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Microbes & Immunity Big data and DNN-based DTI model in CHP

On the left side of Figure 4, the activation of toll-like (GTP)-bound state, it can activate T-cell lymphoma
receptors (TLR) 2 and TLR4 in the microenvironment invasion and metastasis-inducing protein 1 (TIAM1),
leads to the recruitment of guanine nucleotide exchange which activates the phosphorylation of p21-activated
factors, which activate receptor Ras-related C3 botulinum kinases (PAKs) to cause the phosphorylation of TF LIM
toxin substrate 1 (Rac1). Activated Rac1 plays a key role domain kinase 1, subsequently inactivating cofilin that
in cytoskeletal reorganization, reactive oxygen species affects cytoskeleton dynamics and cell motility. TIAM1
(ROS) production, and downstream signaling pathways also facilitates Rho GTPase activation. Consequently,
modulation. In addition, the binding of an antigen to it regulates the formation of stress fibers and focal
the B-cell receptor (BCR) triggers receptor clustering adhesions, contributing to cell contraction and adhesion.
and spleen tyrosine kinase (Syk) phosphorylation. Once Ral guanine nucleotide dissociation stimulator-like (RGL)
Syk is phosphorylated and activated, it leads to the proteins are direct downstream effectors of Ras. Once
phosphorylation of downstream signaling molecules. activated by Ras, RGL proteins facilitate the exchange of
Cytokines bind to their specific receptors, which guanosine diphosphate for GTP on RalA and RalB, thus
are associated with JAKs. Subsequently, a cluster of activating these GTPases. Then, Sec5 interacts with
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differentiation 19 (CD19) enhances BCR signaling by RalA and RalB, acting as an effector that links them to
providing docking sites for signaling molecules that amplify the exocytosis complex and thereby influencing vesicle
Syk activation. Activated Rac1 promotes cytoskeletal trafficking and exocytosis. Sec5 can also recruit TANK-
reorganization, which is important for various B-cell binding kinase 1 (TBK1) to the exocytosis complex,
functions, while simultaneously activating PI3K. Although where TBK1 can be activated. This recruitment is thought
CD19 does not directly interact with JAKs, cytokine to play a role in the spatial regulation of TBK1 activity,
signaling through JAK-STAT pathways can modulate B-cell integrating signals from vesicle trafficking with innate
responses. Enhanced CD19 signaling may lead to the immune responses. TBK1 can directly phosphorylate
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activation of PI3K. When upstream signals activate PI3K, components of the NF-κB pathway, including RelA,
it produces phosphatidylinositol 4,5-bisphosphate and enhancing its transcriptional activity. Collectively, the
phosphatidylinositol (3,4,5)-trisphosphate (PIP3) at the cell sustained MAPK pathway activation perpetuates lung
membrane. PIP3 serves as a binding site for proteins with inflammation, oxidative injury, apoptosis of epithelial
Pleckstrin homology domains, including phosphoinositide- and endothelial cells, and the accumulation of fibroblasts
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dependent kinase-1 (PDK1). This recruitment brings and myofibroblasts, thereby driving disease symptoms
PDK1 to the cell membrane, where it can phosphorylate its in CHP. In fibroblasts and myofibroblasts, PI3K/AKT
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substrate kinases. Once PDK1 is activated, it phosphorylates signaling enhances proliferation, migration, and resistance
TF S6 kinase 1 (S6K1) and S6K2 at a critical threonine to apoptosis, upregulates the expression of extracellular
residue, which is essential for their activation. Activated matrix proteins (e.g., collagens and fibronectin), and
TF S6K1/2 phosphorylates our target genes S6 and EIF4B, potentiates TGF-β-induced myofibroblast activation and
promoting the translation of mRNAs involved in ribosome differentiation. 40
biogenesis and protein synthesis. 34 In summary, the activation of the cytokine TLR2/4
For the other cytokine proteins in the CHP and BCR in the PI3K signaling pathway causes the
microenvironment, mutations in Ras or rapidly phosphorylation of our target genes, S6 and EIF4B, through
accelerated fibrosarcoma (Raf) can lead to uncontrolled a series of signaling protein transduction mechanisms,
cell proliferation and cancer. Once activated, Raf which consequently enhances protein synthesis and
phosphorylates and activates MEK, which, in turn, proliferation. The Ras protein upstreams the target gene
phosphorylates and activates ERK. Activated ERK IL8 cytokine through ERK signaling transduction and
translocates to the nucleus and regulates the expression has an effect on cell survival and cell motility through
of upstream genes involved in cell proliferation, GTPase activity. The dysregulated PI3K/AKT cascade
differentiation, and survival. The phosphorylation of promotes aberrant epithelial repair, fibroblast activation
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ERK1/2 inactivates TF forkhead box O (FOXO) and and proliferation, and persistent inflammation, collectively
contributes to the inflammatory response by enhancing contributing to the initiation and symptom of pulmonary
the production of pro-inflammatory mediators, such fibrosis in CHP patients.
as interleukin-8 (IL-8) chemokine, which subsequently
influences protein synthesis pathways. Moreover, ERK 3.2.1. The role of transforming growth factor-β
signaling promotes lung epithelial cell proliferation signaling pathways in the pathogenesis of CHP
and activates pro-fibrotic pathways, including TGF-β The TGF-β signaling pathway plays a pivotal role in the
signaling. When Ras is activated guanosine triphosphate pathogenesis of CHP, a lung disease characterized by
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Volume 2 Issue 2 (2025) 93 doi: 10.36922/mi.4620