bluuebunny/crossref_metadata_2025 huggingface dataset:
ANALISIS STRUKTUR DENGAN DINDING PENGISI DAN TANPA DINDING PENGISI PADA GEDUNG BERTINGKAT TERHADAP PERILAKU DINAMIK DENGAN METODE TIME HISTORY
Authors: CAHAYA TIARA , Islam Mukhlis , Afrizal Yuzuar , Wahyuni Ade Sri , Gunawan Agustin
Published: May 2023

This study aims to compare structural modeling with the addition of wall elements and without walls with the help of SAP2000 software. The method used in this study is time history analysis using the San Fernando groundmotion data. Based on the modeling that has been done, the participation of the variance mass has reached 90% for structures with walls in mode 278 while without walls in mode 243. The addition of walls in this study resulted in a decrease in the drift value. The average percentage of settlement of each floor is 40.12% for the X direction and 30.26% for the Y direction. The addition of walls can also reduce the period value of the structure, where the structure with walls has a period value of 1.0804 seconds while the structure without walls is 1 ,2016 sec.
 
Keywords: Building Structure, Infill Wall, Drift, Time History Analysis
AKSARAY’DA BULUNAN HİYEROGLİF LUVİCE YAZITLAR IŞIĞINDA GEÇ HİTİT DÖNEMİNDE TUZ GÖLÜ BÖLGESİNİN SİYASİ YAPISI
Authors: BARDAKCI Kürşat
Published: May 2023

Tuz Gölü havzası iklim yapısından dolayı, eskiçağ Anadolu’sunda diğer bölgelere nazaran daha az yerleşime sahne olmuştur. Buna paralel olarak bölgede, özellikle Geç Hitit dönemini aydınlatacak filolojik ve arkeolojik kalıntılar oldukça kısıtlıdır. Yine de M.Ö. 8. yüzyıla tarihlenen Burunkaya kaya yazıtı ve Aksaray Steli’nden konumuz kapsamında yer alan bölgenin siyasi durumu hakkında temel bilgilere sahibiz. Nitekim Burunkaya kaya yazıtına göre söz konusu bölgede kral Hartapu’nun egemen olduğu anlaşılmaktadır. Sözü edilen bu yazıtta Hartapu, muhtemelen kendisine isyan eden birisine/birilerine ceza verdiğinden bahseder. Hartapu’dan sonra bölgeye kimin hâkim olduğu ise kesin olarak bilinmemektedir. Aksaray Steli’nden anlaşıldığına göre, kısa süren bu karanlık dönemin ardından bölgeye Kiyakiyas egemen olmuştur. Bu stelde Kiyakiyas, Luvi baş tanrısı Tarhunzas’ın bölgeyi kendisine verdiğini söylemektedir. Burada Kiyakiyas, saltanatı meşrulaştırmak için böyle bir yola başvurmuş gibidir. Sözü edilen bu veriler, hiyeroglif yazıtlar ışığında ortaya çıkarılmış yorum ve değerlendirmelerdir. Bu yorum ve değerlendirmelerin yeni ve farklı görüşlere de temel oluşturacağı düşüncesindeyiz.
ATATÜRK DÖNEMİ TBMM ZABIT CERİDELERİNE GÖRE TÜRK KADINININ BİREY OLMA SÜRECİ (1920-1938)
Authors: DOĞUALP ÇİÇEK Hazine
Published: May 2023

Atatürk Dönemi Türk kadın haklarının gelişim sürecinin ele alındığı bu çalışmada zaman, mekân ve dinî inanca göre kadınlara olan yaklaşım incelenmeye çalışılmıştır. İslamiyet öncesi Türk tarihinde erkekle denk tutulan kadın, İslamiyetle birlikte değişen kültürün de etkisiyle geri planda kalmıştır. Zamanla hakları kesintiye uğrayan Türk kadınları, Cumhuriyetin ilanı ve Atatürk’ün dünya görüşü çerçevesinde yeniden şekillenmiş ve hak ettiği yeri bulmuştur. Eğitimden istihdama kadar birçok yönde erkekle eş tutulan Türk kadını eğitim ve kültürde de yükselmiş, çağdaş bir kimliğe bürünmüştür.

Atatürk Dönemi kadın hakları meselesi üzerinde durulan ve bilimsel alanda çok çalışılan bir konu olmuştur. Ancak bu çalışmalar kaynak bakımından birbirini tekrar etmiş ya da içerik olarak yüzeysel, bilinegelmiş konulardan oluşmuştur. Kanunların oluşum sürecini gözler önüne seren ve meclisteki görüşmelerin kayıt altına alındığı TBMM Zabıt Cerideleri ise çalışmalarda belli başlı konular dışında kullanılmamıştır. Bu nedenle çalışmanın ana kaynağını TBMM Zabıt Cerideleri oluşturmuştur. Atatürk Dönemi meclis zabıtlarının ele alındığı çalışmada kadınların sosyal, siyasi, eğitim, ekonomik ve medeni hallerini ilgilendiren tüm kayıtlar kullanılmaya özen gösterilmiştir.
The relationship between education and economic growth: A cross-country analysis
Authors: Bah Ibrahim Abubakarr
Published: May 2023

This study investigates the effects of education on economic growth in 89 low, middle, and high-income countries using an index of human capital developed by Penn World Table and economic growth data from the World Bank’s World Development Indicators. This study specifies a growth accounting empirical model to examine the effects of education on economic growth. Using systems Generalized Method of Moments estimation technique on annual data covering the periods from 2002 to 2020, the results show that education significantly enhances economic growth. On average, an increase in the education index by 0.1 increases the growth of real GDP per capita by 0.8 percentage points. The results also show that education does have higher returns for low- and middle-income countries compared to high-income countries. The results of this study lend credence to the argument that poor countries should focus and pool adequate resources towards education as a means to achieving growth.
Desempenho e caracterização de biodiesel de cártamo em blendas com diesel puro em conjunto motogerador
Authors: Nobre Felipe Luiz de Lemos , Santos Reginaldo Ferreira , Ruppenthal João Gabriel , Zanini Bárbara , Siqueira Jair Antonio Cruz , Pazuch Félix Augusto , Souza Samuel Nelson Melegari de
Published: May 2023

O consumo de combustíveis fósseis vem diminuindo nos últimos anos, porém, a demanda elétrica mundial só aumenta com o crescimento populacional. É importante contar com formas alternativas e menos poluentes de geração de energia, entre elas o biodiesel, que pode ser obtido de diferentes culturas energéticas, como o cártamo (Carthamus tinctorius L.). A viscosidade e o ponto de fulgor afetam diretamente o desempenho do motor, por isso é importante reduzir os valores desses parâmetros no biodiesel. O objetivo deste trabalho foi avaliar e caracterizar a produção de biodiesel a partir de sementes de cártamo, identificando o rendimento do processo e a eficiência de geração de energia do biocombustível, além do consumo específico do motor. O processo de produção para a obtenção de biodiesel a partir de sementes de cártamo foi avaliado, construindo um fluxograma com balanço de massa. Foram analisadas as características da torta, do óleo e do biodiesel resultantes do processo. E avaliou-se o consumo específico e a geração de energia das misturas B00, B05, B10, B20, B30, B40, B50, B60 e B100, constatando que não há diferença significativa para o consumo específico e geração de energia entre as misturas nas cargas avaliadas, apresentando diferenças significativas apenas em relação ao diesel.
Conjunto de cuidados para prevenção da recorrência de úlcera venosa: revisão de escopo
Authors: Santos Giulia Viana dos , Silva Matheus Gabriel , Bispo Monise de Melo , Dantas Dandara Nayara Azevedo , Mesquita Simone Karine da Costa , Araújo Rhayssa de Oliveira e
Published: May 2023

Objetivo: Mapear um conjunto de cuidados para a prevenção da recorrência de úlceras venosas, baseada em evidências científicas. Métodos: Revisão de escopo realizada nas bases de dados Medical Literature Analysis and Retrieval System On-line/ National Library of Medicine, Scopus, CINAHL, Catálogo de teses e dissertações da CAPES, Cochrane e LILACS, entre outubro de 2021 a janeiro de 2022. Foram utilizados os descritores Varicose, Ulcer, Care, Recurrence, Varicose Ulcer. Os critérios de elegibilidade foram: estudos sem restrição de idioma, sem recorte temporal, disponíveis em texto completo e com foco nas medidas de prevenção da recorrência de úlcera venosa. Resultados: Cinco cuidados para prevenção de úlcera venosa foram encontrados: educação em saúde (cartilhas, panfletos, e-learning, estratégias efetivas para cooperação do paciente), terapia compressiva (meias adequadas, média ou alta compressão, escolhida a mais forte de acordo com a tolerância, compressão multicamadas), cuidados com membros inferiores (elevação das pernas de 30min a quatro horas por dia, hidratação da pele, prevenção de acidentes com as pernas, evitar longos períodos sentados, em pé e exercícios para panturrilha, tornozelo e caminhadas), nutrição (controle do sobrepeso e conhecimento sobre nutrição adequada) e procedimentos invasivos (escleroterapia com espuma associada à compressão, desbridamento radical, enxerto e correção cirúrgica da insuficiência venosa). Os cuidados devem ser realizados em um ambiente com acompanhamento e apoio (acessando exames, consultas, acompanhamento especializado, apoio social e altos níveis de autoeficácia). Conclusão: atuar integrando cuidados de diferentes abordagens é importante para o alcance da prevenção efetiva de recorrência de úlceras venosas.
A atuação do enfermeiro no pós-operatório de cirurgia cardíaca: uma revisão integrativa da literatura
Authors: Santos Fabiana Bispo Braga , Pereira Leonardo dos Santos , Pradonoff Priscila Oliveira , Marinho Patrícia Dias Barreto , Prado Tatiana dos Santos Bernardo , Silva Mariana Veiga da , Sampaio Carlos Eduardo Peres
Published: May 2023

Objetivo: Identificar as evidências científicas acerca da assistência prestada do enfermeiro nos cuidados frente ao paciente submetido a cirurgia cardíaca e discutir o papel do enfermeiro neste contexto de cuidado, com base nas evidências encontradas. Método: Trata-se de uma revisão integrativa de literatura, descritiva e do tipo pesquisa bibliográfica de cunho qualitativo. Utilizou-se o método de Bardin, com busca de dados realizada através das plataformas online dos bancos de dados contidos na BVS devidamente publicados nos periódicos no lapso temporal de 2017 a 2022.Resultados: Na categoria I:Evidencia-se que a cirurgia impõe constantes mudanças de ordem física, social e psicológica para aquele paciente e apontam para respostas positivas às intervenções musicais. Na categoria II: Os artigos mencionam sobre a dor aguda com um maior nível de evidencia e aponta que a enfermagem está em constante preocupação com o cuidado técnico à beira do leito e que o processo de enfermagem contribui para uma assistência de qualidade. Conclusão: Foram esclarecidos os avanços no tratamento cirúrgico cardíaco, os principais diagnósticos, metas e intervenções de enfermagem desde o momento do seu rastreamento, tratamento e recuperação. Espera-se que este estudo venha a ajudar o enfermeiro atuante no pós-operatório, para que este possa embasar suas atividades diárias junto aos pacientes.
Mobilização precoce no paciente crítico
Authors: Silva Laila Michele Moreira da
Published: May 2023

A mobilização precoce desempenha um papel crucial na promoção da independência funcional e bem-estar psicológico dos pacientes internados em UTI. Este trabalho tem como objetivo identificar o que está contemplado na produção científica nacional sobre a mobilização precoce ao paciente critico. Estudo de revisão de literatura. A busca foi realizada na biblioteca virtual Pubmed, BVS e Scielo. Os filtros inseridos para a busca foram: trabalhos nacionais e internacionais, completos e disponíveis em português e inglês, que discorreram sobre o tema proposto para o estudo, de 2017 a 2022. Foram encontrados 4 artigos na Scielo; 10 artigos na PubMed e 30 na BVS. Foram selecionados 17 artigos e o restante descartado pelo título. Após a leitura completa dos artigos, foram incluídos 10 para confecção desse artigo. Separando em 3 categorias, que são elas: Importância da Mobilização em pacientes críticos; O papel do fisioterapeuta na mobilização na UTI do paciente crítico e Visões conflitantes sobre contraindicações e seus critérios de mobilização. Conclui-se que a utilização da mobilização precoce como terapia para pacientes internados em UTI tem se mostrado segura e eficaz, pois ameniza os impactos negativos associados a períodos prolongados de repouso no leito.
Conhecimento de estudantes de medicina de uma universidade de Santa Catarina, Brasil, sobre o autismo
Authors: Coelho Amanda Rosa , Kelner Milena , Pinculini Ana Paula Gonçalves , Fidelis Laís Daniela
Published: May 2023

A partir da 5ª edição do Manual Diagnóstico e Estatístico de Transtornos Mentais (DSM-V), o autismo passou a ser chamado de Transtorno do Espectro Autista (TEA) e é caracterizado como um transtorno de neurodesenvolvimento que resulta em comprometimento da comunicação, comportamento e interação social. O diagnóstico é realizado através de critérios clínicos e deve ocorrer precocemente com a finalidade de melhorar o prognóstico do portador desse transtorno. O presente estudo objetivou avaliar o conhecimento dos estudantes de medicina em uma universidade no estado de Santa Catarina/Brasil em relação ao autismo. Para tanto, fez-se um estudo exploratório e descritivo com abordagem quantitativa e amostra não probabilística com estudantes do ciclo clínico e internato de medicina. Os dados foram coletados por meio de um questionário pré-estruturado e validado, o qual foi traduzido e adaptado pelas autoras para mensurar o conhecimento técnico-científico a respeito do autismo. A partir dos questionários analisados, notou-se que grande parte dos estudantes já tiveram contato com um indivíduo portador do TEA e possuem bom conhecimento sobre o seu quadro clínico. Entretanto, os dados revelam um hiato importante de conhecimento entre os estudantes de medicina no que se refere a relação já desmitificada do autismo com a vacinação e as principais ferramentas de rastreio da doença. Ademais, grande parte dos estudantes não se sentem preparados para atender um portador do transtorno e seus familiares de forma que ações educacionais intervencionistas de qualidade, inquestionavelmente, podem acrescentar e aprimorar o conhecimento e a confiança dos estudantes de medicina.
Método alternativo para a determinação da consistência em argamassas de revestimento
Authors: Lima Karina Paula Barbosa de Andrade , Cunha Ana Luíza Xavier , Brito Eyshila Paloma Costa de , Gomes Lucas Ítalo Santos , Rocha Liliane Guimarães , Moraes Alex Souza , Araújo Fernanda Wanderley Correa de , Holanda Romildo Morant de
Published: May 2023

A trabalhabilidade de argamassas de revestimento está diretamente ligada à qualidade da aplicação e pela aderência ao substrato, sendo a principal propriedade a ser considerada em estado fresco. Os equipamentos de laboratório são bens dispendiosos, e que muitas vezes não cabem no orçamento das universidades. Propõe-se avaliar um método alternativo para determinação de índices de consistência em argamassas de revestimento, visando ampliar o acesso ao desenvolvimento de pesquisas. Foram produzidos dois traços de argamassas de revestimento, o de 1:1:6 (A-T1) e o de 1:2:9 (A-T2), e comparados com uma argamassa industrializada (A-IND). Desenvolvido e calibrado, o equipamento adaptado foi utilizado nos ensaios de consistência e as relações água/aglomerantes foram definidas. Então, foram moldados corpos de prova cilíndricos para avaliação da resistência à compressão. Os dados do ensaio mecânico foram usados na análise de variância e no teste de médias de Tukey. Utilizando espalhamentos de 260 ± 5 mm, a resistência à compressão não apresentou diferença significativa entre a argamassa industrializada e a A-T1, parâmetro que ratifica a aplicabilidade do método.
Oncocercose: a doença tropical negligenciada que acomete a Etnia Yanomami
Authors: Viana Felipe Savio de Souza , Freires Breno Spinassé , Oliveira Jorge Luiz Ribeiro de , Nascimento José Valdemir do , Souza Iara Leão Luna de
Published: May 2023

A oncocercose, doença causada pela Onchocerca volvulus é transmitida via dípteros hematófagos do gênero Simulium, também conhecidos como “moscas negras” ou “borrachudos”. Essa doença se desenvolve no ser humano e pode causar dermatite oncocercosa, além de evoluir para a cegueira, fato que justifica ser conhecida, popularmente, como “cegueira dos rios”. Ela está elencada no grupo de Doenças Tropicais Negligenciadas e tem como meta de erradicação o ano de 2025. O objetivo deste estudo foi avaliar a incidência de oncocercose na Terra Indígena Yanomami e Ye`kwana, principal foco de concentração dessa doença nas Américas. Para isso, foi realizada uma revisão de literatura nas bases de dados Medline, PubMed e Scielo, além dos boletins epidemiológicos nacionais. Nesse estudo, observou-se que entre os Yanomami esta doença é considerada endêmica e, apesar de vários programas de controle lançados local e mundialmente, esses grupos indígenas continuam apresentando casos da doença, devido à dificuldade dos serviços de saúde indígena em acessar os grupos indígenas para realizar cobertura preventiva em toda a população de forma adequada, bem como, aspectos socioculturais marcado pela mobilidade territorial que caracteriza este grupo étnico. A problemática dessa doença é a presença de nódulos subcutâneos, erupção cutânea, gerodermia e a cegueira. Logo, ressalta-se a persistência da oncocercose entre Yanomamis, que continuam enfrentando problemas devido a oncocercose, sendo estes, constantemente, negligenciados pela saúde pública brasileira.
Laserterapia no tratamento coadjuvante da necrose tecidual decorrente do uso de preenchedores dérmicos
Authors: Barbedo Alessandra , Suguihara Roberto Teruo , Muknicka Daniella Pilon
Published: May 2023

O aumento da expectativa de vida da população trouxe à tona os efeitos do envelhecimento cutâneo e despertaram o interesse em tratamentos de rejuvenescimento da pele. Os preenchimentos de tecidos moles com ácido hialurônico ocupam o segundo lugar entre os procedimentos estéticos pouco invasivos, estando atrás apenas da aplicação de toxina botulínica. O uso generalizado de preenchimentos dérmicos para alcançar o rejuvenescimento, levou a um aumento nos relatos de complicações associadas. Em casos danos vasculares com preenchimentos com ácido hialurônico, o uso precoce e intensivo da hialuronidase é altamente recomendado para limitar os comprometimentos teciduais. A laserterapia aparece como terapia de escolha no tratamento das lesões das feridas pois diminui consideravelmente o tempo de cicatrização, tem ação antimicrobiana e aumenta a circulação sanguínea local. O objetivo desse trabalho é oferecer uma revisão de literatura para basear os profissionais no estudo das complicações advindas dos preenchimentos faciais e servir de base para futuros estudos na área. Conclui-se com essa revisão de literatura que, apesar dos preenchimentos com ácido hialurônico serem considerados um procedimento seguro, o profissional precisa estar habilitado e conhecer profundamente anatomia e os materiais injetáveis. Detectar os primeiros sinais de intercorrências e agir de maneira mais precoce, tem se mostrado de extrema importância além de saber empregar as melhores medidas terapêuticas, o que pode evitar danos irreversíveis ao paciente.
The Meaning of Register in Yoga from a Sociolinguistic Perspective
Authors: Lailiyah Nur , Waryanti Endang
Published: May 2023

This study describes the form and meaning of registers in yoga in Kediri and explores the influence on yoga practitioners (yogis). The data sources for this research consisted of informants, including Acarya (instructors) and Yogis, while the data was in the form of lexicons uttered by Yogis and Acarya. Data were collected by observing techniques with advanced techniques; listening, engaging, and talking. The data analysis technique uses the theory of register forms resulting from a combination adapted to the register forms in yoga. This study found that there were 53 registers in yoga exercises consisting of two forms, namely, single and complex. There are 29 singular forms and 24 complex forms. The yoga register also strongly influences Yogis (doers), including spirituality, attitudes, and  relationships with others. Also, it overcomes health problems faced daily which focus on meditation activities. Meanwhile, the meaning of register in the choice of speech style is intended by Acharya to inspire enthusiasm and freshness in communicating; besides that, it also marks a communication function that has the uniqueness of being a registered marker that has a specific meaning based on context.
Agroforestry—a key tool in the climate-smart agriculture context: a review on coconut cultivation in Sri Lanka
Authors: Dissanayaka D. M. N. S. , Dissanayake D. K. R. P. L. , Udumann S. S. , Nuwarapaksha T. D. , Atapattu Anjana J.
Published: May 2023

Long-term monoculture of coconuts has resulted in several land-use-related concerns, such as decreasing land productivity, degraded soil, and ineffective resource utilization on a local and global level. Modifying traditional coconut farming with agroforestry concepts is a well-suited predominant nature-based solution for Sri Lanka as well as for other coconut-growing countries to achieve environmental, social, and economic benefits. By intentionally and intensively integrating annual and perennial plants with farm animals in a dynamic and interactive manner, this land-use system creates a sustainable harmonious mini-ecosystem with landscape restoration. Agroforestry mixed with coconut cultivation decreases the risk of crop failure, generates additional income sources, and balances the ecosystem functions by increasing species richness, enhancing soil physical, biological, and chemical properties, opening new carbon sequestration pathways, purifying air and water sources, and being an excellent feedstock source for bioenergy generation. This environmentally friendly farming will promote the Kyoto Protocol and lessen global warming by limiting the atmospheric buildup of greenhouse gases. A proper and accurate plan is required to implement a successful and profitable long-lived coconut-based agroforestry system. The objective of this paper is to recognize the various agroforestry concepts applicable to coconut-based farming, highlight the wide range of benefits and ecosystem services that can be gained through in-situ and ex-situ agroforestry practices, and explore the challenges that may arise during the integration of agroforestry techniques into a coconut-based farming system.
Sulfasalazine induces autophagy inhibiting neointimal hyperplasia following carotid artery injuries in mice
Authors: Zhang Weichang , Yan Cheng , Xiao Yangyan , Sun Yuxin , Lin Youjun , Li Qinglong , Cai Wenwu
Published: May 2023

Background: Neointimal hyperplasia (NH) is a crucial pathophysiological feature in vascular transplant and in-stent restenosis. Excessive proliferation and migration of vascular smooth muscle cells (VSMCs) play important roles in neointimal hyperplasia. This study aims to explore the potentialities and mechanism of sulfasalazine (SSZ) in the prevention of restenosis.

Methods: Sulfasalazine was encapsulated in nanoparticles made of poly (lactic-co-glycolic acid) (PLGA). In vivo, carotid ligation injury was induced in mice to induce Neointimal hyperplasia, with or without sulfasalazine containing nanoparticles (NP-SSZ) treatment. After 4 weeks, the arteries were collected for histology, immunofluorescence, Western blotting (WB) and qRT-PCR. In vitro, vascular smooth muscle cells were treated with TNF-α to induce cell proliferation and migration, followed by SSZ or vehicle treatment. WB was performed to further explore its mechanism.

Results: The ratio of intima to media thickness (I/M) was increased after ligation injury on day 28, while the ratio was significantly reduced in the NP-SSZ treatment group. The dual positive nuclei of Ki-67 and α-SMA were 47.83% ± 9.15%, whereas only 29.83% ± 5.98% in the NP-SSZ-treated group (p < 0.05). Both MMP-2 and MMP-9 were decreased in the NP-SSZ treatment group (p < 0.05, p < 0.05, respectively) compared to the control group. The levels of the targeted inflammatory genes (TNF-α, VCAM-1, ICAM-1, MCP-1) were lower in the NP-SSZ treatment group compared with the control group. In vitro, the proliferating cell nuclear antigen (PCNA) expression was significantly decreased in the SSZ treatment group. The cell viability of VSMCs was markedly increased in the TNF-α treatment group, whereas sulfasalazine treatment inhibited this effect. LC3 II and P62 protein expression were higher in the SSZ group than in the vehicle group both in vitro and in vivo. The phosphorylation of NF-kB (p-NF-kB) and the phosphorylation of mTOR (p-mTOR) were decreased in the TNF-α+ SSZ group, whereas the P62 and LC3 II expression levels were increased. However, the expression level of p-mTOR, P62, and LC3 II was reversed after co-treatment with the agonist of mTOR MHY1485, whereas the p-NF-kB expression level was unchanged.

Conclusion: sulfasalazine inhibited vascular smooth muscle cells proliferation and migration in vitro and Neointimal hyperplasia in vivo through NF-kB/mTOR-mediated autophagy.
Rethinking the potential and necessity of drug delivery systems in neovascular age-related macular degeneration therapy
Authors: Huang Xi , Zhang Li , Fu Yanyan , Zhang Meixia , Yang Qian , Peng Jinrong
Published: May 2023

Age-related macular degeneration (AMD) is the predominant threat to human vision and ultimately results in blindness. With the increase in the aging population, it has become a more crucial issue to human health. AMD is a multifactorial disease with the unique feature of uncontrollable angiogenesis during initiation and progression. Although increasing evidence indicates that AMD is largely hereditary, the predominant efficient treatment is antiangiogenesis, which mainly involves VEGF and HIF-α as therapeutic targets. The repeated administration of this treatment over the long term, generally through intravitreal injection, has called for the introduction of long-term drug delivery systems, which are expected to be achieved by biomaterials. However, the clinical results of the port delivery system indicate that the optimization of medical devices toward prolonging the activities of therapeutic biologics in AMD therapy seems more promising. These results indicate that we should rethink the possibility and potential of biomaterials as drug delivery systems in achieving long-term, sustained inhibition of angiogenesis in AMD therapy. In this review, the etiology, categorization, risk factors, pathogenesis, and current clinical treatments of AMD are briefly introduced. Next, the development status of long-term drug delivery systems is discussed, and the drawbacks and shortages of these systems are emphasized. By comprehensively considering the pathological aspect and the recent application of drug delivery systems in AMD therapy, we hope to find a better solution for the further development of long-term therapeutic strategies for AMD.
α-Synuclein is required for sperm exocytosis at a post-fusion stage
Authors: Buzzatto Micaela Vanina , Berberián María Victoria , Di Bartolo Ary Lautaro , Masone Diego , Tomes Claudia Nora
Published: May 2023

The sperm acrosome is a large dense-core granule whose contents are secreted by regulated exocytosis at fertilization through the opening of numerous fusion pores between the acrosomal and plasma membranes. In other cells, the nascent pore generated when the membrane surrounding a secretory vesicle fuses with the plasma membrane may have different fates. In sperm, pore dilation leads to the vesiculation and release of these membranes, together with the granule contents. α-Synuclein is a small cytosolic protein claimed to exhibit different roles in exocytic pathways in neurons and neuroendocrine cells. Here, we scrutinized its function in human sperm. Western blot revealed the presence of α-synuclein and indirect immunofluorescence its localization to the acrosomal domain of human sperm. Despite its small size, the protein was retained following permeabilization of the plasma membrane with streptolysin O. α-Synuclein was required for acrosomal release, as demonstrated by the inability of an inducer to elicit exocytosis when permeabilized human sperm were loaded with inhibitory antibodies to human α-synuclein. The antibodies halted calcium-induced secretion when introduced after the acrosome docked to the cell membrane. Two functional assays, fluorescence and transmission electron microscopies revealed that the stabilization of open fusion pores was responsible for the secretion blockage. Interestingly, synaptobrevin was insensitive to neurotoxin cleavage at this point, an indication of its engagement in cis SNARE complexes. The very existence of such complexes during AE reflects a new paradigm. Recombinant α-synuclein rescued the inhibitory effects of the anti-α-synuclein antibodies and of a chimeric Rab3A-22A protein that also inhibits AE after fusion pore opening. We applied restrained molecular dynamics simulations to compare the energy cost of expanding a nascent fusion pore between two model membranes and found it higher in the absence than in the presence of α-synuclein. Hence, our results suggest that α-synuclein is essential for expanding fusion pores.
Venetoclax durable response in adult relapsed/refractory Philadelphia-negative acute lymphoblastic leukemia with JAK/STAT pathway alterations
Authors: Ferrari Anna , Cangini Delia , Ghelli Luserna di Rorà Andrea , Condorelli Annalisa , Pugliese Marta , Schininà Giovanni , Cosentino Sebastiano , Fonzi Eugenio , Domizio Chiara , Simonetti Giorgia , Leotta Salvatore , Milone Giuseppe , Martinelli Giovanni
Published: May 2023

High-risk relapsed/refractory adult Philadelphia-negative (Ph−) B-cell acute lymphoblastic leukemia (B-ALL) is a great challenge due to limited possibilities to achieve and maintain a complete response. This also applies to cases with extramedullary (EM) involvement that have poor outcomes and no accepted standard therapeutic approaches. The incidence of EM localization in relapsed/refractory B-ALL is poorly investigated: data on patients treated with blinatumomab reported a 40% rate. Some responses were reported in EM patients with relapsed/refractory B-ALL treated with inotuzumab ozogamicin or CAR-T. However, molecular mechanisms of response or refractoriness are usually investigated neither at the medullary nor at EM sites. In the complex scenario of pluri-relapsed/refractory B-ALL patients, new target therapies are needed. Our analysis started with the case of an adult pluri-relapsed Ph− B-ALL patient, poorly sensitive to inotuzumab ozogamicin, donor lymphocyte infusions, and blinatumomab in EM disease, who achieved a durable/complete response after treatment with the BCL2-inhibitor venetoclax. The molecular characterization of medullary and EM samples revealed a tyrosine kinase domain JAK1 mutation in the bone marrow and EM samples at relapse. By comparing the expression level of BCL2- and JAK/STAT pathway-related genes between the patient samples, 136 adult JAK1wt B-ALL, and 15 healthy controls, we identified differentially expressed genes, including LIFR, MTOR, SOCS1/2, and BCL2/BCL2L1, that are variably modulated at diverse time points and might explain the prolonged response to venetoclax (particularly in the EM site, which was only partially affected by previous therapies). Our results suggest that the deep molecular characterization of both medullary and EM samples is fundamental to identifying effective and personalized targeted therapies.
Single-cell atlas of dental pulp stem cells exposed to the oral bacteria Porphyromonas gingivalis and Enterococcus faecalis
Authors: Zhang Wen , Xu Tiansong , Li Xueying , Zhang Yifei , Zou Xiaoying , Chen Feng , Yue Lin
Published: May 2023

Introduction:Porphyromonas gingivalis and Enterococcus faecalis promote the development of pulpitis and periapical periodontitis. These bacteria are difficult to eliminate from the root canal systems, leading to persistent infection and poor treatment outcomes. We explored the response of human dental pulp stem cells (hDPSCs) to bacterial invasion and the mechanisms underlying the impact of residual bacteria on dental pulp regeneration.

Methods: Single-cell sequencing was used to categorize the hDPSCs into clusters based on their response to P. gingivalis and E. faecalis. We depicted a single-cell transcriptome atlas of hDPSCs stimulated by P. gingivalis or E. faecalis.

Results: The most differentially expressed genes in the Pg samples were THBS1, COL1A2, CRIM1, and STC1, which are related to matrix formation and mineralization, and HILPDA and PLIN2, which are related to the cellular response to hypoxia. A cell cluster characterized by high expression levels of THBS1 and PTGS2 was increased after P. gingivalis stimulation. Further signaling pathway analysis showed that hDPSCs prevented P. gingivalis infection by regulating the TGF-β/SMAD, NF-κB, and MAPK/ERK signaling pathways. Differentiation potency and pseudotime trajectory analyses showed that hDPSCs infected by P. gingivalis undergo multidirectional differentiation, particularly to the mineralization-related cell lineage. Furthermore, P. gingivalis can create a hypoxia environment to effect cell differentiation. The Ef samples were characterized by the expression of CCL2, which is related to leukocyte chemotaxis, and ACTA2, which is related to actin. There was an increased proportion of a cell cluster that was similar to myofibroblasts and exhibited significant ACTA2 expression. The presence of E. faecalis promoted the differentiation of hDPSCs into fibroblast-like cells, which highlights the role of fibroblast-like cells and myofibroblasts in tissue repair.

Discussion: hDPSCs do not maintain their stem cell status in the presence of P. gingivalis and E. faecalis. They differentiate into mineralization-related cells in the presence of P. gingivalis and into fibroblast-like cells in the presence of E. faecalis. We identified the mechanism underlying the infection of hDPSCs by P. gingivalis and E. faecalis. Our results will improve understanding of the pathogenesis of pulpitis and periapical periodontitis. Furthermore, the presence of residual bacteria can have adverse effects on the outcomes of regenerative endodontic treatment.
Epigenetic and transcriptomic alterations in the ClC-3-deficient mice consuming a normal diet
Authors: Jing Zhenghui , Zhang Haifeng , Wen Yunjie , Cui Shiyu , Ren Yuhua , Liu Rong , Duan Sirui , Zhao Wenbao , Fan Lihong
Published: May 2023

Introduction: Metabolic disorders are an important health concern that threatens life and burdens society severely. ClC-3 is a member of the chloride voltage-gated channel family, and ClC-3 deletion improved the phenotypes of dysglycemic metabolism and the impairment of insulin sensitivity. However, the effects of a healthy diet on transcriptome and epigenetics in ClC-3−/− mice were not explained in detail.

Methods: Here, we performed transcriptome sequencing and Reduced Representation Bisulfite Sequencing for the liver of 3 weeks old WT and ClC-3−/− mice consuming a normal diet to insight into the epigenetic and transcriptomic alterations of ClC-3 deficient mice.

Results: In the present study, we found that ClC-3−/− mice that were younger than 8 weeks old had smaller bodies compared to ClC-3+/+ mice with ad libitum self-feeding normal diet, and ClC-3−/− mice that were older than 10 weeks old had a similar body weight. Except for the spleen, lung, and kidney, the average weight of the heart, liver, and brain in ClC-3−/− mice was lower than that in ClC-3+/+ mice. TG, TC, HDL, and LDL in fasting ClC-3−/− mice were not significantly different from those in ClC-3+/+ mice. Fasting blood glucose in ClC-3−/− mice was lower than that in ClC-3+/+ mice; the glucose tolerance test indicated the response to blood glucose increasing for ClC-3−/− mice was torpid, but the efficiency of lowering blood glucose was much higher once started. Transcriptomic sequencing and reduced representation bisulfite sequencing for the liver of unweaned mice indicated that ClC-3 deletion significantly changed transcriptional expression and DNA methylation levels of glucose metabolism-related genes. A total of 92 genes were intersected between DEGs and DMRs-targeted genes, of which Nos3, Pik3r1, Socs1, and Acly were gathered in type II diabetes mellitus, insulin resistance, and metabolic pathways. Moreover, Pik3r1 and Acly expressions were obviously correlated with DNA methylation levels, not Nos3 and Socs1. However, the transcriptional levels of these four genes were not different between ClC-3−/− and ClC-3+/+ mice at the age of 12 weeks.

Discussion: ClC-3 influenced the methylated modification to regulate glucose metabolism, of which the gene expressions could be driven to change again by a personalized diet-style intervention.
Synthesis, anti-aging and mechanism of magnolol derivatives
Authors: Pang Xinxin , Mao Li , Ye Danyang , Wang Wenqi , Yang Hongliu , Fan Xiaoxiao , Yang Yuping , Su Zhijun , Ma Tao , Sun Mingqian , Liu Yonggang
Published: May 2023

Magnolol (M), a hydroquinone containing an allyl side chain, is one of the major active components of Houpoea officinalis for antioxidation and anti-aging. To enhance the antioxidant activity of magnolol, the different sites of magnolol were structurally modified in this experiment, and a total of 12 magnolol derivatives were obtained. Based on the preliminary exploration of the anti-aging effect of magnolol derivatives in a Caenorhabditis elegans (C. elegans) model. Our results indicate that the active groups of magnolol exerting anti-aging effects were allyl groups and hydroxyl on the phenyl. Meanwhile, the anti-aging effect of the novel magnolol derivative M27 was found to be significantly superior to that of magnolol. To investigate the effect of M27 on senescence and the potential mechanism of action, we investigated the effect of M27 on senescence in C. elegans. In this study, we investigated the effect of M27 on C. elegans physiology by examining body length, body curvature and pharyngeal pumping frequency. The effect of M27 on stress resistance in C. elegans was explored by acute stress experiments. The mechanism of M27 anti-aging was investigated by measuring ROS content, DAF-16 nuclear translocation, sod-3 expression, and lifespan of transgenic nematodes. Our results indicate that M27 prolonged the lifespan of C. elegans. Meanwhile, M27 improved the healthy lifespan of C. elegans by improving pharyngeal pumping ability and reducing lipofuscin accumulation in C. elegans. M27 increased resistance to high temperature and oxidative stress in C. elegans by reducing ROS. M27 induced DAF-16 translocation from cytoplasm to nucleus in transgenic TJ356 nematodes and upregulated the expression of sod-3 (a gene downstream of DAF-16) in CF1553 nematodes. Furthermore, M27 did not extend the lifespan of daf-16, age-1, daf-2, and hsp-16.2 mutants. This work suggests that M27 may ameliorate aging and extend lifespan in C. elegans through the IIS pathway.
Variation in CD8 T cell IFNγ differentiation to strains of Toxoplasma gondii is characterized by small effect QTLs with contribution from ROP16
Authors: Kongsomboonvech Angel K. , García-López Laura , Njume Ferdinand , Rodriguez Felipe , Souza Scott P. , Rosenberg Alex , Jensen Kirk D. C.
Published: May 2023

Introduction

Toxoplasma gondii induces a strong CD8 T cell response characterized by the secretion of IFNγ that promotes host survival during infection. The initiation of CD8 T cell IFNγ responses in vitro differs widely between clonal lineage strains of T. gondii, in which type I strains are low inducers, while types II and III strains are high inducers. We hypothesized this phenotype is due to a polymorphic “Regulator Of CD8 T cell Response” (ROCTR).

Methods

Therefore, we screened F1 progeny from genetic crosses between the clonal lineage strains to identify ROCTR. Naïve antigen-specific CD8 T cells (T57) isolated from transnuclear mice, which are specific for the endogenous and vacuolar TGD057 antigen, were measured for their ability to become activated, transcribe Ifng and produce IFNγ in response to T. gondii infected macrophages.

Results

Genetic mapping returned four non-interacting quantitative trait loci (QTL) with small effect on T. gondii chromosomes (chr) VIIb-VIII, X and XII. These loci encompass multiple gene candidates highlighted by ROP16 (chrVIIb-VIII), GRA35 (chrX), TgNSM (chrX), and a pair of uncharacterized NTPases (chrXII), whose locus we report to be significantly truncated in the type I RH background. Although none of the chromosome X and XII candidates bore evidence for regulating CD8 T cell IFNγ responses, type I variants of ROP16 lowered Ifng transcription early after T cell activation. During our search for ROCTR, we also noted the parasitophorous vacuole membrane (PVM) targeting factor for dense granules (GRAs), GRA43, repressed the response suggesting PVM-associated GRAs are important for CD8 T cell activation. Furthermore, RIPK3 expression in macrophages was an absolute requirement for CD8 T cell IFNγ differentiation implicating the necroptosis pathway in T cell immunity to T. gondii.

Discussion

Collectively, our data suggest that while CD8 T cell IFNγ production to T. gondii strains vary dramatically, it is not controlled by a single polymorphism with strong effect. However, early in the differentiation process, polymorphisms in ROP16 can regulate commitment of responding CD8 T cells to IFNγ production which may have bearing on immunity to T. gondii.
TREK channels in Mechanotransduction: a Focus on the Cardiovascular System
Authors: Herrera-Pérez Salvador , Lamas José Antonio
Published: May 2023

Mechano-electric feedback is one of the most important subsystems operating in the cardiovascular system, but the underlying molecular mechanism remains rather unknown. Several proteins have been proposed to explain the molecular mechanism of mechano-transduction. Transient receptor potential (TRP) and Piezo channels appear to be the most important candidates to constitute the molecular mechanism behind of the inward current in response to a mechanical stimulus. However, the inhibitory/regulatory processes involving potassium channels that operate on the cardiac system are less well known. TWIK-Related potassium (TREK) channels have emerged as strong candidates due to their capacity for the regulation of the flow of potassium in response to mechanical stimuli. Current data strongly suggest that TREK channels play a role as mechano-transducers in different components of the cardiovascular system, not only at central (heart) but also at peripheral (vascular) level. In this context, this review summarizes and highlights the main existing evidence connecting this important subfamily of potassium channels with the cardiac mechano-transduction process, discussing molecular and biophysical aspects of such a connection.
Mapping alteration zones in the Southern section of Yulong copper belt, Tibet using multi-source remote sensing data
Authors: Wu Changyu , Dai Jingjing , Zhou Aorigele , He Liang , Tian Bin , Lin Wenhai , Zhao Tianchen , Bai Longyang
Published: May 2023

Methods for extracting mineralized alteration information using remote sensing images have recently become both efficient and cost-effective. Technology involving the extraction of alteration information based on multi-spectral data has been widely practiced and effectively verified. In recent years, research on fine mineral extraction methods based on hyperspectral data has also been rapidly developing. The Yulong copper belt is a porphyry copper belt located in China with high prospects for mineralization. However, most previous studies focused on the northern section of the Yulong copper belt, with limited exploration of the southern section. In this study, alteration information of the southern section of the Yulong copper belt was extracted from remote sensing data from Landsat-8 OLI, ASTER, and ZY1-02D, and the prospecting potential of this area was evaluated. Principal component analysis was used to extract iron oxide and hydroxyl alteration from Landsat-8 data, in addition to Al hydroxyl and propylitic alterations from ASTER data. Considering the challenge of the extraction of too many pseudo-anomalies using traditional methods, the mixture-tuned matched filtering (MTMF) method was used to more accurately extract iron oxide alterations. Regarding hyperspectral data, the minimum noise fraction and pure pixel index algorithms were used to extract white mica and carbonatite endmembers. The MTMF method was also used for alteration mapping, which took advantage of sub-pixel abundance mapping to finely divide the white mica and carbonatite alterations into five classes. The extraction results of multi-source remote sensing data were then compared and analyzed to avoid occasional single-image extraction results, which confirmed the superiority of the hyperspectral remote sensing and MTMF methods. Combined with field verification, the mineralization alteration information coincided with the spatial location of the Secuo, Mamupu, and Jicuo deposits, which confirmed the accuracy of alteration information extraction. The results of this study confirmed the application potential of remote sensing alteration information extraction in the field of mineral resource exploration. The results have important reference significance for further geological prospecting and exploration in the southern section of the Yulong copper belt.
Efficacy and Safety of intravenous monoclonal antibodies in patients with moderate-to-severe active Graves’ophthalmopathy: a systematic review and meta-analysis
Authors: Hu Yu , Chen Jinhua , Lin Ken , Yu Xijie
Published: May 2023

Backgrounds

The effects of various treatments on Graves’ ophthalmopathy (GO) have been studied. As monoclonal antibodies (mAbs) have been proposed for the treatment of moderate to severe GO, direct comparisons between different mAbs are lacking.We therefore conducted this meta-analysis to objectively compare the efficacy and safety of intravenous mAbs.

Methods

To identify eligible trials, references published before September 2022 were electronically searched in PubMed, Web of Science, Pubmed, Embase,Cochrane Library, CBM, CNKI,Wan-Fang and ICTRP databases.The Newcastle-Ottawa scale (NOS) and the Cochrane Risk of Bias Assessment Tool were used to assess the risk of bias of the original studies.The primary and secondary outcomes were the response and inactivation rates, with the secondary outcomes being the clinical activity score (CAS),the improvement of proptosis and diplopia improvement,and the adverse event rate. Publication bias was evaluated, along with subgroup and sensitivity analyses.

Results

A total of 12 trials with 448 patients were included. The meta-analysis showed that TCZ (tocilizumab) was most likely to be the best treatment in terms of response according to indirect contrast, followed by TMB (teprotumumab) and RTX (rituximab).TCZ, followed by TMB and RTX, was also most likely to be the best treatment in terms of reducing proptosis. In terms of improving diplopia, TMB was most likely to be the best treatment, followed by TCZ and RTX.TCZ was the highest probability of safety, followed by RTX and TMB.

Conclusions

Based on the best available evidence,TCZ should be the preferred treatment for moderate to severe GO.In the absence of head-to-head trials,indirect comparisons of treatments are routinely used to estimate the effectiveness of the treatments of interest. In addition,the optimal dose and potential mechanism of action of monoclonal antibodies remain to be established,and it is encouraging that the treatment paradigm for GO may change in the future.

This study was designed in accordance with the Preferred Reporting Items for conducting Systematic Reviews and Meta-Analyses (PRISMA)(27).

Systematic Review Registration

http://www.crd.york.ac.uk/prospero, identifier CRD42023398170.