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  • 1
    Online Resource
    Online Resource
    Springer Science and Business Media LLC ; 2023
    In:  Journal of Atmospheric Chemistry Vol. 80, No. 1 ( 2023-03), p. 53-76
    In: Journal of Atmospheric Chemistry, Springer Science and Business Media LLC, Vol. 80, No. 1 ( 2023-03), p. 53-76
    Type of Medium: Online Resource
    ISSN: 0167-7764 , 1573-0662
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 793876-7
    detail.hit.zdb_id: 1475524-5
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  • 2
    Online Resource
    Online Resource
    MDPI AG ; 2019
    In:  International Journal of Molecular Sciences Vol. 20, No. 13 ( 2019-07-04), p. 3292-
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 20, No. 13 ( 2019-07-04), p. 3292-
    Abstract: During the last 100 years, cell signaling has evolved into a common mechanism for most physiological processes across systems. Although the majority of cell signaling principles were initially derived from hormonal studies, its exponential growth has been supported by interdisciplinary inputs, e.g., from physics, chemistry, mathematics, statistics, and computational fields. As a result, cell signaling has grown out of scope for any general review. Here, we review how the messages are transferred from the first messenger (the ligand) to the receptor, and then decoded with the help of cascades of second messengers (kinases, phosphatases, GTPases, ions, and small molecules such as cAMP, cGMP, diacylglycerol, etc.). The message is thus relayed from the membrane to the nucleus where gene expression ns, subsequent translations, and protein targeting to the cell membrane and other organelles are triggered. Although there are limited numbers of intracellular messengers, the specificity of the response profiles to the ligands is generated by the involvement of a combination of selected intracellular signaling intermediates. Other crucial parameters in cell signaling are its directionality and distribution of signaling strengths in different pathways that may crosstalk to adjust the amplitude and quality of the final effector output. Finally, we have reflected upon its possible developments during the coming years.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    Language: English
    Publisher: MDPI AG
    Publication Date: 2019
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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  • 3
    Online Resource
    Online Resource
    Elsevier BV ; 2024
    In:  Computers, Environment and Urban Systems Vol. 109 ( 2024-04), p. 102075-
    In: Computers, Environment and Urban Systems, Elsevier BV, Vol. 109 ( 2024-04), p. 102075-
    Type of Medium: Online Resource
    ISSN: 0198-9715
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2024
    detail.hit.zdb_id: 2017202-3
    SSG: 3,6
    SSG: 3,7
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  • 4
    In: Vaccines, MDPI AG, Vol. 7, No. 4 ( 2019-10-18), p. 156-
    Abstract: Leishmaniasis is a neglected protozoan parasitic disease that occurs in 88 countries but a vaccine is unavailable. Vaccination with live, killed, attenuated (physically or genetically) Leishmania have met with limited success, while peptide-, protein-, or DNA-based vaccines showed promise only in animal models. Here, we critically assess several technical issues in vaccination and expectation of a host-protective immune response. Several studies showed that antigen presentation during priming and triggering of the same cells in infected condition are not comparable. Altered proteolytic processing, antigen presentation, protease-susceptible sites, and intracellular expression of pathogenic proteins during Leishmania infection may vary dominant epitope selection, MHC-II/peptide affinity, and may deter the reactivation of desired antigen-specific T cells generated during priming. The robustness of the memory T cells and their functions remains a concern. Presentation of the antigens by Leishmania-infected macrophages to antigen-specific memory T cells may lead to change in the T cells’ functional phenotype or anergy or apoptosis. Although cells may be activated, the peptides generated during infection may be different and cross-reactive to the priming peptides. Such altered peptide ligands may lead to suppression of otherwise active antigen-specific T cells. We critically assess these different immunological issues that led to the non-availability of a vaccine for human use.
    Type of Medium: Online Resource
    ISSN: 2076-393X
    Language: English
    Publisher: MDPI AG
    Publication Date: 2019
    detail.hit.zdb_id: 2703319-3
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  • 5
    Online Resource
    Online Resource
    MDPI AG ; 2021
    In:  International Journal of Molecular Sciences Vol. 22, No. 12 ( 2021-06-17), p. 6508-
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 22, No. 12 ( 2021-06-17), p. 6508-
    Abstract: The central protein in the oncogenic circuitry is the Ras GTPase that has been under intense scrutiny for the last four decades. From its discovery as a viral oncogene and its non-oncogenic contribution to crucial cellular functioning, an elaborate genetic, structural, and functional map of Ras is being created for its therapeutic targeting. Despite decades of research, there still exist lacunae in our understanding of Ras. The complexity of the Ras functioning is further exemplified by the fact that the three canonical Ras genes encode for four protein isoforms (H-Ras, K-Ras4A, K-Ras4B, and N-Ras). Contrary to the initial assessment that the H-, K-, and N-Ras isoforms are functionally similar, emerging data are uncovering crucial differences between them. These Ras isoforms exhibit not only cell-type and context-dependent functions but also activator and effector specificities on activation by the same receptor. Preferential localization of H-, K-, and N-Ras in different microdomains of the plasma membrane and cellular organelles like Golgi, endoplasmic reticulum, mitochondria, and endosome adds a new dimension to isoform-specific signaling and diverse functions. Herein, we review isoform-specific properties of Ras GTPase and highlight the importance of considering these towards generating effective isoform-specific therapies in the future.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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  • 6
    In: IUBMB Life, Wiley, Vol. 71, No. 11 ( 2019-11), p. 1685-1700
    Abstract: Toll‐like receptors (TLRs) are a subset of pattern recognition receptors (PRR) in innate immunity and act as a connecting link between innate and adaptive immune systems. During Leishmania infection, the activation of TLRs influences the pathogen‐specific immune responses, which may play a decisive role in determining the outcome of infection, toward elimination or survival of the pathogen. Antigen‐presenting cells (APCs) of the innate immune system such as macrophages, dendritic cells (DCs), neutrophils, natural killer (NK) cells, and NKT cells express TLR2, which plays a crucial role in the parasite recognition and elicitation of immune responses in Leishmania infection. Depending on the infecting Leishmania species, the TLR2 pathways may result in a host‐protective or a disease‐exacerbating response. While Leishmania major and Leishmania donovani infections trigger TLR2‐related host‐protective and non‐protective immune responses, Leishmania mexicana and Leishmania infantum infections are reported to elicit TLR2‐mediated host‐protective responses and Leishmania amazonensis and Leishmania braziliensis infections are reported to evoke a disease‐exacerbating response. These findings illustrate that TLR2‐related effector functions are diverse and may be exerted in a species‐ or strain‐dependent manner. TLR2 agonists or antagonists may have therapeutic potentials to trigger the desired immune response during leishmaniasis. In this review, we discuss the TLR2‐related immune responses during leishmaniasis and highlight the novel insights into the possible role of TLR2‐driven resistance or susceptibility to Leishmania .
    Type of Medium: Online Resource
    ISSN: 1521-6543 , 1521-6551
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2019
    detail.hit.zdb_id: 2009952-6
    detail.hit.zdb_id: 2485214-4
    SSG: 12
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  • 7
    In: Cytokine, Elsevier BV, Vol. 169 ( 2023-09), p. 156301-
    Type of Medium: Online Resource
    ISSN: 1043-4666
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2023
    detail.hit.zdb_id: 1463198-2
    SSG: 12
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  • 8
    Online Resource
    Online Resource
    MDPI AG ; 2023
    In:  Kinases and Phosphatases Vol. 1, No. 2 ( 2023-04-21), p. 97-116
    In: Kinases and Phosphatases, MDPI AG, Vol. 1, No. 2 ( 2023-04-21), p. 97-116
    Abstract: Ras, a GTP-GDP binary switch protein, transduces signals from diverse receptors to regulate various signaling networks. Three Ras genes encode for protein isoforms, namely, Harvey Ras (H-Ras), Kirsten Ras (K-Ras, with two splice variants, K-Ras4A and K-Ras4B), and Neuroblastoma Ras (N-Ras). The isoforms undergo a series of post-translational modifications that enable their membrane attachment and biological activity. The activation of Ras isoforms is tightly regulated, and any dysregulation affects cellular processes, such as cell division, apoptosis, differentiation, cell migration, etc. The Ras gene is highly prone to mutation, and ~30% of cancers carry somatic mutations in Ras, whereas germline mutations clinically manifest as various rasopathies. In addition to regulation by the Guanine nucleotide exchange factors and the GTPase activation proteins, Ras signaling, and localization are also regulated by phosphorylation-dephosphorylation, ubiquitination, nitrosylation, and acetylation. Herein, we review the regulation of Ras signaling and localization by various regulatory enzymes in depth and assess the current status of Ras drug discovery targeting these regulatory enzymes.
    Type of Medium: Online Resource
    ISSN: 2813-3757
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
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  • 9
    Online Resource
    Online Resource
    Wiley ; 2023
    In:  European Journal of Immunology Vol. 53, No. 7 ( 2023-07)
    In: European Journal of Immunology, Wiley, Vol. 53, No. 7 ( 2023-07)
    Abstract: Ras GTPases, well characterized for their role in oncogenesis, are the cells’ molecular switches that signal to maintain immune homeostasis through cellular development, proliferation, differentiation, survival, and apoptosis. In the immune system, T cells are the central players that cause autoimmunity if dysregulated. Antigen‐specific T‐cell receptor (TCR) stimulation activates Ras‐isoforms, which exhibit isoform‐specific activator and effector requirements, functional specificities, and a selective role in T‐cell development and differentiation. Recent studies show the role of Ras in T‐cell‐mediated autoimmune diseases; however, there is a scarcity of knowledge about the role of Ras in T‐cell development and differentiation. To date, limited studies have demonstrated Ras activation in response to positive and negative selection signals and Ras isoform‐specific signaling, including subcellular signaling, in immune cells. The knowledge of isoform‐specific functions of Ras in T cells is essential, but still inadequate to develop the T‐cell‐targeted Ras isoform‐specific treatment strategies for the diseases caused by altered Ras‐isoform expression and activation in T cells. In this review, we discuss the role of Ras in T‐cell development and differentiation, critically analyzing the isoform‐specific functions.
    Type of Medium: Online Resource
    ISSN: 0014-2980 , 1521-4141
    URL: Issue
    RVK:
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 1491907-2
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  • 10
    Online Resource
    Online Resource
    Springer Science and Business Media LLC ; 2020
    In:  Cell Communication and Signaling Vol. 18, No. 1 ( 2020-12)
    In: Cell Communication and Signaling, Springer Science and Business Media LLC, Vol. 18, No. 1 ( 2020-12)
    Abstract: Ras are small cellular GTPases which regulate diverse cellular processes. It has three isoforms: H-Ras, K-Ras, and N-Ras. Owing to the N-terminus (1–165 residues) sequence homology these isoforms were thought to be functionally redundant. However, only K-Ras-deficient mice but not H-Ras- and N-Ras-deficient mice show embryonic lethality. Similarly, mutations in a given Ras isoform are associated with a particular type of cancer. Moreover, we have previously reported that Ras isoforms perform unique functions in Leishmania major infection. Thus, Ras isoforms are implicated to have signaling and functional specificity but the mechanism remains to be elucidated . Result Using CD40 as a model receptor, we showed that depending on the strength of signaling, specific Ras isoforms are activated. Weak CD40 signal activates N-Ras, whereas strong signal activates H-Ras and K-Ras. Additionally, we showed that suppression of N-Ras expression reduced CD40-induced extracellular signal–regulated kinase-1/2 (ERK-1/2) activation and Interleukin (IL)-10 production; whereas suppression of H-Ras or K-Ras reduced CD40-induced p38 mitogen-activated protein kinase (p38MAPK) activation and IL-12 production. Furthermore, we showed that Ras isoforms have activator (GEF) specificity as weak CD40 signal-activated N-Ras requires Sos-1/2 whereas strong CD40 signal-activated H-Ras/K-Ras requires Ras-GRP as the guanine-nucleotide exchange factor (GEF) inducing ERK-1/2- or p38MAPK-mediated IL-10 or IL-12 productions, respectively, in macrophages. Silencing of syk reduced CD40-induced N-Ras activation but silencing of lyn inhibited H-Ras and K-Ras activation. In CD40 signaling, Ras isoforms also showed effector specificity; while H-Ras and K-Ras showed specificity for phosphatidyl inositol-3 kinase activation at high dose of CD40 stimulation, N-Ras primarily associated with Raf-1 at low dose of CD40 stimulation. Moreover, fractal analysis showed that functional site surface roughness for H-Ras (SurfaceFD = 2.39) and K-Ras (SurfaceFD = 2.39) are similar but significantly different from N-Ras (SurfaceFD = 2.25). Conclusion The activator and effector specificities of Ras isoforms in CD40 signaling indicated their differential involvement in CD40 pathway and in maintaining the reciprocity. Our observations reveal Ras-regulated signaling outcome and its potential for developing Ras isoform-targeted immunotherapy and prophylaxis. Graphical abstract
    Type of Medium: Online Resource
    ISSN: 1478-811X
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2126315-2
    SSG: 12
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