N. Kamada

发表

Role of the gut microbiota in immunity and inflammatory disease

Sang-Uk Seo, Gabriel Núñez, Grace Y Chen, 2013, Nature Reviews Immunology.

Quantitative proteomics identifies STEAP4 as a critical regulator of mitochondrial dysfunction linking inflammation and colon cancer

B. Győrffy, J. Greenson, K. Hardiman, 2017, Proceedings of the National Academy of Sciences.

IL-22 controls iron-dependent nutritional immunity against systemic bacterial infections

G. Núñez, E. Tolosano, Yun-Gi Kim, 2017, Science Immunology.

The regenerating family member 3 β instigates IL-17A-mediated neutrophil recruitment downstream of NOD1/2 signalling for controlling colonisation resistance independently of microbiota community structure

B. Ryffel, M. Chamaillard, H. Sokol, 2018, Gut.

Control of pathogens and pathobionts by the gut microbiota

Gabriel Núñez, Grace Y Chen, G. Núñez, 2013, Nature Immunology.

TL1A produced by lamina propria macrophages induces Th1 and Th17 immune responses in cooperation with IL‐23 in patients with Crohn's disease

T. Hibi, T. Kanai, T. Takayama, 2010, Inflammatory bowel diseases.

Aim2-Mediated/IFN-β-Independent Regulation of Gastric Metaplastic Lesions via CD8+ T Cells.

Henry R. Haley, G. Luker, M. Cascalho, 2020, JCI insight.

Expression and regulation of proton‐coupled oligopeptide transporters in colonic tissue and immune cells of mice

Ping Li, N. Kamada, Huidi Jiang, 2018, Biochemical pharmacology.

Periodontal connection with intestinal inflammation: Microbiological and immunological mechanisms

N. Kamada, S. Kitamoto, Sho Kitamoto, 2022, Periodontology 2000.

Th1/Th17 immune response is induced by mesenteric lymph node dendritic cells in Crohn's disease.

T. Hibi, Toshiro Sato, N. Kamada, 2009, Gastroenterology.

A specific gene-microbe interaction drives the development of Crohn’s disease–like colitis in mice

G. Núñez, N. Inohara, A. Nusrat, 2019, Science Immunology.

Maternal gut microbiome–induced IgG regulates neonatal gut microbiome and immunity

G. Núñez, N. Inohara, M. Y. Zeng, 2022, Science Immunology.

Interleukin-22 regulates the complement system to promote resistance against pathobionts after pathogen-induced intestinal damage.

G. Núñez, N. Inohara, M. Hasegawa, 2014, Immunity.

Antigen-presenting Ability Lamina Propria Exhibit Potent Macrophages in Intestinal + Human Cd14

T. Hibi, T. Kanai, T. Takayama, 2022 .

Natural Killer Cells in he Intestinal Mucosa of Patients With Crohn ’ s Disease

T. Hibi, T. Kanai, S. Okamoto, 2022 .

OXPHOS Promotes Apoptotic Resistance and Persistence in TH17 cells

C. Lyssiotis, Brian Magnuson, W. Zou, 2021, bioRxiv.

Generation of systemic antitumour immunity via the in situ modulation of the gut microbiome by an orally administered inulin gel

Jin Heon Jeon, Grace Y Chen, Olamide Animasahun, 2021, Nature Biomedical Engineering.

Gut microbiota-mediated generation of saturated fatty acids elicits inflammation in the liver in murine high-fat diet-induced steatohepatitis

M. Kimura, H. Saito, T. Kanai, 2017, BMC Gastroenterology.

Indoleamine 2,3-Dioxygenase 1, Increased in Human Gastric Pre-Neoplasia, Promotes Inflammation and Metaplasia in Mice and Is Associated With Type II Hypersensitivity/Autoimmunity.

A. Bass, R. Bowlby, W. Leung, 2018, Gastroenterology.

The Butyrate-Producing Bacterium Clostridium butyricum Suppresses Clostridioides difficile Infection via Neutrophil- and Antimicrobial Cytokine–Dependent but GPR43/109a-Independent Mechanisms

N. Kamada, H. Nagao-Kitamoto, S. Kitamoto, 2021, The Journal of Immunology.

Humoral Immunity in the Gut Selectively Targets Phenotypically Virulent Attaching-and-Effacing Bacteria for Intraluminal Elimination.

G. Núñez, M. Cascalho, Yun-Gi Kim, 2015, Cell host & microbe.

Inhibition of neutrophil elastase prevents the development of murine dextran sulfate sodium-induced colitis

H. Ogata, T. Hibi, Toshiro Sato, 2006, Journal of Gastroenterology.

Intracellular bacteria recognition contributes to maximal interleukin (IL)‐12 production by IL‐10‐deficient macrophages

T. Kanai, K. Matsuoka, N. Kamada, 2011, Clinical and experimental immunology.

Tetomilast suppressed production of proinflammatory cytokines from human monocytes and ameliorated chronic colitis in IL‐10‐deficient mice

T. Hibi, S. Okamoto, T. Hisamatsu, 2008, Inflammatory bowel diseases.

Nonpathogenic Escherichia coli Strain Nissle 1917 Inhibits Signal Transduction in Intestinal Epithelial Cells

H. Ogata, T. Hibi, S. Okamoto, 2007, Infection and Immunity.

Regional Control of Regulatory Immune Cells in the Intestine

J. Kao, N. Kamada, A. Hayashi, 2018, Current Pathobiology Reports.

Competition between colitogenic Th1 and Th17 cells contributes to the amelioration of colitis

H. Ogata, T. Hibi, T. Kanai, 2010, European journal of immunology.

Exclusive increase of CX3CR1+CD28−CD4+ T cells in inflammatory bowel disease and their recruitment as intraepithelial lymphocytes

T. Hibi, H. Goto, T. Imai, 2007, Inflammatory bowel diseases.

Bile acid metabolism regulated by the gut microbiota promotes non-alcoholic steatohepatitis-associated hepatocellular carcinoma in mice

H. Saito, Mitsuhiro Watanabe, Yoshimasa Saito, 2018, Oncotarget.

A complex microworld in the gut: Harnessing pathogen-commensal relations

Grace Y Chen, G. Núñez, N. Kamada, 2012, Nature Medicine.

The ever-expanding function of NOD2: autophagy, viral recognition, and T cell activation.

N. Warner, G. Núñez, Yun-Gi Kim, 2011, Trends in immunology.

Protective Role of Commensals against Clostridium difficile Infection via an IL-1β–Mediated Positive-Feedback Loop

G. Núñez, N. Inohara, M. Hasegawa, 2012, The Journal of Immunology.

Commensal Lactobacillus Controls Immune Tolerance during Acute Liver Injury in Mice.

M. Hattori, H. Saito, H. Ebinuma, 2017, Cell reports.

Monocytes via Inflammatory Typhimurium Salmonella Promotes Systemic Dissemination of Specific MyD 88 Signaling − Mesenchymal Cell

G. Núñez, N. Inohara, M. Y. Zeng, 2017 .

Macrophages and Dendritic Cells Emerge in the Liver during Intestinal Inflammation and Predispose the Liver to Inflammation

T. Hibi, A. Yoshimura, Toshiro Sato, 2014, PloS one.

Nucleotide-Binding Oligomerization Domain 1 Mediates Recognition of Clostridium difficile and Induces Neutrophil Recruitment and Protection against the Pathogen

G. Núñez, Yun-Gi Kim, N. Inohara, 2011, The Journal of Immunology.

and Protection against the Pathogen and Induces Neutrophil Recruitment difficile Clostridium 1 Mediates Recognition of Nucleotide-Binding Oligomerization Domain

G. Núñez, Yun-Gi Kim, N. Inohara, 2011 .

IL-10 produced by macrophages regulates epithelial integrity in the small intestine

K. Honda, K. Atarashi, A. Nusrat, 2019, Scientific Reports.

Nonpathogenic Escherichia coli Strain Nissle1917 Prevents Murine Acute and Chronic Colitis

T. Hibi, Toshiro Sato, Tatsuo Suzuki, 2005, Inflammatory bowel diseases.

Multiple effects of dendritic cell depletion on murine norovirus infection.

G. Núñez, C. Wobus, N. Kamada, 2013, The Journal of general virology.

Microbiota-induced IL-1β, but not IL-6, is critical for the development of steady-state TH17 cells in the intestine

G. Núñez, Yun-Gi Kim, Michael H. Shaw, 2012, The Journal of experimental medicine.

A novel apoptosis-inducing monoclonal antibody (anti-LHK) against a cell surface antigen on colon cancer cells

H. Ogata, T. Hibi, T. Mimori, 2005, Journal of Gastroenterology.

Both exogenous commensal and endogenous self antigens stimulate T cell proliferation under lymphopenic conditions.

W. Paul, G. Núñez, G. Foucras, 2012, Cellular immunology.

TACI deficiency enhances antibody avidity and clearance of an intestinal pathogen.

A. E. Sousa, J. Platt, R. Bram, 2014, The Journal of clinical investigation.

Increased Expression of DUOX2 Is an Epithelial Response to Mucosal Dysbiosis Required for Immune Homeostasis in Mouse Intestine.

J. Merchant, A. Shreiner, J. Kao, 2015, Gastroenterology.

The tuning of the gut nervous system by commensal microbiota.

J. Kao, N. Kamada, 2013, Gastroenterology.

Distinct Commensals Induce Interleukin-1β via NLRP3 Inflammasome in Inflammatory Monocytes to Promote Intestinal Inflammation in Response to Injury.

G. Núñez, H. Mobley, Yun-Gi Kim, 2015, Immunity.

OXPHOS promotes apoptotic resistance and cellular persistence in TH17 cells in the periphery and tumor microenvironment

S. Carty, C. Lyssiotis, Jason Lin, 2022, Science Immunology.

Tryptophan Catabolism Restricts IFN-γ–Expressing Neutrophils and Clostridium difficile Immunopathology

R. Lutter, V. Young, G. Huffnagle, 2014, The Journal of Immunology.

Dietary L-serine confers a competitive fitness advantage to Enterobacteriaceae in the inflamed gut

A. Hirayama, N. Barnich, C. Alteri, 2019, Nature Microbiology.

Oral nanomedicine for modulating immunity, intestinal barrier functions, and gut microbiome.

J. Moon, N. Kamada, Yonghyun Lee, 2021, Advanced drug delivery reviews.

Regulation of virulence: the rise and fall of gastrointestinal pathogens

P. Kuffa, N. Kamada, H. Nagao-Kitamoto, 2016, Journal of Gastroenterology.

Intestinal Dysbiosis and Biotin Deprivation Induce Alopecia through Overgrowth of Lactobacillus murinus in Mice.

M. Hattori, Toshiro Sato, T. Kanai, 2017, Cell reports.

NLRC4-driven interleukin-1β production discriminates between pathogenic and commensal bacteria and promotes host intestinal defense

G. Núñez, Shiho Suzuki, Yun-Gi Kim, 2012, Nature Immunology.

A potential pathogenic association between periodontal disease and Crohn’s disease

W. Giannobile, Hidekazu Suzuki, K. Hozumi, 2021, JCI insight.

Homeostatic (IL-7) and effector (IL-17) cytokines as distinct but complementary target for an optimal therapeutic strategy in inflammatory bowel disease

T. Hibi, T. Kanai, Mamoru Watanabe, 2009, Current opinion in gastroenterology.

Diet-dependent, microbiota-independent regulation of IL-10-producing lamina propria macrophages in the small intestine

K. Honda, Yongjia Feng, D. Teitelbaum, 2016, Scientific Reports.

A Dietary Fiber-Deprived Gut Microbiota Degrades the Colonic Mucus Barrier and Enhances Pathogen Susceptibility

P. Wilmes, B. Henrissat, G. Núñez, 2016, Cell.

Imbalance of NKp44(+)NKp46(-) and NKp44(-)NKp46(+) natural killer cells in the intestinal mucosa of patients with Crohn's disease.

T. Hibi, T. Kanai, T. Takayama, 2010, Gastroenterology.

IL23 differentially regulates the Th1/Th17 balance in ulcerative colitis and Crohn’s disease

T. Hibi, K. Isobe, S. Okamoto, 2008, Gut.

Microbiota-Derived Lactate Accelerates Intestinal Stem-Cell-Mediated Epithelial Development.

K. S. Kim, Yong-soo Lee, S. Hwang, 2018, Cell host & microbe.

The Intermucosal Connection between the Mouth and Gut in Commensal Pathobiont-Driven Colitis

W. Giannobile, N. Inohara, A. Nusrat, 2020, Cell.

The Innate Immune System: A Trigger for Many Chronic Inflammatory Intestinal Diseases

G. Rogler, N. Kamada, 2016, Inflammatory Intestinal Diseases.

NFIL3 Is a Regulator of IL-12 p40 in Macrophages and Mucosal Immunity

T. Hibi, S. Smale, S. Plevy, 2011, The Journal of Immunology.

Unique CD14 intestinal macrophages contribute to the pathogenesis of Crohn disease via IL-23/IFN-gamma axis.

T. Hibi, Toshiro Sato, K. Akagawa, 2008, Journal of Clinical Investigation.

Nod2-mediated recognition of the microbiota is critical for mucosal adjuvant activity of cholera toxin

P. Rosenstiel, M. Chamaillard, D. Philpott, 2016, Nature Medicine.

Intestinal macrophages arising from CCR2+ monocytes control pathogen infection by activating innate lymphoid cells

G. Núñez, Yun-Gi Kim, P. Kuffa, 2015, Nature Communications.

The Nod2 sensor promotes intestinal pathogen eradication via the chemokine CCL2-dependent recruitment of inflammatory monocytes.

N. Warner, G. Núñez, Yun-Gi Kim, 2011, Immunity.

A single strain of Clostridium butyricum induces intestinal IL-10-producing macrophages to suppress acute experimental colitis in mice.

T. Hibi, A. Yoshimura, Toshiro Sato, 2013, Cell host & microbe.

Hyaluronic acid-bilirubin nanomedicine for targeted modulation of dysregulated intestinal barrier, microbiome, and immune responses in colitis.

J. Moon, S. Jon, N. Kamada, 2019, Nature Materials.

Gut pathobionts underlie intestinal barrier dysfunction and liver T helper 17 cell immune response in primary sclerosing cholangitis

M. Hattori, K. Honda, A. Yoshimura, 2019, Nature Microbiology.

Th17 Cell Induction by Adhesion of Microbes to Intestinal Epithelial Cells

M. Hattori, K. Honda, H. Morita, 2015, Cell.

DUOX2 variants associate with preclinical disturbances in microbiota-immune homeostasis and increased inflammatory bowel disease risk.

A. Magis, G. Omenn, M. Conomos, 2021, The Journal of clinical investigation.

Flagellin-mediated activation of IL-33-ST2 signaling by a pathobiont promotes intestinal fibrosis

P. Higgins, N. Barnich, P. Kuffa, 2019, Mucosal Immunology.

Cross-talk Between ROR&ggr;t+ Innate Lymphoid Cells and Intestinal Macrophages Induces Mucosal IL-22 Production in Crohn's Disease

Toshiro Sato, T. Kanai, M. Matano, 2014, Inflammatory bowel diseases.

Host-microbial Cross-talk in Inflammatory Bowel Disease

N. Kamada, H. Nagao-Kitamoto, Hiroko Nagao-Kitamoto, 2017, Immune network.

TGR5 signalling inhibits the production of pro-inflammatory cytokines by in vitro differentiated inflammatory and intestinal macrophages in Crohn's disease

T. Hibi, Toshiro Sato, T. Kanai, 2013, Immunology.

Activated hepatic stellate cells mediate the differentiation of macrophages

T. Hibi, T. Kanai, M. Adachi, 2013, Hepatology research : the official journal of the Japan Society of Hepatology.

Pathogenic role of the gut microbiota in gastrointestinal diseases

P. Kuffa, N. Kamada, H. Nagao-Kitamoto, 2016, Intestinal research.

CD4+ tissue-resident memory T-cells expand and are a major source of mucosal tumor necrosis factor α in active Crohn's Disease.

P. Higgins, W. Zou, J. Kao, 2019, Journal of Crohn's & colitis.

Contribution of the Gut Microbiota to Intestinal Fibrosis in Crohn's Disease

N. Kamada, D. Watanabe, 2022, Frontiers in Medicine.

Functional Characterization of Inflammatory Bowel Disease–Associated Gut Dysbiosis in Gnotobiotic Mice

P. Higgins, A. Hirayama, V. Young, 2016, Cellular and molecular gastroenterology and hepatology.

Regulation of the immune system by the resident intestinal bacteria.

G. Núñez, N. Kamada, 2014, Gastroenterology.

Role of the Gut Microbiota in the Development and Function of Lymphoid Cells

G. Núñez, N. Kamada, 2013, The Journal of Immunology.

Monocyte Chemoattractant Protein-1 Contributes to Gut Homeostasis and Intestinal Inflammation by Composition of IL-10–Producing Regulatory Macrophage Subset

T. Hibi, T. Kanai, Y. Takada, 2010, The Journal of Immunology.

The Role of Dietary Nutrients in Inflammatory Bowel Disease

N. Kamada, Kohei Sugihara, Tina L. Morhardt, 2019, Front. Immunol..

Fecal microbiota transplantation prevents Candida albicans from colonizing the gastrointestinal tract

M. Yoneyama, N. Kamada, T. Yaguchi, 2019, Microbiology and immunology.

Regulated Virulence Controls the Ability of a Pathogen to Compete with the Gut Microbiota

G. Núñez, Yun-Gi Kim, J. Puente, 2012, Science.

Abnormally Differentiated Subsets of Intestinal Macrophage Play a Key Role in Th1-Dominant Chronic Colitis through Excess Production of IL-12 and IL-23 in Response to Bacteria1

T. Hibi, Toshiro Sato, K. Akagawa, 2005, The Journal of Immunology.

Response to Bacteria Excess Production of IL-12 and IL-23 in Th 1-Dominant Chronic Colitis through Intestinal Macrophage Play a Key Role in Abnormally Differentiated Subsets of

T. Hibi, Toshiro Sato, K. Akagawa, 2005 .

Inflammatory bowel disease and carcinogenesis

N. Kamada, H. Nagao-Kitamoto, S. Kitamoto, 2022, Cancer and Metastasis Reviews.

Subset Producing Regulatory Macrophage - IL-10 Intestinal Inflammation by Composition of Contributes to Gut Homeostasis and Monocyte Chemoattractant Protein-1

T. Kanai, Y. Takada, T. Takayama, 2010 .

Mucolytic bacteria license pathobionts to acquire host-derived nutrients during dietary nutrient restriction

T. Schmidt, N. Barnich, C. Alteri, 2022, bioRxiv.

The Bacterial Connection between the Oral Cavity and the Gut Diseases

T. Schmidt, N. Kamada, H. Nagao-Kitamoto, 2020, Journal of dental research.

Microbial adaptation to the healthy and inflamed gut environments

N. Kamada, S. Kitamoto, Yijie Guo, 2020, Gut microbes.

Diet–Microbiota Interactions in Inflammatory Bowel Disease

N. Kamada, Kohei Sugihara, 2021, Nutrients.

The pathogenic oral–gut–liver axis: new understandings and clinical implications

N. Kamada, Jin Imai, S. Kitamoto, 2021, Expert review of clinical immunology.

Bile acids induce monocyte differentiation toward interleukin‐12 hypo‐producing dendritic cells via a TGR5‐dependent pathway

T. Hibi, T. Kanai, H. Itoh, 2012, Immunology.

Human CD14+ Macrophages in Intestinal Lamina Propria Exhibit Potent Antigen-Presenting Ability1

Tetsuro Takayama, Toshifumi Hibi, Takanori Kanai, 2009, The Journal of Immunology.

Interaction between the inflammasome and commensal microorganisms in gastrointestinal health and disease

Daisuke Watanabe, N. Kamada, Yijie Guo, 2021, EMBO molecular medicine.

Retinoic acid contributes to the induction of IL‐12‐hypoproducing dendritic cells

T. Hibi, S. Okamoto, T. Hisamatsu, 2009, Inflammatory bowel diseases.

Distinct Commensals Indu ce Interleukin-1 b via NLRP 3 Inflammasome in Inflammatory Monocytes to Promote Intestinal Inflammation in Response to Injury Graphical Abstract Highlights

G. Núñez, H. Mobley, Yun-Gi Kim, 2022 .

Dietary histidine ameliorates murine colitis by inhibition of proinflammatory cytokine production from macrophages.

T. Hibi, H. Ohtsu, K. Shimbo, 2009, Gastroenterology.

IL-10 produced by macrophages regulates epithelial integrity in the small intestine

K. Honda, K. Atarashi, A. Nusrat, 2019, Scientific Reports.

Imbalance in intestinal microflora constitution could be involved in the pathogenesis of inflammatory bowel disease.

H. Ogata, T. Hibi, H. Higuchi, 2008, International journal of medical microbiology : IJMM.

Adherent-invasive E. coli – induced specific IgA limits pathobiont localization to the epithelial niche in the gut

N. Barnich, K. Hozumi, Masashi Ohno, 2023, Frontiers in Microbiology.

Lamina propria c-kit+ immune precursors reside in human adult intestine and differentiate into natural killer cells.

T. Hibi, Toshiro Sato, F. Kinjo, 2007, Gastroenterology.

CD14+ intestinal macrophages contribute to the pathogenesis of Crohnʼs disease via IL-23/IFN-gamma axis.: O-0028.

T. Hibi, T. Takayama, S. Okamoto, 2008 .

CD115− monocytic myeloid-derived suppressor cells are precursors of OLFM4high polymorphonuclear myeloid-derived suppressor cells

S. Seong, N. Kamada, Sang-Uk Seo, 2023, Communications Biology.

Establishment of novel prediction system of intestinal absorption in humans using human intestinal tissues.

T. Hibi, Toshiro Sato, T. Kanai, 2013, Journal of pharmaceutical sciences.

TNFRSF13B polymorphisms counter microbial adaptation to enteric IgA

Peter L. Freddolino, R. Geha, J. Platt, 2021, JCI insight.

Natural IgA and TNFRSF13B polymorphism: a double edged sword fueling balancing selection

Peter L. Freddolino, R. Geha, J. Platt, 2021, bioRxiv.

Interleukin-22-mediated host glycosylation prevents Clostridioides difficile infection by modulating the metabolic activity of the gut microbiota

P. Higgins, R. Jenq, N. Karlsson, 2020, Nature Medicine.

Untangling the oral-gut axis in the pathogenesis of intestinal inflammation.

N. Kamada, S. Kitamoto, Sho Kitamoto, 2022, International immunology.

Gut pathobionts underlie intestinal barrier dysfunction and liver T helper 17 cell immune response in primary sclerosing cholangitis

M. Hattori, K. Honda, A. Yoshimura, 2019, Nature Microbiology.

IL-15 promotes inflammatory Th17 cells in the intestine

J. Nemzek, J. Kao, S. Bishu, 2023, bioRxiv.

Lipopolysaccharide O structure of adherent and invasive Escherichia coli regulates intestinal inflammation via complement C3

G. Núñez, C. Alteri, N. Inohara, 2020, PLoS pathogens.

Human CD14(+) macrophages in intestinal lamina propria exhibit potent antigenpresenting ability: P-0161.

T. Hibi, S. Okamoto, N. Kamada, 2009 .

Citrobacter rodentium Induces Tissue-Resident Memory CD4+ T Cells

P. Higgins, W. Zou, J. Kao, 2019, Infection and Immunity.

Mesenchymal Cell–Specific MyD88 Signaling Promotes Systemic Dissemination of Salmonella Typhimurium via Inflammatory Monocytes

G. Núñez, N. Inohara, Wan-Uk Kim, 2017, The Journal of Immunology.

Machine learning-assisted immune profiling stratifies peri-implantitis patients with unique microbial colonization and clinical outcomes

W. Giannobile, Hom-lay Wang, K. Kornman, 2021, Theranostics.

Pathogenic associations between oral and gastrointestinal diseases.

Kira L. Newman, K. Newman, N. Kamada, 2022, Trends in molecular medicine.

Tu1794 – Adherent-Invasive Escherichia Coli Colonization Promotes Intestinal Fibrosis Via Activation of Il-33/St2 Signaling

P. Higgins, N. Barnich, P. Kuffa, 2019, Gastroenterology.

Intestinal overgrowth of Candida albicans exacerbates bleomycin‐induced pulmonary fibrosis in mice with dysbiosis

H. Iwamoto, N. Hattori, T. Nakashima, 2023, The Journal of pathology.

The Fecal Microbiome in Quiescent Crohns Disease with Persistent Gastrointestinal Symptoms Show Enrichment of Oral Microbes But Depletion of Butyrate and Indole Producers

V. Young, J. Golob, N. Kamada, 2023, medRxiv.

Clinical strategies for the blockade of IL-18 in inflammatory bowel diseases.

T. Kanai, T. Hisamatsu, N. Kamada, 2013, Current drug targets.