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Supplemental Experimental Materials and Methods

Hepatocellular carcinoma (HCC) typically develops on a background of chronic hepatitis for which the proinflammatory cytokine IL6 is conventionally considered a crucial driving factor. Paradoxically, IL6 also acts as a hepatoprotective factor in chronic liver injury. Here we used the multidrug-resistant gene 2 knockout (Mdr2−/−) mouse model to elucidate potential roles of IL6 in chronic hepatitis–associated liver cancer. Long-term analysis of three separate IL6/Stat3 signaling–deficient Mdr2−/− strains revealed aggravated liver injury with increased dysplastic nodule formation and significantly accelerated tumorigenesis in all strains. Tumorigenesis in the IL6/Stat3-perturbed models was strongly associated with enhanced macrophage accumulation and hepatosteatosis, phenotypes of nonalcoholic steatohepatitis (NASH), as well as with significant reductions in senescence and the senescence-associated secretory phenotype (SASP) accompanied by increased hepatocyte proliferation. These findings reveal a crucial suppressive role for IL6/Stat3 signaling in chronic hepatitis–associated hepatocarcinogenesis by impeding protumorigenic NASH-associated phenotypes and by reinforcing the antitumorigenic effects of the SASP.Significance:These findings describe a context-dependent role of IL6 signaling in hepatocarcinogenesis and predict that increased IL6-neutralizing sgp130 levels in some patients with NASH may herald early HCC development.See related commentary by Huynh and Ernst, p. 4671

Children’s participation in a child-friendly school is important for ensuring that children are involved, respected, and heard in school policies to fulfill their rights. This paper aims to describe the children’s participation in the implementation program. Qualitative and quantitative methods were used through interviews, observation at two schools, and questionnaires as data collection techniques. Data analyses were carried out interactively within the children’s rights analytical framework. The result shows that children’s participation is defined as involvement in various schools’ activities and not at the level of ideas. Keywords: Child-Friendly School, Children’s Right, Student’s Perception.

Klitih/Nglitih comes from the Javanese language, which means looking for activities in your spare time. Meanwhile, "Klitih/Nglitih" in the context of juvenile delinquency means travelling around using a motorcycle that a group of students has carried out. This study aims to explain the background of the "Klitih" that often occurs in Yogyakarta and the pattern of interaction in the "Klitih" group. This qualitative research uses a case study in the "Klitih" group in Yogyakarta. Based on the research that has been done, it is found that revenge and showing off are the backgrounds for "Klitih", which often occurs in Yogyakarta. The recruitment process from members to former members becomes a pattern of interaction repeatedly appearing in the "Klitih" group.

This study aims to determine the motives of women doing child marriage. This research was conducted in Saradan Village, Baturetno District, Wonogiri Regency. This study uses qualitative research with a phenomenological approach. Data collection comes from interviews, documentation, and observation. The primary interviews were conducted by women who had child marriages. The data collection technique used is purposive sampling. The data validity testing technique used is source triangulation. The results of the study show as follows: the motives of women marrying at the age of children can be divided into two, namely because of reasons and by motives. Because the motives are 1) Lack of parental attention and supervision, 2) The economic situation of the low-income family, 3) The psychological condition of teenagers, and 4) Low education. While To Motive is 1) Having a better economic life, 2) Having a happy family life, 3) Getting a person who can give attention, affection and responsibility to his life.

This study aims to determine the process of establishing family-based social services in Griya Bahagia PMI Surakarta and explain the form of implementation of family-based social services in Griya Bahagia seen from the performance of family functions in social services. This study uses the Social Construction Theory of Peter L. Berger and Thomas Luckmann, where the formation process of Griya Bahagia with a family-based social service system is inseparable from the social construction process, which includes the working mechanism of externalization, objectivation, and internalization that are dialectical. This research is a type of qualitative research with a phenomenological approach. The results of this study indicate that; (1) The purpose of establishing Griya Bahagia PMI is to humanize the neglected elderly like family. Therefore, to support the process of establishing family-based social services, Griya Bahagia then runs several program activities that aim to facilitate administrators in providing family-based social services to the elderly, (2) Several forms of implementing family-based social services at Griya Bahagia are manifested in various states of activities where each activity implements family functions in it.

Hepatocellular carcinoma (HCC) typically develops on a background of chronic hepatitis for which the proinflammatory cytokine IL6 is conventionally considered a crucial driving factor. Paradoxically, IL6 also acts as a hepatoprotective factor in chronic liver injury. Here we used the multidrug-resistant gene 2 knockout (Mdr2−/−) mouse model to elucidate potential roles of IL6 in chronic hepatitis–associated liver cancer. Long-term analysis of three separate IL6/Stat3 signaling–deficient Mdr2−/− strains revealed aggravated liver injury with increased dysplastic nodule formation and significantly accelerated tumorigenesis in all strains. Tumorigenesis in the IL6/Stat3-perturbed models was strongly associated with enhanced macrophage accumulation and hepatosteatosis, phenotypes of nonalcoholic steatohepatitis (NASH), as well as with significant reductions in senescence and the senescence-associated secretory phenotype (SASP) accompanied by increased hepatocyte proliferation. These findings reveal a crucial suppressive role for IL6/Stat3 signaling in chronic hepatitis–associated hepatocarcinogenesis by impeding protumorigenic NASH-associated phenotypes and by reinforcing the antitumorigenic effects of the SASP. Significance: These findings describe a context-dependent role of IL6 signaling in hepatocarcinogenesis and predict that increased IL6-neutralizing sgp130 levels in some patients with NASH may herald early HCC development. See related commentary by Huynh and Ernst, p. 4671

Penelitian ini sangat penting dilakukan karena di era generasi 4.0 mengalami perkembangan IPTEK sangat pesat. Penelitian ini bertujuan untuk menjelaskan (1) Mengkaji fungsi dalam mata pelajaran seni budaya Karawitan.(2) Mengkaji tentang bagaimana pola interaksi mata pelajaran seni budaya Karawitan dalam internalisasi tata krama Jawa makna pada siswa SMA Negeri 1 Boyolali. Penelitian ini merupakan penelitian kualitatif dengan pendekatan studi kasus. Teknik pengumpulan data dengan metode wawancara, observasi dan dokumentasi baik foto maupun video. Informan dalam sumber data penelitian ini adalah kepala sekolah, guru, siswa dan ahli karawitan. Penentuan subjek penelitian/informan dilakukan dengan cara purposisve sampling. Sedangkan tekhnik uji validitas data dengan cara triangulasi sumber.. Fokus teori penelitian ini menggunakan teori Interaksionisme Simbolik Herbert Blumer. Hasil yang diperoleh berdasarkan penelitian yang telah dilakukan adalah : (1) fungsi mata pelajaran seni budaya karawitan bagi SMA Negeri 1 Boyolali sebagai mata pelajaran yang sejajar dengan mata pelajaran lain. (2) internalisasi tata krama jawa melalui mata pelajaran seni karawitan dilakukan dengan interaksi simbolik melalui isyarat dan kode dalam seni karawitan.

La Cámara de Ganaderos de Upala es una organización conformada por 140 productores debidamente registrados, con dos años de fundación. Creada con el fin de solidarizarse con los productores después del huracán Otto, ocurrido en 2016 afectando la zona Note de Costa Rica. El proyecto que se plantea es un análisis económico y técnico para el posible establecimiento de una subasta ganadera en la zona de Upala, Costa Rica para el año 2019. El elemento diferenciador sería un margen de comisión competitivo ante las subastas cercanas y una administración directa que beneficia a la cámara y a los ganaderos oferentes de ganado. Se realizó mediante revisión de información secundaria, consulta a expertos, visitas programadas y generación de indicadores financieros, esto con el fin de generar un marco contextual de los alcances de la actividad desde un ángulo financiero y respecto a los principales requerimientos técnicos para una operación máxima de la actividad en estudio. Los principales resultados generados de la investigación fueron: una inversión inicial de ₡13 717 644,65; donde no se incurre en desembolsos de infraestructura y otros rubros que aumentan esta partida, una tasa interna de retorno positiva de 32,92%, un valor actual neto de ₡2 615 472,31 derivado de la actividad mediante una tasa de costo de capital de 15,01% y una un período de retorno de 3,45 años. Como recomendación, la implementación de este proyecto analizado desde los enfoques técnicos y económicos muestra que existe viabilidad para realizar el proyecto, el cual debido a su magnitud es una opción que potencia el fortalecimiento de la cámara y les brinda preparación para proyectos futuros de mayor tamaño.

The non-coding genome is substantially larger than the protein-coding genome but is largely unexplored by genetic association studies. Here, we performed region-based burden analysis of >25,000 variants in untranslated regions of 6,139 amyotrophic lateral sclerosis (ALS) whole-genomes and 70,403 non-ALS controls. We identified Interleukin-18 Receptor Accessory Protein (IL18RAP) 3′UTR variants significantly enriched in non-ALS genomes, replicated in an independent cohort, and associated with a five-fold reduced risk of developing ALS. Variant IL18RAP 3′UTR reduces mRNA stability and the binding of RNA-binding proteins. Variant IL18RAP 3′UTR further dampens neurotoxicity of human iPSC-derived C9orf72-ALS microglia that depends on NF-κB signaling. Therefore, the variant IL18RAP 3′UTR provides survival advantage for motor neurons co-cultured with C9-ALS microglia. The study reveals direct genetic evidence and therapeutic targets for neuro-inflammation, and emphasizes the importance of non-coding genetic association studies.One Sentence SummaryNon-coding genetic variants in IL-18 receptor 3’UTR decrease ALS risk by modifying IL-18-NF-κB signaling in microglia.

Esta investigación analiza la incursión de las mujeres en política en Costa Rica, específicamente de aquellas que compitieron por ocupar curules en la Asamblea Legislativa en el lapso 1953-1990. Ese período estuvo enmarcado por dos eventos cruciales en términos de género: el primer ejercicio de la doble modalidad del sufragio por parte de las costarricenses (1953) y la aprobación de la Ley de Promoción de la Igualdad Social de la Mujer en 1990. Los hallazgos se organizan en tres capítulos. El primer capítulo identifica a las candidatas a diputadas, sigue su trayectoria y esboza un perfil sociodemográfico. Además, repasa antecedentes de la participación de las mujeres en política y las acciones del Tribunal Supremo de Elecciones frente a la oleada de electoras que debió ser acreditada de cara a los comicios de 1953. El análisis encuentra 715 nominaciones de mujeres en las papeletas legislativas; sólo 42 llegan al Congreso. La infrarrepresentación de las mujeres en la escena política es notoria en distintas escalas de poder y en la estructura de los partidos: en las asambleas distritales, cantonales, provinciales y nacionales, así como en los Comités Ejecutivos (secretarías, tesorerías y presidencias). El perfil sociodemográfico que entrega esta investigación da cuenta del variopinto grupo de mujeres que ha intervenido en política y evidencia, al mismo tiempo, la disposición de las costarricenses de incursionar en ese ámbito. El segundo capítulo analiza las rupturas y resistencias en el discurso de la prensa a partir del análisis de La Nación y La República. Se concluye que el complejo entramado cultural que configura la condición marginal de las mujeres en el período estudiado abarca manifestaciones explícitas, como las opiniones vertidas en artículos de opinión y reportajes, hasta construcciones que pasan inadvertidas y parecen ingenuas, como la diagramación de los diarios, la focalización del contenido de ciertas secciones periodísticas y la publicidad que refuerza roles de género con discursos multimodales. El análisis permite afirmar que el año 1977 representa un parteaguas en términos de género, no porque antes no se denunciaran situaciones discriminatorias sino porque tienen lugar eventos que dejan ver un despertar de conciencia en las mujeres que, tras reconocerse como personas discriminadas, ejecutan acciones específicas para superar esa condición. El tercer y último capítulo analiza la propaganda electoral. Ahonda en los discursos dirigidos a las mujeres en calidad de electoras y en los que se divulgaron sobre las candidatas a diputadas. También recupera el trabajo de los comités femeninos y propone una tipificación de las adhesiones que se publicaron en la prensa. El discurso del miedo fue una práctica frecuente y varía según el contexto: la posguerra civil (1948), la Guerra Fría, la Revolución Cubana, los conflictos militares en Centroamérica y la invasión estadounidense a Panamá, por citar unos ejemplos. El análisis evidencia que las candidatas a diputadas rara vez aparecen en la propaganda publicada en los diarios. Esta invisibilización tiene lugar en medio de estrategias discursivas de legitimación y deslegitimación en una sociedad que había normalizado el ejercicio del poder por parte de los hombres. UCR::Vicerrectoría de Investigación::Sistema de Estudios de Posgrado::Ciencias Sociales::Maestría Académica en Historia

Argonaute 2 (AGO2), the effector protein partner of microRNAs (miRNAs) in the cytoplasmic RNA induced silencing complex, is further involved in nuclear RNA processing. However, a role for AGO2 in regulation of alternative polyadenylation was not yet demonstrated. Here, we reveal unexpected abundance of AGO2 in mouse neuronal nuclei and characterize nuclear AGO2 interactors by mass spectrometry. We discover that AGO2 broadly regulated alternative polyadenylation (APA) in neuronal cells. Specifically, we demonstrate how two isoforms of Ret mRNA, which encodes a receptor tyrosine kinase are regulated by AGO2-depenent APA, affecting downstream GDNF signaling in primary motor neurons.

Gencarnya serangan media sosial dalam kehidupan manusia dewasa ini yang saat ini sungguh tidak bisa dielakkan. Berbagai persoalan dan masalah timbul seiring dengan penggunaan media sosial di masyarakat. Banyak pro dan kontra terkait dengan munculnya berbagai dampak digunakannya media sosial. Kasus-kasus pornografi, penculikan, bahkan terorisme, bullying dan body shaming di media sosial turut ditengarai karena tidak bijaknya para pengguna media sosial, khususnya para remaja. Artikel ini merupakan hasil dari program pengabdian masyarakat yang dilakukan oleh Riset Group Habitus dengan Forum Anak Surakarta. Pengabdian ini bertujuan untuk memeberikan pemahaman atau literasi kepada remaja dan anak terkait penggunaan media sosial sehat. Remaja sebagai pengguna media sosial yang paling aktif oleh karenanya perlu dibekali dengan berbagai pemahaman yang positif terkait bagaimana penggunaan media sosial yang sehat. Metode yang digunakan adalah dengan memberikan penyuluhan berupa ceramah dan diskusi. Hasil pengabdian ini menunjukkan bahwa keberadaan media sosial saat ini memang sudah menjadi kesatuan bagi anak khususnya dalam Forum Anak Kota Surakarta. Dalam kegiatan yang sudah dilakukan diperoleh hasil bahwasannya anak dalam kesehariannya banyak menggunakan waktunya untuk menggunakan media sosial. Keseharian anak sudah dibelenggu oleh keberadaan media sosial itu sendiri

IL-6 signaling via its receptor (IL-6R) and co-receptor (gp130) performs multiple roles in regulating metabolic homeostasis. However, gp130 is also expressed systemically in a soluble form (sgp130), which limits soluble IL-6 receptor (sIL-6R)-mediated signaling – also called trans-signaling. Here we find that transgenic peripheral sgp130-mediated trans-signaling blockade induces mature-onset obesity, while differentially affecting age-dependent behavioral determinants of energy expenditure. In youth, trans-signaling blockade increases feeding associated with reduced leptin sensitivity but increases energy expenditure to maintain metabolic balance. In aging, reduced physical activity predisposes mice to adiposity, adipose tissue macrophage recruitment, hepatosteatosis, hyperglycemia, and insulin resistance. Mechanistically, trans-signaling blockade reduces hepatic Stat3 phosphorylation and suppresses PPARα, associated with miR-21 upregulation, while pharmacological activation of PPARα prevents obesity and hepatosteatosis, and rescues insulin sensitivity. Together these experiments reveal a role for peripheral IL-6 trans-signaling in metabolic homeostasis and provide clinical significance to elevated sgp130 levels found in some obese and diabetic patients.

The noncoding genome is substantially larger than the protein-coding genome but has been largely unexplored by genetic association studies. Here, we performed region-based rare variant association analysis of25,000 variants in untranslated regions of 6,139 amyotrophic lateral sclerosis (ALS) whole genomes and the whole genomes of 70,403 non-ALS controls. We identified interleukin-18 receptor accessory protein (IL18RAP) 3' untranslated region (3'UTR) variants as significantly enriched in non-ALS genomes and associated with a fivefold reduced risk of developing ALS, and this was replicated in an independent cohort. These variants in the IL18RAP 3'UTR reduce mRNA stability and the binding of double-stranded RNA (dsRNA)-binding proteins. Finally, the variants of the IL18RAP 3'UTR confer a survival advantage for motor neurons because they dampen neurotoxicity of human induced pluripotent stem cell (iPSC)-derived microglia bearing an ALS-associated expansion in C9orf72, and this depends on NF-κB signaling. This study reveals genetic variants that protect against ALS by reducing neuroinflammation and emphasizes the importance of noncoding genetic association studies.