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Articles 1 - 27 of 27
Full-Text Articles in Life Sciences
Investigating The Pi3k/Akt/Atm Pathway, Telomeric Dna Damage, T Cell Death, And Crispr/Cas9-Mediated Gene Editing During Acute And Chronic Hiv Infection, Sushant Khanal
Electronic Theses and Dissertations
Human Immunodeficiency Virus (HIV) infection initiates major metabolic and cell- survival complications. Anti-retroviral therapy (ART) is the current approach to suppress active HIV replication to a level of undetected viral load, but it is not a curative approach. Newer and sophisticated gene editing technologies could indeed be a potent antiviral therapy to achieve a clinical sterilization/cure of HIV infection. Chronic HIV patients, even under a successful ART regimen, exhibit a low-grade inflammation, immune senescence, premature aging, telomeric DNA attrition, T cell apoptosis, and cellular homeostasis. In this dissertation, we investigated CD4 T cell homeostasis, degree of T cell apoptosis, an …
A Functional Study Of Topological Dna Problem In Human T Cells During Chronic Viral Infection, Xindi Dang
A Functional Study Of Topological Dna Problem In Human T Cells During Chronic Viral Infection, Xindi Dang
Electronic Theses and Dissertations
T cells play an important role in adaptive immune system against viral infections, while premature aging and dysfunction of T cells induced by unrepaired DNA damages are always non-negligible snags during the long-term of fighting with chronic viral infections, such as Hepatitis B virus (HBV), Hepatitis C virus (HCV) or Human Immunodeficiency Virus (HIV) infection. In this dissertation, we investigated the role of topological DNA damage in reprogramming telomeric DNA damage responses (DDR), mitochondrial metabolisms, and T cell functions using CD4+ T cells derived from individuals with chronic viral infections or healthy subjects treated with topoisomerase inhibitors. The healthy human …
Exploration Of Ataxia Telangiectasia And Rad3-Related’S (Atr’S) Role In Cell Death Regulation: Implications In Development, Cancer, And Stroke, Brian Cartwright
Exploration Of Ataxia Telangiectasia And Rad3-Related’S (Atr’S) Role In Cell Death Regulation: Implications In Development, Cancer, And Stroke, Brian Cartwright
Electronic Theses and Dissertations
From gametogenesis until death an organism’s genome is under constant bombardment from endogenous and exogenous sources of DNA damage. To maintain genomic integrity amid this damage, cells have evolved responses which allow them to either preserve viability for recovery or initiate self-destructive pathways depending on the severity of DNA damage. One protein involved in initiating and carrying out these responses is the protein kinase ataxia telangiectasia and Rad3-related (ATR). ATR is known primarily for its regulatory role in initiating the checkpoint-signaling cascade following DNA damage and replicative stress. These signaling events lead to cell cycle arrest, DNA repair, or apoptosis …
Telomeric Dna Damage And Repair Machineries In Hiv Infection, Lam Nguyen
Telomeric Dna Damage And Repair Machineries In Hiv Infection, Lam Nguyen
Electronic Theses and Dissertations
In this thesis, we investigated T cell homeostasis and DNA damage repair machineries in HIV infection. We found that the frequencies of CD4T cells were low, which is associated with cell apoptosis in HIV patients compared to healthy subjects. Importantly, these events were closely correlated to the increase in T cell exhaustion, senescence, DNA damage, and telomere attrition. Mechanistically, while the DNA damage sensors Mer11, Rad50, and NBS1 (MRN) complexes remained intact, the ataxia-telangiectasia mutated (ATM) kinase and its downstream checkpoint kinase 2 (CHK2) were significantly inhibited during HIV infection. Additionally, telomeric repeat-binding factor 2 (TRF2) that functions to protect …
The Comparison Of Effects Of Synthetic And Natural Arachidin-3 On Rotavirus Infected Cells, Rebekah Napier-Jameson
The Comparison Of Effects Of Synthetic And Natural Arachidin-3 On Rotavirus Infected Cells, Rebekah Napier-Jameson
Electronic Theses and Dissertations
Rotavirus (RV) causes severe, life-threatening diarrhea, in infants, young children and immunocompromised adults. There are several effective vaccines for young children, however they are strain specific and are not protective against many RV strains in developing countries. Therefore, it is important to investigate anti-RV therapeutic agents. Our laboratory has shown arachidin-1 (A1) and arachadin-3 (A3) significantly inhibit RV replication in two cell lines, however the molecular mechanism(s) of action are not known. A synthetic molecule of A3 (sA3) has been produced, but its’ antiviral effects have not been examined. Our hypothesis is that sA3 produces the same effects on RV-infected …
The Regulation Of Rotavirus–Infected Ht29.F8 And Ma104 Cells Treated With Arachidin 1 Or Arachidin 3, Caleb M. Witcher
The Regulation Of Rotavirus–Infected Ht29.F8 And Ma104 Cells Treated With Arachidin 1 Or Arachidin 3, Caleb M. Witcher
Electronic Theses and Dissertations
Rotavirus (RV) infections cause severe life threatening diarrhea in young children and immunocompromised individuals. Several effective vaccines have been developed for young children but are not protective against all strains of RV, and there are no anti-RV therapeutics. Our laboratory has discovered a decrease in the number of infectious simian RV particles (SA114f) in human intestinal cell line, HT29.f8 cells with the addition of either of two stilbenoids, arachidin-1 (A1) or arachidin-3 (A3). This suggests effects on the host cell and RV replication. We examined the cellular effects of human RV strain (Wa) on a human intestinal cell line (HT29.f8) …
Identifying The Signaling Mechanisms Of Egfr-Mediated Apoptosis., Nicole Marion Jackson
Identifying The Signaling Mechanisms Of Egfr-Mediated Apoptosis., Nicole Marion Jackson
Electronic Theses and Dissertations
The Epidermal Growth Factor Receptor (EGFR) is a 170-kilodalton transmembrane protein that belongs to the ErbB family of receptor tyrosine kinases. Upon ligand-mediated activation, the EGFR is responsible for cell growth, proliferation, and tissue homeostasis; however, the EGFR is overexpressed in many human malignancies, including MDA-MB-468 cells, a metastatic breast epithelial cell line. Studies within this cell line, and other cell lines characterized with high EGFR levels, have shown that EGF stimulation results in the induction of apoptosis. However, the mechanisms and signaling effectors implicated in this process have yet to be elucidated. The overarching research goal of this dissertation …
Tnf-Like Weak Inducer Of Apoptosis (Tweak) : Not So Weak After All., Joseph Dekward Mcmillan Iv
Tnf-Like Weak Inducer Of Apoptosis (Tweak) : Not So Weak After All., Joseph Dekward Mcmillan Iv
Electronic Theses and Dissertations
Background: Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a proinflammatory cytokine belonging to the TNF super family. TWEAK produces a variety of cellular responses through the binding to fibroblast growth factor inducible 14 (Fn14), a member of TNF receptor superfamily. Although Fn14 lacks a death domain, TWEAK has been found to induce apoptosis in some cell types by perturbing the activity of certain pathways such as TNF-receptor signaling. TWEAK is also known to regulate proliferation and differentiation of myogenic cells. We have previously reported that the TWEAK-Fn14 system causes skeletal muscle wasting both in vitro and in …
Investigation Of Novel Functions For Dna Damage Response And Repair Proteins In Escherichia Coli And Humans, Benjamin A. Hilton
Investigation Of Novel Functions For Dna Damage Response And Repair Proteins In Escherichia Coli And Humans, Benjamin A. Hilton
Electronic Theses and Dissertations
Endogenous and exogenous agents that can damage DNA are a constant threat to genome stability in all living cells. In response, cells have evolved an array of mechanisms to repair DNA damage or to eliminate the cells damaged beyond repair. One of these mechanisms is nucleotide excision repair (NER) which is the major repair pathway responsible for removing a wide variety of bulky DNA lesions. Deficiency, or mutation, in one or several of the NER repair proteins is responsible for many diseases, including cancer. Prokaryotic NER involves only three proteins to recognize and incise a damaged site, while eukaryotic NER …
Modulation Of Cell Death Signaling And Cell Proliferation By The Interaction Of Homoserine Lactones And Paraoxonase 2., Aaron Mackallan Neely
Modulation Of Cell Death Signaling And Cell Proliferation By The Interaction Of Homoserine Lactones And Paraoxonase 2., Aaron Mackallan Neely
Electronic Theses and Dissertations
Pseudomonas aeruginosa produces N-(3-oxododecanoyl)-homoserine lactone (C12) as a quorum-sensing molecule that functions to facilitate bacteria-bacteria communication. C12 has also been reported to affect many aspects of human host cell physiology, including evoking cell death in various types of cells. However, the signaling pathway(s) leading to C12-triggerred cell death remains unclear. To clarify cell death signaling induced by C12, we examined mouse embryonic fibroblasts (MEFs) deficient in one or more caspases. Our data indicate that, unlike most apoptotic inducers, C12 evokes a novel form of apoptosis in cells, probably through the direct induction of mitochondrial membrane permeabilization. Previous studies indicate that …
The Apoptotic And Inhibitory Effects Of Phylloquinone In The U937 Cell Line, Tesha E. Blair
The Apoptotic And Inhibitory Effects Of Phylloquinone In The U937 Cell Line, Tesha E. Blair
Electronic Theses and Dissertations
Phylloquinone is a natural analog of vitamin K that has been shown to both inhibit cancer cell growth and induce apoptosis in several cancer cell lines. This study examined these effects in a non-Hodgkin lymphoma cell line, known as U937. Cell growth inhibition and apoptosis were assessed through the quantification of cell density and area, following treatment with several concentrations of phylloquinone. In addition, apoptosis was detected and quantified using immunofluorescent markers of apoptosis (i.e. annexin V, APO-BrdU). Treatment with phylloquinone resulted in reduced overall cell density, increased overall cell area, and an increased frequency of apoptosis in U937 cells. …
Systems Biology Approach To Understanding The Control Of Glucose Metabolism In Healthy And Apoptotic Neurons, Hoda Gebril
Systems Biology Approach To Understanding The Control Of Glucose Metabolism In Healthy And Apoptotic Neurons, Hoda Gebril
Electronic Theses and Dissertations
Apoptosis plays a crucial role in sculpting the developing central nervous system (CNS) but can, under certain conditions, contribute to neurodegeneration in the mature CNS. Metabolic disturbances have long been associated with apoptosis-inducing agents, however, the mechanism underlying such changes remains controversial. In this study, our hypotheses was that decreased ATP turnover may bring about other metabolic changes in apoptotic neurons. Accordingly, change in metabolic reactions other than ATP turnover may not be important in the study of apoptotic mechanism. In a living cell, metabolic reactions are highly connected and thus are highly sensitive to kinetic change in one or …
The Physiological Stress Response Caused By Hypoxia And Reperfusion Injury In Striped Bass (Morone Saxatilis) And Nile Tilapia (Oreochromis Niloticus), Amanda C. Reynolds
The Physiological Stress Response Caused By Hypoxia And Reperfusion Injury In Striped Bass (Morone Saxatilis) And Nile Tilapia (Oreochromis Niloticus), Amanda C. Reynolds
Electronic Theses and Dissertations
Approximately five million people in the United States are affected by cardiovascular related diseases yearly contributing to 300,000 annual deaths, making CVD the leading cause of mortality worldwide. It has been suggested that apoptosis (programmed cell death) contributes to the pathogenesis of cardiovascular diseases. When blood flow is reduced or cut off from the heart, usually by a thrombus, this results in oxygen deprivation (hypoxia) to the cardiomyocytes (heart cells). In response to this hypoxic stress, cardiomyocytes will undergo apoptosis. Since many species of fish can survive levels of hypoxia that would be fatal to mammals, fish are an ideal …
Mitochondrial Involvement In Neuronal Cell Death, Josie J. Gray
Mitochondrial Involvement In Neuronal Cell Death, Josie J. Gray
Electronic Theses and Dissertations
Neuronal cell death via apoptosis or necrosis underlies several devastating neurodegenerative diseases associated with aging. Mitochondrial dysfunction resulting from oxidative or nitrosative stress often acts as an initiating stimulus for intrinsic apoptosis or necrosis. These events frequently occur in conjunction with imbalances in the mitochondrial fission and fusion equilibrium, although the cause and effect relationships remain elusive. In this thesis, I demonstrate in primary rat cerebellar granule neurons (CGNs) that oxidative or nitrosative stress induces an N-terminal cleavage of optic atrophy-1 (OPA1), a dynamin-like GTPase that regulates mitochondrial fusion and maintenance of cristae architecture. This cleavage event is indistinguishable from …
Rho Gtpases In Neuronal Apoptosis And Neurodegeneration, Trisha Stankiewicz
Rho Gtpases In Neuronal Apoptosis And Neurodegeneration, Trisha Stankiewicz
Electronic Theses and Dissertations
Several studies have identified Rho family GTPases (i.e. Rho, Rac, Cdc42) as mediators of diverse critical cellular processes, such as actin cytoskeleton remodeling, gene transcription, cell-cell adhesion, and cell cycle progression. However, more recent data highlight an essential role for Rho GTPases as regulators of neuronal morphology and neuronal survival. In particular, Rac GTPase generally induces neurite outgrowth and promotes neuronal survival while Rho GTPase typically provokes neurite retraction and induces neuronal apoptosis. However, the precise signaling pathways that regulate neuronal survival downstream of Rho GTPases and the potential involvement of dysregulated activity of Rho GTPases as a causative factor …
Cellular Coping Mechanisms To Hypoxia In The Longhorn Sculpin (Myoxocephalus Octodecemspinosus) Brain, Kelly Heino
Cellular Coping Mechanisms To Hypoxia In The Longhorn Sculpin (Myoxocephalus Octodecemspinosus) Brain, Kelly Heino
Electronic Theses and Dissertations
The loss of neurological function due to hypoxia remains to be a challenge in many species due to the lack of knowledge and understanding of cellular responses. To investigate cellular responses and survival strategies of the brain during hypoxia and post-hypoxia recovery in a moderate hypoxia-tolerant species, with the hopes of identifying possible therapeutic remedies, thirty Longhorn sculpin, Myoxocephalus octodecimspinosus, were challenged with acute hypoxia (40% O2 saturation for 1 h) and twelve additional sculpin were used as controls (~90% O2 saturation). Fish were sampled at each of the following time points: control/normoxic conditions (T=0 h); hypoxic conditions …
Novel Roles Of Replication Protein A Phosphorylation In Cellular Response To Dna Damage, Moises A. Serrano
Novel Roles Of Replication Protein A Phosphorylation In Cellular Response To Dna Damage, Moises A. Serrano
Electronic Theses and Dissertations
Human replication protein A (RPA) is an eukaryotic single-stranded DNA binding protein directly involved in a variety of DNA metabolic pathways including replication, recombination, DNA damage checkpoints and signaling, as well as all DNA repair pathways. This project presents 2 novel roles of RPA in the cellular response to DNA damage. The first elucidates the regulation of RPA and p53 interaction by DNA-dependent protein kinase (DNA-PK), ataxia telangiectasia mutated (ATM) and ATM- and Rad3-related (ATR) in homologous recombination (HR). HR and nonhomologous end joining (NHEJ) are 2 distinct DNA double-stranded break (DSB) repair pathways. Here, we report that DNA-PK, the …
Cerium Oxide Nanoparticles Sensitize Pancreatic Cancer Cells To Radiation By Promoting Acidic Ph, Ros, And Jnk Dependent Apoptosis, Melissa Wason
Cerium Oxide Nanoparticles Sensitize Pancreatic Cancer Cells To Radiation By Promoting Acidic Ph, Ros, And Jnk Dependent Apoptosis, Melissa Wason
Electronic Theses and Dissertations
Side effects of radiation therapy (RT) remain the most challenging issue for pancreatic cancer treatment. In this report we determined whether and how cerium oxide nanoparticles (CONPs) sensitize pancreatic cancer cells to RT. CONP pretreatment enhanced radiation-induced reactive oxygen species (ROS) production preferentially in acidic cell-free solutions as well as acidic human pancreatic cancer cells. In acidic environments, CONPs favor the scavenging of superoxide radical over the hydroxyl peroxide resulting in accumulation of the latter whereas in neutral pH CONPs scavenge both. CONP treatment prior to RT markedly potentiated the cancer cell apoptosis both in culture and in tumors and …
The Role Of Mitochondrial Omi/Htra2 Protease In Protein Quality Control And Mitophagy, Camilla Ambivero
The Role Of Mitochondrial Omi/Htra2 Protease In Protein Quality Control And Mitophagy, Camilla Ambivero
Electronic Theses and Dissertations
Omi/HtrA2 is a mitochondrial serine protease with a dual and opposite function depending on its subcellular localization. Most of the previous studies focused on Omi/HtrA2’s pro-apoptotic function when the protein is released to the cytoplasm. It is becoming apparent that the main function of Omi/HtrA2 is within the mitochondria, where it has a pro-survival role. However, its mechanism is still poorly understood. To this end, we used the yeast two-hybrid system to dissect the Omi/HtrA2 pathway by identifying novel interactors and substrates. Our studies revealed a novel function of Omi/HtrA2 in the regulation of a deubiquitinating (DUB) complex. In addition …
Signals Delivered By Interleukin-7 Regulate The Activities Of Bim And Jund In T Lymphocytes, Shannon Moore Ruppert
Signals Delivered By Interleukin-7 Regulate The Activities Of Bim And Jund In T Lymphocytes, Shannon Moore Ruppert
Electronic Theses and Dissertations
Interleukin-7 (IL-7) is an essential cytokine for lymphocyte growth that has the potential for promoting proliferation and survival. While the survival and proliferative functions of IL-7 are well established, the identities of IL-7 signaling components in pathways other than JAK/STAT, that accomplish these tasks remain poorly defined. To this end, we used IL-7 dependent T-cells to examine those components necessary for cell growth and survival. Our studies revealed two novel signal transducers of the IL-7 growth signal: BimL and JunD. IL-7 promoted the activity of JNK (Jun N-terminal Kinase), and that JNK, in turn, drove the expression of JunD, a …
The Dynamic Functions Of Bax Are Dependent On Key Structural And Regulatory Features, Rebecca Boohaker
The Dynamic Functions Of Bax Are Dependent On Key Structural And Regulatory Features, Rebecca Boohaker
Electronic Theses and Dissertations
Bax is an essential mediator of cell fate. Since its discovery in 1985 as a protein that interacts with the anti-apoptotic protein, Bcl-2, key elements related to its function, structure and regulation remains to be determined. To this end, mitochondrial metabolism was examined in non-apoptotic Bax-deficient HCT-116 cells as well as primary hepatocytes from Bax-deficient mice. Although mitochondrial density and mitochondrial DNA content was the same in Bax-containing and Bax -deficient cells, MitoTracker staining patterns differed, suggesting the existence of Bax -dependent functional differences in mitochondrial physiology. Oxygen consumption and cellular ATP levels were reduced in Bax -deficient cells, while …
Nutraceutical Antioxidants And Their Therapeutic Potential In Neurodegeneration, Erika Kristine Ross
Nutraceutical Antioxidants And Their Therapeutic Potential In Neurodegeneration, Erika Kristine Ross
Electronic Theses and Dissertations
Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease that affects motor neurons of the brain and spinal cord. Many studies indicate that mitochondrial oxidative stress (MOS) is a principal mechanism underlying the pathophysiology of this and other devastating neurodegenerative diseases. Here, we investigated a unique whey protein supplement (Immunocal®) to determine its neuroprotective efficacy in several in vitro models of MOS and in an in vivo mouse model of ALS. This non-denatured whey supplement contains cystine which is an oxidized form of cysteine, an essential precursor for synthesis of the endogenous antioxidant, glutathione (GSH). In primary cultured rat cerebellar …
Transplantation Of Pluripotent Stem Cells Confers Cardiac Protection In Dox-Induced Heart Failure Through Notch-1 Pathway, Hilda Merino-Chavez
Transplantation Of Pluripotent Stem Cells Confers Cardiac Protection In Dox-Induced Heart Failure Through Notch-1 Pathway, Hilda Merino-Chavez
Electronic Theses and Dissertations
Doxorubicin (DOX) is the antineoplastic drug of preference used to treat a wide variety of malignancies, with high survival rates among treated patients. However, the benefits of this drug have become less appealing due to the side effects that occur such as DOX-induced cardiomyopathy (DIC) and an increased risk of myocardial infarction (MI). Therefore, there is an urgent need to explore the therapeutic options to treat DIC. In this context, adult stem cells have been used as a source to reduce cardiomyocyte apoptosis in DIC; however, the effects of transplanted embryonic stem (ES) cells and induced pluripotent stem (iPS) cells …
Biophysical Characterization Of The Membrane Binding Domain Of The Pro-Apoptotic Protein Bax, Pranav Garg
Biophysical Characterization Of The Membrane Binding Domain Of The Pro-Apoptotic Protein Bax, Pranav Garg
Electronic Theses and Dissertations
The BCL-2 family of proteins tightly regulates the delicate balance between life and death. The pore forming Bax is a pro-apoptotic member belonging to this protein family. At the onset of apoptosis, monomeric cytoplasmic Bax translocates to the outer mitochondrial membrane, forms oligomeric pores thereby letting mitochondrial cytochrome c enter the cytosol and initiate the apoptotic cascade. The C-terminal "helix 9" is thought to mediate the membrane binding of BAX. A 20-amino acid peptide corresponding to Bax C-terminus (VTIFVAGVLTASLTIWKKMG) and two mutants where the two lysines are replaced with Glu (charge reversal mutant, EE) or Leu (charge neutralization mutant, LL) …
The Sheddase Activity Of Adam10/Adam17 On Cxcl16 Increases Proliferation And Survival Of Colorectal Cancer Cells, Tamu C. Talton
The Sheddase Activity Of Adam10/Adam17 On Cxcl16 Increases Proliferation And Survival Of Colorectal Cancer Cells, Tamu C. Talton
Electronic Theses and Dissertations
CXCL16 is an interferon-inducible chemokine of the CXC-subfamily and functions as an adhesion molecule, when membrane bound, and a chemoattractant when soluble. Upregulation of cell associated CXCL16 (cCXCL16) in colorectal cancer is associated with increased tumor infiltrating lymphocytes and good prognosis. ADAM10 and ADAM17 are metalloproteinases responsible for cleaving CXCL16, releasing soluble CXCL16 (sCXCL16) and contributing to proliferation and migration of mesangial cells, in kidney inflammatory disease. We hypothesize that cCXCL16 is a substrate for ADAM10 and ADAM17 cleavage in colorectal cancer, releasing sCXCL16, which mediates cell proliferation. To this end, we first identified CXCL16 in the human colon carcinoma …
Neuroprotective Effects Of Anthocyanins On Neuronal Death Induced By Inhibition Of Bcl-2 And Oxidative Stress, Natalie A. Kelsey
Neuroprotective Effects Of Anthocyanins On Neuronal Death Induced By Inhibition Of Bcl-2 And Oxidative Stress, Natalie A. Kelsey
Electronic Theses and Dissertations
Neurodegenerative diseases such as Parkinson’s and amyotrophic lateral sclerosis have devastating consequences to the afflicted patients. A major cellular pathophysiology underlying these diseases is mitochondrial oxidative stress (MOS) leading to neuronal death. Here, we investigated the neuroprotective effects of a novel class of nutraceuticals, anthocyanins, against MOS-induced death in primary cultures of rat cerebellar granule neurons (CGNs). Anthocyanins are natural antioxidants whose neuroprotective potential has yet to be examined in detail. Kuromanin and callistephin are anthocyanins derived from black rice and strawberries, respectively. Glutathione (GSH)-sensitive MOS and intrinsic apoptosis were induced in CGNs by the Bcl-2 inhibitor, HA14-1. Callistephin and …
Cd40-Mediated Signaling Of Interleukin-1(Beta) Synthesis And Rescue From Apoptosis In Monocytes: Modulation By Il-4 And Il-10, Jonathan C. Poe
Cd40-Mediated Signaling Of Interleukin-1(Beta) Synthesis And Rescue From Apoptosis In Monocytes: Modulation By Il-4 And Il-10, Jonathan C. Poe
Electronic Theses and Dissertations
To date, the cellular mechanisms involved in the progression of diseases characterized by chronic inflammation, such as rheumatoid arthritis (RA), remain largely unknown. However, cell-to-cell contact interactions between CD4+ helper T (Th) cells and monocytes have been implicated in the induction and maintenance of pro-inflammatory cytokine synthesis that is characteristic to the pathogenesis of RA. One such cytokine produced during monocyte-Th cell contact is interleukin (IL)-1 β, a mediator directly involved in the characteristic tissue destruction that occurs in the synovia of individuals with RA. Previous studies in our laboratories have shown that ligation of CD40 on monocytes with CD40 …