• However, the tumor microenvironment (TME) imposes different mechanisms that facilitate the impairment of DC functions, such as inefficient antigen presentation or polarization into immunosuppressive DCs. (mdpi.com)
  • In the tumor microenvironment, tumor-associated macrophages (TAMs) display an array of phenotypes beyond the M1/M2 paradigm, ranging from antitumoral to immunosuppressive, proangiogenic, immunomodulatory and tissue-remodeling phenotypes ( 7 - 9 ). (frontiersin.org)
  • Another myeloid population in the tumor microenvironment (TME) are DCs, that originate from different precursors and display various phenotypes, ranging from immunosuppressive monocyte-derived DCs (Mo-DCs) to immunocompetent cDC1 and cDC2 subsets ( 22 ). (frontiersin.org)
  • Tumors exhibit significant myeloid cell infiltrates, which are actively recruited to the tumor microenvironment. (hindawi.com)
  • Finally, we will comment on the mechanisms regulating myeloid cell recruitment to the tumor microenvironment and on the potential of myeloid cells as new targets for cancer therapy. (hindawi.com)
  • Via direct actions on cancer cells and indirect actions on the tumor microenvironment, radiation has the potential to enhance epithelial-to-mesenchymal transition, invasion, migration, angiogenesis and metastasis. (biomedcentral.com)
  • In this review, we provide a brief summary of the combination OV-antibody therapies that target tumor cells, tumor microenvironment and immune cells to help define key parameters influencing which approach is superior, thereby improving insight into the rational design of OV treatment strategies. (bmj.com)
  • Lytic death of cancer cells and the associated release of damage-associated or pathogen-associated molecular patterns (DAMPs, PAMPs) creates a proinflammatory tumor microenvironment (TME) that may lead to an anticancer immune response. (bmj.com)
  • γδ T cells recruited into the tumor microenvironment can act as effector cells to mediate cancer immune surveillance. (explorationpub.com)
  • Therefore, an in-depth understanding of γδ T cells that play conflicting roles in the tumor microenvironment is necessary. (explorationpub.com)
  • TGF-beta and immune cells: an important regulatory axis in the tumor microenvironment and progression. (academicinfluence.com)
  • In this review, we discuss how rudimentary defense mechanisms deployed by myeloid cells can promote tumor progression. (frontiersin.org)
  • Myeloid cells promote tumor growth by stimulating tumor angiogenesis, suppressing tumor immunity, and promoting metastasis to distinct sites. (hindawi.com)
  • Tumor-associated glycans play a significant role in promoting aggressive and metastatic behavior of malignant cells [ 1 - 5 ], participating in cell-cell and cell-extracellular matrix interactions that promote tumor cell adhesion and migration. (biomedcentral.com)
  • Myeloid cells are a heterogeneous population of bone marrow-derived cells that play a critical role during growth and metastasis of malignant tumors. (hindawi.com)
  • Local invasion and distant metastasis are the cause of death in most malignant tumors. (biomedcentral.com)
  • Malignant tumors consist of cancer cells and tumor-associated host cells, both participating in invasion and distant metastasis. (biomedcentral.com)
  • Angiogenesis, the growth of new blood vessels, occurs at different stages during embryonic development, physiological processes such as wound healing and reproduction, and numerous diseases, including inflammation, tumor progression, and metastasis [ 1 ]. (hindawi.com)
  • This suggested that EPCs are able to differentiate into endothelial cells and that such cells are incorporated into sites of active angiogenesis including ischemia, tumor angiogenesis, and metastasis in adult organisms [ 16 , 17 ]. (hindawi.com)
  • One of the first molecules implicated in enhancement of distant metastasis after irradiation of the primary tumor was angiostatin, produced by the primary tumor and keeping metastasis dormant. (biomedcentral.com)
  • Hypoxia stimulates hypoxia inducible factor (HIF)-dependent expression of CXCL12 and KITL promoting mobilization from the bone marrow and recruitment to primary tumor and metastatic sites of CXCR4 + CD11b + bone marrow-derived cells and KITbCD11b + cells assisting vasculogenesis and metastasis respectively (Kuonen et al. (biomedcentral.com)
  • The role of CS-GAGs in metastasis was tested using the 4T1 murine mammary cell line (10 mice per group). (biomedcentral.com)
  • Materials and Methods: C57BL/6J ob/+ mice, given either water or 20% ethanol, were injected intravenously with B16-BL6 melanoma cells to determine pulmonary metastasis. (iiarjournals.org)
  • Abrogation of TGF beta signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis. (academicinfluence.com)
  • In the context of cancer, appropriately activated DCs can induce anti-tumor immunity by activating innate immune cells and tumor-specific lymphocytes that target cancer cells. (mdpi.com)
  • The immunosurveillance of transformed cells by the immune system remains one of the most controversial and poorly understood areas of immunity. (silverchair.com)
  • Gene-targeted mice have greatly aided our understanding of the key effector molecules in tumor immunity. (silverchair.com)
  • mAbs specific for immunoregulators have sometimes proven useful in establishing the importance of such molecules in immunity against experimental tumors ( 1 - 3 ). (silverchair.com)
  • In MCA- ( 10 ) and other carcinogen-induced cutaneous malignancy models ( 17 ), the importance of antitumor immunity mediated by NK cells, NK T cells, and γδ + T cells has also been illustrated. (silverchair.com)
  • Interestingly, the most primordial defense responses employed by myeloid cells against pathogens, such as complement activation, antibody-dependent cell cytotoxicity and phagocytosis, actually seem to favor cancer progression. (frontiersin.org)
  • Neutrophils also contribute to tumor progression, yet establishing the difference between PMN-MDSCs and tumor-associated neutrophils (TAN) remains challenging ( 11 , 15 , 16 ). (frontiersin.org)
  • Importantly, during tumor progression, myeloid cells are implicated in promoting tumor angiogenesis, causing resistance against antiangiogenic therapies in cancer, and suppressing the immune response during cancer [ 3 - 5 ]. (hindawi.com)
  • Yet, far less attention is paid to the effects of these treatments on tumor progression as reflected by the metastatic process. (biomedcentral.com)
  • references 5 , 14 , and 16 ), key molecules of both the innate and adaptive immune systems, contribute to tumor prevention in mice treated with the chemical carcinogen, methylcholanthrene (MCA), or in mice deficient for p53 expression. (silverchair.com)
  • It is now known that new blood vessels originate from preexisting vessels by activation, proliferation and migration of endothelial cells through a process named "angiogenesis" [ 4 ]. (hindawi.com)
  • Specific growth factors, such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), stimulate the proliferation and migration of naturally quiescent endothelial cells, resulting in the formation of new vessel structures during embryonic development and tumor growth [ 7 ]. (hindawi.com)
  • Overall, our study demonstrates the coordinated expression of functionally related genes during proliferation and differentiation of rainbow trout adipocyte cells. (biomedcentral.com)
  • Myeloid innate immune cells, such as granulocytes, monocytes, macrophages and dendritic cells (DCs), play an important role in cancer-cell recognition, initiation of inflammation and antitumor responses ( 2 ). (frontiersin.org)
  • Among glycans that play a critical role in stromal tumor cell interactions are glycosaminoglycans (GAGs) attached to proteoglycans (PGs). (biomedcentral.com)
  • In order to understand the development of adiposity, it is crucial to identify the factors and mechanisms that regulate the recruitment of mesenchymal stem cells (MSCs) of the vascular stromal fraction of the adipose tissue and its transformation into lipid-filled adipocytes. (biomedcentral.com)
  • In addition to TAMs, solid tumors are also infiltrated by immunosuppressive, immature myeloid progenitor cells, commonly referred to as monocytic or polymorphonuclear myeloid-derived suppressor cells (M/PMN-MDSC) ( 11 - 13 ). (frontiersin.org)
  • Furthermore, we describe a subset of myeloid cells with immunosuppressive activity (known as myeloid-derived suppressor cells). (hindawi.com)
  • The effects of ethanol on cell phenotypes and markers of the epithelial-to-mesenchymal transition were determined in cell culture. (iiarjournals.org)
  • Dendritic cells (DCs) are specialized antigen-presenting cells that have a notable role in the initiation and regulation of innate and adaptive immune responses. (mdpi.com)
  • Pathogen clearance is mediated by mechanisms such as phagocytosis, respiratory burst with the production of ROS and RNS and release of bacteriostatic peptides, but also through the cell-extrinsic initiation of inflammation via the release of proinflammatory cytokines and chemokines ( 24 ). (frontiersin.org)
  • Nevertheless, experimental tumor models examined to date have provided limited information on tumor initiation and development. (silverchair.com)
  • The innate immune response by myeloid cells occurs as a succession of events starting at signaling through cytosolic or surface PRRs, followed by effector responses including the release of cytokines, reactive oxygen species (ROS), reactive nitrogen species (RNS), antibacterial peptides and degranulation ( Figure 1 ). (frontiersin.org)
  • Herein, we describe spontaneous tumor development in gene-targeted mice lacking interferon (IFN)-γ and/or perforin (pfp), or the immunoregulatory cytokines, interleukin (IL)-12, IL-18, and tumor necrosis factor (TNF). (silverchair.com)
  • A range of antibody formats has been considered, including whole antibody molecules of different isotypes, fragments such as F(ab), single-chain variable fragment (scFv) and nanobodies and bispecific and trispecific agents that can mediate a variety of functions such as T-cell activation or binding and inactivation of pro-tumorigenic cytokines. (bmj.com)
  • Under nontumor conditions, these cells provide the first line of protection against pathogens. (hindawi.com)
  • Their advantage lies in the ability to perceive tumors with a low mutation load, thus establishing the first line of defense against pathogens. (explorationpub.com)
  • Upon culture in endothelial growth media, these cells expressed endothelial lineage markers, such as CD31, Tie2, and VEGF receptor 2 (VEGFR2), and incorporated into blood vessels in ischemic tissues. (hindawi.com)
  • In addition, CSPG4 and CHST11 were over-expressed in tumor-containing clinical tissue specimens compared with normal tissues. (biomedcentral.com)
  • Ab-3 shows no reaction with a variety of normal tissues .CEA is not found in benign glands, stroma, or malignant prostatic cells. (samatashkhis.com)
  • Oncolytic or 'cancer-lysing' viruses (OVs) are cytotoxic anticancer agents that preferentially replicate within and kill tumor cells, largely sparing normal tissues. (bmj.com)
  • PRR on myeloid cells can be triggered by pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs), but also indirectly by secondary mechanisms such as complement activation and circulating antibodies (Abs), resulting in cytolytic and phagocytic effector mechanisms. (frontiersin.org)
  • In cell culture, ethanol inhibited B16-BL6 cell motility, invasion, and anchorage-independent growth. (iiarjournals.org)
  • The virus is infectious for many cancer cell lines (see below), and has oncolytic properties demonstrated in animal models and in naturally-occurring cancers in animals. (wikipedia.org)
  • Adipogenesis has been extensively studied in mammals [ 7 ] and several cell and animal models have been successfully used to describe the chronology of the molecular events governing this process. (biomedcentral.com)
  • In this review, we use the Heilig nomenclature to describe human γδ T cells [ 1 ]. (explorationpub.com)
  • These observations stimulated an intensive search for the mechanisms regulating tumor angiogenesis. (hindawi.com)
  • First, γδ T cells exposed to complicated cytokine networks are potentially affected by multiple inhibitory mechanisms. (explorationpub.com)
  • Metastatic cancer cells are released from the primary tumor or from other metastases, at an undefined moment of its development, to arrive in the circulation and home at distant sites, where the ecosystem permits them to survive and either remain dormant as micro-metastases or grow to form macro-metastases (Mareel et al. (biomedcentral.com)
  • Elimination of the primary tumor, either by irradiation or by surgery, shifts the balance towards pro-angiogenesis and growth of the lung metastases (Table 1 ) (Camphausen et al. (biomedcentral.com)
  • however, as cancer cells gain the ability to metastasize, E-cadherin expression is significantly reduced, which allows the cancer cells to disseminate to form distant metastases ( 18 ). (iiarjournals.org)
  • Bicarbonate Increases Tumor pH and Inhibits Spontaneous Metastases. (kreftfri.no)
  • However, these immunotherapeutic approaches are hampered by the tumor-promoting nature of myeloid cells, including monocytes, macrophages, and neutrophils. (frontiersin.org)
  • The innate immune system is mainly composed of myeloid lineage cells, such as macrophages, neutrophils, and mast cells [ 2 ]. (hindawi.com)
  • Although tumor cells were first thought to drive the cellular events underpinning tumor angiogenesis and growth, considerable evidence has now emerged for the central role of tumor infiltrating myeloid cells such as monocytes, macrophages, and neutrophils in this phenomenon [ 8 - 12 ]. (hindawi.com)
  • Recruitment of CD11b + CD11c + myelomonocytic cells to the metastatic site was also found after whole thorax irradiation at a dose of 15 Gy of mice that significantly enhanced seeding and metastatic growth of intravenously injected cancer cells. (biomedcentral.com)
  • A particle according to any one of the preceding claims, wherein the heterologous polypeptide sterically hinders binding of d e viral glycoprotein to its cognate receptor on the eukaryotic cell. (sumobrain.com)
  • This antibody has a high affinity for CEA and shows no detectable reactivity to nonspecific cross-reacting antigen (NCA), biliary glycoprotein (BGP) and human polymorphonuclear leucocytes. (samatashkhis.com)
  • In 1971, Dr. Judah Folkman observed that neovascularization occurs around tumors and proposed that new blood vessel growth is necessary to supply nutrients and oxygen to tumor cells during exponential tumor growth [ 6 ]. (hindawi.com)
  • Growth inhibitor from BSC-1 cells closely related to platelet type beta transforming growth factor. (academicinfluence.com)
  • Transforming growth factor production by chemically transformed cells. (academicinfluence.com)
  • A highly immunogenic tumor transfected with a murine transforming growth factor type beta 1 cDNA escapes immune surveillance. (academicinfluence.com)
  • These cells were therefore described as bone marrow derived endothelial progenitor cells (EPCs). (hindawi.com)
  • These cells form ecosystems at the primary and at the metastatic site, mutually communicating with one another and with stem cell-generating organs such as the bone marrow. (biomedcentral.com)
  • 2001 ). Molecular communication between ecosystems is also witnessed by the vasculogenic and pro-metastatic tumor bed effect as discussed by Kuonen et al. (biomedcentral.com)
  • This study was performed to identify the carrier proteoglycan (PG) and the sulfotransferase gene involved in synthesis of the surface P-selectin-reactive CS-GAGs in human breast cancer cells with high metastatic capacity, as well as to determine a direct role for CS-GAGs in metastatic spread. (biomedcentral.com)
  • CSPG4 serves as a P-selectin ligand through its CS chain and participates in P-selectin binding to the highly metastatic breast cancer cells. (biomedcentral.com)
  • Removal of CS-GAGs greatly reduces metastatic lung colonization by 4T1 cells. (biomedcentral.com)
  • In previous studies we found that CS/DS-GAGs are expressed on the cell surface of murine and human breast cancer cell lines with high metastatic capacity and that they play a major role in P-selectin binding and P-selectin-mediated adhesion of cancer cells to platelets and endothelial cells [ 24 ]. (biomedcentral.com)
  • Conclusion: In both animal and in cell culture conditions, ethanol inhibited the metastatic ability of B16-BL6 melanoma cells. (iiarjournals.org)
  • Specifically, cancer cells that transition from an epithelial to a mesenchymal phenotype have a higher metastatic ability than those with an epithelial phenotype ( 15 ). (iiarjournals.org)
  • Activity and pharmacology of homemade silver nanoparticles in refractory metastatic head and neck squamous cell cancer. (kreftfri.no)
  • These cells may be a key factor ultimately mediating the deviation of the antagonistic response between tumor inhibition and tumor promotion. (explorationpub.com)
  • However, the clinical application of tumor-infiltrating γδ T cells has certain limitations. (explorationpub.com)
  • Finally, it retrospectively analyze the activation strategies and clinical relevance of existing γδ T cell adoptive immunotherapies. (explorationpub.com)
  • The aim of this study was to evaluate the impact of ocrelizumab, a monoclonal anti-CD20 antibody, on SARS-CoV-2-specific T cell and B cell responses in patients with relapsing-remitting multiple sclerosis (RRMS). (bvsalud.org)
  • The antibody is useful for studying the phenomenon of cell death by apoptosis as a pathogenic mechanism of numerous pathologies: nerve damage, neurodegenerative diseases, cardiovascular diseases, autoimmune diseases, AIDS and malignancies. (samatashkhis.com)
  • This Antibody was verified by Cell treatment to ensure that the antibody binds to the antigen stated. (thermofisher.com)
  • Taking advantage of the diverse γδ TCR repertoire or other ligand-receptor interactions, γδ T cells can recognize a broad spectrum of tumor-associated antigens (TAAs) in a major histocompatibility complex (MHC)-independent manner, thereby activating downstream pleiotropic effects. (explorationpub.com)
  • Tumor-stroma interactions. (academicinfluence.com)
  • Although tumor-promoting functions have been attributed to other granulocytes, like eosinophils ( 17 ), basophils ( 18 ) and mast cells ( 19 ), further research is required to fully elucidate their role in cancer, as antitumoral roles have also been described ( 20 , 21 ). (frontiersin.org)
  • Vasculogenesis is the coalescence of new blood vessels from individual endothelial cells or progenitor cells. (hindawi.com)
  • Subsequent studies described a VEGFR2 and AC133 expressing subpopulation of these CD34 positive circulating cells that could form endothelial colonies in vitro [ 14 , 15 ]. (hindawi.com)
  • CTR1 Silencing Inhibits Angiogenesis by Limiting Copper Entry into Endothelial Cells , PLOS ONE 8(9): e71982. (kreftfri.no)
  • SeV replication occurs exclusively in the cytoplasm of the host cell. (wikipedia.org)
  • The presence of TAMs in most solid tumors is correlated with poor prognosis and overall survival of patients ( 10 ). (frontiersin.org)
  • 13 ] isolated mononuclear cells from human peripheral blood that were enriched for expression of the hematopoietic stem cell marker CD34 [ 13 ]. (hindawi.com)
  • Methods: To this end, peripheral blood mononuclear cells (PBMCs) were isolated from n = 23 patients with RRMS. (bvsalud.org)
  • Single cells and organisms may adapt to harmful oxidative stress conditions, through stress-activated factors. (springer.com)
  • Over the past decade, cancer immunotherapy has been steering immune responses toward cancer cell eradication. (frontiersin.org)
  • Hence, myeloid cells play a dual role in cancer as they can initiate antitumor responses and communicate with cells of the adaptive immune system, but also promote local inflammation leading to chronic cancer-associated inflammation ( 5 , 6 ). (frontiersin.org)
  • There is good evidence that cancer cells disseminate from the primary site early during tumor development (Hosseini et al. (biomedcentral.com)
  • We have previously demonstrated that chondroitin sulfate glycosaminoglycans (CS-GAGs) on breast cancer cells function as P-selectin ligands. (biomedcentral.com)
  • Quantitative real-time PCR (qRT-PCR) and flow cytometry assays were used to detect the expression of genes involved in the sulfation and presentation of chondroitin in several human breast cancer cell lines. (biomedcentral.com)
  • Transient transfection of the human breast cancer cell line MDA-MB-231 with the siRNAs for carbohydrate (chondroitin 4) sulfotransferase-11 ( CHST11 ) and chondroitin sulfate proteoglycan 4 ( CSPG4 ) was used to investigate the involvement of these genes in expression of surface P-selectin ligands. (biomedcentral.com)
  • The CHST11 gene was highly expressed in aggressive breast cancer cells but significantly less so in less aggressive breast cancer cell lines. (biomedcentral.com)
  • The carrier proteoglycan CSPG4 was highly expressed on the aggressive breast cancer cell lines and contributed to the P-selectin binding and CS-A expression. (biomedcentral.com)
  • There is evidence suggesting that the phenotype of the cancer cells influences their ability to metastasize ( 14 ). (iiarjournals.org)
  • Such treatment was associated with upregulation of invasion- and inflammation-promoting soluble factors, such as matrix metalloproteinase 2 (MMP2), its activator MMP14, tissue inhibitors of matrix metalloproteinase 2 (TIMP2), chemokine ligand 2 (CCL2), and urokinase-type plasminogen activator (uPA), the latter two being linked to the recruitment of the monocytic cells. (biomedcentral.com)
  • Activated γδ T cells exhibit strong cytotoxic activity and cytokine secretion functions and are effective antitumor lymphocytes with simple and direct recognition modes and rapid responses. (explorationpub.com)
  • HO-1 and their products exert beneficial effects through the protection against oxidative injury, regulation of apoptosis, modulation of inflammation as well as contribution to angiogenesis. (springer.com)
  • Immune cells abundantly infiltrate tumors, creating a complex environment mediated by repetitive cycles of antitumor responses and immune evasion ( 1 ). (frontiersin.org)
  • Interferon-γ (IFN-γ)/interleukin-2 (IL-2) and granzyme B (GzB)/perforin (PFN) double-color enzyme-linked immunospot (ELISPOT) assays or single-color ELISPOT assays were performed to measure SARS-CoV-2 antigen-specific T cell and B cell responses. (bvsalud.org)
  • His work covers various topics, including B cell responses to viral infection and vaccination, human primary immunodeficiency, and biology of lymphocyte development and function and to elucidate etiology of immunological disorders. (stanford.edu)
  • Despite inducing antitumor responses in some patients, OVs used alone as directly cytolytic agents are usually not effective in conferring complete tumor clearance. (bmj.com)
  • Additionally, these cells show highly flexible and dynamic plasticity and are extremely easily polarized into regulatory phenotypes. (explorationpub.com)
  • Mammalian cells require oxygen and nutrients for their survival and are therefore located within 100 to 200 m of blood vessels, the diffusion limit of oxygen. (hindawi.com)
  • SeV's ability to fuse eukaryotic cells and to form syncytium was used to produce hybridoma cells capable of manufacturing monoclonal antibodies in large quantities. (wikipedia.org)
  • A particle according to claim 1 or 2, wherein the heterologous polypeptide has specific binding affinity for a cognate receptor on die surface of an eukaryotic cell, binding to which does not allow infection of the cell by the viral particle. (sumobrain.com)
  • A particle according to claim 1 or 2, wherein the heterologous polypeptide has no specific binding affinity for a eukaryotic cell surface component. (sumobrain.com)
  • A particle according to any one of the preceding claims, wherein heterologous polypeptide sterically hinders fusion of an enveloped viral particle with an eukaryotic cell to which it is bound. (sumobrain.com)
  • A particle according to any one of the preceding claims, wherein the protease cleavage site is accessible to the relevant protease (i.e. that which recognises the cleavage site) before the viral particle becomes bound to an eukaryotic cell. (sumobrain.com)
  • A particle according to any one of claims 1 to 9, wherein the protease cleavage site becomes accessible to die relevant protease only after the viral particle has become bound to an eukaryotic cell. (sumobrain.com)
  • A particle acording to claim 11 , wherein the protease cleavage site becomes accessible after the heterologous polypeptide has bound to its cognate receptor on the eukaryotic cell. (sumobrain.com)
  • Type I, which is quantitative, results from heterozygous point mutations or major gene deletions leading to low antithrombin antigen and activity levels. (medscape.com)
  • Oncolytic viruses (OVs) provide the promise of tumor-selective cytotoxicity coupled with amplification of the therapeutic agent (the virus) in situ within the tumor improving its therapeutic index. (bmj.com)
  • In this review, we discuss the role of myeloid cells in promoting tumor angiogenesis. (hindawi.com)
  • Then, he moved to Stanford University for a postdoctoral fellowship on the role of transcription factor Pbx1, a leukemia proto-oncogene, on B cell development. (stanford.edu)
  • Despite the arsenal of defense strategies against foreign invaders, myeloid cells succumb to the instructions of an established tumor. (frontiersin.org)
  • Enzymatic removal of tumor-cell surface CS-GAGs significantly inhibited lung colonization of the 4T1 murine mammary cell line ( P = 0.0002). (biomedcentral.com)
  • Single loss of IL-12, IL-18, or TNF was not sufficient for spontaneous tumor development. (silverchair.com)
  • Adipogenesis has been described as a two-step developmental process consisting on the commitment of undifferentiated MSCs into preadipocytes and the further development of these cells into fully functional mature adipocytes [ 4 ]. (biomedcentral.com)
  • We have previously shown that fish primary preadipocytes differentiate into mature adipocytes in vitro and that these cells represent a very helpful model system to study adipose tissue development in fish [ 5 , 6 ]. (biomedcentral.com)
  • Similar to αβ T cells, γδ T cells also develop in embryos, and their intra-thymic development shows strict regulation and flexible plasticity [ 2 ]. (explorationpub.com)