Literatura científica selecionada sobre o tema "E161.3 .p38 1993"

Mitogen-activated protein kinase (MAPK) p38 is activated in response to stress stimuli and growth factors relevant to the pathogenesis of diabetic nephropathy. We postulated that mesangial cells exposed to high glucose and to endothelin-1 (ET-1), angiotensin II (ANG II), and platelet-derived growth factor (PDGF) demonstrate enhanced p38 activity and subsequent activation of the cAMP responsive element binding (CREB) transcription factor. Primary rat mesangial cells exposed to 5.6 (NG) or 30 mM glucose (HG) or NG plus 24.4 mM sorbitol (osmotic control) for ≤4 days were acutely stimulated with ET-1, ANG II, or PDGF. After 3 days of HG, p38 phosphorylation and kinase activity increased twofold ( P < 0.05 vs. NG, n = 5). No change in p38 activity was observed with sorbitol. In HG, activation of p38 by ET-1, ANG II, or PDGF was enhanced compared with NG and was protein kinase C (PKC) independent. In HG, CREB phosphorylation in response to ET-1, ANG II, and PDGF stimulation was enhanced compared with NG and was abolished by p38 inhibition with SB202190. To conclude, in HG, mesangial cell p38 is activated, which in turn stimulates CREB phosphorylation. Furthermore, in HG, mesangial cell p38 responsiveness to ET-1, ANG II, and PDGF and consequent CREB phosphorylation are enhanced through a PKC-independent pathway, which may contribute to the pathogenesis of diabetic nephropathy.

Background:Behçet’s Disease (BD) is a systemic vasculitis of unknown etiology[1]. Monocytes closely related to inflammation potentially contribute to BD’s pathogenesis. They are classified into three subsets: classical monocytes (CM), intermediate monocytes (IM) and non-classical monocytes (NCM). Abnormalities of monocyte subsets have been reported in many infectious, inflammatory and autoimmune diseases[2-6], but their implication in BD remains elusive.Objectives:To investigate the distribution, phenotypes and functions of monocyte subsets in BD and explore their roles in BD pathogenesis.Methods:The frequencies and phenotypes of monocyte subsets in BD and healthy controls (HC) were determined by flow cytometry, and their correlation with clinical parameters was analyzed. Intracellular cytokines and phosphorylated signal proteins [phosphorylated p65(p-p65) and phosphorylated p38(p-p38)] were determined in LPS-activated monocyte subsets by flow cytometry. Monocyte subsets of BD and HC were sorted and co-cultured with naïve CD4 + T cells, and Th1 cell frequencies were measured on day 5.Results:A higher IM (9.0±3.6 % vs. 4.5±2.0%, p<0.01) and lower NCM (2.6±1.2% vs. 4.2±2.0%, p<0.01) population in BD patients were noted. BD IM were positively correlated with CRP (r=0.5456, p<0.05), ESR (r=0.4683, p=0.05), and the serum level of TNF-a (r=0.7372, p<0.001) and IL-6(r=0.5013, p<0.05). BD NCM were negatively correlated with CRP (r=0.4822, p<0.05) and the serum level of IgM (r=-0.7830, p<0.001). Moreover, BD IM decreased (12.3±3.8% vs. 5.7±3.6%, p<0.05), while BD NCM increased (2.6±1.3% vs. 3.5±1.5%, p<0.01) after BD patients achieved remission. CD11b and CD64 expression on CM, IM and NCM in BD were enhanced. BD CM promoted TNF-a (61.0±11.4% vs 48.3±9.9%, p<0.05) and IL-6 (7.2±5.4% vs1.9±1.7%, p<0.05) production and facilitated Th1 differentiation. BD IM promoted IL-6 production (6.2±3.8% vs 2.6±1.6%, p<0.05). Furthermore, we demonstrated a higher level of p-p65 (12.8±2.9% vs 3.3±1.1%, p<0.01) in BD CM and increased p-p65 (3.2±0.6% vs 0.01±0.01%, p<0.01) and p-p38 (1.1±0.6% vs 0.03±0.01%, p<0.01) in BD IM.Conclusion:To our knowledge, our study is the first study on monocyte subsets in BD. Our data highlighted the aberrant populations of IM and CM in BD, potentially implicated in BD pathogenesis.References:[1]Ahmet, Gül, Pathogenesis of Behçet’s disease: autoinflammatory features and beyond, Semin. Immunopathol. 37 (2015) 413-418.[2]G.Fingerle, A.Pforte, B.Passlick, et al.The novel subset of CD14+/CD16+ blood monocytes is expanded in sepsis patients, Blood. 82 (1993) 3170-3176.[3]M.Moniuszko, A. Bodzenta-Lukaszyk, K. Kowal, et al. Enhanced frequencies of CD14++CD16+, but not CD14+CD16+, peripheral blood monocytes in severe asthmatic patients, Clin. Immunol. 130 (2009) 338-346.[4]M.D.Sanchez, Y.Garcia, C.Montes,et al.Functional and phenotypic changes in monocytes from patients with tuberculosis are reversed with treatment, Microbes. Infec. 8 (2006) 2492-2500.[5]S.Koch, T.Kucharzik, J.Heidemann,et al. Investigating the role of proinflammatory CD16+ monocytes in the pathogenesis of inflammatory bowel disease, Clin. Exp. Immunol. 161 (2010) 332-341.[6]H. Zhu, F. Hu, X. Sun,et al.CD16(+) Monocyte Subset Was Enriched and Functionally Exacerbated in Driving T-Cell Activation and B-Cell Response in Systemic Lupus Erythematosus, Front. immunol. 7 (2016) 512.Disclosure of Interests:None declared

Abstract The inhibitory effects exerted by transforming growth factor-β (TGF-β) on adult erythropoiesis has been well established. Canonical SMAD-depedent TGF-β signaling inhibits erythroid differentiation at multiple levels: it induces hematopoietic stem cells into quiescence (Chabanon et at Stem Cells. 2008;26:3150), it elicits a Smad5-dependent inhibition of progenitor cell proliferation (Bruno et al, Blood 1998; 91:1971) by increasing the length of G1 through reduction of G1 cyclin and cyclin-dependent protein kinases (Jacobsen et al, Blood 1995; 86:2957; Geng and Weinberg, PNAS 1993; 90:10315) and triggers Smad4-signaling accelerating terminal erythroid maturation (Zermati et al, Exp hematol 2000; 28:885; Choi et al MCB 2005;271:23). TGF-β is expressed by almost every cell type, but is produced in the greatest amount by megakaryocytes (Assonian et al, JBC 1983;258:7155; Massague, Cell 2008;134, 215). TGF-β has been implicated in the pathogenesis of primary myelofibrosis (PMF) by Schmitt et al (Blood. 2000;96:1342). Plasma, bone marrow and spleen washes of PMF patients, as well as those from murine PMF models, contain 2 fold-greater levels of total and bioactive TGF-β than those from normal controls (Zingariello et al, Blood 2013;121:3345). In addition, megakaryocytes from PMFpatients contain greater amounts of TGF-β than those from other MPNs such as polycythemia vera (PV) and essential thrombocythemia (Ciurea et al, Blood 2007;110:986). Published data, however, also suggest that malignant MPN cells are insensitive to TGF-β. Microarray analyses of PMF bone marrow and spleen cells revealed TGF-β signaling abnormalities which predict activation of non-canonical p38/ERK-dependent rather than canonical SMAD-dependent signaling (Ciaffoni et al, BCMD 2015;54:234). In addition, by phosphoproteomic profiling of PV erythroblasts (Erys) expanded in vitro express lower levels of pSmad2 as compared to Erys from healthy controls (Hricik et al. AJH 2013;88:723). The hypothesis that malignant MPN cells are insensitive to TGF-β was tested here by evaluating the effect of SB431542 [1,3,10 and 26µM], a small molecule inhibitor of TGF-β receptor 1, on ex vivo erythropoiesis in cultures generated by peripheral blood mononuclear cells from patients with JAK2 V617+-PV (n=2) and JAK2 V617F+ or CALR pQ365f+-PMF. Identical experiments were performed with Erys generated from adult peripheral blood (AB, n=3) and cord blood (CB, n=2) of healthy controls. All cultures were stimulated with SCF, IL-3 and EPO with and without dexamethasone (Dex). In cultures of JAK2 V617F+ -PV, SB431542 increased by 2-fold the numbers of progenitor cells observed by day 6, but had no effect on that of Erys observed by day 12-17 [fold increase (FI) ~4 fold in all cases]. Moreover, neither the number of progenitor cells nor that of Erys were affected by SB431542 treatment in cultures generated from JAK2 V617F+ (n=1) and CALR pQ365fs+ -PMF (n=1) patients (Fig. 1). This lack of effects was observed in cultures with and without Dex. By contrast, as expected, in cultures of AB, SB431542 significantly increased by 2.5-fold the number of progenitor cells observed by day 6 and that of Erys observed by day 14-17 (Fig. 1). This increase was associated with greater retention of an immature erythroid phenotype (CD36+ CD235a+ cells 16% vs 3%) and an increased proliferative index (>3 Erys in metaphases per field vs 0). This was observed up to day 17 in cultures both with and without Dex. The effects of SB431542 in cultures of CB were, however, affected by the presence of Dex. In cultures without Dex, SB431542 increased by 2-fold the number of progenitor cells by day 6 but had no effect on that of Erys by day 12-17 (FI=10-15 and CD36+CD235a+ cells >60%). In the presence of Dex, SB431542 did not affect the number of progenitor cells at day 6 but reduced that of Erys by 3-fold on day 12-17. These results suggest that in the case of CB, TGF-β promotes erythroid maturation in synergy with Dex. In conclusion, SB431542 promoted proliferation and maturation of normal adult progenitor cells but had no effect on PMF progenitor cells suggesting that treatments with TGF-β receptor 1 inhibitors may reactivate normal hematopoiesis in PMF patients by providing a proliferative advantage to the resident non-diseased hematopoietic stem cells over the malignant clone. This therapeutic approach will be explored in a MPD-RC, multi-center, phase II trial in patients with PMF. Disclosures Hoffman: Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; All Cells, LLC: Consultancy, Membership on an entity's Board of Directors or advisory committees; Promedior: Research Funding. Mascarenhas:Roche: Research Funding; Incyte Corporation: Research Funding; Kalobios: Research Funding; CTI Biopharma: Research Funding; Novartis Pharmaceuticals Corporation: Research Funding; Promedior: Research Funding.

Sign language, which is the main means of communication for the deaf, has many different variations in each region. As a diversity of languages and cultural identities for people with hearing impairment, regional languages also need to be preserved. Bandung as a city that has the highest type of deaf out of all persons with disabilities in it, has a large and active deaf community in introducing distinctive gestures. In fact, several studies have shown that the development of regional sign language led to the start of the construction of the first special school in the city of Bandung, but there has been no research on sign language in the Bandung area itself. The new media can help maintain the typical Bandung sign language to last longer so that it does not experience changes, transitions and language death. The digital dictionary was chosen to be a medium for documentation of Bandung sign language because it fits the needs of problems regarding language resistance. A digital operating system can be summarized in a single unit in the form of an application that can run on two types of devices, namely desktop and mobile. Referring to the design of a digital dictionary that functions as a tool, it requires usability flexibility, so that the application will be designed on mobile media (mobile apps). The design of the dictionary uses a visual aid in the form of 3-dimensional (3D) animation as a conveyer of the language you are looking for and what you want to know. So the purpose of the linguistic study of Bandung sign language is to be able to document the language in a digital dictionary in the form of a 3D animation display. This research uses the design thinking method with a qualitative approach. Data collection was carried out directly in the Deaf community in the city of Bandung and will develop collectively in line with the findings of regional Bandung sign language.Keywords:sign, language, animation, dictionary, Bandung. AbstrakBahasa isyarat yang menjadi alat komunikasi utama bagi penyandang tunarungu (Tuli) memiliki berbagai macam variasi berbeda pada setiap daerah. Sebagai satu keragaman bahasa dan identitas budaya bagi penyandang Tuli, bahasa daerah juga perlu dilestarikan. Bandung sebagai kota yang memiliki jenis Tuli tertinggi dari seluruh penyandang disabilitas di dalamnya, memiliki komunitas Tuli yang besar dan aktif dalam mengenalkan gerak isyarat khas. Bahkan beberapa penelitian menunjukkan bahwa perkembangan bahasa isyarat daerah mengarah pada dimulainya pembangunan sekolah luar biasa pertama yang berada di kota Bandung, namun penelitian bahasa isyarat derah Bandung sendiri belum ada. Media yang baru dapat membantu mempertahankan bahasa isyarat khas Bandung untuk bertahan lebih lama agar tidak mengalami perubahan, peralihan dan kematian bahasa. Kamus digital dipilih untuk menjadi media dokumentasi bahasa isyarat Bandung karena sesuai dengan kebutuhan dari permasalahan mengenai ketahanan bahasa. Sistem operasi digital dapat diringkas dalam satu kesatuan berbentuk aplikasi yang dapat dijalankan pada dua jenis device, yaitu desktop dan mobile. Mengacu pada perancangan kamus digital yang berfungsi sebagai alat bantu maka membutuhkan fleksibilitas kegunaan, sehingga aplikasi akan dirancang pada media yang bersifat mobile (mobile apps). Perancangan kamus menggunakan peraga dalam bentuk animasi jenis 3 dimensi (3D) sebagai penyampai bahasa yang dicari maupun yang ingin diketahui. Sehingga tujuan dari studi linguistik mengenai bahasa isyarat Bandung adalah untuk dapat menjadi dokumentasi bahasa ke dalam kamus digital dalam bentuk peraga animasi 3D. Penelitian menggunakan metode design thinking dengan pendekatan kualitatif. Pengumpulan data dilakukan secara langsung pada komunitas di Tuli di Kota Bandung dan akan berkembang secara kolektif seiring dengan temuan bahasa isyarat daerah Bandung.Kata Kunci: bahasa, isyarat, animasi, kamus, Bandung. Authors:Afif Wahyu Farosa : Institut Teknologi BandungIrfansyah : Institut Teknologi Bandung References:Agung, L., Kartasudjana, T., & Permana, A. W. (2021). Estetika Nusantara dalam Karakter Gim Lokapala. Gorga: Jurnal Seni Rupa, 10(2), 473-477. https://doi.org/10.24114/gr.v10i2.28556Agustina, A. (2010). Aplikasi Kamus Digital Istilah-Istilah Biologi dengan Menggunakan Visual Basic 6, 0. Doctoral dissertation, Universitas Sumatera Utara. https://repositori.usu.ac.id/handle/123456789/75947 Ahmad, F. (2015). Aplikasi Kamus Digital Bahasa Indonesia-Bahasa Arab Dengan Menggunakan Metode Prototyping. Skripsi, Fakultas Ilmu Komputer. Barkhuus, L., Polichar, V.E. Empowerment through seamfulness: smart phones in everyday life. 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Background: Outcomes after subarachnoid hemorrhage (SAH) have been rarely examined in large cohorts. Methods: This is an extension of the International Stroke Outcomes Study (INSTRUCT) pooling 13 ‘ideal’ stroke incidence studies (n=657 with SAH from 1993-2017, median age 56 years; 46% men). The primary outcomes were mortality and functional outcome (mRS score 3-5). Harmonized study factors included age, sex, behaviors (current smoking, alcohol intake), comorbidities (history of hypertension, ischemic heart disease, atrial fibrillation), stroke severity (e.g. NIHSS score) and year of stroke. In the pooled dataset, we estimated predictors of mortality using Poisson regression, to estimate incidence rate ratio (IRR) at 1 month (11 studies), 1 year (12 studies) and 5 years (7 studies). Generalized equation estimates in the log-binomial family were used to calculate risk ratios (RRs) for predictors of poor functional outcome at 1 month (5 studies) and 1 year (8 studies). Results: Mortality was 33% at 1 month, 43% at 1 year, and 47% at 5 years (Fig 1). Poor functional outcome was 25% at 1 month and 15% at 1 year (Fig 1). In multivariable analysis, age and stroke severity were associated with mortality at all time points, together with current smoking at 1 and 5 years, and history of hypertension at 5 years (Fig 2). Poor functional outcome was predicted by age (RR 1.03; 95% CI 1.01-1.04) at 1 month and by age (RR 1.04; 95% CI 1.00-1.08) and stroke severity (RR 1.94; 95% CI 1.02-2.87) at 1 year. Conclusion: Risk factors that predict SAH incidence including hypertension and smoking make outcomes worse. Better management of older patients and those with severe strokes could improve outcomes after SAH.