbed integrity of the intestinal barrier perform a role in the promotion of inflammatory liver damage. These phenomena are also found in chronic excessive use of alcohol. The intestinal microbiota has an important role in maintaining the homeostasis of the organism, and its role in the treatment of ALD has been widely investigated. Prebiotics, probiotics, postbiotics, and symbiotics represent therapeutic interventions that can have a significant effect on the prevention and treatment of ALD.
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Calabrese, Armando, Antonio D'Uffizi, Nathan Levialdi Ghiron, Luca Berloco, Elaheh Pourabbas, and Nathan Proudlove. "Design and development of a digital diagnostic clinical pathway: evidence from an action research study." European Journal of Innovation Management 27, no. 9 (February 9, 2024): 94–126. http://dx.doi.org/10.1108/ejim-06-2023-0483.
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PurposeThe primary objective of this paper is to show a systematic and methodological approach for the digitalization of critical clinical pathways (CPs) within the healthcare domain.Design/methodology/approachThe methodology entails the integration of service design (SD) and action research (AR) methodologies, characterized by iterative phases that systematically alternate between action and reflective processes, fostering cycles of change and learning. Within this framework, stakeholders are engaged through semi-structured interviews, while the existing and envisioned processes are delineated and represented using BPMN 2.0. These methodological steps emphasize the development of an autonomous, patient-centric web application alongside the implementation of an adaptable and patient-oriented scheduling system. Also, business processes simulation is employed to measure key performance indicators of processes and test for potential improvements. This method is implemented in the context of the CP addressing transient loss of consciousness (TLOC), within a publicly funded hospital setting.FindingsThe methodology integrating SD and AR enables the detection of pivotal bottlenecks within diagnostic CPs and proposes optimal corrective measures to ensure uninterrupted patient care, all the while advancing the digitalization of diagnostic CP management. This study contributes to theoretical discussions by emphasizing the criticality of process optimization, the transformative potential of digitalization in healthcare and the paramount importance of user-centric design principles, and offers valuable insights into healthcare management implications.Originality/valueThe study’s relevance lies in its ability to enhance healthcare practices without necessitating disruptive and resource-intensive process overhauls. This pragmatic approach aligns with the imperative for healthcare organizations to improve their operations efficiently and cost-effectively, making the study’s findings relevant.