1,721,213 research outputs found
Distributed hole detection algorithms for wireless sensor networks
No full textWe present two novel distributed algorithms for hole detection in a wireless sensor network (WSN) based on the distributed Delaunay triangulation of the underlying communication graph. The first, which we refer to as the distance-vector hole determination (DVHD) algorithm, is based on traditional distance vector routing for multi-hop networks and shortest path lengths between node pairs. The second, which we refer to as the Gaussian curvature-based hole determination (GCHD) algorithm, applies the Gauss-Bonnet theorem on the Delaunay graph to calculate the number of holes based on the graph's Gaussian curvature. We present a detailed comparative performance analysis of both methods based on simulations, showing that while DVHD is conceptually simpler, the GCHD algorithm shows better performance with respect to run-time and message count per node
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Allosteric mechanisms and consequences of Gi activation via the Guanine-nucleotide Exchange Modulator, GIV
No full textHeterotrimeric G proteins act as molecular switches that gate the flow of information from extracellular cues to intracellular effectors that control cell behavior. Canonically, G Protein-Coupled Receptors (GPCRs) activate G proteins by stimulating GDP to GTP exchange on the G subunit. It has also been extensively documented that G proteins can be non-canonically activated downstream of non-GPCRs, including Receptor Tyrosine Kinases (RTKs). RTKs are traditionally thought to transduce completely distinct signals via phosphorylation of downstream signaling adaptors, but increasing evidence suggests that these two signaling hubs cross-talk to form an integrated signaling network. One recently discovered cross-talk mechanism is mediated via the novel guanine-nucleotide exchange modulator (GEM), GIV. GIV’s C-terminus possesses a unique molecular make-up, containing an SH2-like domain and a GEM motif. The combination of these protein-binding modules allows the formation of RTK-GIV-Gi complexes where GIV can activate Gi in response to growth factor stimulation. Unlike canonical GPCR-mediated G protein signaling however, the structural basis for non-canonical GIV-mediated G protein activation, particularly downstream of growth factor stimulation, remained largely unknown. My dissertation work sought to fill this gap in knowledge by unravelling what binding of GIV may structurally do to Gi to stimulate GDP release, as well as investigating alternative RTK-dependent and GIV-dependent mechanisms of G protein activation. Using structural, computational, and biochemical approaches, I revealed the structural and dynamical basis for GPCR-independent Gi activation by GEMs and found key similarities and differences between GPCR-dependent and -independent G protein activation, specifically identifying the hydrophobic core of Gi as a common allosteric route toward GDP release utilized by both GPCRs and GEMs. Furthermore, I investigated an alternative but parallel GIV-dependent mechanism of RTK-mediated G protein activation via direct RTK phosphorylation of tyrosine residues within the interdomain cleft of Gi. These RTK phosphorylated tyrosines are essential for Gi activation and signaling in cells, and cancer mutation of these tyrosines results in hyperactive G protein. Taken together, my dissertation has formed a holistic understanding, at the atomic level, of the diverse allosteric mechanisms and consequences of non-canonical GIV-mediated G protein activation
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Elucidating the Role of GIV/Girdin in PD-1/PDL1 immune checkpoint blockade therapy
No full textProgrammed cell death - 1 (PD1) is a well-studied inhibitory immune checkpoint receptor that is expressed in immune cells especially activated T-cells, resulting in increased immune tolerance. PD1 binds to its ligand PD-L1, over expressed in the tumor cells, in a ‘handshake’ fashion. This immune handshake facilitates the cancer cells to evade host immune surveillance. Monoclonal antibodies against either PD1 or PDL1, resulting in inhibition of PD1/PDL1 ‘handshake’, known as immune checkpoint blockade (ICB) therapies has shown promising results against multiple cancers, including non-small cell lung cancer (NSCLC). Tumor associated macrophages (TAMs) expressing PD1 have been implicated in progressive disease states in murine models of cancer and poor prognosis in human cancers. GIV/Girdin is a multimodal signal protein known to modulate inflammation and determine whether cells migrate or proliferate. The current study highlights the phenotypic variabilities of tumor growth in myeloid-specific GIV knockout versus GIV-wild type mice, in a syngeneic lung cancer model. GIV-KO mice developed significantly larger tumors as compared to the wild type, due to higher expression of TAM-associated PD1. Upon monoclonal antibody-mediated blockade of PD1, GIV-KO mice demonstrated better response and complete recovery, as compared to the GIV-WT mice. Elaborate biochemical studies depicted that GIV’s C-terminally located TILL-like BB loop (TILL) essentially binds to the putative TILL motif of PD1, which in turn initiates the cascade of endocytic pathways and affects PD1 receptor availability. This work aims at illustrating role of GIV in enhancing the efficacy of prevalent PD1 ICB therapies via effective modulation of TAM inflammatory responses in the tumor microenvironment
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Investigating the role of GIV/Girdin in the circadian rhythm macrophages
No full textMacrophages, a.k.a ‘big eaters’ are key cells in our immune system. These effector cells of the innate immune system phagocytose bacteria and secrete both pro-inflammatory and antimicrobial mediators. In addition, macrophages also play a pivotal role in eliminating diseased and damaged cells. Macrophages have a strong intrinsic circadian rhythm that regulates the diurnal rhythmicity of their immune responses, including immunosurveillance, infiltration to sites of injury, pathogen recognition, pathogen clearance, and the timely resolution of inflammation. A healthy macrophage circadian rhythm is crucial for appropriate defensive responses and is completely lost during the immunosenescence chapter of life one experiences on aging. Here we have stumbled upon a novel regulator of the macrophage circadian rhythm, GIV/Girdin, a multi-modular G protein activator and a potent inhibitor of cAMP. Using publicly available datasets, we show that GIV expression undergoes rhythmic cycling that is lost in aged mice. GIV depleted Raw 264.7 macrophages show significant variation in the expression of their peripheral clock genes. We also demonstrated that peritoneal macrophages display significant diurnal variation in their expression of Cry1 and Klf-4, two genes crucial for a healthy macrophage circadian rhythm and time-of-day dependent immune responses. In-vivo studies revealed that the loss of GIV significantly alters the circadian variation in phagocytic activity against E.coli as well as the infiltration of inflammatory macrophages to sites of peritoneal injury. In this thesis, we seek to dissect the extensive role that GIV might play in modulating the circadian rhythm of macrophages and how we might manipulate this new player pharmacologically to improve macrophage immune responses against pathogens
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GIV and NOD2 coordinate bacterial clearance in macrophages
No full textCrohn’s disease is a prevalent inflammatory bowel disease characterized by chronic inflammation of the gastrointestinal tract due to a hyperactive immune system. The disease is predominantly caused by a mutation in the nucleotide-binding oligomerization domain-containing protein 2 (NOD2) gene which detects a constituent of bacteria, muramyl dipeptide (MDP), and triggers protective inflammatory immune promoting bacterial clearance. However, the cellular mechanisms underlying how these mutations lead to chronic inflammation remain incompletely understood. Previous studies have shown that the guanine nucleotide-binding (G) protein ⍺-subunit (G⍺)-interacting vesicle-associated protein (GIV, also known as “Girdin”) is essential in modulating the innate immune sensors including Toll-like receptor 4 (TLR4) and NOD2. In this thesis, we aim to understand the cellular and molecular mechanisms underlying the interactions between GIV and NOD2 in macrophage, which are critical in bacteria sensing and clearance. Using biochemical and functional immunology studies, our research shows that GIV binds to NOD2 and is required for effective MDP/NOD2-mediated protective signaling and bacterial clearance. We further found that GIV and NOD2 mutually regulate each other’s functions for effective intracellular bacteria sensing by NOD2 and cAMP/PKA dependent phagolysosome maturation and bacterial clearance by GIV. In conclusion, this crosstalk is essential for gut immune homeostasis, provides valuable insight into the cellular mechanisms underlying Crohn’s disease, and can be exogenously manipulated for therapeutic purposes to enhance infection resolution and restore gut homeostasis
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GIV Promotes Atherogenesis by Dampening Cyclic AMP/PKA Signals and Cholesterol Efflux Through ABCA1
No full textAtherosclerosis remains a leading cause of cardiovascular disease and mortality worldwide, driven in part by dysfunctional immune signaling and impaired lipid
metabolism in foamy macrophages. This study investigates the role of Gα-interacting,
Vesicle-associated Protein (GIV, a.k.a. Girdin), a multimodular protein and non-canonical
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activator of the heterotrimeric GTPase Gαi, in promoting atherogenesis through
regulation of cholesterol efflux. Using a myeloid-specific GIV knockout mouse model, we
demonstrate that GIV promotes lipid accumulation and exacerbates atherosclerotic
plaque burden. Mechanistically, GIV suppresses the expression of the ATP-binding
cassette transporter A1 (ABCA1), inhibits cholesterol efflux, and dampens the antiatherogenic cAMP→PKA signaling axis. Notably, GIV directly binds the C-terminus of
ABCA1, disrupting its membrane localization and transport function and stabilizes the
inhibitory ABCA1•LXRα complex. Upon stimulation with oxidized LDL, a dynamic
macromolecular complex is assembled between ABCA1•GIV•Gαi. Together, these
findings establish GIV as a multifaceted pro-atherogenic factor and unveil a new
mechanistic model of cholesterol efflux regulation in macrophages, with potential
therapeutic implications for lipid-driven immune pathology
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Negative regulation of TLR4 signaling by GIV/Girdin shapes macrophage inflammatory responses
No full textVarious insults (e.g. bacterial/viral infection, foreign bodies, or trauma) can trigger an acute inflammatory response which is generally protective; it contains and extinguishes the insult/trigger, removes damaged tissues, and prompts tissue repair. However, an uncontrolled or prolonged inflammatory response can lead to excessive tissue destruction and is a pathologic hallmark of inflammatory diseases including sepsis, arthritis, inflammatory bowel disease (IBD), organ fibrosis, type-II-diabetes, and cancers. Toll-like receptor 4 (TLR4) signaling in response to the Gram-negative bacterial antigen lipopolysaccharide (LPS) is a powerful inducer of inflammatory responses in macrophages and is critical for the control of bacterial infections and re-establishment of tissue homeostasis. However, uncontrolled activation of TLR4 can result in acute sepsis, and contribute to chronic inflammatory diseases. Therefore, understanding the intricate regulatory mechanisms of TLR4 inflammatory responses is essential for development of novel therapeutics combating inflammation-driven disease. In this work, we describe a novel mechanism for negative regulation of TLR4 signaling by the Guanine Exchange Modulator (GEM) family member, GIV, and its impact on macrophage inflammatory responses both in vitro and in vivo animal models of inflammatory disease
Effect of addition of Aluminum and Titanium on the evolution of phase and mechanical properties of high entropy alloys
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Parsing the Role of PPARs in Macrophage Processes
No full textCells are richly equipped with nuclear receptors, which act as ligand-regulated transcription factors. Peroxisome proliferator activated receptors (PPARs), members of the nuclear receptor family, have been extensively studied for their roles in development, differentiation, and homeostatic processes. In the recent past, there has been substantial interest in understanding and defining the functions of PPARs and their agonists in regulating innate and adaptive immune responses as well as their pharmacologic potential in combating acute and chronic inflammatory disease. In this review, we focus on emerging evidence of the potential roles of the PPAR subtypes in macrophage biology. We also discuss the roles of dual and pan PPAR agonists as modulators of immune cell function, microbial infection, and inflammatory diseases
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