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Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterized by fibroblast proliferation and excess deposition of collagen and other extracellular matrix (ECM) proteins, which lead to distorted lung architecture and function (1). Given that anti-inflammatory or immunosuppressive therapy currently used for IPF does not improve disease progression therapies targeted to blocking the mechanisms of fibrogenesis are needed (1). Although transforming growth factor-β. (TGF-β) functions are crucial in fibrosis (2,3), antagonizing this pathway in bleomycin-induced pulmonary fibrosis, an animal model of IPF, does not prevent fibrosis completely (4-7), indicating an additional pathway also has a key role in fibrogenesis. Given that the loss of cytosolic phospholipase [A.sub.2] [(cPLA.sub.2)] suppresses bleomycin-induced pulmonary fibrosis (8), we examined the roles of prostaglandins using mice lacking each prostoaglandin receptor (9-15). Here we show that loss of prostaglandin F (PGF) receptor (FP) selectively attenuates pulmonary fibrosis while maintaining similar levels of alveolar inflammation and TGF-β. stimulation as compared to wild-type (WT) mice, and that FP deficiency and inhibition of TGF-β. signaling additively decrease fibrosis. Furthermore, [PGF.sub.2α] is abundant in bronchoalveolar lavage fluid (BALF) of subjects with IPF and stimulates proliferation and collagen production of lung fibroblasts via FP, independently of TGF-β These findings show that [PGF.sub.2α]-FP signaling facilitates pulmonary fibrosis independently of TGF-β and suggests this signaling pathway as a therapeutic target for IPF., [cPLA.sub.2] cleaves phospholipids in response to stimuli and releases arachidonic acid, which is metabolized by cyclooxygenase (COX) to produce prostaglandins and by 5-lipoxygenase to produce leukotrienes. Prostaglandins, including [PGD.sub.2], [PGE.sub.2], [...]

Two distinct helper T ([T.sub.H]) subsets, [T.sub.H]1 and [T.sub.H]17, mediate tissue damage and inflammation in animal models of various immune diseases such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel diseases and allergic skin disorders. These experimental findings, and the implication of these [T.sub.H] subsets in human diseases, suggest the need for pharmacological measures to manipulate these [T.sub.H] subsets. Here we show that prostaglandin [E.sub.2] ([PGE.sub.2]) acting on its receptor EP4 on T cells and dendritic cells not only facilitates [T.sub.H]1 cell differentiation but also amplifies interleukin-23--mediated [T.sub.H]17 cell expansion in vitro. Administration of an EP4-selective antagonist in vivo decreases accumulation of both [T.sub.H]1 and [T.sub.H]17 cells in regional lymph nodes and suppresses the disease progression in mice subjected to experimental autoimmune encephalomyelitis or contact hypersensitivity. Thus, [PGE.sub.2]-EP4 signaling promotes immune inflammation through [T.sub.H]1 differentiation and [T.sub.H]17 expansion, and EP4 antagonism may be therapeutically useful for various immune diseases., Autoaggressive [T.sub.H] cells can induce tissue damage and inflammation and are believed to be crucial in the pathogenesis of various immune diseases (1,2). Recent studies suggest that, among the three [...]

Antigen-specific immune responses in the skin are initiated by antigen uptake into Langerhans cells and the subsequent migration of these cells to draining lymph nodes. Although prostaglandin E[sub.2] (PGE[sub.2]) is produced substantially in skin exposed to antigen, its role remains unclear. Here we show that although Langerhans cells express all four PGE receptor subtypes, their migration to regional lymph nodes was decreased only in EP4-deficient (Ptger4[sup.-/-]) mice and in wild-type mice treated with an EP4 antagonist. An EP4 agonist promoted the migration of Langerhans cells, increased their expression of costimulatory molecules and enhanced their ability to stimulate T cells in the mixed lymphocyte reaction in vitro. Contact hypersensitivity to antigen was impaired in Ptger4[sup.-/-] mice and in wild-type mice treated with the EP4 antagonist during sensitization. PGE[sub.2]-EP4 signaling thus facilitates initiation of skin immune responses by promoting the migration and maturation of Langerhans cells., Author(s): Kenji Kabashima [1, 2]; Daiji Sakata [1]; Miyako Nagamachi [1, 2]; Yoshiki Miyachi [2]; Kayo Inaba [3]; Shuh Narumiya (corresponding author) [1] The skin is exposed to multiple antigens [...]

Effective tumor immunotherapy requires physical contact of T cells with cancer cells. However, tumors often constitute a specialized microenvironment that excludes T cells from the vicinity of cancer cells, and its underlying mechanisms are still poorly understood. DOCK2 is a Rac activator critical for migration and activation of lymphocytes. We herein show that cancer-derived cholesterol sulfate (CS), a lipid product of the sulfotransferase SULT2B1b, acts as a DOCK2 inhibitor and prevents tumor infiltration by effector T cells. Using clinical samples, we found that CS was abundantly produced in certain types of human cancers such as colon cancers. Functionally, CS-producing cancer cells exhibited resistance to cancer-specific T-cell transfer and immune checkpoint blockade. Although SULT2B1b is known to sulfate oxysterols and inactivate their tumor-promoting activity, the expression levels of cholesterol hydroxylases, which mediate oxysterol production, are low in SULT2B1b-expressing cancers. Therefore, SULT2B1b inhibition could be a therapeutic strategy to disrupt tumor immune evasion in oxysterol-non-producing cancers. Thus, our findings define a previously unknown mechanism for tumor immune evasion and provide a novel insight into the development of effective immunotherapies. [ABSTRACT FROM AUTHOR]

IL-31 is a major pruritogen associated with atopic dermatitis (AD). Although a specific antibody for IL-31 receptor has been shown to alleviate pruritus in patients with AD, therapeutic approaches to inhibition of IL-31 production remain unexploited. IL-31 production by T H cells critically depends on the transcription factor EPAS1, which mediates IL31 promoter activation in collaboration with SP1. We aimed at developing small-molecule inhibitors that selectively block IL-31 production by T H cells. We generated the reporter cell line that inducibly expressed EPAS1 in the presence of doxycycline to mediate Il31 promoter activation, and we screened 9600 chemical compounds. The selected compounds were further examined by using T H cells from a spontaneous mouse model of AD and T H cells from patients with AD. We have identified 4-(2-(4-isopropylbenzylidene)hydrazineyl)benzoic acid (IPHBA) as an inhibitor of IL 31 induction. Although IPHBA did not affect nonspecific T-cell proliferation, IPHBA inhibited antigen-induced IL-31 production by T H cells from both an AD mouse model and patients with AD without affecting other cytokine production and hypoxic responses. In line with this, itch responses induced by adoptive transfer of IL-31–producing T H cells were attenuated when mice were orally treated with IPHBA. Mechanistically, IPHBA inhibited the association between EPAS1 and SP1, resulting in defective recruitment of both transcription factors to the specific sites of the IL31 promoter. We also determined the structure-activity relationship of IPHBA by synthesizing and analyzing 201 analogous compounds. IPHBA could be a potential drug leading to inhibition of EPAS1-driven IL-31 production. [Display omitted] [ABSTRACT FROM AUTHOR]

Innate lymphoid cells (ILCs) are a family of developmentally related leukocytes that rapidly secrete polarized sets of cytokines to combat infection and promote tissue repair at mucosal barriers. Among them, group 3 ILCs (ILC3s) play an important role in maintenance of the gut homeostasis by producing IL-22, and their development and function critically depend on the transcription factor RORγt. Although recent evidence indicates that RORγt+ ILC3s are reduced in the gut in the absence of the Cdc42 activator DOCK8 (dedicator of cytokinesis 8), the underlying mechanism remains unclear. We found that genetic deletion of Dock8 in RORγt+-lineage cells markedly reduced ILC3s in the lamina propria of the small intestine. By analyzing BrdU incorporation, it was revealed that DOCK8 deficiency did not affect the cell proliferation. Furthermore, when lineage marker-negative (Lin–) α4β7+ CD127+ RORγt– fetal liver cells were cultured with OP9 stromal cells in the presence of stem cell factor (SCF) and IL-7 in vitro , RORγt+ ILC3s normally developed irrespective of DOCK8 expression. However, DOCK8-deficient ILC3s exhibited a severe defect in survival of ILC3s under the condition with or without IL-7. Similar defects were observed when we analyzed Dock8 VAGR mice having mutations in the catalytic center of DOCK8, thereby failing to activate Cdc42. Thus, DOCK8 acts in cell-autonomous manner to control survival of ILC3s in the gut through Cdc42 activation. [ABSTRACT FROM AUTHOR]

A hallmark of humoral immune responses is the production of antibodies. This process involves a complex cascade of molecular and cellular interactions, including recognition of specific antigen by the B cell receptor (BCR), which triggers activation of B cells and differentiation into plasma cells (PCs). Although activation of the small GTPase Rac has been implicated in BCR-mediated antigen recognition, its precise role in humoral immunity and the upstream regulator remain elusive. DOCK2 is a Rac-specific guanine nucleotide exchange factor predominantly expressed in hematopoietic cells. We found that BCR-mediated Rac activation was almost completely lost in DOCK2- deficient B cells, resulting in defects in B cell spreading over the target cell-membrane and sustained growth of BCR microclusters at the interface. When wild-type B cells were stimulated in vitro with anti-IgM F(ab')2 antibody in the presence of IL-4 and IL-5, they differentiated efficiently into PCs. However, BCR-mediated PC differentiation was severely impaired in the case of DOCK2-deficient B cells. Similar results were obtained in vivo when DOCK2-deficient B cells expressing a defined BCR specificity were adoptively transferred into mice and challenged with the cognate antigen. In addition, by generating the conditional knockout mice, we found that DOCK2 expression in B-cell lineage is required to mount antigen-specific IgG antibody. These results highlight important role of the DOCK2-Rac axis in PC differentiation and IgG antibody responses. [ABSTRACT FROM AUTHOR]

[Display omitted] Drug-induced anaphylaxis is triggered by the direct stimulation of mast cells (MCs) via Mas-related G protein–coupled receptor X2 (MRGPRX2; mouse ortholog MRGPRB2). However, the precise mechanism that links MRGPRX2/B2 to MC degranulation is poorly understood. Dedicator of cytokinesis 2 (DOCK2) is a Rac activator predominantly expressed in hematopoietic cells. Although DOCK2 regulates migration and activation of leukocytes, its role in MCs remains unknown. We aimed to elucidate whether—and if so, how—DOCK2 is involved in MRGPRX2/B2-mediated MC degranulation and anaphylaxis. Induction of drug-induced systemic and cutaneous anaphylaxis was compared between wild-type and DOCK2-deficient mice. In addition, genetic or pharmacologic inactivation of DOCK2 in human and murine MCs was used to reveal its role in MRGPRX2/B2-mediated signal transduction and degranulation. Induction of MC degranulation and anaphylaxis by compound 48/80 and ciprofloxacin was severely attenuated in the absence of DOCK2. Although calcium influx and phosphorylation of several signaling molecules were unaffected, MRGPRB2-mediated Rac activation and phosphorylation of p21-activated kinase 1 (PAK1) were impaired in DOCK2-deficient MCs. Similar results were obtained when mice or MCs were treated with small-molecule inhibitors that bind to the catalytic domain of DOCK2 and inhibit Rac activation. DOCK2 regulates MRGPRX2/B2-mediated MC degranulation through Rac activation and PAK1 phosphorylation, thereby indicating that the DOCK2-Rac-PAK1 axis could be a target for preventing drug-induced anaphylaxis. [ABSTRACT FROM AUTHOR]

UV radiation induces systemic immunosuppression. Because nonsteroidal anti-inflammatory drugs suppress UV-induced immunosuppression, prostanoids have been suspected as a crucial mediator of this UV effect. However, the identity of the prostanoid involved and its mechanism of action remain unclear. Here, we addressed this issue by subjecting mice deficient in each prostanoid receptor individually or mice treated with a subtype-specific antagonist to UV irradiation. Mice treated with an antagonist for prostaglandin E receptor subtype 4 (EP4), but not those deficient in other prostanoid receptors, show impaired UV-induced immunosuppression, whereas administration of an EP4 agonist rescues the impairment of the UV-induced immunosuppression in indomethacin-treated mice. The EP4 antagonist treatment suppresses an increase in the number of CD4+/forkhead box P3-positive (Foxp3+) regulatory T cells (Treg cells) in the peripheral lymph nodes (LNs) and dendritic cells expressing DEC205 in the LNs and the skin after UV irradiation. Furthermore, the EP4 antagonist treatment down-regulates UV-induced expression of receptor activator of NF-κB ligand (RANKL) in skin keratinocytes. Finally, administration of anti-RANKL antibody abolishes the restoration of UV-induced immunosuppression by EP4 agonism in indomethacin-treated mice. Thus, prostaglandin E2 (PGE2)-EP4 signaling mediates IN-induced immunosuppression by elevating the number of Treg cells through regulation of RANKL expression in the epidermis. [ABSTRACT FROM AUTHOR]

Three distinct subsets of T helper (Th) cells, Th1, Th2, and Th17, not only contribute to host defense against pathogens, but also cause many types of immune diseases. Differentiation and functions of these T cell subsets are mainly regulated by specific cytokines. Intriguingly, recent studies have revealed that prostanoids including various types of prostaglandins (PGs) and thromboxane (TX) are also involved in these processes. Prostanoids exert their actions by binding to their specific receptors. They include PGD receptor, EP1, EP2, EP3, and EP4 subtypes of PGE receptor, PGF receptor, PGI receptor, and TX receptor. From many in vitro findings, prostanoids, especially PGE2, were traditionally believed to be an immunosuppressant. However, studies using mice deficient in each type or subtype of prostanoid receptors and their selective agonists and antagonists have revealed that prostanoids collaborate with cytokines, and critically regulate T cell proliferation, differentiation and functions. Recent studies have revealed that PGE2 facilitates Th1 cell differentiation and Th17 cell expansion in collaboration with IL-12 and IL-23, respectively, and that these PGE2 actions contribute to development of immune diseases mediated by these Th subsets. Furthermore, studies using the receptor-deficient mice have also revealed that other prostanoids including PGD2 and PGI2 contribute to regulation of immune diseases of the Th2 type such as allergic asthma. These findings shed a new light on the roles of prostanoids in T cell-mediated immunity and immune diseases. © 2010 IUBMB IUBMB Life, 62(8): 591–596, 2010. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterized by fibroblast proliferation and excess deposition of collagen and other extracellular matrix (ECM) proteins, which lead to distorted lung architecture and function. Given that anti-inflammatory or immunosuppressive therapy currently used for IPF does not improve disease progression therapies targeted to blocking the mechanisms of fibrogenesis are needed. Although transforming growth factor-β (TGF-β) functions are crucial in fibrosis, antagonizing this pathway in bleomycin-induced pulmonary fibrosis, an animal model of IPF, does not prevent fibrosis completely, indicating an additional pathway also has a key role in fibrogenesis. Given that the loss of cytosolic phospholipase A2 (cPLA2) suppresses bleomycin-induced pulmonary fibrosis, we examined the roles of prostaglandins using mice lacking each prostoaglandin receptor. Here we show that loss of prostaglandin F (PGF) receptor (FP) selectively attenuates pulmonary fibrosis while maintaining similar levels of alveolar inflammation and TGF-β stimulation as compared to wild-type (WT) mice, and that FP deficiency and inhibition of TGF-β signaling additively decrease fibrosis. Furthermore, PGF2α is abundant in bronchoalveolar lavage fluid (BALF) of subjects with IPF and stimulates proliferation and collagen production of lung fibroblasts via FP, independently of TGF-β. These findings show that PGF2α-FP signaling facilitates pulmonary fibrosis independently of TGF-β and suggests this signaling pathway as a therapeutic target for IPF. [ABSTRACT FROM AUTHOR]

Two distinct helper T (TH) subsets, TH1 and TH17, mediate tissue damage and inflammation in animal models of various immune diseases such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel diseases and allergic skin disorders. These experimental findings, and the implication of these TH subsets in human diseases, suggest the need for pharmacological measures to manipulate these TH subsets. Here we show that prostaglandin E2 (PGE2) acting on its receptor EP4 on T cells and dendritic cells not only facilitates TH1 cell differentiation but also amplifies interleukin-23–mediated TH17 cell expansion in vitro. Administration of an EP4-selective antagonist in vivo decreases accumulation of both TH1 and TH17 cells in regional lymph nodes and suppresses the disease progression in mice subjected to experimental autoimmune encephalomyelitis or contact hypersensitivity. Thus, PGE2-EP4 signaling promotes immune inflammation through TH1 differentiation and TH17 expansion, and EP4 antagonism may be therapeutically useful for various immune diseases. [ABSTRACT FROM AUTHOR]

Physical interaction of T cells and dendritic cells (DCs) is essential for T cell proliferation and differentiation, but it has been unclear how this interaction is regulated physiologically. Here we show that DCs produce thromboxane A[SUB2] (TXA[SUB2]), whereas naive T cells express the thromboxane receptor (TP).In vitro, a TP agonist enhances random cell movement (chemokinesis) of naive but not memory T cells, impairs DC-T cell adhesion, and inhibits DC-dependent proliferation of T cells.In vivo, immune responses to foreign antigens are enhanced in TP-deficient mice, which also develop marked lymphadenopathy with age. Similar immune responses were seen in wild-type mice treated with a TP antagonist during the sensitization period. Thus, TXA[SUB2]-TP signaling modulates acquired immunity by negatively regulating DC-T cell interactions. [ABSTRACT FROM AUTHOR]

Antigen-specific immune responses in the skin are initiated by antigen uptake into Langerhans cells and the subsequent migration of these cells to draining lymph nodes. Although prostaglandin E[SUB2] (PGE[SUB2]) is produced substantially in skin exposed to antigen, its role remains unclear. Here we show that although Langerhans cells express all four PGE receptor subtypes, their migration to regional lymph nodes was decreased only in EP4-deficient (Ptger4[SUP-/-]) mice and in wild-type mice treated with an EP4 antagonist. An EP4 agonist promoted the migration of Langerhans cells, increased their expression of costimulatory molecules and enhanced their ability to stimulate T cells in the mixed lymphocyte reaction in vitro. Contact hypersensitivity to antigen was impaired in Ptger4[SUP-/-] mice and in wild-type mice treated with the EP4 antagonist during sensitization. PGE[SUB2]-EP4 signaling thus facilitates initiation of skin immune responses by promoting the migration and maturation of Langerhans cells. [ABSTRACT FROM AUTHOR]

Intestinal microfold cells (M cells) in Peyer's patches are a special subset of epithelial cells that initiate mucosal immune responses through uptake of luminal antigens. Although the cytokine receptor activator of nuclear factor-κB ligand (RANKL) expressed on mesenchymal cells triggers differentiation into M cells, other environmental cues remain unknown. Here, we show that the metastasis-promoting protein S100A4 is required for development of mature M cells. S100A4-producing cells are a heterogenous cell population including lysozyme-expressing dendritic cells and group 3 innate lymphoid cells. We found that in the absence of DOCK8, a Cdc42 activator critical for interstitial leukocyte migration, S100A4-producing cells are reduced in the subepithelial dome, resulting in a maturation defect of M cells. While S100A4 promotes differentiation into mature M cells in organoid culture, genetic inactivation of S100a4 prevents the development of mature M cells in mice. Thus, S100A4 is a key environmental cue that regulates M cell differentiation in collaboration with RANKL. • DOCK8 plays a key role in the development of mature M cells in Peyer's patches • DOCK8 controls the localization of S100A4-producing cells in the subepithelial dome • S100A4 protein promotes M cell maturation in organoid culture • Deficiency of S100A4 prevents the development of mature M cells in mice Kunimura et al. find that in the absence of DOCK8, S100A4-producing cells are reduced in the subepithelial dome, resulting in a maturation defect of M cells in Peyer's patches. In vitro and in vivo studies demonstrate that S100A4 protein is a key environmental factor that promotes M cell maturation. [ABSTRACT FROM AUTHOR]

Effective cancer immunotherapy requires physical contact of T cells with cancer cells. However, tumors often constitute special microenvironments that exclude T cells and resist immunotherapy. Cholesterol sulfate (CS) is a product of sulfotransferase SULT2B1b and acts as an endogenous inhibitor of DOCK2, a Rac activator essential for migration and activation of lymphocytes. We have recently shown that cancer-derived CS prevents tumor infiltration by effector T cells. Therefore, SULT2B1b may be a therapeutic target to dampen CS-mediated immune evasion. Here, we identified 3β-hydroxy-5-cholenoic acid (3β-OH-5-Chln) as a cell-active inhibitor of SULT2B1b. 3β-OH-5-Chln inhibited the cholesterol sulfotransferase activity of SULT2B1b in vitro and suppressed CS production from cancer cells expressing SULT2B1b. In vivo administration of 3β-OH-5-Chln locally reduced CS level in murine CS-producing tumors and increased infiltration of CD8+ T cells. When combined with immune checkpoint blockade or antigen-specific T cell transfer, 3β-OH-5-Chln suppressed the growth of CS-producing tumors. These results demonstrate that pharmacological inhibition of SULT2B1b can promote antitumor immunity through suppressing CS-mediated T cell exclusion. • 3β-hydroxy-5-cholenoic acid is identified as a cell-active inhibitor of SULT2B1b • 3β-OH-5-Chln can promote infiltration of effector T cells into CS-producing tumors. • Pharmacological inhibition of SULT2B1b dampens CS-mediated T cell exclusion. • Targeting SULT2B1b can be an effective approach to promote antitumor immunity. [ABSTRACT FROM AUTHOR]

Dedicator of cytokinesis 8 (DOCK8) is a guanine nucleotide exchange factor (GEF) for Cdc42. In humans, homozygous or compound heterozygous deletions in DOCK8 cause a combined immunodeficiency characterized by various allergic diseases including food allergies. Although group 2 innate lymphoid cells (ILC2s) contribute to the development of allergic inflammation by producing interleukin (IL)-5 and IL-13, the role of ILC2s in DOCK8 deficiency has not been fully explored. With the use of cytometry by time-of-flight (CyTOF), we performed high-dimensional phenotyping of intestinal immune cells and found that DOCK8-deficient (Dock8 −/−) mice exhibited expansion of ILC2s and other leukocytes associated with type 2 immunity in the small intestine. Moreover, IL-5– and IL-13–producing cells markedly increased in Dock8 −/− mice, and the majority of them were lineage-negative cells, most likely ILC2s. Intestinal ILC2s expanded when DOCK8 expression was selectively deleted in hematopoietic cells. Importantly, intestinal ILC2 expansion was also observed in Dock8 VAGR mice having mutations in the catalytic center of DOCK8, thereby failing to activate Cdc42. Our findings indicate that DOCK8 is a negative regulator of intestinal ILC2s to inhibit their expansion via Cdc42 activation, and that deletion of DOCK8 causes a skewing to type 2 immunity in the gut. • DOCK8 deficiency increases ILC2s and other leukocytes involved in type 2 immunity. • DOCK8 expression in hematopoietic cells is required to inhibit ILC2 expansion. • DOCK8 inhibits ILC2 expansion in the gut via Cdc42 activation. [ABSTRACT FROM AUTHOR]

Rac1 is a member of the Rho family of small GTPases that regulates cytoskeletal reorganization, membrane polarization, cell migration and proliferation. Recently, a self-activating mutation of Rac1, Rac1 P29S , has been identified as a recurrent somatic mutation frequently found in sun-exposed melanomas, which possesses increased inherent GDP/GTP exchange activity and cell transforming ability. However, the role of cellular Rac1-interacting proteins in the transforming potential of Rac1 P29S remains unclear. We found that the catalytic domain of DOCK1, a Rac-specific guanine nucleotide exchange factor (GEF) implicated in malignancy of a variety of cancers, can greatly accelerate the GDP/GTP exchange of Rac1 P29S . Enforced expression of Rac1 P29S induced matrix invasion and macropinocytosis in wild-type (WT) mouse embryonic fibroblasts (MEFs), but not in DOCK1-deficient MEFs. Consistently, a selective inhibitor of DOCK1 that blocks its GEF function suppressed the invasion and macropinocytosis in WT MEFs expressing Rac1 P29S . Human melanoma IGR-1 and breast cancer MDA-MB-157 cells harbor Rac1 P29S mutation and express DOCK1 endogenously. Genetic inactivation and pharmacological inhibition of DOCK1 suppressed their invasion and macropinocytosis. Taken together, these results indicate that DOCK1 is a critical regulator of the malignant phenotypes induced by Rac1 P29S , and suggest that targeting DOCK1 might be an effective approach to treat cancers associated with Rac1 P29S mutation. [ABSTRACT FROM AUTHOR]