bluuebunny/crossref_metadata_2025 huggingface dataset:
Erythrocytes deliver Tat to interferon-γ-treated human dendritic cells for efficient initiation of specific type 1 immune responses in vitro
Authors: Corinti Silvia , Chiarantini Laura , Dominici Sabrina , Laguardia Maria Elena , Magnani Mauro , Girolomoni Giampiero
Published: September 2022

Dendritic cells (DC) can represent an important target for vaccine development against viral infections. Here, we studied whether interferon-γ (IFN-γ) could improve the functions of DC and analyzed human red blood cells (RBC) as a delivery system for Tat protein. Monocyte-derived DC were cultured in human serum and matured with monocyte-conditioned medium (MCM) in the presence or not of IFN-γ. Tat was conjugated to RBC (RBC-Tat) through avidin-biotin bridges. Stimulation of DC with IFN-γ increased the release of interleukin (IL)-12 and tumor necrosis factor-α and inhibited the production of IL-10. Moreover, IFN-γ-treated DC up-regulated the release of CXCL10 (IP-10) markedly and reduced the secretion of CCL17 TARC significantly, attracting preferentially T-helper (Th)1 and Th2 cells, respectively. DC internalized RBC-Tat efficiently. Compared with DC pulsed with soluble Tat, DC incubated with RBC-Tat elicited specific CD4+ and CD8+ T-cell responses at a much lower antigen dose. DC matured in the presence of MCM were more effective than immature DC in inducing T-cell proliferation and IFN-γ release. Finally, immature and mature DC exposed to IFN-γ were better stimulators of allogeneic T cells and induced a higher IFN-γ production from Tat-specific CD4+ and CD8+ T lymphocytes. In conclusion, erythrocytes appear an effective tool for antigen delivery into DC, and IFN-γ could be used advantageously for augmenting the ability of DC to induce type 1 immune responses.
Transforming growth factor β signal transduction
Authors: Dennler Sylviane , Goumans Marie-José , ten Dijke Peter
Published: September 2022

Transforming growth factor beta1 (TGF-β1) is the prototypic member of a large family of structurally related pleiotropic-secreted cytokines that play a pivotal role in the control of differentiation, proliferation, and state of activation of many different cell types including immune cells. TGF-β family members have potent immunosuppressor activities in vitro and in vivo. These cytokines trigger their biological effects by inducing the formation of a heteromeric transmembrane serine/threonine kinase receptor complex. These receptors then initiate intracellular signaling through activation of Smad proteins, and specific Smads become phosphorylated and associate with other Smads. These heteromeric Smad complexes accumulate in the nucleus, where they modulate the expression of target genes. Recent data support the notion that Smads are important intracellular effectors of TGF-β in immune cells. Here, we review recent advances in TGF-β signal transduction in immune cells.
Adhesion to extracellular matrix proteins modulates bovine neutrophil responses to inflammatory mediators
Authors: Borgquist Jessica D , Quinn Mark T , Swain Steve D
Published: September 2022

The neutrophil inflammatory response can be altered profoundly by contact with extracellular matrix proteins (ECMs). We characterized functional responses (intracellular calcium, actin polymerization, degranulation, adhesion, and oxidative burst) of bovine neutrophils adhered to selected ECM proteins [collagen IV, laminin, fibronectin, thrombospondin, and heparan sulfate proteoglycan (HSP)] in response to interleukin-8 (IL-8) and platelet-activating factor (PAF). Neutrophil adhesion to ECMs altered responses to PAF and IL-8, although some functions were more responsive to modulation. The most susceptible function was reactive oxygen species (ROS) production. ROS production in response to PMA and TNF-α was supported differentially by various ECMs, and PAF and IL-8 “priming” had strikingly different effects, depending on the ECM present. Although PAF and IL-8 inhibited TNF-α-induced ROS production in neutrophils adhered to collagen, fibronectin, and laminin, PAF enhanced ROS production strongly in HSP-adherent cells. This study illustrates how neutrophils can integrate multiple stimuli, resulting in complex modulation of their functional response.
The immunosuppressive effects of chronic morphine treatment are partially dependent on corticosterone and mediated by the μ-opioid receptor
Authors: Wang Jinghua , Charboneau Richard , Balasubramanian Sudha , Barke Roderick A , Loh Horace H , Roy Sabita
Published: September 2022

Wild-type and μ-opioid receptor knockout (MORKO) mice were used to investigate the role of corticosterone (CORT) and the μ-opioid receptor (MOR) in chronic morphine-mediated immunosuppression. We found that although plasma CORT concentrations in CORT infusion (10 mg/kg/day) and morphine-pellet implantation (75 mg) mice were similar (400–450 ng/ml), chronic morphine treatment resulted in a significantly higher (two- to threefold) inhibition of thymic, splenic, and lymph node cellularity; inhibition of thymic-lymphocyte proliferation; inhibition of IL-2 synthesis; and activation of macrophage nitric oxide (NO) production when compared with CORT infusion. In addition, results show that the inhibition of IFN-γ synthesis and splenic- and lymph node-lymphocyte proliferation and activation of macrophage TNF-α and IL-1β synthesis occurred only with chronic morphine treatment but not with CORT infusion. These morphine effects were abolished in MORKO mice. The role of the sympathetic nervous system on morphine-mediated effects was investigated by using the ganglionic blocker chlorisondamine. Our results show that chlorisondamine was able to only partially reverse morphine's inhibitory effects. The results clearly show that morphine-induced immunosuppression is mediated by the MOR and that although some functions are amplified in the presence of CORT or sympathetic activation, the inhibition of IFN-γ synthesis and activation of macrophage-cytokine synthesis is CORT-independent and only partially dependent on sympathetic activation.
Differential and competitive activation of human immune cells by distinct classes of CpG oligodeoxynucleotide
Authors: Gürsel Mayda , Verthelyi Daniela , Gürsel Ihsan , Ishii Ken J , Klinman Dennis M
Published: September 2022

Synthetic oligodeoxynucleotides (ODN) expressing “CpG motifs” show promise as immune adjuvants, antiallergens, anticancer, and immunoprotective agents. Two structurally distinct classes of CpG ODN have been identified that stimulate human PBMC. This work establishes that both types of ODN bind to and are internalized by the same individual B cells, NK cells, and monocytes. However, the intracellular localization of “D” and “K” ODN differs, as does their functional activity: “K” type ODN trigger monocytes and B cells to proliferate and secrete IL-6 and IgM, whereas “D” type ODN induce NK cells to produce IFN-γ and monocytes to differentiate into CD83+/CD86+ dendritic cells. In monocytes, these two types of ODN (which differ in backbone composition and CpG motif) cross-inhibit one another's activity. Thus, different types of CpG ODN have distinct and in some cases incompatible effects on the same cells, a finding with important implications for the therapeutic use of these agents.
Recognition and phagocytosis of apoptotic T cells by resident murine tissue macrophages require multiple signal transduction events
Authors: Hu Bin , Punturieri Antonello , Todt Jill , Sonstein Joanne , Polak Timothy , Curtis Jeffrey L
Published: September 2022

Macrophages (Mø) ingest apoptotic cells with unique effects on their cytokine production, but the signaling pathways involved are virtually unknown. Signal transduction in response to recognition of apoptotic thymocytes by resident murine alveolar (AMø) or peritoneal (PMø) Mø was studied by in vitro phagocytosis assay. Phagocytosis was decreased in a dose-dependent and nontoxic manner by inhibiting phosphatidylinosiol 3 kinase (wortmannin and LY294002), protein tyrosine phosphorylation (herbimycin A, genistein, piceatannol, and for AMø only, PP2), and protein kinase C (staurosporine, Gö 6976, and calphostin C). Exposure of Mø to apoptotic or heat-killed thymocytes, but not to viable thymocytes, activated ERK1/2 rapidly, as detected by specific phosphorylation, but did not activate NF-κB or MAP kinases p38 or JNK. Mø phagocytosis of apoptotic T cells requires tyrosine, serine/threonine, and lipid phosphorylation. Mø recognition of apoptotic T cells triggers rapid but limited MAP kinase activation.
Regulation ofNRAMP1gene expression by 1α,25-dihydroxy-vitamin D3 in HL-60 phagocytes
Authors: Roig E A , Richer E , Canonne-Hergaux F , Gros P , Cellier M F M
Published: September 2022

The natural resistance-associated macrophage protein 1 (Nramp1) is a proton-dependent transporter of divalent metals. We studied NRAMP1 expression during HL-60 differentiation induced by VD and VD agonists. NRAMP1 and CD14 gene expression differed in kinetics of induction, mRNA levels and stability, and response to VD combined with PMA, whereas a combination of VD and IFN-γ induced similar up-regulation. NRAMP1 protein expression paralleled the accumulation of mRNA and was localized in the phagosomal membrane after phagocytosis. A promoter construct extending 647 bp upstream of NRAMP1 ATG showed myeloid-specific transcription in transient trasfection assays, which was up-regulated by VD in HL-60. In HL-60 clones stably transfected with this construct, transcription was apparently induced through indirect VD genomic effects, and there was accordance between the levels of reporter transcription and endogenous NRAMP1 mRNA in response to VD but not to IFN-γ. Thus, VD genomic effects stimulate NRAMP1 transcription and protein expression in maturing phagocytes.
Regulation of cyclooxygenase-2 by nitric oxide in activated hepatic macrophages during acute endotoxemia
Authors: Ahmad Nosheen , Chen Li C , Gordon Marion A , Laskin Jeffrey D , Laskin Debra L
Published: September 2022

Eicosanoids generated via cyclooxygenase-2 (COX-2) and nitric oxide produced from inducible nitric oxide synthase (NOSII) have been implicated in endotoxin-induced tissue injury. In the present studies, we characterized COX-2 and NOSII activity in rat hepatic macrophages and their interaction during acute endotoxemia. Kupffer cells from control animals were found to constitutively express COX-2 and NOSII mRNA and protein. Whereas treatment of the cells with lipopolysaccharide (LPS) and/or interferon-γ (IFN-γ) had no major effect on COX-2, NOSII expression increased. Induction of acute endotoxemia resulted in a rapid and transient increase in constitutive COX-2 expression and prostaglandin E2 (PGE2) production by liver macrophages as well as NOSII expression and nitric oxide release. Cells from endotoxin-treated rats were also sensitized to generate more nitric oxide and express increased NOSII in response to LPS and IFN-γ. Inhibition of NOSII with aminoguanidine reduced COX-2 mRNA and protein expression as well as PGE2 production by activated macrophages from endotoxemic, but not control animals. In contrast, SC236, a specific COX-2 inhibitor, had no effect on NOSII mRNA or protein levels or on nitric oxide production by hepatic macrophages, even after endotoxin administration. These data suggest that activation of COX-2 may be important in the pathophysiological response of hepatic macrophages to endotoxin. Moreover, nitric oxide is involved in regulating COX-2 in activated liver macrophages during acute endotoxemia.
Immune escape of tumors: apoptosis resistance and tumor counterattack
Authors: Igney Frederik H , Krammer Peter H
Published: September 2022

Interactions between the immune system and malignant cells play an important role in tumorigenesis. Failure of the immune system to detect and reject transformed cells may lead to cancer development. Tumors use multiple mechanisms to escape from immune-mediated rejection. Many of these mechanisms are now known on a cellular and molecular level. Despite this knowledge, cancer immunotherapy is still not an established treatment in the clinic. This review discusses the immune escape mechanisms used by tumors with an emphasis on mechanisms related to apoptosis.
Centrifugation attenuates the fluid shear response of circulating leukocytes
Authors: Fukuda Shunichi , Schmid-Schönbein Geert W
Published: September 2022

Human leukocytes retract pseudopods in response to physiological fluid shear, a phenomenon that serves to keep circulating leukocytes in a spherical state. We show here that leukocyte fluid shear response is attenuated irreversibly by centrifugation. Inhibition of shear response depends on duration and magnitude of acceleration during centrifugation and time duration after centrifugation. Even after low-speed centrifugation, leukocytes no longer retract pseudopods during shear application. After centrifugation at higher acceleration, leukocytes project pseudopods instead of retracting during shear application, which can be suppressed by a calcium channel blocker. We examined the role of fluid shear response in vivo by reintroduction of centrifuged cells into the rat circulation. Centrifuged leukocytes have a significantly enhanced tendency to migrate into tissue. These observations indicate that centrifugation may irreversibly damage the fluid shear response of leukocytes. It causes an impaired leukocyte behavior after reintroduction into the circulation, suggesting that shear response is a requirement for normal passage of leukocytes through the microcirculation.
Human monocyte scavenger receptors are pattern recognition receptors for (1→3)-β-D-glucans
Authors: Rice Peter J , Kelley Jim L , Kogan Grigorij , Ensley Harry E , Kalbfleisch John H , Browder I William , Williams David L
Published: September 2022

Glucans are cell wall constituents of fungi and bacteria that bind to pattern recognition receptors and modulate innate immunity, in part, by macrophage activation. We used surface plasmon resonance to examine the binding of glucans, differing in fine structure and charge density, to scavenger receptors on membranes isolated from human monocyte U937 cells. Experiments were performed at 25°C using a biosensor surface with immobilized acetylated low density lipoprotein (AcLDL). Inhibition of the binding by polyinosinic acid, but not polycytidylic acid, confirmed the interaction of scavenger receptors. Competition studies showed that there are at least two AcLDL binding sites on human U937 cells. Glucan phosphate interacts with all sites, and the CM-glucans and laminarin interact with a subset of sites. Polymer charge has a dramatic effect on the affinity of glucans with macrophage scavenger receptors. However, it is also clear that human monocyte scavenger receptors recognize the basic glucan structure independent of charge.
Polysaccharide purified fromGanoderma luciduminhibits spontaneous and Fas-mediated apoptosis in human neutrophils through activation of the phosphatidylinositol 3 kinase/Akt signaling pathway
Authors: Hsu Ming-Jen , Lee Shiuh-Sheng , Lin Wan-Wan
Published: September 2022

Ganoderma lucidum has been widely used as a remedy to promote health and longevity in China. The polysaccharide component with a branched (1→3)-β-D-glucan moiety from G. lucidum (PS-G) has shown evidence of enhancement of immune responses and of eliciting anti-tumor effects. In this study, we investigated the effect of PS-G on neutrophil viability, which is manifested by spontaneous apoptosis. Annexin V staining and MTT assays reveal that PS-G is able to inhibit spontaneous and Fas-induced neutrophil apoptosis, and this effect of PS-G is enhanced by the presence of zVAD (a caspase inhibitor) and GM-CSF. The antiapoptotic effect of PS-G is diminished by the presence of wortmannin and LY294002 (two PI-3K inhibitors), but is not altered by PD98059 (a MEK inhibitor). Western blotting indicates the stimulating effect of PS-G on Akt phosphorylation and its inhibition of procaspase 3 degradation, which occurs in neutrophils undergoing spontaneous apoptosis or triggered death by Fas. Taken together, PS-G elicitation of antiapoptotic effects on neutrophils primarily relies on activation of Akt-regulated signaling pathways.
Numerical and functional alterations of circulating γδ T lymphocytes in aged people and centenarians
Authors: Argentati Katy , Re Francesca , Donnini Alessia , Tucci Maria G , Franceschi Claudio , Bartozzi Beatrice , Bernardini Giovanni , Provinciali Mauro
Published: September 2022

The aim of this study was to evaluate the peripheral representation, in vitro expansion, cytokine production, and cytotoxicity of γδ T lymphocytes from 104 healthy subjects ranging in age from 19 to 103 years. We demonstrated that the absolute number of circulating γδ+ T cells was reduced significantly in old people and centenarians in comparison with young subjects as a consequence of the age-related decreased lymphocyte number. The decrease was a result of an age-dependent reduction of Vδ2 T cells, whereas the absolute number of Vδ1 T cells was unaffected by age. As a consequence, the Vδ2/Vδ1 ratio was inverted in old subjects and centenarians. A higher percentage of γδ+ T cells producing tumor necrosis factor α was found in old donors and centenarians, whereas no age-related difference was observed in interferon -γ production. After a 10-day in vitro expansion, a twofold lower expansion index of γδ T cells, and particularly of a Vδ2, but not of a Vδ1 subset, was found in old people and centenarians in comparison with young subjects. The cytotoxicity of sorted γδ T cells was preserved in old people and centenarians. The alteration of γδ T cells could contribute to the age-related derangement of T cell-mediated, adoptive responses and may represent a new characteristic of immunosenescence.
Differential involvement of CD40, CD80, and major histocompatibility complex class I molecules in cytotoxicity induction and interferon-γ production by human natural killer effectors
Authors: Terrazzano Giuseppe , Zanzi Delia , Palomba Carmen , Carbone Ennio , Grimaldi Serena , Pisanti Simona , Fontana Silvia , Zappacosta Serafino , Ruggiero Giuseppina
Published: September 2022

Natural killer (NK) cells are physiologically involved in the immune response against viruses, intracellular bacteria, and parasites as well as against malignant diseases. In addition to the cytotoxic activity, NK lymphocytes mediate a variety of homeostatic effects by producing cytokines. This study focused on the differential role of CD40 and CD80 costimulatory molecules and major histocompatibility complex class I (MHC-I) antigens in the regulation of cytotoxicity and of interferon (IFN)-γ secretion of resting and interleukin (IL)-2-activated human NK cells. CD40 and CD80 molecules were observed to play a specific role in the induction of cytotoxic function but not in IFN-γ production of IL-2-activated NK effectors. In addition, a critical role of CD94-dependent MHC-I recognition for the regulation of IFN-γ production and target lysis was demonstrated. These data provide a possible mechanism underlying functional interactions between NK lymphocytes and CD40/CD80-expressing cell targets, as represented by dendritic cells.
Leptin inhibits the anti-CD3-driven proliferation of peripheral blood T cells but enhances the production of proinflammatory cytokines
Authors: Lord Graham M , Matarese Giuseppe , Howard Jane K , Bloom Stephen R , Lechler Robert I
Published: September 2022

There is increasing evidence that leptin affects immune responses and that in the absence of leptin, immunity is suboptimal. Most data so far indicate that leptin increases proinflammatory immune responses by an effect on T cells and macrophages. Here we show that, under certain circumstances, leptin can inhibit T cell proliferative responses. Separation of the responding T cells into different subpopulations revealed an interesting heterogeneity of cellular behavior in that naïve and memory T cells were differentially affected by leptin. The anti-CD3-driven proliferation of memory T cells was inhibited by leptin, whereas that of naïve T cells was markedly enhanced. Despite the inhibition of proliferation of the memory T cells, their production of interferon-γ was substantially increased. These data show that leptin can inhibit certain immune responses in vitro. However, despite this inhibition of proliferation, the production of proinflammatory cytokines is significantly enhanced by leptin. The findings demonstrated here show further complexity in the actions of leptin on the immune system.
Scavenger receptor cysteine-rich domains 9 and 11 of WC1 are receptors for the WC1 counter receptor
Authors: Ahn J S , Konno A , Gebe J A , Aruffo A , Hamilton M J , Park Y H , Davis W C
Published: September 2022

Workshop cluster 1 (WC1) is a member of the scavenger receptor cysteine-rich (SRCR) superfamily that includes CD5, CD6, CD163, and M160. Bovine WC1 consists of 11 SRCR domains, a unique domain 1, and two homologous 5 SRCR domain cassettes, WC1 domains 2–6 and 7–11. The porcine orthologue of WC1 contains five SRCR domains with a different domain arrangement. Although the function of WC1 is unknown, WC1 is proposed to be an accessory or homing molecule. Thus, identification of cells that express the counter receptor for WC1 (WC1-CR) is critical to understanding the function of WC1. For this reason, we constructed WC1-human immunoglobulin G1 fusion proteins to identify the binding domain of WC1 and cells that express the WC1-CR. Immunohistochemical analysis revealed WC1 domains 9 and 11 bind cells with macrophage and dendritic cell morphology and cells in ellipsoids in the spleen. These results and the finding of conserved signaling motifs in the cytoplasmic tail suggest WC1 may be an accessory molecule.
CpG-DNA stimulates cellular and humoral immunity and promotes Th1 differentiation in aged BALB/c mice
Authors: Maletto Belkys , Rópolo Andrea , Morón Victor , Pistoresi-Palencia María Cristina
Published: September 2022

We examined whether CpG-DNA could be used as adjuvant to induce a T helper cell type-1 (Th1) immunity in aged BALB/c mice that showed a Th2 polarization. Bordetella pertussis and complete Freund's adjuvant (CFA) were used as well. Immunization with ovalbumin (OVA)/CpG-DNA showed that the immunoglobulin G (IgG)2a/IgG1 ratio and OVA-specific T cell response were similar in young and aged mice. OVA/CpG-DNA induced the secretion of interferon-γ (IFN-γ) and absence of interleukin (IL)-5. Similar results were found in mice immunized with OVA/CFA. When mice were immunized with OVA/B. pertussis, we found that the IgG2a/IgG1 ratio and OVA-specific T cell response were lower in aged mice and elicited IFN-γ and IL-5. In vitro CpG-DNA stimulated antigen-presenting cells to display IL-12 and up-regulate the expression of major histocompatibility complex class II and B7-2 on B cells as efficiently in aged as in young mice, but the up-regulation of B7-1 was stronger i aged mice. The findings demonstrate that CpG-DNA is able to induce a young-like Th1 specific immune response in aged mice.
Multiple signals are required for maturation of human dendritic cells mobilized in vivo with Flt3 ligand
Authors: Mosca Paul J , Hobeika Amy C , Colling Kirsten , Clay Timothy M , Thomas Elaine K , Caron Dania , Lyerly H Kim , Morse Michael A
Published: September 2022

The ligand for the receptor tyrosine kinase fms-like tyrosine kinase 3(Flt3L) is a growth factor for hematopoietic progenitors and inducesexpansion of the two distinct lineages of dendritic cells (DC) that have been described in humans. These two lineages, DC1 and DC2, have been described according to their ability to induce naive T celldifferentiation to T helper cell type 1 (Th1) and Th2 effector cells, respectively. The immunoregulatory potential of DC1 and DC2 depends on their state of maturation and activation, which can be mediated byseveral molecules. Because monocyte-derived DC1 produce interleukin-12(IL-12) when stimulated with CD40 ligand (CD40L), we hypothesized thatsimilar results would be obtained with DC1 mobilized by Flt3L. Unexpectedly, we found that immature DC expanded in vivo by Flt3Ltreatment could not be stimulated to produce IL-12 in vitro using CD40Land/or interferon-γ (IFN-γ) alone. Instead, we found that Flt3L-mobilized DC from cancer patients require a sequence of specificsignals for maturation, which included initial treatment withgranulocyte macrophage-colony stimulating factor followed by acombination of maturation signals such as CD40L and IFN-γ. Flt3L-mobilized DC matured in this manner possessed greater Tcell-stimulatory function than nonmatured DC. The ability to generatephenotypically mature, IL-12-producing DC1 from peripheral bloodmononuclear cells mobilized by Flt3L will have important implicationsfor the development of effective cancer immunotherapystrategies.
The mononuclear phagocyte system revisited
Authors: Hume David A , Ross Ian L , Himes S Roy , Sasmono R Tedjo , Wells Christine A , Ravasi Timothy
Published: September 2022

The mononuclear phagocyte system (MPS) was defined as a family of cells comprising bone marrow progenitors, blood monocytes, and tissue macrophages. In this review, we briefly consider markers for cells of this lineage in the mouse, especially the F4/80 surface antigen and the receptor for macrophage colony-stimulating factor. The concept of the MPS is challenged by evidence that there is a separate embryonic phagocyte lineage, the blurring of the boundaries between macrophages and other cells types arising from phenotypic plasticity and transdifferentiation, and evidence of local renewal of tissue macrophage populations as opposed to monocyte recruitment. Nevertheless, there is a unity to cells of the MPS suggested by their location, morphology, and shared markers. We discuss the origins of macrophage heterogeneity and argue that macrophages and antigen-representing dendritic cells are closely related and part of the MPS.
A role for endogenous IL-12 in tumor immunity: IL-12 is required for the acquisition of tumor-migratory capacity by T cells and the development of T cell-accepting capacity in tumor masses
Authors: Uekusa Yasuhiro , Gao Ping , Yamaguchi Nobuya , Tomura Michio , Mukai Takao , Nakajima Chigusa , Iwasaki Masayuki , Takeuchi Noritame , Tsujimura Takahiro , Nakazawa Mitsuhiro , Fujiwara Hiromi , Hamaoka Toshiyuki
Published: September 2022

Interleukin (IL)-12 plays a central role in the initiation and regulation of T cell-mediated immune responses. The present study investigated how IL-12, endogenously produced during tumor vaccination, functions for anti-tumor immune responses. Mice were given anti-IL-12 monoclonal antibody during immunization with attenuated syngeneic tumor cells. Splenic T cells from anti-IL-12-treated immunized mice exhibited comparable levels of tumor-neutralizing activity with those from tumor-immunized mice without anti-IL-12 treatment. When these two groups of mice were directly challenged with viable tumor cells, tumor rejection was induced only in anti-IL-12-untreated mice. T cell infiltration was observed at the site of tumor challenge in these mice, whereas such a T cell infiltration did not occur in anti-IL-12-treated mice. The tumor-migratory capacity was directly assessed by transferring spleen cells from tumor-immunized mice into syngeneic, tumor-bearing recipient mice and by quantitating donor cells migrating into recipients’ tumor masses. T cells from anti-IL-12-treated tumor-immunized mice were found to exhibit a markedly reduced tumor-migratory capacity when compared with that of anti-IL-12-untreated mice. Moreover, the migration of T cells from anti-IL-12-untreated mice to tumor masses prepared in anti-IL-12-treated mice was severely reduced. These results indicate that endogenously produced IL-12 has dual roles in anti-tumor-immune resistance: One is to confer T cells with a tumor-migratory capacity, and the other is to allow tumor masses to develop the capacity to accept tumor-migrating T cells.
Induction of regulatory T cells by the immunomodulating cytokines α-melanocyte-stimulating hormone and transforming growth factor-β2
Authors: Namba Kenichi , Kitaichi Nobuyoshi , Nishida Tomomi , Taylor Andrew W
Published: September 2022

Recently, we have reported that the cytokines α-melanocyte-stimulating hormone (α-MSH) and transforming growth factor-β2 (TGF-β2) work in synergy to induce the activation of regulatory T (Treg) cells. When we used α-MSH and TGF-β2 to generate ocular autoantigen-specific Treg cells and adoptively transferred them into mice susceptible to experimental autoimmune uveoretinitis (EAU), there was suppression in the incidence and severity of EAU. Specificity to a retinal autoantigen was required for the Treg cells to suppress EAU. When stimulated, these Treg cells produced TGF-β1, and their production of interferon-γ, interleukin (IL)-10, and IL-4 was suppressed. Also, the Treg cells are suppressed in their proliferative response. Our results demonstrate that α-MSH with TGF-β2 induce Treg cells that can subdue a tissue-specific autoimmune response. This also promotes the possibility of using these immunomodulating cytokines to purposely induce antigen-specific Treg cells to prevent and suppress autoimmune disease.
Secretion of interleukin-10 or interleukin-12 by LPS-activated dendritic cells is critically dependent on time of stimulus relative to initiation of purified DC culture
Authors: Jiang Hui-Rong , Muckersie Elizabeth , Robertson Marie , Xu Heping , Liversidge Janet , Forrester John V
Published: September 2022

Dendritic cells (DC) are key regulators of adaptive immunity with the potential to induce T cell activation/immunity or T cell suppression/tolerance. DC are themselves induced by “maturation” signals such as bacterial lipopolysaccharide (LPS). We demonstrate here that LPS can stimulate DC to display similar maturation phenotypes but to differentiate toward an interleukin (IL)-10high- or IL-12high-secretor profile depending on the timing of maturation signal induction. Immediate/early administration of LPS induced purified bone marrow-derived DC (BMDC) to differentiate as IL-10highIL-12low-secreting cells, termed early DC (eDC). Conversely, delayed administration of LPS altered the DC cytokine profile to IL-10lowIL-12high, termed later DC (lDC). The presence of IL-4 enhanced the yield and maturation of BMDC but inhibited LPS-induced IL-10 production by eDC. In contrast, interferon-γ reduced the yield of DC but promoted the level of LPS-induced IL-10 production by lDC. Our data provide new evidence that ex vivo manipulation and the cytokine environment regulate DC maturation status and cytokine-secretor phenotype with implications for the control of T cell differentiation and function via DC-based immunotherapeutic strategies.
Acute mast cell-dependent neutrophil recruitment in the skin is mediated by KC and LFA-1: inhibitory mechanisms of dexamethasone
Authors: Schramm Rene , Schaefer Thilo , Menger Michael D , Thorlacius Henrik
Published: September 2022

This study examined adhesive and signaling pathways and anti-inflammatory mechanisms of dexamethasone in acute mast cell-dependent neutrophil recruitment in the skin in mice. Mast cell activation dose- and time-dependently triggered influx of predominately neutrophils and secretion of cytokine-induced neutrophil chemoattractant (KC). Neutralization of KC attenuated neutrophil recruitment upon mast cell activation. Mast cell activation- and KC-induced neutrophil responses were significantly decreased in lymphocyte function-associated antigen-1 (LFA-1)-deficient mice. Dexamethasone inhibited neutrophil accumulation elicited by mast cell activation. It is interesting that dexamethasone significantly reduced the mast cell-dependent secretion of KC, whereas neutrophil recruitment induced by exogenous KC was insensitive to dexamethasone treatment. Thus, KC is a fundamental mediator of neutrophil recruitment in acute mast cell-dependent skin inflammation, and mast cell activation- and KC-induced neutrophil responses are LFA-1-dependent. Moreover, dexamethasone inhibits mast cell-regulated skin infiltration of neutrophils mainly by attenuating KC secretion. Thus, this study elucidates important interactions between chemokines and adhesion molecules in mast cell-dependent neutrophil recruitment and provides new insight into mechanisms of dexamethasone in skin inflammation.
Involvement of CD44 in leukocyte trafficking at the blood-retinal barrier
Authors: Xu Heping , Manivannan Ayyakkannu , Liversidge Janet , Sharp Peter F , Forrester John V , Crane Isabel J
Published: September 2022

In the present study, we investigated the involvement of CD44 in leukocyte trafficking in vivo at the blood-retinal barrier using experimental autoimmune uveoretinitis (EAU) as a model system. Leukocyte trafficking was evaluated using adoptive transfer of calcein-AM (C-AM)-labeled spleen cells harvested from syngeneic mice at prepeak severity of EAU to mice at a similar stage of disease. CD44 and its ligand hyaluronan were up-regulated in the eye during EAU. CD44-positive leukocytes were found sticking in the retinal venules and postcapillary venules but not in the retinal arterioles nor in mesenteric vessels. Preincubation of in vitro C-AM-labeled leukocytes with anti-CD44 monoclonal antibodies (mAb; IM7) or high molecular weight hyaluronic acid (HA) before transfer significantly suppressed leukocyte rolling but not sticking in retinal venules and also reduced cell infiltration in the retinal parenchyma. Administration of the HA-specific enzyme hyaluronidase to mice before cell transfer also reduced leukocyte infiltration, suggesting that CD44-HA interactions are involved in leukocyte recruitment in EAU. This was further supported by the observation that disease severity was reduced by administration of anti-CD44 mAb (IM7) at the early leukocyte-infiltration stage. Further studies also indicated that CD44 activation was associated with increased levels of apoptosis, and this may also be in part responsible for the reduction in disease severity. These findings demonstrate that CD44 is directly involved in leukocyte-endothelial interaction in vivo and influence the trafficking of primed leukocytes to the retina and their overall survival.
Functional cross-talk between cytokine receptors revealed by activating mutations in the extracellular domain of the β-subunit of the GM-CSF receptor
Authors: Blake Timothy J , Jenkins Brendan J , D'Andrea Richard J , Gonda Thomas J
Published: September 2022

Several reports have suggested an interaction between the erythropoietin receptor (EpoR) and the shared signaling subunit (hβc) of the human granulocyte macrophage-colony stimulating factor (GM-CSF), interleukin (IL)-3, and IL-5 receptors, although the functional consequences of this interaction are unclear. We previously showed that in vivo expression of constitutively active extracellular (EC) mutants of hβc induces erythrocytosis and Epo independence of erythroid colony-forming units (CFU-E). This occurs despite an apparent requirement of these mutants for the GM-CSF receptor α-subunit (GMRα), which is not expressed in CFU-E. Here, we show that coexpression of hβc EC mutants and EpoR in BaF-B03 cells, which lack GMRα, results in factor-independent proliferation and JAK2 activation. Mutant receptors that cannot activate JAK2 fail to produce a functional interaction. As there is no detectable phosphorylation of hβc on intracellular tyrosine residues, EpoR displays constitutive tyrosine phosphorylation. These observations suggest that JAK2 activation mediates cross-talk between EC mutants of hβc and EpoR. The implications of these data are discussed as are our findings that activated hβc mutants can functionally interact with certain other cytokine receptors.
Identifying Khizr: On the Paths of Goethe and Iqbal
Authors: Sahota G. S.
Published: September 2022

Through an analysis of the legendary Islamic figure Khizr in the works of Norman O. Brown, Muhammad Iqbal, and Johann Wolfgang Goethe, this essay proposes world literature as a methodology for deriving possible alternatives to existing worlds. By tracing the dialectic of individual and collective selfhood in the figure of Khizr, the author delineates the fault lines that the encounter with this elusive figure portends for bourgeois imperialist regimes of identity. The counterpoint conveyed through the figure of Khizr is one that unveils paths toward practices of self-de-particularization and a symbolism of collective unity. Even in the twenty-first century, the figure of Khizr continues to serve as a potential for reawakening a linkage between Marxism, Islamic mysticism, the poetics of prophecy, the politics of nonidentity, and the philology of cultural contact zones.
Apocalyptic Style and Prophetic Diction
Authors: Tiffany Daniel
Published: September 2022

This short essay makes inquiries and observations about how Norman O. Brown understands the confluence of poetry and prophecy, especially concerning the sorts of language he associates with “prophetic” poetry. Specifically, the essay attempts to identify more clearly the particular features of the diction of prophetic poetry, as Brown conceives it, and how it relates to the expressive substance of his own diction in the innovative critical texts he produced. The diction of Brown's own “prophetic” texts can be at once libertine and bossy, silly and imposing, initiatory and constraining. The alternation in Brown's texts between didactic assertion, libertine refrains, and borrowed scraps of obscure patois, embodies the violent oscillation of prophetic language, as Brown conceives it, which veers between elevated and vernacular registers of language.
The Poetics of Defeat
Authors: Cantor Jay
Published: September 2022

In this version of a talk at the Norman O. Brown conference, Jay Cantor traces the path from Life Against Death into and through Love's Body to outline the liberatory impulse that animated Brown's entire opus. The anti-identitarian character of this liberation found Brown turning on his earlier work—Love's Body was a torpedo aimed at Life Against Death—but never relinquishing his deep commitment, made in full cognizance of the psychic, historical, and political inducements to despair, to new poetics, new politics, and new corporeality.
Reverse End-to-Side Nerve Transfer for Severe Ulnar Nerve Injury: A Western Canadian Multicentre Prospective Nonrandomized Cohort Study
Authors: Curran Matthew W. T. , Olson Jaret L. , Morhart Michael J. , Wu Simon S. Z. , Midha Raj , Berger Michael J. , Chan K. Ming
Published: September 2022

BACKGROUND:

Reverse end-to-side (RETS) nerve transfer has become increasingly popular in patients with severe high ulnar nerve injury, but the reported outcomes have been inconsistent.

OBJECTIVE:

To evaluate the “babysitting effect,” we compared outcomes after anterior interosseous nerve RETS transfer with nerve decompression alone. To evaluate the source of regenerating axons, a group with end-to-end (ETE) transfer was used for comparisons.

METHODS:

Electrophysiology measures were used to quantify the regeneration of anterior interosseous nerve (AIN) and ulnar nerve fibers while functional recovery was evaluated using key pinch and Semmes-Weinstein monofilaments. The subjects were followed postsurgically for 3 years.

RESULTS:

Sixty-two subjects (RETS = 25, ETE = 16, and decompression = 21) from 4 centers in Western Canada were enrolled. All subjects with severe ulnar nerve injury had nerve compression at the elbow except 10 in the ETE group had nerve laceration or traction injury. Postsurgically, no reinnervation from the AIN to the abductor digiti minimi muscles was seen in any of the RETS subjects. Although there was no significant improvement in compound muscle action potentials amplitudes and pressure detection thresholds in the decompression and RETS group, key pinch strength significantly improved in the RETS group (P < .05).

CONCLUSION:

The results from published clinical trials are conflicting in part because crossover regeneration from the donor nerve has never been measured. Unlike those with ETE nerve transfers, we found that there was no crossover regeneration in the RETS group. The extent of reinnervation was also no different from decompression surgery alone. Based on these findings, the justifications for this surgical technique need to be carefully re-evaluated.
Time to Repay or Time to Delay? The Effect of Having More Time before a Payday Loan Is Due
Authors: Carter Susan Payne , Liu Kuan , Skiba Paige Marta , Sydnor Justin
Published: September 2022

We examine the effect of state laws on minimum payday loan durations that give some borrowers an additional pay cycle to repay their initial loan with no other changes to contract terms. Neoclassical models predict this “grace period” would reduce borrowers’ need for costly loan rollovers. However, in reality, borrowers’ repayment behavior with grace periods is very similar to borrowers with shorter loans, merely pushed out a few weeks. Potential explanations include heuristic repayment decisions and naïve present focus. A calibrated model suggests that present-focused borrowers get less than one-half of the benefit from a grace period that time-consistent borrowers would. (JEL G23, G51)
Capital Destruction and Economic Growth: The Effects of Sherman’s March, 1850–1920
Authors: Feigenbaum James , Lee James , Mezzanotti Filippo
Published: September 2022

Using General Sherman’s March through Georgia, South Carolina, and North Carolina during the Civil War, we study the effect of capital destruction on medium- and long-run local economic activity, and the role of financial markets in recovery. We show that the march’s capital destruction led to a large contraction in agricultural investment, farming asset prices, and manufacturing activity compared to neighboring counties. Elements of the decline in agriculture persisted through 1920. Exploiting variation in local access to antebellum credit, we argue that the underdevelopment of financial markets played a role in weakening the recovery. (JEL N21, N51, N52, N61, N91, N92, Q10)
Optimizing the quality of epitaxial Y3Fe5O12 thin films via a two-step post-annealing process
Authors: Xie Yunfei , Yang Yucong , Liu Donghua , Chen Shuyao , Gao Dong , Tan Bi , Gong Tao , Chen Qiuli , Bi Lei , Liu Tao , Deng Longjiang
Published: September 2022

Background: Yttrium iron garnet (Y3Fe5O12, YIG) is a prototype magnetic garnet, which possesses the lowest magnetic damping (α) value so far on the earth among all discovered or synthesized materials. This makes it the best candidate for categories of next generation spintronic devices, possessing great application potentials.

Methods: A two-step annealing method, with first annealing carried out at a relative low temperature and second annealing at a relatively higher temperature, had been used for the first time to crystallize room temperature sputtered amorphous Y3Fe5O12 (YIG) films on Gd3Ga5O12 (GGG) substrates. The crystalline structure, surface morphology, static and dynamic magnetic properties of the obtained YIG films were characterized through X-ray diffraction (XRD), atomic force microscopy (AFM), vibrating sample magnetometer (VSM) and ferromagnetic resonance (FMR) systems, respectively.

Results: It was found that the YIG films obtained via this elaborate annealing method, have a much smoother surface, lower coercivity field, and better dynamic magnetic properties, than that of the YIG films annealed by ordinary one-step approach. Particularly, the ferromagnetic resonance (FMR) linewidth of the best two-step annealed 25 nm YIG film is lower than ~7 Oe at frequency of 10 GHz.

Conclusions: Our work clarifies that this two-step annealing approach can effectively improve the quality of the obtained epitaxial YIG films on GGG substrates.
Progression of chronic kidney disease in patients with hypertension or type 2 diabetes mellitus, can it be delayed?
Authors: Sequira Leena , Prabhu A. Ravindra , S Mayya Shreemathi , Prasad Nagaraju Shankar , S Nayak Baby
Published: September 2022

Background: In India, the number of patients with type II diabetes mellitus in 2006 was 40.9 million and is expected to increase by 2025 to 69.9 million. Annually 1,00,000 new patients get diagnosed with End-Stage Renal Disease and require maintenance dialysis. Diabetes Mellitus and hypertension were the usual triggers of Chronic Kidney Disease (CKD). A structured education program helps in the prevention of diabetes and hypertension related complications. 

Methods: This quasi-experimental study was conducted among 88 participants who had hypertension, diabetes mellitus, or both for five or more years with an objective to find the effect of a Disease Management Program on delaying progression of CKD in patients with hypertension or diabetes mellitus. 

 The baseline data were collected on demographic proforma, serum creatinine, blood pressure, and random blood sugar, and the patients were taught the management of hypertension and diabetes mellitus. In the fourth and the eighth month, blood pressure and blood sugar were reassessed. At one-year blood pressure, blood sugar, and serum creatinine were tested. Baseline and one-year follow-up blood pressure, blood sugar, and estimated Glomerular Filtration Rate were compared. Descriptive statistics and "Wilcoxon signed-rank test" were used to analyze the data.  

 Results: In one year, the mean systolic blood pressure reduced by six mm of Hg and mean blood sugar by 24 mg/dl. The prevalence of CKD stage three and above (< 60 ml/min/m2) was nine (10.22%). The median decline in eGFR was 5 ml/min/m2 (Z= 5.925, P< 0.001). 

Conclusion: The Disease Management Program led to improvements in blood pressure and diabetes control and median progression of CKD was estimated at five ml/min/m2/year.
Chosen Roman and Canon law institutes in Recent Positive Law of the Slovak Republic
Authors: Čunderlík Čerbová Veronika
Published: September 2022

The essence of Senatus Consultum Vellaeanum (hereinafter referred to as the “SCV”) was to forbid intercession of women in case of debt of another person. The art of Roman lawyers to deal with different circumstances of a case can be observed and situations in which protection of a woman is required can be discovered in the individual fragments of the SCV. Canonical equity (aequitas) is a relative idea that calculates with a higher principle of justice or the moderation of law in its application. After analysis of the individual cases, it can be stated that the aim of the SCV was to protect women, who in these cases acted as the weaker party, based on the general experience that in the majority of cases women are emotionally more inclined to help, and act with undue confidence in the ability of the other person to honour his promise; they are unable, especially, to withstand the importunacy of their husbands or friends, and they are generally prone to be influenced by unscrupulous or wellmeant, but unsound advice. Under the influence of emotions and strong life situations, women tend to be naive, very optimistic, and negligent about their own interests. The common purpose of protection – a person emotionally distressed, trustful, negligent about his/her own interests, who has become an entity of a contractual relationship, in which the said person’s rights are grossly disproportionate to the rights arising from the contractual relationship – can be identified even in civil usury, which is part of Slovak positive law. Legal protection against usury is, likewise, an expression of the requirement of justice and good morals in legal relations. Based on the given conclusions, it can be stated that the essence and aim of the SCV and canonical equity has found its representation also in the legal order of the Slovak Republic.