bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of extracellular signal-regulated protein kinase cascade in macrophage killing ofCandida albicans
Authors: Ibata-Ombetta Stella , Jouault Thierry , Trinel Pierre-André , Poulain Daniel
Published: September 2022

The pathogenic yeast Candida albicans and its derivedmolecules stimulate a wide range of macrophage secretory functions andmay adapt to escape being killed by this phagocyte. In this study,phagocytosis of C. albicans and of the nonpathogenic yeastSaccharomyces cerevisiae was shown to be associated withphosphorylation of the mitogen-activated protein kinase(MAPK)/extracellularly regulated kinase (ERK) pathway in the absence ofsignificant activation of either p38MAPK or stress-activated proteinkinase/c-Jun N-terminal kinase. However, although 80% of endocytosedC. albicans survived after 1 h, 80% of S.cerevisiae cells were killed. Considerable quantitativedifferences were observed between the two species in the sequentialphosphorylation of MAPK/ERK kinase (MEK), extracellularly regulatedkinase-1, and 90-kDa-ribosomal S6 kinases. A lower level of activationof the pathway by C. albicans was associated with aspecies-specific overexpression of the MEK phosphatase MAPK phosphatase(MKP)-1. Killing of both C. albicans and S.cerevisiae could be reduced using PD98059, which mimics MKP-1 andinhibits MEK phosphorylation, suggesting that specific MKP-1 activationby C. albicans could contribute to its ability to escapethe yeast lytic potential of macrophages.
Induction of interleukin-8 in human neutrophils after MHC class II cross-linking with superantigens
Authors: Lei Li , Altstaedt Julia , von der Ohe Maren , Proft Thomas , Gross Ulrike , Rink Lothar
Published: September 2022

Neutrophils have been shown to express major histocompatibility complex class II (MHC II) after stimulation. However, reports concerning the functional effect of MCH II expression are still lacking. In our hands, granulocyte-monocyte colony-stimulating factor (GM-CSF) alone and in combination with interferon (IFN)-γ, but not IFN-γ or interleukin (IL)-3, induced a significant level of expression of human leukocyte antigen DR on neutrophils. The addition of staphylococcal enterotoxin E to neutrophils resulted in a significant increase in IL-8 production only after prestimulation with GM-CSF alone or in combination with IFN-γ but had no effect on neutrophils preincubated with IFN-γ alone or IL-3. Staphylococcal enterotoxin A, another bivalent superantigen, also stimulated production of IL-8 by preincubated polymorphonuclear neutrophils, whereas staphylococcal enterotoxin A mutants that are not able to cross-link MHC II molecules failed to induce IL-8 production. Taken together, our results clearly demonstrate that after induction of MHC II, neutrophils are able to respond to MHC II-specific stimulation. These findings support the ideas that the induced MHC II complex is completely functional and that neutrophils may be able to present antigens.
MC148 encoded by human molluscum contagiosum poxvirus is an antagonist for human but not murine CCR8
Authors: Lüttichau Hans R , Gerstoft Jan , Schwartz Thue W
Published: September 2022

The viral CC chemokines MC148, encoded by the poxvirus molluscum contagiosum, and viral macrophage inflammatory protein (vMIP)-I and vMIP-II, encoded by human herpesvirus 8, were probed on the murine CC receptor (CCR) 8 in parallel with human CCR8. In calcium mobilization assays, vMIP-I acted as a high-affinity agonist, whereas vMIP-II acted as a low-affinity antagonist on the murine CCR8 as well as the human CCR8. MC148 was found to bind and block responses through the human CCR8 with high affinity, but surprisingly MC148 was unable to bind and block responses through the murine CCR8. Because MC148 is the only high-affinity antagonist known to target and be selective for CCR8, MC148 is a valuable tool to decipher the role played by CCR8 in the immune system. This study shows that MC148 could not be used in murine inflammatory models; however, it will be interesting to see whether it can be used in other animal models to delineate the role played by CCR8.
FcγR-mediated phagocytosis by human macrophages involves Hck, Syk, and Pyk2 and is augmented by GM-CSF
Authors: Kedzierska Katherine , Vardaxis Nicholas J , Jaworowski Anthony , Crowe Suzanne M
Published: September 2022

The receptors for the constant region of immunoglobulin G (FcγR) arewidely expressed on cells of hemopoietic lineage and plays an importantrole in host defense. We investigated the signaling pathways duringFcγR-mediated phagocytosis in human monocyte-derived macrophages(MDMs) and examined the effect of granulocyte-macrophagecolony-stimulating factor (GM-CSF) on these events. FcγR-mediatedphagocytosis resulted in enhanced tyrosine phosphorylation of a widerange of cellular proteins and activation of tyrosine kinases Hck, Syk,and Pyk2, as well as the multidomain adapter protein paxillin.Stimulation of MDMs with GM-CSF augmented FcγR-mediated phagocytosisand increased the levels of tyrosine phosphorylation in phagocytosingMDM cultures, indicating tyrosine kinase-mediated activation. GM-CSFtreatment of MDMs without a phagocytic stimulus did not activate Syk,suggesting that GM-CSF may act either distally to Syk in theFcγR-mediated signaling cascade or on a parallel pathway activated bythe FcγR. This study shows that early signaling events duringFcγR-mediated phagocytosis in human MDMs involve activation of Syk,Hck, and paxillin. It also provides the first evidence for Pyk2activation during phagocytosis and a baseline for further studies onthe effect of GM-CSF on FcγR-mediated phagocytosis.
A defect in HIV-1 transgenic murine macrophages results in deficient nitric oxide production
Authors: Dickie Peter , Roberts Amanda , Lee Raymond
Published: September 2022

HIV transgenic mice bearing multiple copies of a noninfectious(Δgag/pol) proviral DNA were tested for the systemicproduction of nitric oxide (NO). Serum levels of NO metabolites werereduced about 50% in HIV transgenic mice compared with nontransgenicsibling mice. This difference persisted when NO production was inducedwith peritoneal injections of bacterial endotoxin (LPS). Peritonealinflammatory macrophages, but not resident peritoneal macrophages, derived from HIV-1 transgenic mice and activated in vitro with LPS andIFN-γ (or tumor necrosis factor α and IFN-γ) also produced about50% less NO than did macrophages harvested from nontransgeniclittermates. Isogenic, transgenic mice bearing mutated nefor vpr genes had normal serum levels of NO metabolites andtheir macrophages produced normal levels of NO when stimulated. Anexplanation for the reduced NO response of HIV[Vpr+Nef+] macrophageswas not apparent from measured levels of iNOS expression, viral geneexpression, or arginase activity in activated macrophages. Inhibitionof nitric oxide synthase (NOS) isoforms with l-NAME oraminoguanidine blocked time-dependent increases in HIV gene expressionin activated macrophages cultured ex vivo. Inhibition withl-NAME occurred despite high levels of NO generated byiNOS, and exogenously supplied NO induced HIV gene expression onlyweakly, suggesting that cNOS had the greater influence on proviral geneinduction. This system is presented as a model of HIV-1 proviral geneexpression and dysfunction in macrophages.
Role of Src kinases and Syk in Fcγ receptor-mediated phagocytosis and phagosome-lysosome fusion
Authors: Majeed Meytham , Caveggion Elena , Lowell Clifford A , Berton Giorgio
Published: September 2022

Phagocytosis is increased by Fcγ receptors (FcγRs), and studies with syk−/− macrophages demonstrated that Syk kinase is required for FcγR phagocytosis. Similar studies with macrophages lacking the Src family kinases Hck, Fgr, and Lyn showed that these kinases are not required for phagocytosis but that they enhance the rate of particle engulfment. In this report we show that both wild-type and hck−/−fgr−/− macrophages expressed Fyn, Src, and Yes and that these kinases were activated on ingestion of immunoglobulin G (IgG)-coated particles and redistributed, together with Syk, to actin-rich phagocytic cups and the phagosomal membrane. At doses blocking IgG-dependent phagocytosis, the tyrosine kinase inhibitors PP1 and piceatannol inhibited both Src family kinase and Syk activities, as well as their redistribution to actin-rich phagocytic cups. Hck, Fgr, and Lyn were dispensable for lysosome-phagosome fusion (PLF) induced by IgG-coated particles. However, PP1 or piceatannol hampered unopsonized yeast-induced PLF despite the fact that they did not block yeast internalization.
In vivo GM-CSF prevents dexamethasone suppression of killing ofAspergillus fumigatusconidia by bronchoalveolar macrophages
Authors: Brummer Elmer , Maqbool Anjum , Stevens David A
Published: September 2022

Dexamethasone (DEX) is a potent immunosuppressive agent used in the treatment of several disorders. However, despite its beneficial effects, DEX puts patients at risk for opportunistic infections, especially pulmonary aspergillosis. Previously we reported that in vitro granulocyte-macrophage colony-stimulating factor (GM-CSF) blocks the immunosuppressive action of DEX on bronchoalveolar macrophages (BAMs). Here we report that BAMs freshly isolated from mice treated intraperitoneally with DEX for 24 h had significantly (P<0.01) reduced killing of conidia, i.e., 15 ± 5% conidia killed by BAMs from DEX-treated mice versus 35 ± 3% by BAMs from mice given saline, 38 ± 5% by BAMs from mice given GM-CSF, and 39 ± 1% by BAMs from mice given both DEX and GM-CSF. On the other hand, in another compartment GM-CSF could not block the DEX reduction of spleen weight and spleen cellularity. Unlike GM-CSF, granulocyte colony-stimulating factor did not block DEX suppression of BAMs. GM-CSF given 24 h before DEX resulted in blocking of DEX suppression of BAM conidiacidal activity. However, when DEX was given 24 h before GM-CSF, DEX suppression of BAM was not reversed. These data show that GM-CSF in vivo blocks the in vivo immunosuppressive effects of DEX on BAM killing of conidia and suggest a potential use of GM-CSF in patients at risk for aspergillosis due to immunosuppressive DEX treatment.
The contribution of oxidative stress in apoptosis of human-cultured astroglial cells induced by supernatants of HIV-1-infected macrophages
Authors: Mollace Vincenzo , Salvemini Daniela , Riley Dennis P , Muscoli Carolina , Iannone Michelangelo , Granato Teresa , Masuelli Laura , Modesti Andrea , Rotiroti Domenicantonio , Nisticó Robert , Bertoli Ada , Perno Carlo-Federico , Aquaro Stefano
Published: September 2022

Apoptosis of neurons and astrocytes has been found in patientsundergoing AIDS dementia complex. We demonstrated that supernatantsfrom human primary macrophages (M/M) infected by HIV-1 lead humanastroglial cells to oxidative stress, as shown by elevated levels of malondialdehyde, and then to apoptosis. Electron microscopy ofastrocytes shortly incubated with HIV-1-infected M/M supernatantsshowed apoptotic blebbing, cytoplasmic loss, and chromatincondensation. Apoptosis was antagonized by pretreating astrocytes withthe nonpeptidic superoxide dismutase (SOD) mimetic M40401 but notwith anti-HIV-1 compounds, thus showing that apoptosis of astrocytesdriven by HIV-1-infected M/M supernatants is mainly mediated byabnormal production of superoxide anions without relationship to HIV-1replication in such cells. Overall results support the role ofoxidative stress mediated by HIV-1-infected M/M as one of the leadingcauses of neurodegeneration in patients with HIV-1 and suggest the useof nonpeptidic SOD mimetics to counteract HIV-1-related neurologicaldisorders.
The loss of IAP expression during HL-60 cell differentiation is caspase-independent
Authors: Doyle B T , O'Neill A J , Newsholme P , Fitzpatrick J M , Watson R W G
Published: September 2022

Human promyelocytic leukaemia cells (HL-60) differentiate into neutrophil-like cells that die spontaneously by apoptosis when treated with retinoic acid (RA). Inhibitors of apoptosis proteins (IAP) bind to and inhibit caspases 3, 7, and 9 activity and the induction of apoptosis. In this study, we demonstrate that undifferentiated HL-60 cells express IAP. During their differentiation, IAP expression is decreased at the mRNA and protein levels. In addition, we show that there is a corresponding increase in the expression and functional activity of active caspases 3 and 9. This activity was associated with the cleavage of XIAP, NAIP, and cIAP-2. Most importantly, we demonstrate that blocking caspase activity does not alter the decrease in IAP protein expression during differentiation but prevents caspase activation, IAP cleavage, and the induction of apoptosis. This result shows that the loss of IAP expression is independent of the induction of apoptosis and is solely related to the differentiation process. However, IAP cleavage is caspase-dependent. Terminal differentiation results in an altered apoptotic phenotype that is associated with the induction of HL-60 cell apoptosis.
The synthetic chemoattractant peptide, Trp-Lys-Tyr-Met-Val-d-Met, enhances monocyte survival via PKC-dependent Akt activation
Authors: Bae Yoe-Sik , Kim Youndong , Park Jun Chul , Suh Pann-Ghill , Ryu Sung Ho
Published: September 2022

Previously, we showed that Trp-Lys-Tyr-Met-Val-d-Met(WKYMVm) stimulates superoxide generation and chemotactic migration inmonocytes and neutrophils. In this study, we examined the effect of WKYMVm on monocyte survival. Serum starvation-induced monocyte deathwas attenuated in the presence of WKYMVm, which was abated when thecells were preincubated with LY294002, suggesting the involvement of phosphoinositide-3-kinase (PI 3-kinase) in the peptide-induced monocytesurvival. WKYMVm stimulated ERK and Akt activity via PI 3-kinaseactivation in monocytes. We also investigated the signaling pathway of WKYMVm-induced ERK and Akt activation. The WKYMVm-induced ERKactivation was PI 3-kinase-dependent but PKC-independent. However, Aktactivation by WKYMVm was dependent not only on PI 3-kinase but also onthe PKC pathway. When monocytes were incubated with WKYMVm, caspase-3activity, which is important for cell death, was inhibited. Pretreatment of the cells with LY294002, GF109203X, and Go 6976 but notPD98059 blocked WKYMVm-induced monocyte survival and caspase-3inhibition. In summary, the novel chemoattractant WKYMVm enhancesmonocyte survival via Akt-mediated pathways, and in this process, PKCand PI 3-kinase act upstream of Akt.
The role of PPARs in inflammation and immunity
Authors: Clark Robert B
Published: September 2022

The family of transcription factors termed peroxisome proliferator-activated receptors (PPARs) has recently been the focus of much interest for their possible role in the regulation of inflammation and immune responses. PPARα and PPARγ have been implicated in the regulation of macrophage and endothelial cell inflammatory responses. Although PPAR activation has generally been shown to have anti-inflammatory effects, opposite effects have been noted, and results often appear to depend on the ligands being used and the inflammatory parameters being measured. Recently, my laboratory and others have described a role for PPARγ in the responses of T lymphocytes. Ligands for PPARγ have been found to inhibit proliferation of activated T cells, and this appears to involve inhibition of IL-2 secretion and/or the induction of apoptosis. However, one problem in the interpretation of many of the studies of PPARγ, inflammation, and immunity is that ligands thought to be specific for PPARγ may have regulatory effects on inflammatory parameters that are PPARγ-independent. Future studies of the role of the PPARs in inflammatory and immune responses should include further studies of T cells, T-cell subsets, and dendritic cells but will have to re-examine the issue of PPAR specificity of the ligands being used. This may require further knockout studies and technology, together with the identification of endogenous and perhaps more specific synthetic PPAR ligands.
Toll-like receptor 2 (TLR2) mediates activation of stress-activated MAP kinase p38
Authors: Vasselon Thierry , Hanlon William A , Wright Samuel D , Detmers Patricia A
Published: September 2022

Early events in the response of cells to lipopolysaccharide (LPS) include activation of NF-κB and stress-activated MAP kinase p38. Recent studies have shown that the human Toll-like receptor 2 (TLR2) mediates activation of NF-κB in response to commercial preparations of LPS (comLPS), membrane lipoproteins, and Gram-positive bacterial products. Here, we show that expression of TLR2 in human embryonic kidney 293 cells enabled p38 phosphorylation in response to comLPS, a synthetic bacterial lipoprotein, and B. subtilis. Activation of p38 was confirmed by an in vitro kinase assay using ATF2 as substrate and by an assay measuring activation of the downstream effector of p38, MAP kinase-activated protein kinase in cells. Thus, TLR2 initiated the signaling pathway for p38 in response to bacterial products.
A novel phenotype for an activated macrophage: the type 2 activated macrophage
Authors: Anderson Charles F , Mosser David M
Published: September 2022

Activated macrophages were used as antigen presenting cells (APCs) to determine the extent to which these APCs could influence an adaptive immune response. We show that activated macrophages induced a strong polarized Th1-like T cell response that was predominated by IFN-γ. However, when antigen was targeted to Fcγ receptors on these macrophages, their phenotype changed, and they now induced a T cell response that was predominated by IL-4. The initial biasing by activated macrophages toward a Th1-like response was a result of activation of the innate immune response, as macrophages from MyD88−/− mice failed to produce Th1-inducing cytokines. The reversal of the Th1 biasing was a result of FcγR ligation, as macrophages lacking the FcR common γ chain failed to reverse this biasing. To show that this biasing could occur in vivo, mice were injected with activated macrophages or activated macrophages whose FcγR had been ligated with an irrelevant immune complex. Mice injected with FcγR-ligated macrophages made more antibody than those receiving conventionally activated macrophages, and the antibody was predominantly of the IgG1 isotype. These studies demonstrate that FcγR ligation on activated macrophages can change the phenotype of these APCs to cells that preferentially drive a Th2-like response. We have termed these cells type 2 activated macrophages.
TGF-β1 and IFN-γ cross-regulate antigen presentation to CD4 T cells by macrophages
Authors: Delvig Alexei A , Lee Jeong J , Chrzanowska-Lightowlers Zosia M A , Robinson John H
Published: September 2022

We studied the interaction of transforming growth factor-β1 (TGF-β1) and interferon-γ (IFN-γ) in regulating Ag presentation in macrophages. TGF-β1 blocked, and IFN-γ enhanced Ag presentation of two T cell epitopes from the group A streptococcal M protein processed from viable Streptococcus pyogenes. Consistent with the functional data, TGF-β1 reduced the constitutive expression of MHC class II transactivator (CIITA), MHC class II (MHC-II), invariant chain, and DO mRNA, whereas IFN-γ up-regulated the expression of CIITA and MHC-II mRNA without affecting invariant chain or DO mRNA. However, neither cytokine affected DM mRNA expression. Treatment of macrophages with the two cytokines in combination showed that TGF-β1 down-regulated IFN-γ-mediated enhancement of antigen presentation and inhibited IFN-γ-inducible CIITA and MHC-II class II mRNA expression. The effect of TGF-β1 on Ag presentation was shown to be independent of the surface expression of CD80, CD86, or CD40 costimulatory molecules by flow cytometry. Our results show that TGF-β1 and IFN-γ cross-regulate Ag presentation by influencing the transcription of several genes associated with antigen presentation function, which may represent an important mechanism limiting T cell activation during an immune response.
Modulation of malignant B cell activation and apoptosis by bcl-2 antisense ODN and immunostimulatory CpG ODN
Authors: Jahrsdörfer B , Jox R , Mühlenhoff L , Tschoep K , Krug A , Rothenfusser S , Meinhardt G , Emmerich B , Endres S , Hartmann G
Published: September 2022

Inhibition of bcl-2 expression by antisense oligodeoxynucleotides (ODN) might render bcl-2 overexpressing malignant B cells more susceptible to chemotherapy. ODN containing unmethylated CG dinucleotides (CpG) are known to activate B cells. We studied the effects of two bcl-2 antisense ODN, with (G3139) or without CG dinucleotides (NOV 2009) within the sequence, and the effects of a nonantisense, CpG-containing ODN (ODN 2006) on activation and apoptosis of malignant B cell lines and primary B-CLL cells. Without cationic lipids, no antisense-mediated inhibition of bcl-2 synthesis was achieved with G3139 and NOV 2009. Instead, G3139, but not NOV 2009, induced similar changes as ODN 2006 in proliferation, expression of costimulatory and antigen-presenting molecules, as well as in bcl-2 and bcl-xL levels of primary B-CLL cells. G3139 and ODN 2006 inhibited in vitro, spontaneous apoptosis in B-CLL cells of patients with high serum thymidine kinase activity (s-TK, marker for proliferative activity of malignant B cells), whereas in patients with low s-TK activity, apoptosis was induced. In conclusion, our results suggest that modulation of malignant B cell apoptosis by G3139 depends on its immunostimulatory properties rather than on antisense-mediated reduction of bcl-2 expression. Immunostimulatory CpG ODN may have a therapeutic potential in patients with B-CLL, especially those with low s-TK activity.
Role of CXCL1 in tumorigenesis of melanoma
Authors: Dhawan Punita , Richmond Ann
Published: September 2022

The CXC chemokine, CXCL1 (melanoma growth-stimulatory activity/growth-regulated protein α), plays a major role in inflammation, angiogenesis, tumorigenesis, and wound healing. Recently, chemokines have been extensively related to cellular transformation, tumor growth, homing, and metastasis. CXCL1 and its mouse homologue MIP-2 have been shown to be involved in the process of tumor formation. When chemokines such as CXCL1 and CXCL8 (IL-8) become disregulated so that they are chronically expressed, tissue damage, angiogenesis, and tumorigenesis can follow. This up-regulation of chemokines has been attributed to constitutive activation of NF-κB. The constitutive NF-κB activation is an emerging hallmark in various types of tumors including breast, colon, pancreatic, ovarian, as well as melanoma. Previous findings from our laboratory and other laboratories have demonstrated the role of endogenous activation of NF-κB in association with enhanced metastatic potential of malignant melanoma cells and suggest that targeting NF-κB may have potential therapeutic effects in clinical trials. An important step in this direction would be to delineate the important intracellular pathways and upstream kinases involved in up-regulation of NF-κB in melanoma cells. In this review, the signaling pathways involved in the disregulation of NF-κB and chemokine expression are discussed.
Complement's participation in acquired immunity
Authors: Nielsen Claus Henrik , Leslie Robert Graham Quinton
Published: September 2022

The preliminary evidence for the involvement of complement in promoting primary humoral responses dates back over a quarter of a century. However, it is only in the course of the past decade or so that the detailed mechanisms underlying complement's influence have been characterized in depth. It is now clear that complement serves as a regulator of several B cell functions, including specific antibody production, antigen uptake, processing and presentation, and shaping of the B cell repertoire. Of key importance, in this respect, is the role played by the B cell-signaling triad consisting of the B cell receptor for antigen (BCR), a complex composed of the iC3b/C3d fragment-binding complement type 2 receptor (CR2, CD21) and its signaling element CD19 and the IgG-binding receptor FcγRIIb (CD32). The positive or negative outcome of signaling through this triad is determined by the context in which antigen is seen, be it alone or in association with natural or induced antibodies and/or C3-complement fragments. The aim of this review is to describe the present status of our understanding of complement's participation in acquired immunity and the regulation of autoimmune responses.
CD4 lymphocytes in the blood of HIV+ individuals migrate rapidly to lymph nodes and bone marrow: support for homing theory of CD4 cell depletion
Authors: Chen Jenny J-Y , Huang Jason C , Shirtliff Mark , Briscoe Elma , Ali Seham , Cesani Fernando , Paar David , Cloyd Miles W
Published: September 2022

The mechanism(s) by which human immunodeficiency virus (HIV) causes depletion of CD4 lymphocytes remains unknown. Evidence has been reported for a mechanism involving HIV binding to (and signaling) resting CD4 lymphocytes in lymphoid tissues, resulting in up-regulation of lymph node homing receptors and enhanced homing after these cells enter the blood, and induction of apoptosis in many of these cells during the homing process, caused by secondary signaling through homing receptors. Supportive evidence for this as a major pathogenic mechanism requires demonstration that CD4 lymphocytes in HIV+ individuals do migrate to lymph nodes at enhanced rates. Studies herein show that freshly isolated CD4 lymphocytes labeled with 111Indium and intravenously reinfused back into HIV+ human donors do home to peripheral lymph nodes at rates two times faster than normal. They also home at enhanced rates to iliac and vertebral bone marrow. In contrast, two hepatitis B virus-infected subjects displayed less than normal rates of blood CD4 lymphocyte migration to peripheral lymph nodes and bone marrow. Furthermore, the increased CD4 lymphocyte homing rates in HIV+ subjects returned to normal levels after effective, highly active antiretroviral therapy treatment, showing that the enhanced homing correlated with active HIV replication. This is the first direct demonstration of where and how fast CD4 lymphocytes in the blood traffic to tissues in normal and HIV-infected humans. The results support the theory that the disappearance of CD4 lymphocytes from the blood of HIV+ patients is a result of their enhanced migration out of the blood (homing) and dying in extravascular tissues.
The viral manipulation of the host cellular and immune environments to enhance propagation and survival: a focus on RNA viruses
Authors: Mahalingam Surendran , Meanger Jayesh , Foster Paul S , Lidbury Brett A
Published: September 2022

Virus infection presents a significant challenge to host survival. The capacity of the virus to replicate and persist in the host is dependent on the status of the host antiviral defense mechanisms. The study of antiviral immunity has revealed efective antiviral host immune responses and enhanced our knowledge of the diversity of viral immunomodulatory strategies that undermine these defences. This review describes the diverse approaches that are used by RNA viruses to trick or evade immune detection and response systems. Some of these approaches include the specific targeting of the major histocompatibility complex-restricted antigen presentation pathways, apoptosis, disruption of cytokine function and signaling, exploitation of the chemokine system, and interference with humoral immune responses. A detailed insight into interactions of viruses with the immune system may provide direction in the development of new vaccine strategies and novel antiviral compounds.
Interferon-γ stimulates the expression of galectin-9 in cultured human endothelial cells
Authors: Imaizumi Tadaatsu , Kumagai Mika , Sasaki Naoko , Kurotaki Hidekachi , Mori Fumiaki , Seki Masako , Nishi Nozomu , Fujimoto Koji , Tanji Kunikazu , Shibata Takeo , Tamo Wakako , Matsumiya Tomoh , Yoshida Hidemi , Cui Xue-Fan , Takanashi Shingo , Hanada Katsumi , Okumura Ken , Yagihashi Soroku , Wakabayashi Koichi , Nakamura Takanori , Hirashima Mitsuomi , Satoh Kei
Published: September 2022

Galectin-9 is a member of the galectin family and has been identified as an eosinophil chemoattractant produced by activated T lymphocytes. Vascular endothelial cells play an important role in the initial step of eosinophil recruitment and activation in immune and inflammatory responses. We have addressed the stimulation of galectin-9 expression in endothelial cells. Galectin-9 was detected in membrane and cytosolic fractions of human umbilical vein endothelial cells stimulated with interferon-γ (IFN-γ). IFN-γ also enhanced the adhesion of human eosinophilic leukemia-1 cells to endothelial monolayers, and it was inhibited by the presence of lactose. Interleukin-4, which induces eotaxin expression, did not affect the expression of galectin-9. The in situ endothelium from patients with inflammatory diseases was found to express galectin-9. IFN-γ-induced production of galectin-9 by endothelial cells may play an important role in immune responses by regulating interactions between the vascular wall and eosinophils.
Human dendritic cells express functional formyl peptide receptor-like-2 (FPRL2) throughout maturation
Authors: Yang De , Chen Qian , Gertz Barry , He Rong , Phulsuksombati Michele , Ye Richard D , Oppenheim Joost J
Published: September 2022

Immature and mature dendritic cells (iDC and mDC, respectively) migrate to different anatomical sites, e.g., sites of antigen (Ag) deposition and secondary lymphoid organs, respectively, to fulfill their roles in the induction of primary, Ag-specific immune responses. The trafficking pattern of iDC andmDC is based on their expression of functional chemotactic receptors and the in vivo sites expressing the corresponding ligands including chemokines and/or classical chemoattractants. In this study, we have evaluated the expression of the formyl peptide receptor like-2 (FPRL2) by human iDC and mDC. We show that iDC respond chemotactically and by Ca2+ mobilization to N-formyl-Met-Leu-Phe and a recently identified synthetic peptide Trp-Lys-Tyr-Met-Val-D-Met (WKYMVm), whereas mDC derived from the same donor only respond to WKYMVm. Furthermore, iDC and mDC express FPRL2 mRNA and protein. As mDC do not express any other members of the human FPR subfamily, FPRL2 expressed by DC must be functional and mediate the effect of WKYMVm on DC. Indeed, treatment of iDC and mDC with WKYMVm induces the internalization of FPRL2. Thus, human myeloid DC express functional FPRL2 and maintain its expression even after maturation, suggesting that the interaction of FPRL2 and its endogenous ligand(s) may be involved in regulating DC trafficking during Ag uptake and processing in the periphery as well as the T cell-stimulating phase of the immune responses.
Experimental basis of hematopoietic stem cell transplantation for treatment of autoimmune diseases
Authors: van Bekkum D W
Published: September 2022

Experiments with animal models of autoimmune disease provided the rational and stimulus for the current, clinical studies of autologous stem cell transplantation for the treatment of a variety of severe, refractory, autoimmune diseases. The discoveries that led to the recognition of the key role of hematopoietic stem cells and the successful treatment of autoimmune diseases with bone marrow transplants are reviewed. The relevance of spontaneous and induced autoimmune disease models for the development of clinical treatment regimens is discussed. Most of the investigations with autologous stem cell transplantation have been performed with induced autoimmune disorders: in rats with adjuvant arthritis and in rats or mice with experimental, allergic encephalomyelitis, the current model for multiple sclerosis. The main aspects of this translational research were the conditioning regimens and the degree of T cell depletion of the graft as determinants of remission induction and the incidence of relapses. The emerging recommendations are compared with the outcome so far of the clinical studies.
Rho family small GTPases control migration of hematopoietic progenitor cells into multicellular spheroids of bone marrow stroma cells
Authors: Bug G , Rossmanith T , Henschler R , Kunz-Schughart L A , Schröder B , Kampfmann M , Kreutz M , Hoelzer D , Ottmann O G
Published: September 2022

Seeding of hematopoietic progenitor cells (HPC) into the bone marrow requires a complex interaction between cell membrane and adhesion systems and cell signaling pathways. We established a multicellular, spheroid coculture model to study HPC migration in a three-dimensional stromal environment. Here, entry of primary CD34+ cells into stroma cell spheroids was independent of the integrins very late antigen (VLA)-4, VLA-5, lymphocyte function-associated antigen-1, and the chemokine receptor CXCR4. Experiments using a panel of bacterial toxins selectively targeting key regulators of cellular locomotion, the Rho family small GTPases Rho, Rac, and Cdc42, revealed a considerable reduction or even abrogation of TF-1 cell migration without an increase of apoptosis or impairment of proliferation. Pertussis toxin, an inhibitor of Gαi proteins, showed a similar effect. In some in vitro invasion assays, phosphatidylinositol-3 kinase (PI-3K) was shown to mediate Rac- and Cdc42-induced cell motility and invasion. However, inhibition of the PI-3K pathway by LY294002 did not impair TF-1 cell migration in our three-dimensional model system.
Multiple control of interleukin-8 gene expression
Authors: Hoffmann Elke , Dittrich-Breiholz Oliver , Holtmann Helmut , Kracht Michael
Published: September 2022

Interleukin (IL)-8, a prototypic human chemokine, was detected more than a decade ago as the founding member of the chemokine superfamily. One of the most remarkable properties of IL-8 is the variation of its expression levels. In healthy tissues, IL-8 is barely detectable, but it is rapidly induced by ten- to 100-fold in response to proinflammatory cytokines such as tumor necrosis factor or IL-1, bacterial or viral products, and cellular stress. Recently, significant advances in the understanding of signaling pathways, which coordinately regulate IL-8 transcription as well as mRNA stabilization in response to external stimuli, have been made. Maximal IL-8 amounts are generated by a combination of three different mechanisms: first, derepression of the gene promoter; second, transcriptional activation of the gene by nuclear factor-κB and JUN-N-terminal protein kinase pathways; and third, stabilization of the mRNA by the p38 mitogen-activated protein kinase pathway. In that way, cells are able to rapidly increase and at the same time, to fine-tune the amount of IL-8 secreted and thereby control the extent of leukocytes attracted to sites of tissue injury.
WISER Survivor Trial: Combined Effect of Exercise and Weight Loss Interventions on Inflammation in Breast Cancer Survivors
Authors: STURGEON KATHLEEN M. , BROWN JUSTIN C. , SEARS DOROTHY D. , SARWER DAVID B. , SCHMITZ KATHRYN H.
Published: September 2022

Purpose

Physical inactivity and obesity increase risk for breast cancer recurrence and cardiovascular death; inflammation is hypothesized to mediate these associations.

Methods

In a four-arm randomized controlled trial, 318 breast cancer survivors with overweight or obesity were randomized to exercise alone, weight loss alone, exercise plus weight loss, or control for 12 months. Inflammation outcomes included C-reactive protein (CRP), serum amyloid A (SAA), intracellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1).

Results

Compared with control, exercise alone increased ICAM-1 (9.3%; 95% confidence interval [CI] = 1.6–16.9) and VCAM-1 (8.6%; 95% CI = 2.6–14.5) but did not change CRP or SAA. Compared with control, weight loss alone reduced CRP (−35.2%; 95% CI = −49.9 to −20.7), and SAA (−25.6%; 95% CI = −39.8 to −11.9) but did not change ICAM-1 or VCAM-1. Compared with control, exercise plus weight loss reduced CRP (−44.1%; 95% CI = −57.1 to −31.1) and SAA (−26.6%; 95% CI = −40.5 to −12.6) but did not change ICAM-1 or VCAM-1. Among 194 participants with elevated CRP at baseline (e.g., >3 mg·L−1), compared with control, weight loss alone (0.17; 95% CI = 0.04–0.30) and exercise plus weight loss (0.31; 95% CI = 0.16–0.46) increased the probability of achieving normal CRP at month 12. In analyses that consolidated randomized groups, body weight and adiposity reductions, but not change in fitness level, correlated with decreased CRP, SAA, and ICAM-1 levels.

Conclusions

In breast cancer survivors with overweight or obesity, weight loss or exercise plus weight loss reduced measures of inflammation that are associated with breast cancer recurrence and cardiovascular death.
Effects of Broad-Spectrum Antibiotic Treatment or Germ-Free Status on Endurance Performance and Exercise Adaptations in Mice
Authors: HUTCHINSON NOAH T. , WANG SELENA S. , DOKHANCHI JACK , JOHNSON RODNEY W. , BUFORD THOMAS W. , ALLEN JACOB M. , WOODS JEFFREY A.
Published: September 2022

Purpose

Endurance exercise alters the gut microbiome independently of diet. The extent to which gut microbes are responsible for physiologic adaptations to exercise training is unknown. The purpose of these experiments was to determine the role of gut microbes in performance and muscle adaptation to 6 wk of voluntary wheel running (VWR) in mice.

Methods

We depleted microbes with broad-spectrum antibiotic (ABX) treatment and used germ-free (GF) mice to determine effects on adaptations to VWR. Male and female C57Bl/6 mice (n = 56) were assigned to daily VWR or sedentary conditions. After the intervention, treadmill endurance and glucose tolerance were assessed, and gastrocnemius and soleus tissues were harvested and analyzed for citrate synthase (CS) enzyme activity and expression of exercise training–sensitive genes.

Results

ABX treatment and GF status resulted in VWR volumes ~22% and 26% lower than controls, respectively. Analysis of variance revealed that, although VWR increased treadmill endurance, ABX had no effect. GF status significantly reduced treadmill performance in trained GF mice after training. VWR increased gastrocnemius CS enzyme activity in all groups, and ABX and GF status did not reduce the VWR effect. VWR also increased muscle expression of PGC1a, but this was not affected by ABX treatment.

Conclusions

ABX treatment and GF status reduced VWR behavior but did not affect VWR-induced adaptations in endurance capacity, CS activity, or expression of muscle metabolic genes. However, GF status reduced endurance capacity. These data indicated that reducing microbes in adulthood does not inhibit endurance training adaptations in C57Bl/6 mice, but that GF mice possess a reduced responsiveness to endurance exercise training, perhaps because of a developmental defect associated with lack of microbes from birth.
Web-based digital twin online laboratories: Methodologies and implementation
Authors: Lei Zhongcheng , Zhou Hong , Hu Wenshan , Liu Guo-Ping
Published: September 2022

Background: Online laboratories that provide online experimentation are crucial for education and research in all fields of engineering. As a transformative technology, the digital twin can be potentially applied into online laboratories to enable physical-digital twin interactions and enhance user experience.

Methods: In this article, web-based digital twin online laboratories are discussed, the methodologies and implementation of which are presented in detail. The digital twin architecture, three-dimensional twin model, web-based digital twin control algorithm design, and real-time physical-twin control are explored to provide a full picture for the design and implementation of digital twin online laboratory systems. To illustrate the effectiveness of the proposed methodologies, a use case with the Networked Control System Laboratory (a previously developed control and automation laboratory) is provided, which details the design and implementation.

Results: A four-tier web architecture has been implemented. With the provided web interface, control algorithms can be designed and employed for real-time digital twin experimentation. The experimental results demonstrated that the physical-digital twin fan speed control system can achieve good control and tracking performance with human-in-the-loop interactions.

Conclusions: This article presents the methodologies and implementation of digital twin web-based online laboratories. The use case verified the proposed web architecture, digital twin implementation, control architecture, and human-in-the-loop interactions for a digital twin experimentation system, which can potentially be used for the design and implementation of other digital-twin applications in different fields.
Abnormal CT findings among patients with abdominal pain in the radiology department of a tertiary care center
Authors: Almushayti Ziyad , Alsalhi Abdulmonem , Alsagri Mazen , Alqarzaee Razan , Alsuwaidan Hamad , Alolayan Fahad , Alosaimi Hamed Turki , Alhussain Saud , Almushayqih Ali , Alolayan Shahad , Alghofaily Khalefa
Published: September 2022

Background: Abdominal pain is a common symptom in people of different ages due to various benign and life-threatening causes. Imaging studies, including computerized tomography (CT) scans, explore the clinical reasons behind this pain to prevent delayed diagnosis. Owing to abnormal findings, timely identification of the exact cause of abdominal pain is important in most diseases so treatment can be started earlier, but it has not yet been studied, making this research novel. This study was conducted to identify the prevalence of abnormal CT scan findings among referred patients with abdominal pain and to confirm or determine other diagnoses compared to other imaging modalities in the Emergency Department (ED).

Methods: This observational retrospective study was conducted at the King Fahad Hospital, a tertiary hospital in Qassim. We included 2,144 patients who visited the ED and underwent abdominal CT scans between January 2021 and January 2022. Data on age, sex, CT findings, and results from other imaging modalities were collected from the Radiology Department.

Results: We found that 2,144 patients referred from the ED to the Radiology Department complained of acute abdominal pain in 2021 for CT diagnosis. Approximately 28.2% of these patients had normal CT diagnoses. The average age at normal CT diagnosis was 38.6 years old. While 52% of CT diagnoses were abnormal, including obstructive ureteric stone (435, 20.3%), appendicitis (205, 9.6%), bowel obstruction (51, 2.4%), renal cancer (27, 1.3%), ovarian cancer (25, 1.2%), and obstructive bladder stone (25, 1.2%), with an average age of 40.4 years old, and 19% with accidental findings.

Conclusions: Most of the cases with abdominal pain showed abnormal results in the CT scan. These results demonstrate the sole inefficiency of CT scan for the diagnosis of abdominal pain. So, clinical evaluations should be used together with abdominal ultrasonography to perform a timely and exact diagnosis.
Investigation of knowledge management and firm competitiveness: core competence as a mediator
Authors: Aziz Iffat , Shafiq Muhammad , Fatima Iram
Published: September 2022

Background: The objective of the current study is to empirically investigate interrelationships among three variables; knowledge management (KM), core competence (CC), and firm competitiveness (FC), and to develop a framework based on empirical evidence for developing countries in South Asia.

Methods: This is a cross-sectional quantitative study using the Pakistan stock exchange (PSX) enlisted manufacturing and service organizations having a sample size of 136 companies. A questionnaire was self-administered to the respondents by executing a comprehensive strategy to get a high response rate. A total of 201 valid and complete responses from four manufacturing (automobiles, food & cosmetics, textile, and pharmaceutical) and one service organization (banks) were received using a Likert scale of five points in the questionnaire to examine the subject agreement level against statements. All hypothesized relationships were analyzed by employing SEM using AMOS ver. 20.

Results: Results of the study confirmed the positive and significant influence of four constructs of knowledge management processes on four constructs of firm competitiveness (innovation, delivery, quality, and financial performance). Further, knowledge management significantly impacts the firm's competitiveness through the mediation of technology, organization and people (TOP) core competence. The findings also supported that managing the intangible resource of the organization can influence the firm's competitiveness and resource-based TOP competence.

Conclusions: The SEM analysis confirmed all hypothetical relationships and supported the knowledge management's direct and indirect effects through core competence on firm competitiveness. The findings showed that the effectiveness of knowledge management will increase the organizations' competitiveness in developing countries' research perspective.
Medication-related burden among patients with diabetes mellitus and its relation to diabetic control parameters: an observational study
Authors: Jamal Noori Ayman , Jabbar Kadhim Dheyaa , Abdulhasan Al-Hilal Muqdad
Published: September 2022

Background: Diabetes mellitus (DM) refers to a group of metabolic abnormalities that are linked with significant morbidity, death, and health-care costs. Management options for patients with chronic illnesses such as diabetes are growing more complicated, which may result in a therapeutic burden for patients. The purpose of this research was to quantify the forms of concerns diabetic individuals have with medication that influence overall burden, as well as to examine the sociodemographic and clinical factors linked with negative medication use experiences and increased levels of burden.

Methods:  The present research was a cross-sectional study of diagnosed diabetes patients who attended the Specialized Center for Endocrinology and Diabetes between 1st of December 2021 and 30th April 2022 in Baghdad, Iraq. The Living with Medicines Questionnaire (LMQ) was used to assess medication-related burden (MRB).

Results: The study recruited 193 patients with diabetes mellitus. The participants were adults with an average age of 50±15 years. More than half (52.8%) of the participating patients were women, and more than half (51.3%) also had one or more other chronic diseases. Additionally, 23.3% of patients had polypharmacy (≥ 5 medications). More than one-third had diabetes complications: neuropathy (45.6%) or retinopathy (38.9%). The mean LMQ score was (122.8±15.5). The research revealed that most of the DM patients experienced a moderate degree of medication burden (72.5%), followed by high burden (14.5%), minimum burden (12.4%), and no burden at all (0.5%) with no patient experiencing extremely high burden (0.0 %). Patients with uncontrolled blood glucose (high HbA1c), neuropathy, or retinopathy had a significantly higher medication burden.

Conclusions: The MRB among diabetic patients is at a very high level. This information may be helpful to health care professionals and policymakers seeking to understand MRB for patients with diabetes. Future studies should focus on developing interventions that help reduce such burdens.