Browsing by Subject "SKIN"

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  • Clement, Cristina C.; D'Alessandro, Angelo; Thangaswamy, Sangeetha; Chalmers, Samantha; Furtado, Raquel; Spada, Sheila; Mondanelli, Giada; Ianni, Federica; Gehrke, Sarah; Gargaro, Marco; Manni, Giorgia; Lopez Cara, Luisa Carlota; Runge, Peter; Tsai, Wanxia Li; Karaman, Sinem; Arasa, Jorge; Fernandez-Rodriguez, Ruben; Beck, Amanda; Macchiarulo, Antonio; Gadina, Massimo; Halin, Cornelia; Fallarino, Francesca; Skobe, Mihaela; Veldhoen, Marc; Moretti, Simone; Formenti, Silvia; Demaria, Sandra; Soni, Rajesh K.; Galarini, Roberta; Sardella, Roccaldo; Lauvau, Gregoire; Putterman, Chaim; Alitalo, Kari; Grohmann, Ursula; Santambrogio, Laura (2021)
    Tryptophan catabolism is a major metabolic pathway utilized by several professional and non-professional antigen presenting cells to maintain immunological tolerance. Here we report that 3-hydroxy-l-kynurenamine (3-HKA) is a biogenic amine produced via an alternative pathway of tryptophan metabolism. In vitro, 3-HKA has an anti-inflammatory profile by inhibiting the IFN-gamma mediated STAT1/NF-kappa Beta pathway in both mouse and human dendritic cells (DCs) with a consequent decrease in the release of pro-inflammatory chemokines and cytokines, most notably TNF, IL-6, and IL12p70. 3-HKA has protective effects in an experimental mouse model of psoriasis by decreasing skin thickness, erythema, scaling and fissuring, reducing TNF, IL-1 beta, IFN-gamma, and IL-17 production, and inhibiting generation of effector CD8(+) T cells. Similarly, in a mouse model of nephrotoxic nephritis, besides reducing inflammatory cytokines, 3-HKA improves proteinuria and serum urea nitrogen, overall ameliorating immune-mediated glomerulonephritis and renal dysfunction. Overall, we propose that this biogenic amine is a crucial component of tryptophan-mediated immune tolerance. 3-hydroxy-L-kynurenamine (3-HKA) is a metabolite deriving from a lateral pathway of tryptophan catabolism. Here the authors identify 3-HKA as a biogenic amine and show it has anti-inflammatory properties that can protect mice against psoriasis and nephrotoxic nephritis.
  • Cuesta-Mateos, Carlo; Fuentes, Patricia; Schrader, Alexandra; Juarez-Sanchez, Raquel; Loscertales, Javier; Mateu-Albero, Tamara; Vega-Piris, Lorena; Espartero-Santos, Marina; Marcos-Jimenez, Ana; Sanchez-Lopez, Blanca Andrea; Perez-Garcia, Yaiza; Jungherz, Dennis; Oberbeck, Sebastian; Wahnschaffe, Linus; Kreutzman, Anna; Andersson, Emma I.; Mustjoki, Satu; Faber, Edgar; Urzainqui, Ana; Fresno, Manuel; Stamatakis, Kostantino; Alfranca, Arantzazu; Terron, Fernando; Herling, Marco; Toribio, Maria Luisa; Munoz-Calleja, Cecilia (2020)
    T-cell prolymphocytic leukemia (T-PLL) is a poor prognostic disease with very limited options of efficient therapies. Most patients are refractory to chemotherapies and despite high response rates after alemtuzumab, virtually all patients relapse. Therefore, there is an unmet medical need for novel therapies in T-PLL. As the chemokine receptor CCR7 is a molecule expressed in a wide range of malignancies and relevant in many tumor processes, the present study addressed the biologic role of this receptor in T-PLL. Furthermore, we elucidated the mechanisms of action mediated by an anti-CCR7 monoclonal antibody (mAb) and evaluated whether its anti-tumor activity would warrant development towards clinical applications in T-PLL. Our results demonstrate that CCR7 is a prognostic biomarker for overall survival in T-PLL patients and a functional receptor involved in the migration, invasion, and survival of leukemic cells. Targeting CCR7 with a mAb inhibited ligand-mediated signaling pathways and induced tumor cell killing in primary samples. In addition, directing antibodies against CCR7 was highly effective in T-cell leukemia xenograft models. Together, these findings make CCR7 an attractive molecule for novel mAb-based therapeutic applications in T-PLL, a disease where recent drug screen efforts and studies addressing new compounds have focused on chemotherapy or small molecules.
  • Riihila, Pilvi; Nissinen, Liisa; Farshchian, Mehdi; Kallajoki, Markku; Kivisaari, Atte; Meri, Seppo; Grenman, Reidar; Peltonen, Sirkku; Peltonen, Juha; Pihlajaniemi, Taina; Heljasvaara, Ritva; Kahari, Veli-Matti (2017)
    Cutaneous squamous cell carcinoma (cSCC) is one of the most common metastatic skin cancers with increasing incidence. We examined the roles of complement component C3 and complement factor B (CFB) in the growth of cSCC. Analysis of cSCC cell lines (n = 8) and normal human epidermal kerati-nocytes (n = 11) with real-time quantitative PCR and Western blotting revealed up-regulation of C3 and CFB expression in cSCC cells. Immunohistochemical staining revealed stronger tumor cell specific Labeling for C3 and CFB in invasive cSCCs (n = 71) and recessive dystrophic epidermolysis bullosa-associated cSCCs (n = 11) than in cSCC in situ (n = 69), actinic keratoses (n = 63), and normal skin (n = 5). Significant up-regulation of C3 and CFB mRNA expression was noted in chemically induced mouse cSCCs, compared to benign papillomas. Knockdown of C3 and CFB expression inhibited migration and proliferation of cSCC cells and resulted in potent inhibition of extracellular signal regulated kinase 1/2 activation. Knockdown of C3 and CFB markedly inhibited growth of human cSCC xenograft tumors in vivo. These results provide evidence for the rotes of C3 and CFB in the development of cSCC and identify them as biomarkers and potential therapeutic targets in this metastatic skin cancer.
  • Ruokolainen, Lasse; Parkkola, Anna; Karkman, Antti; Sinkko, Hanna; Peet, Aleksandr; Hämäläinen, Anu-Maaria; von Hertzen, Leena; Tillmann, Vallo; Koski, Katriina; Virtanen, Suvi M.; Niemelä, Onni; Haahtela, Tari; Knip, Mikael (2020)
    Background Allergic diseases are more common in Finland than in Estonia, which-according to the biodiversity hypothesis-could relate to differences in early microbial exposures. Methods We aimed at defining possible microbial perturbations preceding early atopic sensitization. Stool, nasal and skin samples of 6-month-old DIABIMMUNE study participants with HLA susceptibility to type 1 diabetes were collected. We compared microbiotas of sensitized (determined by specific IgE results at 18 months of age) and unsensitized Estonian and Finnish children. Results Sensitization was differentially targeted between populations, as egg-specific and birch pollen-specific IgE was more common in Finland. Microbial diversity and community composition also differed; the genusAcinetobacterwas more abundant in Estonian skin and nasal samples. Particularly, the strain-level profile ofAcinetobacter lwoffiiwas more diverse in Estonian samples. Early microbiota was not generally associated with later sensitization. Microbial composition tended to differ between children with or without IgE-related sensitization, but only in Finland. While land-use pattern (ie green areas vs. urban landscapes around the children's homes) was not associated with microbiota as a whole, it associated with the composition of the genusAcinetobacter. Breastfeeding affected gut microbial composition and seemed to protect from sensitization. Conclusions In accordance with the biodiversity hypothesis, our results support disparate early exposure to environmental microbes between Finnish and Estonian children and suggest a significant role of the genusAcinetobacterin the allergy gap between the two populations. The significance of the observed differences for later allergic sensitization remains open.
  • Kluger, Nicolas (2016)
    Tattooing can result in a wide variety of complications, whose prevalence and incidence remain still unclear. Hypersensitivity reactions (or allergies) to tattoo pigments are currently the most common complication on a tattoo, however they are not predictable. Infections are nowadays directly related to the lack of asepsis and hygiene during the tattooing procedure or during the healing phase. Patients with a known cutaneous disease should be warned of a potential risk of localization of their disease to the tattoo. A skin eruption restricted to a tattoo may reveal sarcoidosis. Patients with chronic conditions and/or impaired immunity should discuss with their physician about the possibility and when to have a tattoo.
  • Lagus, Heli; Klaas, Mariliis; Juteau, Susanna; Elomaa, Outi; Kere, Juha; Vuola, Jyrki; Jaks, Viljar; Kankuri, Esko (2019)
    Because molecular memories of past inflammatory events can persist in epidermal cells, we evaluated the long-term epidermal protein expression landscapes after dermal regeneration and in psoriatic inflammation. We first characterized the effects of two dermal regeneration strategies on transplants of indicator split-thickness skin grafts (STSGs) in ten adult patients with deep burns covering more than 20% of their body surface area. After fascial excision, three adjacent areas within the wound were randomized to receive a permanent dermal matrix, a temporary granulation-tissue-inducing dressing or no dermal component as control. Control areas were covered with STSG immediately, and treated areas after two-weeks of dermis formation. Epidermis-dermis-targeted proteomics of one-year-follow-up samples were performed for protein expression profiling. Epidermal expression of axonemal dynein heavy chain 10 (DNAH10) was increased 20-fold in samples having had regenerating dermis vs control. Given the dermal inflammatory component found in our dermal regeneration samples as well as in early psoriatic lesions, we hypothesized that DNAH10 protein expression also would be affected in psoriatic skin samples. We discovered increased DNAH10 expression in inflammatory lesions when compared to unaffected skin. Our results associate DNAH10 expression with cell proliferation and inflammation as well as with the epidermal memory resulting from the previous regenerative signals of dermis. This study (ISRCTN14499986) was funded by the Finnish Ministry of Defense and by government subsidies for medical research.
  • Heliö, Krista; Kangas-Kontio, Tiia; Weckström, Sini; Vanninen, Sari U. M.; Aalto-Setälä, Katriina; Alastalo, Tero-Pekka; Myllykangas, Samuel; Heliö, Tiina M.; Koskenvuo, Juha W. (2020)
    Background Dilated cardiomyopathy (DCM) is a condition characterized by dilatation and systolic dysfunction of the left ventricle in the absence of severe coronary artery disease or abnormal loading conditions. Mutations in the titin (TTN) and lamin A/C (LMNA) genes are the two most significant contributors in familial DCM. Previously mutations in the desmoplakin (DSP) gene have been associated with arrhythmogenic right ventricular cardiomyopathy (ARVC) and more recently with DCM. Methods We describe the cardiac phenotype related to a DSP mutation which was identified in ten unrelated Finnish index patients using next-generation sequencing. Sanger sequencing was used to verify the presence of this DSP variant in the probands' relatives. Medical records were obtained, and clinical evaluation was performed. Results We identified DSP c.6310delA, p.(Thr2104Glnfs*12) variant in 17 individuals of which 11 (65%) fulfilled the DCM diagnostic criteria. This pathogenic variant presented with left ventricular dilatation, dysfunction and major ventricular arrhythmias. Two patients showed late gadolinium enhancement (LGE) and myocardial edema on cardiac magnetic resonance imaging (MRI) that may suggest inflammatory process at myocardium. Conclusions The patients diagnosed with DCM showed an arrhythmogenic phenotype as well as SCD at young age supporting the recently proposed concept of arrhythmogenic cardiomyopathy. This study also demonstrates relatively low penetrance of truncating DSP variant in the probands' family members by the age of 40. Further studies are needed to elucidate the possible relations between myocardial inflammation and pathogenic DSP variants.
  • Karppinen, Toni; Ylianttila, Lasse; Kautiainen, Hannu; Reunala, Timo; Snellman, Erna (2015)
    Empowering heliotherapy aims at clinical healing and improved coping with psoriasis and atopic dermatitis, but evidence of long-term effects is scarce. We studied the effect of 2-week empowering heliotherapy in the Canary Islands on clinical outcome and quality of life in 22 psoriasis and 13 atopic dermatitis patients. Empowerment consisted of meeting peers, sharing experiences and performing physical and mental practices. Using the self-administered PASI (SAPASI) psoriasis was alleviated statistically significantly during heliotherapy (p <0.001), and the treatment effect was still detectable 3 months later (p <0.001). Atopic dermatitis was improved (p <0.001) when assessed with the patient-oriented SCORAD (PO-SCORAD), and the effect was still obvious 3 months later (p = 0.002). During heliotherapy the dermatology life quality index (DLQI) improved in both groups (p <0.001), persisting in atopic patients for up to 3 months (p = 0.002), but not in psoriasis patients. In conclusion, a 2-week empowered heliotherapy showed a long-lasting improvement in psoriasis and atopic dermatitis disease activity, and also in the quality of life of atopic patients.
  • Karppinen, Toni; Laine, Juha-Pekka; Kautiainen, Hannu; Pasternack, Rafael; Reunala, Timo; Snellman, Erna (2017)
  • Miroshnikova, Yekaterina A; Cohen, Idan; Ezhkova, Elena; Wickström, Sara A (2019)
    The skin epidermis is a constantly renewing stratified epithelium that provides essential protective barrier functions throughout life. Epidermal stratification is governed by a step-wise differentiation program that requires precise spatiotemporal control of gene expression. How epidermal self-renewal and differentiation are regulated remains a fundamental open question. Cell-intrinsic and cell-extrinsic mechanisms that modify chromatin structure and interactions have been identified as key regulators of epidermal differentiation and stratification. Here, we will review the recent advances in our understanding of how chromatin modifiers, tissue-specific transcription factors, and force-induced nuclear remodeling processes function to shape chromatin and to control epidermal tissue development and homeostasis.
  • Jheon, Andrew H.; Li, Chun-Ying; Wen, Timothy; Michon, Frederic; Klein, Ophir D. (2011)
  • Minh Binh Nguyen,; Cohen, Idan; Kumar, Vinod; Xu, Zijian; Bar, Carmit; Dauber-Decker, Katherine L.; Tsai, Pai-Chi; Marangoni, Pauline; Klein, Ophir D.; Hsu, Ya-Chieh; Chen, Ting; Mikkola, Marja L.; Ezhkova, Elena (2018)
    Merkel cells are innervated mechanosensory cells responsible for light-touch sensations. In murine dorsal skin, Merkel cells are located in touch domes and found in the epidermis around primary hairs. While it has been shown that Merkel cells are skin epithelial cells, the progenitor cell population that gives rise to these cells is unknown. Here, we show that during embryogenesis, SOX9-positive (+) cells inside hair follicles, which were previously known to give rise to hair follicle stem cells (HFSCs) and cells of the hair follicle lineage, can also give rise to Merkel Cells. Interestingly, while SOX9 is critical for HFSC specification, it is dispensable for Merkel cell formation. Conversely, FGFR2 is required for Merkel cell formation but is dispensable for HFSCs. Together, our studies uncover SOX9(+) cells as precursors of Merkel cells and show the requirement for FGFR2-mediated epithelial signalling in Merkel cell specification.
  • Kim, Christine S.; Ding, Xiaolei; Allmeroth, Kira; Biggs, Leah C.; Kolenc, Olivia I.; L'Hoest, Nina; Chacon-Martinez, Carlos Andres; Edlich-Muth, Christian; Giavalisco, Patrick; Quinn, Kyle P.; Denzel, Martin S.; Eming, Sabine A.; Wickström, Sara A. (2020)
    Stem cells reside in specialized niches that are critical for their function. Upon activation, hair follicle stem cells (HFSCs) exit their niche to generate the outer root sheath (ORS), but a subset of ORS progeny returns to the niche to resume an SC state. Mechanisms of this fate reversibility are unclear. We show that the ability of ORS cells to return to the SC state requires suppression of a metabolic switch from glycolysis to oxidative phosphorylation and glutamine metabolism that occurs during early HFSC lineage progression. HFSC fate reversibility and glutamine metabolism are regulated by the mammalian target of rapamycin complex 2 (mTORC2)-Akt signaling axis within the niche. Deletion of mTORC2 results in a failure to re-establish the HFSC niche, defective hair follicle regeneration, and compromised long-term maintenance of HFSCs. These findings highlight the importance of spatiotemporal control of SC metabolic states in organ homeostasis.
  • Salmivuori, M.; Grönroos, M.; Tani, T.; Pölönen, I.; Räsänen, J.; Annala, L.; Snellman, E.; Neittaanmäki, N. (2020)
    Abstract Background In the photodynamic therapy (PDT) of non-aggressive basal cell carcinomas (BCCs), 5-aminolevulinic acid nanoemulsion (BF-200ALA) has shown non-inferior efficacy when compared with methyl aminolevulinate (MAL), a widely used photosensitizer. Hexyl aminolevulinate (HAL) is an interesting alternative photosensitizer. To our knowledge, this is the first study using HAL-PDT in the treatment of BCCs. Objectives To compare the histological clearance, tolerability (pain and post-treatment reaction), and cosmetic outcome of MAL, BF-200 ALA, and low-concentration HAL in the PDT of non-aggressive BCCs. Methods Ninety-eight histologically verified non-aggressive BCCs met the inclusion criteria, and 54 patients with 95 lesions completed the study. The lesions were randomized to receive LED-PDT in two repeated treatments with MAL, BF-200 ALA, or HAL. Efficacy was assessed both clinically and confirmed histologically at three months by blinded observers. Furthermore, cosmetic outcome, pain, post-treatment reactions fluorescence, and photobleaching were evaluated. Results According to intention-to-treat analyses, the histologically confirmed lesion clearance was 93.8% (95% confidence interval [CI] = 79.9?98.3) for MAL, 90.9% (95% CI = 76.4?96.9) for BF-200 ALA, and 87.9% (95% CI = 72.7?95.2) for HAL, with no differences between the arms (p=0.84). There were no differences between the arms as regards pain, post-treatment reactions, or cosmetic outcome. Conclusions PDT with low-concentration HAL and BF-200 ALA have a similar efficacy, tolerability, and cosmetic outcome compared to MAL. HAL is an interesting new option in dermatological PDT, since good efficacy is achieved with a low concentration.
  • Lagus, Heli; Kankuri, Esko; Nuutila, Kristo; Juteau, Susanna; Sarlomo-Rikala, Maarit; Vuola, Jyrki (2018)
    Cellular grafts used for skin repair require rapid integration with the host tissue to remain viable and especially to nourish the epidermal cells. Here, we evaluated the responses in the split-thickness skin grafts (STSGs) grafted on three differently treated wound beds: directly on excised wound bed (EX), on an artificial dermal template (DT) and on granulation tissue (GT) induced by cellulose sponge. In ten burn patients, after excision, a test area was divided into three sections: One transplanted with STSG instantaneously and two sections had a pre-treatment for 2 weeks with either DT or a cellulose sponge inducing granulation tissue formation and thereafter grafted with STSGs. One week after grafting, the STSGs on GT demonstrated most endothelial CD31(+) staining, largest average vessel diameters as well as most CD163(+) staining of M2-like macrophages and most MIB1(+) proliferating epidermal cells, suggesting an active regenerative environment. STSGs on DT had smallest vessel diameters and the least CD163(+) macrophages. STSGs on EX had the least CD31(+) cells and the least MIB1(+) proliferating cells. After 3 months, this reactivity in STSGs had subsided, except increased dermal cell proliferation was observed in STSGs on EX. Results show that pre-treatment of wound bed and induction of granulation tissue formation can accelerate host-graft interaction by stimulating graft vasculature and inducing cell proliferation.
  • Peuhu, Emilia; Salomaa, Siiri I.; De Franceschi, Nicola; Potter, Christopher S.; Sundberg, John P.; Pouwels, Jeroen (2017)
    SHARPIN (Shank-Associated RH Domain-Interacting Protein) is a component of the linear ubiquitin chain assembly complex (LUBAC), which enhances TNF-induced NF-kappa B activity. SHARPIN-deficient (Sharpin(cpdm/cpdm)) mice display multi-organ inflammation and chronic proliferative dermatitis (cpdm) due to TNF-induced keratinocyte apoptosis. In cells, SHARPIN also inhibits integrins independently of LUBAC, but it has remained enigmatic whether elevated integrin activity levels in the dermis of Sharpin(cpdm/cpdm) mice is due to increased integrin activity or is secondary to inflammation. In addition, the functional contribution of increased integrin activation to the Sharpin(cpdm/cpdm) phenotype has not been investigated. Here, we find increased integrin activity in keratinocytes from Tnfr1(-/-) Sharpin(cpdm/cpdm) double knockout mice, which do not display chronic inflammation or proliferative dermatitis, thus suggesting that SHARPIN indeed acts as an integrin inhibitor in vivo. In addition, we present evidence for a functional contribution of integrin activity to the Sharpin(cpdm/cpdm) skin phenotype. Treatment with an integrin beta 1 function blocking antibody reduced epidermal hyperproliferation and epidermal thickness in Sharpin(cpdm/cpdm) mice. Our data indicate that, while TNF-induced cell death triggers the chronic inflammation and proliferative dermatitis, absence of SHARPIN-dependent integrin inhibition exacerbates the epidermal hyperproliferation in Sharpin(cpdm/cpdm) mice.
  • Mandelin, Johanna M.; Eklund, Kari K.; Reitamo, Sakari (2010)
  • Kluger, Nicolas; Koskenmies, Sari; Jeskanen, Leila; Övermark, Meri; Saksela, Olli (2014)
  • Marzabani, Rezvan; Rezadoost, Hassan; Choopanian, Peyman; Kolahdooz, Sima; Mozafari, Nikoo; Mirzaie, Mehdi; Karimi, Mehrdad; Nieminen, Anni; Jafari, Mohieddin (2021)
    Introduction Vitiligo pathogenesis is complicated, and several possibilities were suggested. However, it is well-known that the metabolism of pigments plays a significant role in the pathogenicity of the disease. Objectives We explored the role of amino acids in vitiligo using targeted metabolomics. Methods The amino acid profile was studied in plasma using liquid chromatography. First, 22 amino acids were derivatized and precisely determined. Next, the concentrations of the amino acids and the molar ratios were calculated in 31 patients and 34 healthy individuals. Results The differential concentrations of amino acids were analyzed and eight amino acids, i.e., cysteine, arginine, lysine, ornithine, proline, glutamic acid, histidine, and glycine were observed differentially. The ratios of cysteine, glutamic acid, and proline increased significantly in Vitiligo patients, whereas arginine, lysine, ornithine, glycine, and histidine decreased significantly compared to healthy individuals. Considering the percentage of skin area, we also showed that glutamic acid significantly has a higher amount in patients with less than 25% involvement compared to others. Finally, cysteine and lysine are considered promising candidates for diagnosing and developing the disorder with high accuracy (0.96). Conclusion The findings are consistent with the previously illustrated mechanism of Vitiligo, such as production deficiency in melanin and an increase in immune activity and oxidative stress. Furthermore, new evidence was provided by using amino acids profile toward the pathogenicity of the disorder.
  • Meakin, Paul J.; Morrison, Vicky L.; Sneddon, Claire C.; Savinko, Terhi; Uotila, Liisa; Jalicy, Susan M.; Gabriel, Jennie L.; Kang, Li; Ashford, Michael L. J.; Fagerholm, Susanna C. (2015)
    Beta2-integrins are important in leukocyte trafficking and function, and are regulated through the binding of cytoplasmic proteins, such as kindlin-3, to their intracellular domain. Here, we investigate the involvement of beta2-integrins in the regulation of metabolic disease using mice where the kindlin-3 binding site in the beta2-integrin cytoplasmic tail has been mutated (TTT/AAA-beta2-integrin knock-in (KI) mice), leading to expressed but dysfunctional beta2-integrins and significant neutrophilia in vivo. Beta2-integrin KI mice fed on a high fat diet showed normal weight gain, and normal accumulation of macrophages and lymphocytes in white adipose tissue (WAT) and liver, but increased neutrophil numbers especially in WAT. In addition, beta2-integrin KI mice fed on a high fat diet showed significantly increased peripheral insulin resistance in response to high-fat feeding. However, this was associated with improved glucose disposal following glucose load. Interestingly, beta2-integrin KI neutrophils produced more elastase in vitro, in response to stimulation. Beta2-integrin KI mice displayed variability of tissue inflammatory status, with liver and WAT exhibiting little or no difference in inflammation compared to high fat fed controls, whereas skeletal muscle demonstrated a raised inflammatory profile in association with higher elastase levels and diminished signalling through the IRS1-PKB pathway. In conclusion, although expression of dysfunctional beta2-integrins increased neutrophil production and infiltration into tissue, skeletal muscle was the most affected tissue exhibiting evidence of higher neutrophil activity and insulin resistance. Thus, beta2-integrins modulate glucose homeostasis during high fat feeding predominantly through actions on skeletal muscle to affect metabolic phenotype in vivo.