bluuebunny/crossref_metadata_2025 huggingface dataset:
PENINGKATAN KREATIVITAS ANAK USIA DINI MELALUI CERITA BERGAMBAR PADA KELOMPOK B DI PAUD NASYA
Authors: Syamsia  , Kamariah
Published: October 2023

Tujuan penelitian ini adalah mengetahui peningkatan kreativitas anak usia dini dengan metode membaca cerita bergambar di PAUD Nasya pada kelompok B. Studi ini menggunakan metode penelitian kualitatif. Metode penelitian ini merinci sejumlah variable yang terkait dengan masalah yang diteliti untuk memberikan gambaran menyeluruh tentang setting sosial dan untuk menjelaskan fenomena atau kenyataan sosial. Selanjutnya, peneliti menyajikan informasi yang relevan tentang kualitas diskriptif yang unik dan alamiah. Kualitas diskriptif ini benar-benar diperoleh dari pembelajaran yang dilakukan pada kelompok B, di PAUD Nasya. Sumber data yang diambil oleh peneliti termasuk kegiatan bermain anak saat guru bercerita dengan media buku cerita bergambar. Respon anak-anak ketika ibu guru bercerita juga dicatat sebagai informan utama. Selain itu, anak-anak dan guru memberikan penjelasan melalui observasi, wawancara, dan dokumentasi. Hasil pengamatan tentang penggunaan media cerita bergambar menunjukkan bahwa kemampuan kreatif anak usia dini benar-benar meningkat. Kreatifitas tersebut tumbuh menjadi imajinasi anak dalam menggambar.
NILAI PENDIDIKAN KARAKTER DENGAN DIRI SENDIRI DALAM NOVEL SEKUNTUM CINTA UNTUK ADELIA KARYA EVA LIANA
Authors: Janah Nor , Komalasari Ida , Aswadi Dana
Published: October 2023

Pendidikan karakter dalam konteks sekarang sangat relevan untuk mengatasi krisis moral yang sedang melanda negara kita. Krisis-krisis moral itu adalah: pergaulan bebas; maraknya angka kekerasan anak-anak dan remaja; kejahatan terhadap teman; pencurian; tawuran pelajaran; kecurangan ujian; penyalahgunaan obat-obatan; pornografi; pelecehan seksual; tindak korupsi, mengunsumsi bahkan menjadi pencandu narkoba, menjadi kelompok geng motor yang anarkis, dan lain-lain. Bisa kita amati dalam kehidupan sehari-hari.

Penelitian ini, peneliti menggunakan pendekatan sosiologi sastra. Jenis penelitian yang digunakan dalam penelitian ini adalah penelitian kepustakaan. Disebut penelitian kepustakaan karena data-data atau bahan yang diperlukan dalam menyelesaikan penelitian ini berasal dari perpustakaan baik berupa buku, jurnal, kamus, dokumen, dan majalah. Metode adalah cara bagaimana penelitian itu dilakukan. Metode yang digunakan dalam penelitian ini adalah metode deskriptif analisis.

Hasil penelitian nilai-nilai pendidikan karakter dengan diri sendiri dalam novel Sekuntum Cinta untuk Adelia Karya Eva Liana mencakup nilai sebagai berikut. (1) jujur, (b) disiplin, (c) kerja keras, (d) kreatif, (e) mandiri, (f) gemar membaca, dan (g) tanggung jawab.
PENINGKATAN KETERAMPILAN MEMBACA PERMULAAN DENGAN MENGGUNAKAN MEDIA KARTU KATA PADA SISWA KELAS 1 SD NEGERI RUMINTIN 2 TAHUN 2022
Authors: Normaniah
Published: October 2023

Penelitian ini bertujuan untuk meningkatkan keterampilan membaca permulaan dengan menggunakan media kartu kata pada siswa kelas 1 SD Negeri  Rumintin 2  Kecamatan Tapin Selatan Kabupaten Tapin. Jenis penelitian ini adalah Penelitian Tindakan Kelas kolaborasi yang dilakukan sebanyak dua siklus. Desain penelitian menggunakan model Kemmis Mc. Teggart dengan subjek penelitian siswa kelas 1 yang berjumlah 16 siswa. Teknik pengumpulan data menggunakan 1) tes membaca lisan dan tes tertulis memahami bacaan, 2) observasi, dan 3) dokumentasi. Teknik analisis data menggunakan analisis statistik deskriptif yaitu dengan mencari rerata. Indikator keberhasilan siswa yang harus dicapai dengan rerata kelas 70 dan ketuntasannya 80%.

   Hasil penelitian menunjukkan bahwa pembelajaran membaca permulaan dengan menggunakan media kartu kata dapat meningkatkan keterampilan membaca siswa kelas 1 SD Negeri Rumintin Keterampilan membaca pada pra siklus sebesar 60,31 dan ketuntasanya 37,5%, pada siklus I meningkat menjadi 67,34 dengan ketuntasan 56,25%, peningkatan pada siklus II 72,66 dengan ketuntasan 93,75%. Pada tindakan ini keterampilan membaca siswa dengan lafal, intonasi dan membaca memahami meningkat hingga mencapai kriteria ketuntasan yang ditetapkan yaitu dengan rata-rata kelas 70 dan ketuntasan kelas 80%. Pada siklus I digunakan kartu kata dengan ukuran 13 x 6 cm dan setiap kata dengan satu warna, pada siklus II digunakan kartu kata yang lebih lebih besar 18 x 6 cm dan setiap kata terdapat pemengaalan kata yang dipisahkan dengan warna yang berbeda.
ANALISIS KESANTUNAN BERBAHASA SISWA DI LINGKUNGAN PKBM SURYA MUDA TAHUN PEMBELAJARAN 2022/2023
Authors: Misna
Published: October 2023

Analisis Kesantunan Berbahasa di lingkungan PKBM Surya Muda. Penelitian ini membahas tentang kesantunan berbahasa di lingkungan PKBM Surya Muda. Penelitian ini dilakukan dalam dua tahap yaitu tahap pengumpulan data, tahap analisis data. Tahap pengumpulan data diadakan penelitian lapangan untuk mendapatkan data primer dengan menggunakan teknik observasi (pengamatan),teknik simak libat cakap, teknik rekaman. Sedangkan pada tahap analisis data, penulis menggunakan teknis analisis deskriptif. Analisis tersebut digunakan untuk memperoleh gambaran tentang kesantunan berbahasa PKBM Surya Muda. Hasil penelitian yang diperoleh menujukkan bahwa unsur kesopanan berbahasa masih kurang diterapkan dalam percakapan siswa tersebut. Hal ini menandakan bahwa ada berbagai macam faktor yang menyertai proses komunikasi. Diantaranya adalah situasi percakapan, objek yang dibicarakan dan individu pemakai bahasa yang terlibat, kurang mampu melihat ksesuaian dan ketetapan pemakaian kosakata dalam percakapan. Hal ini terlihat dari penerapan dalam percakapan melalui maksim kebijaksanaan, kedermawanan, penghargaan, kesederhanaan dan permufakatan. Dengan demikian dapat disimpulkan bahwa unsur kesopanan berbahasa masih kurang diterapkan dalam percakapan melalui maksim kebijaksanaan, kedermawanan, penghargaan, kesederhanaan dan permufakatan pada PKBM Surya Muda.
‘Viewless Forms’/ Form-of-Life: Death, Story and Poiēsis in Texts for Nothing
Authors: Carville Conor
Published: October 2023

Beckett’s thirteen short prose pieces Texts for Nothing seems to shuttle between two discrete worlds that somehow bear upon each other, although the nature of the relation between them is highly mobile. One possible approach to the work is through Beckett’s reference to the idea of a ‘form of life’ in TFN6: ‘Or to know it’s life still, a form of life, ordained to end, as others ended and will end’ ( Beckett, 1995 , 125). The phrase holds out the possibility of a graspable difference between the two worlds abovementioned: in one of them life has form, in the other, it does not. Beckett’s source for the term, which goes back to Goethe, is Ernst Cassirer’s Kant’s Life and Thought. ‘Form of life’ can also be found sporadically in Wittgenstein’s Philosophical Investigations and, more consistently in the work of Giorgio Agamben, to whose thought I appeal to at the end of this essay. But before that I consider in detail the way Texts for Nothing grapples with the question of how a form can be given to a life, and in particular the opposition between narrative and poesis that the work grapples with.
Before Play, With Play, After Play: The Shaping of ‘formal integrity’ in the Early Drafts of Play
Authors: Beloborodova Olga
Published: October 2023

The present essay argues that Beckett's concept of ‘formal integrity’, which he first articulated in his discussion of Film with the production team in 1964, was in fact shaped long before Film was on Beckett's writing desk. Rather, it emerged gradually during the early genesis of Play, the work that has often been associated with Film as the two were written around the same time and deal with similar themes. In order to make this point, the essay engages with the draft material in a recently discovered notebook that contains the earliest stage of the play's genesis – the manuscripts that were long considered lost and not recoverable. While paying due attention to the relevance to Play of the other works populating the notebook, the main focus lies on the development of what it terms Beckett's conceptual (rather than textual) writing style, which is a consequence of his quest for ‘formal integrity’. More specifically, the essay demonstrates that this ‘formal integrity’ goes beyond Beckett's extreme attention to Play's form (something that has been noted in literature), but hinges on correspondences between both formal and textual elements. In other words, it refers just as much to the content as it does to form, but content differently conceived as compared to his earlier plays.
BERAAT KARARININ İSTİNAF KANUN YOLUNDA BOZULMASI SONRASINDA VERİLEN MAHKÛMİYET KARARININ TEMYİZ EDİLEBİLİRLİĞİNE İLİŞKİN TARTIŞMA
Authors: BİRTEK Fatih
Published: October 2023

2016 yılı itibariyle Türk ceza muhakemesindeki yargılama sistemi üç dereceli hale gelmiştir. Bu sistem içerisinde, istinaf kanun yolu hem maddi hem de hukuki meselenin denetlendiği “ikinci derece” bir kanun yolu olarak işlev görmekte ve adil yargılanma hakkı açısından önemli bir güvence teşkil etmektedir.
İstinaf kanun yolunda, ilk derece mahkemesinin kararındaki hukuka ve usule aykırılıkların “düzeltilmesi” kural iken “bozma” istisnadır. Bu sebeple CMK’de bozma kararı verilebilecek haller sınırlı bir şekilde sayılmıştır. İlk derece mahkemelerinin, bozma kararına karşı direnmeleri mümkün olmadığından (CMK m. 284/1), bozmadan sonraki serbestlik kuralı uyarınca yeni bir karar verilmesi gerekmektedir.
Sanık hakkında verilen beraat kararının istinaf kanun yolunda bozulmasından sonra, ilk derece mahkemesinin “mahkûmiyet” kararı vermesi ve bu kararın da istinaf kanun yolunda kesinleşmesi söz konusu olabilecektir. Direnme yasağı nedeniyle, bozmadan sonra tesis olunan mahkûmiyet kararı bölge adliye mahkemesi ceza dairesinin kararı gibi değerlendirilerek, bozmadan sonra tesis olunan ve istinaf kanun yolunda kesinleşmesi gereken mahkûmiyet kararı bakımından, temyiz kanun yolunun açık olup olmadığı uygulamada tartışmalıdır.
ERMENİSTAN’IN KOLEKTİF GÜVENLİK ANTLAŞMASI ÖRGÜTÜ’NÜ (KGAÖ) II. DAĞLIK KARABAĞ SAVAŞI’NA DAHİL ETMEYE YÖNELİK EYLEMLERİNİN ULUSLARARASI HUKUK AÇISINDAN DEĞERLENDİRİLMESİ
Authors: İSAYEV Tuğçe
Published: October 2023

II. Dağlık Karabağ Savaşı esnasında Ermenistan KGAÖ’nün yanında yer alması için kolektif güvenlik mekanizmasını devreye sokmayı hedeflemiştir. Kolektif güvenlik mekanizmasının devreye girebilmesi için KGAÖ’ye üye devletlerden birine yönelik bir saldırı olması şarttır. Bu doğrultuda, Ermenistan II. Dağlık Karabağ Savaşı’nı Dağlık Karabağ’ın dışına ve kendi ülkesine doğru genişletmeye çalışmıştır. Ermenistan hedefine ulaşmak için II. Dağlık Karabağ Savaşı esnasında Dağlık Karabağ savaş alanının dışına, savaş alanından kilometrelerce uzakta olan Azerbaycan şehirlerine, sivil yerleşim yerlerine ve sivillere saldırmış, Azerbaycan’ın da aynı şekilde karşılık vermesini, Ermenistan şehirlerine, sivil yerleşim yerlerine ve sivillere saldırmasını beklemiştir. Çalışmada, Ermenistan’ın KGAÖ’yü II. Dağlık Karabağ Savaşı’na dahil etmeye yönelik eylemlerini uluslararası hukuk açısından değerlendirmek amaçlanmaktadır. Bu çalışma ile ulaşılan sonuç çerçevesinde Ermenistan’ın KGAÖ’yü II. Dağlık Karabağ Savaşı’na dahil etmeye yönelik eylemleri başarısız olmuştur. Ermenistan KGAÖ’yü II. Dağlık Karabağ Savaşı’na dahil etmeye yönelik eylemleri ile insancıl hukuk kurallarını ihlal etmiştir ve bu durum Ermenistan’ın uluslararası sorumluluğunun doğmasına sebep olmuştur.
HÜKÜMET DIŞI KURULUŞLARIN ULUSLARARASI ANTLAŞMA KURALLARININ OLUŞUMU VE UYGULANMASI SÜRECİNE ETKİLERİ
Authors: ÖZKERİM GÜNER Neslihan
Published: October 2023

İkinci Dünya Savaşından bu yana hükümet dışı kuruluşların (HDK) sayıları gittikçe artmaktadır. Bu kuruluşların ortak bir tanımı bulunmamaktadır; ancak özellikleri konusunda uzlaşılmıştır. 1990’ların başından beri uluslararası hukuk kişiliğinin kazanılması konusundaki çabalar yetersiz kalmışsa da gelişen uluslararası hukuk anlayışında hükümet dışı kuruluşların da uluslararası hukuk kişiliği tartışılmaktadır. Hükümet dışı kuruluşların uluslararası hukuk kurallarının oluşturulması ve uygulanması hususunda etkisi bulunmaktadır. Özellikle insancıl hukuk, insan hakları, çevrenin korunması alanlarında kamuoyu oluşturmaktan, konferansların düzenlenmesine, uluslararası antlaşmaların kaleme alınmasından, uygulanmasına kadar birçok süreçte doğrudan ya da dolaylı etkileri olduğu yadsınamaz. Çalışmada uluslararası antlaşma örneklerinden yola çıkılarak, hükümet dışı kuruluşların uluslararası antlaşma kurallarının oluşumu ve uygulanması süreçlerine etkileri incelenmiştir.
BLOKZİNCİR-KRİPTO VARLIK BAĞLANTILI YAYGIN SAHTEKARLIK TÜRLERİNİN DOLANDIRICILIK VE İLİŞKİLİ SUÇLAR YÖNÜNDEN ANALİZİ
Authors: BAŞBÜYÜK İsa
Published: October 2023

Blokzincir, akıllı sözleşme ve kripto varlıklar gibi teknolojik gelişmeler, bir taraftan kullanıcıların elektronik ortamda anonim ve aracısız işlem yapabilmesini mümkün kılarken, diğer taraftan malvarlığını hedef alan sahtekarlıkların işlenme yöntemine yeni bir boyut kazandırmıştır. En yaygın şekliyle “sözde kripto para borsaları, sahte kripto varlıklar, likidite boşaltma, fiyat manipülasyonu girişimleri, sözde yatırım ve madencilik uygulamaları” formunda karşılaşılan bu tarz sahtekarlıklar genelde dolandırıcılık suçuyla birlikte anılmaktadır. Ancak kripto varlık alanındaki yenilikçi vakıalar, yanlış beyan veya asılsız vaatlerle mağduru kandırarak menfaat sağlamaya ikna etmeyi yasaklayan Türk Ceza Kanunu m. 157’de tanımlanan dolandırıcılık suçunun kapsamını tartışmaya açmakta ve yeni düzenleme ihtiyacını gündeme getirmektedir. Bu çalışmanın konusu, öncelikle kripto varlık bağlantılı sahtekarlık olaylarını analiz edip, ortaya çıkış şekillerine göre sınıflandırmak; sonrasında ise sahtekarlık türü özelinde TCK m. 157’de düzenlenen dolandırıcılık suçunun uygulanabilirliğini test etmektir. Böylece dolandırıcılık suçunu tanımlayan düzenlemenin kripto varlık bağlantılı sahtekarlıklarla mücadelede yetersiz kaldığı noktaları ortaya çıkarmak ve yeni düzenlemede bulunması gereken özelliklere dikkat çekmek amaçlanmaktadır.
Inferno: The Human Mind Inflamed
Authors: Karmouty Eman
Published: October 2023

Many writers have been inspired by Dante’s Inferno; Tennyson, T. S. Eliot, Ezra Pound and Seamus Heaney. August Strindberg’s own Inferno, does not only record personal suffering and mental torture, but a period of doubt, when assailed by feelings of desperation and estrangement he set himself up as a scientist. It also casts some of his dramatic works, as The Father, Miss Julie and others, in different perspectives, allotting them alternative readings. .
Islamophobia and the Intellectuals
Authors: Al-Dabbagh Abdulla
Published: October 2023

In a widely-read report, Islamophobia has been defined as “an outlook or world-view involving an unfounded dread or dislike of Muslims, which results in practices of exclusion and discrimination”. Yet, it has led to considerable controversy among intellectuals in Britain recently. A number of writers and journalists have openly defended Islamophobia and identified themselves with it, expressing frankly racist attitudes towards Muslims in the process. This, in turn, has led a number of other writers and intellectuals to respond and to condemn those standpoints. What is interesting is that awareness of the racism inherent in Islamophobia, in its European as well as its American forms, has spread among mainstream public opinion in addition to the intellectuals. As for the academic circles, at least one full-length book on the subject plus numerous articles have been published in recent years and a number of conferences have been held devoted to it. This paper, focusing specifically on the British context, will trace the background to Islamophobia and gives other examples from Europe and the United States..
The Increase of Literal Translation: A Feature of Globalization
Authors: Moayad Tara
Published: October 2023

Due to globalization translation has become more vital than it has ever been in human life for the transmission of human knowledge and communication. In this paper I argue, by means of an analytical and deductive approach that it is literal translation in particular that is gaining pace. The aim of translation has become that of speed and cost-effectiveness, which resulted in numerous translation errors. The increase of literal translation can also be attributed to the global impact of the Lingua Franca-language of the global village. .
Konstruksi Pendengar Radio pada Masyarakat Indonesia (Studi Kasus pada Aplikasi Noice)
Authors: Hayati Kumala , Ariestanty Camelia
Published: October 2023

Kehadiran teknologi telah mengubah kehidupan manusia. Teknologi membuat hidup manusia menjadi semakin mudah. Teknologi telah membuat cara pendengar menikmati radio juga turut berubah. Lahirnya aplikasi Noice membuat radio bertransformasi menjadi bentuk digital. Tulisan ini akan menjelaskan bagaimana radio mengonstruksi pendengarnya dengan bentuk teknologi yang baru. Metode penelitian dalam tulisan ini adalah observasi dan wawancara mendalam pada beberapa informan. Hasil dari tulisan ini adalah pendengar mempunyai pilihan cara untuk mendengarkan radio yaitu melalui perangkat yang telah terpasang di mobil dan melalui gadget masing – masing (streaming). Pilihan konten juga penting bagi pendengar karena menyesuaikan dengan tujuan dari aktivitas mendengarkan radio itu sendiri. Hadirnya teknologi radio dalam bentuk aplikasi berbasis internet dapat memengaruhi perilaku, membentuk persepsi dan mengelola tindakan khalayak.

Kata kunci            : konvergensi, digitalisasi, radio, determinisme teknologi
Teachers’ approaches to social inclusion in second language teaching for adult migrants
Authors: Colliander Helena , Nordmark Sofia
Published: October 2023

Adult education has been used as a means to enhance citizens' opportunities to participate and be included in society, but adult education may also construe students as excluded. This study focuses on how teachers in second language education for migrants conceptualise and enact teaching for social inclusion. It draws on Fraser's concept of social justice and Biesta’s aims of sound education. The article is based on observations and interviews with teachers. The findings highlight that the teaching is enacted to develop the students’ language skills for formal qualification and everyday life as well as their knowledge of Civics and norms in Swedish society. Thus, conceptualising the students as emerging participants, lacking skills and knowledge as language users and citizens. This teaching enactment reflects qualification and socialisation as central aims of education, but less of subjectification processes. Consequently, social inclusion is conceptualised as migrants adjusting to society in predefined ways.
Algumas Reflexões Sobre Ritmo - Prólogo do livro “Rhythmic Mastery” de Alice Artzt
Authors: Tateishi Angel , Artzt Alice
Published: October 2023

Quando pensamos em encontrar tesouros, pensamos em uma longa jornada onde no fim encontram-se coisas valiosas escondidas e inatingíveis. Mas, às vezes, os tesouros estão bem na nossa frente, no primeiro passo da jornada. Esse é o caso quando lemos o livro "Rhythmic Mastery" de Alice Artztz. Em seu livro, encontramos um mapa do tesouro na terceira página, a página de agradecimentos. Nossa guia, Alice Artzt, nos instrui: "Gostaria de agradecer a Sergio Abreu por seus extensos conselhos durante a escrita deste livro e por sua inestimável colaboração no Prólogo." Assim temos o prólogo "Algumas Reflexões sobre o Ritmo", escrito por Alice Artztz e Sergio Abreu. Ali está o nosso tesouro, logo no início deste grande livro. E tal tesouro cultural deve ser trazido à luz e compartilhado. Essa é a razão de traduzir O prólogo para o português.
Validation of a minimally-invasive method for sampling epithelial-associated microorganisms on the rumen wall
Authors: Henniger Madison T. , Rowan Troy N. , Beever Jonathan E. , Mulon Pierre-Yves , Smith Joe S. , Voy Brynn H. , Wells Jim E. , Kuehn Larry A. , Myer Phillip R.
Published: October 2023

The rumen microbiome provides approximately 70% of the required energy for the host by converting low-quality feedstuffs into usable energy for ruminants. The energy produced by the microorganisms is subsequently absorbed through the rumen epithelium and used towards growth and energy maintenance. There is evidence that ruminal epimural microbes directly interact with the rumen epithelium, acting as an intermediary communicator between the rumen liquid fraction and the host. Epimural microbiota have been demonstrated to be distinct from the ruminal liquid microbiome and perform unique roles within the rumen environment. However, methods to sample epimural communities from the rumen wall are limited and typically invasive, requiring animal fistulation or harvesting. To characterize the epimural communities present on the rumen wall, a novel and minimally-invasive surgical method was developed to swab the epithelium of the ventral sac of the rumen. The objective of this study was to validate this sampling method by comparing epimural and liquid fraction bacterial communities. During a 70-day feeding trial, Angus steers (n = 45) were sampled on day 35 using the novel surgery method and tubed on day 70 to sample rumen liquid content. Genomic DNA was used to generate amplicon libraries of the V4 region of the 16S rRNA gene. There were no differences between alpha diversity indices when comparing rumen versus epimural bacterial communities (P > 0.05). The Bray-Curtis dissimilarity was used to ordinate ASV counts, and then tested for differences between rumen and epimural communities using a PERMANOVA with 999 permutations (P < 0.05). Differential abundances of bacterial communities were tested using ANCOM-BC and MaAsLin2, where significance was determined by Q < 0.05 and overlap between both analysis methods. Within the 91 taxa that differed in abundance, 451 ASVs were found to be different between sample types (Q < 0.05). Unique ASVs associated with Prevotella, Succinivibrio, family-level Eubacterium, and family-level Succinivibrio were in greater abundance for the rumen epithelial-associated bacterial communities (Q < 0.05). The results demonstrate that the novel method of sampling from the rumen wall can capture differences between epimural and ruminal fluid bacterial communities, thus facilitating studies investigating the interactions between epimural bacteria with the host.
Role of blood flow in endothelial functionality: a review
Authors: Zhou Hui Lin , Jiang Xi Zhuo , Ventikos Yiannis
Published: October 2023

Endothelial cells, located on the surface of blood vessel walls, are constantly stimulated by mechanical forces from the blood flow. The mechanical forces, i.e., fluid shear stress, induced by the blood flow play a pivotal role in controlling multiple physiological processes at the endothelium and in regulating various pathways that maintain homeostasis and vascular function. In this review, research looking at different blood fluid patterns and fluid shear stress in the circulation system is summarized, together with the interactions between the blood flow and the endothelial cells. This review also highlights the flow profile as a response to the configurational changes of the endothelial glycocalyx, which is less revisited in previous reviews. The role of endothelial glycocalyx in maintaining endothelium health and the strategies for the restoration of damaged endothelial glycocalyx are discussed from the perspective of the fluid shear stress. This review provides a new perspective regarding our understanding of the role that blood flow plays in regulating endothelial functionality.
An update on methods for detection of prognostic and predictive biomarkers in melanoma
Authors: Adeuyan Oluwaseyi , Gordon Emily R. , Kenchappa Divya , Bracero Yadriel , Singh Ajay , Espinoza Gerardo , Geskin Larisa J. , Saenger Yvonne M.
Published: October 2023

The approval of immunotherapy for stage II-IV melanoma has underscored the need for improved immune-based predictive and prognostic biomarkers. For resectable stage II-III patients, adjuvant immunotherapy has proven clinical benefit, yet many patients experience significant adverse events and may not require therapy. In the metastatic setting, single agent immunotherapy cures many patients but, in some cases, more intensive combination therapies against specific molecular targets are required. Therefore, the establishment of additional biomarkers to determine a patient’s disease outcome (i.e., prognostic) or response to treatment (i.e., predictive) is of utmost importance. Multiple methods ranging from gene expression profiling of bulk tissue, to spatial transcriptomics of single cells and artificial intelligence-based image analysis have been utilized to better characterize the immune microenvironment in melanoma to provide novel predictive and prognostic biomarkers. In this review, we will highlight the different techniques currently under investigation for the detection of prognostic and predictive immune biomarkers in melanoma.
Molecular detection of per- and polyfluoroalkyl substances in water using time-of-flight secondary ion mass spectrometry
Authors: Yu Xiao-Ying , Yang Cuiyun , Gao Jun , Xiong John , Sui Xiao , Zhong Lirong , Zhang Yuchen , Son Jiyoung
Published: October 2023

Detection of per- and polyfluoroalkyl substances (PFASs) is crucial in environmental mitigation and remediation of these persistent pollutants. We demonstrate that time-of-flight secondary ion mass spectrometry (ToF-SIMS) is a viable technique to analyze and identify these substances at parts per trillion (ppt) level in real field samples without complicated sample preparation due to its superior surface sensitivity. Several representative PFAS compounds, such as perfluorooctanesulfonic acid (PFOS), perfluorobutanoic acid (PFBA), perfluoropentanoic acid (PFPeA), perfluoheptanoic acid (PFHpA), and perfluorononanoic acid (PFNA), and real-world groundwater samples collected from monitoring wells installed around at a municipal wastewater treatment plant located in Southern California were analyzed in this work. ToF-SIMS spectral comparison depicts sensitive identification of pseudo-molecular ions, characteristic of reference PFASs. Additionally, principal component analysis (PCA) shows clear discrimination among real samples and reference compounds. Our results show that characteristic molecular ion and fragments peaks can be used to identify PFASs. Furthermore, SIMS two-dimensional (2D) images directly exhibit the distribution of perfluorocarboxylic acid (PFCA) and PFOS in simulated mixtures and real wastewater samples. Such findings indicate that ToF-SIMS is useable to determine PFAS compounds in complex environmental water samples. In conclusion, ToF-SIMS provides simple sample preparation and high sensitivity in mass spectral imaging, offering an alternative solution for environmental forensic analysis of PFASs in wastewater in the future.
Synthesis of nanoporous carbonaceous materials at lower temperatures
Authors: Zhang Liping , Gonçalves Alexandre A. S. , Jaroniec Mietek
Published: October 2023

Nanoporous carbonaceous materials are ideal ingredients in various industrial products due to their large specific surface area. They are typically prepared by post-synthesis activation and templating methods. Both methods require the input of large amounts of energy to sustain thermal treatment at high temperatures (typically >600°C), which is clearly in violation of the green-chemistry principles. To avoid this issue, other strategies have been developed for the synthesis of carbonaceous materials at lower temperatures (<600°C). This mini review is focused on three strategies suitable for processing carbons at lower temperatures, namely, hydrothermal carbonization, in situ hard templating method, and mechanically induced self-sustaining reaction. Typical procedures of these strategies are demonstrated by using recently reported examples. At the end, some problems associated with the strategies and potential solutions are discussed.
Immune evasion strategies of bovine viral diarrhea virus
Authors: Pang Feng , Long Qinqin , Wei Min
Published: October 2023

Bovine viral diarrhea virus (BVDV) is a significant pathogen that causes great economic losses in the global livestock industry. During the long-term interactions between BVDV and its hosts, the virus has evolved multiple strategies to evade the host’s innate immunity and adaptive immunity, thereby promoting viral survival and replication. This review focuses on the most recent research on immune evasion strategies employed by BVDV, including evading type I IFN signaling pathway, evading host adaptive immunity, mediating NF-κB signaling pathway, mediating cell apoptosis and inducing autophagy. Unraveling BVDV’s immune evasion strategies will enhance our understanding of the pathogenesis of BVDV and contribute to the development of more effective therapies for the prevention, control and eradication of BVDV.
Long-term clinical outcomes for patients with uncrossable patent foramen ovale
Authors: Shin Yonghoon , Jang Albert Youngwoo , Won Yoonsun , Yang Taeil , Kim Joohan , Lee Joonpyo , Seo Jeongduk , Kim Minsu , Oh Pyung Chun , Chung Wook-Jin , Moon Jeonggeun , Kang Woong Chol
Published: October 2023

Introduction

Patent foramen ovale (PFO) closure is performed in selected patients with cryptogenic stroke to prevent recurrence. The prognosis of patients with uncrossable PFO after failed guidewire or catheter passage during the procedure remains unknown. We compared the long-term prognosis between uncrossable PFO and successful PFO closure in patients with high-grade PFO shunts.

Methods

We analyzed patients who underwent PFO closure for stroke or transient ischemic attack (TIA) prevention at Gachon University Gil Medical Center between April 2010 and March 2022. The primary outcome was a composite of recurrent stroke or TIA. Secondary outcomes included stroke, TIA, all-cause death, and a composite of stroke, TIA, and all-cause death.

Results

Of 286 patients, 245 were included in the analysis after excluding those with transseptal puncture technique usage or concurrent atrial septal defect. Among them, 82 had uncrossable PFO, and 163 underwent successful PFO closure. Large shunts were more prevalent in the PFO closure group compared to the uncrossable PFO group (62.0% vs. 34.1%, P < 0.001), and resting shunts were also more common in the PFO closure group (17.8% vs. 2.4%, P < 0.001). Stroke or TIA occurred in 2 patients (2.4%) in the uncrossable PFO group and 8 patients (4.9%) in the PFO closure group (hazard ratio, 1.44; 95% confidence interval, 0.30–6.81; P = 0.647). Additionally, no disparities in the occurrence of stroke or TIA were found in subgroups divided by baseline characteristics, RoPE score, or shunt grade.

Conclusion

Clinical outcomes for patients with uncrossable PFO seem similar to those with successful PFO closure.
PACAP regulates VPAC1 expression, inflammatory processes and lipid homeostasis in M1- and M2-macrophages
Authors: Witzel Roman , Block Annika , Pollmann Solvey , Oetzel Leandra , Fleck Fenja , Bonaterra Gabriel A. , Kinscherf Ralf , Schwarz Anja
Published: October 2023

Background

Pituitary adenylate cyclase-activating polypeptide (PACAP) acts as an anti-atherogenic neuropeptide and plays an important role in cytoprotective, as well as inflammatory processes, and cardiovascular regulation. Therefore, the aim of this study is to investigate the regulatory effects of PACAP and its receptor VPAC1 in relation to inflammatory processes and lipid homeostasis in different macrophage (MΦ) subtypes.

Methods

To investigate the role of PACAP deficiency in the pathogenesis of atherosclerosis under standard chow (SC) or cholesterol-enriched diet (CED) in vivo, PACAP−/− mice were crossbred with ApoE−/− to generate PACAP−/−/ApoE−/− mice. Lumen stenosis in the aortic arch and different MΦ-subtypes were analyzed in atherosclerotic plaques by quantitative immunohistochemistry. Undifferentiated bone marrow-derived cells (BMDC) from 30-weeks-old ApoE−/− and PACAP−/−/ApoE−/− mice were isolated, differentiated into BMDM1- and BMDM2-MΦ, and incubated with oxidized low-density lipoprotein (oxLDL). In addition, PMA-differentiated human THP-1 MΦ were further differentiated into M1-/M2-MΦ and subsequently treated with PACAP38, the VPAC1 agonist [(Ala11,22,28)VIP], the antagonist (PG 97–269), and/or oxLDL. Uptake/accumulation of oxLDL was analyzed by oxLDL-DyLight™488 and Bodipy™ 493/503. The mRNA expression was analyzed by qRT-PCR, protein levels by Western blot, and cytokine release by ELISA.

Results

In vivo, after 30 weeks of SC, PACAP−/−/ApoE−/− mice showed increased lumen stenosis compared with ApoE−/− mice. In atherosclerotic plaques of PACAP−/−/ApoE−/− mice under CED, immunoreactive areas of VPAC1, CD86, and CD163 were increased compared with ApoE−/− mice. In vitro, VPAC1 protein levels were increased in PACAP−/−/ApoE−/− BMDM compared with ApoE−/− BMDM, resulting in increased TNF-α mRNA expression in BMDM1-MΦ and decreased TNF-α release in BMDM2-MΦ. Concerning lipid homeostasis, PACAP deficiency decreased the area of lipid droplets in BMDM1-/M2-MΦ with concomitant increasing adipose differentiation-related protein level. In THP-1 M1-/M2-MΦ, the VPAC1 antagonist increased the uptake of oxLDL, whereas the VPAC1 agonist decreased the oxLDL-induced intracellular triglyceride content.

Conclusion

Our data suggest that PACAP via VPAC1 signaling plays an important regulatory role in inflammatory processes in atherosclerotic plaques and in lipid homeostasis in different MΦ-subtypes, thereby affecting foam cell formation. Therefore, VPAC1 agonists or PACAP may represent a new class of anti-atherogenic therapeutics.
How to effectively overcome fixation: a systematic review of fixation and defixation studies on the basis of fixation source and problem type
Authors: Wang Shijun , Okada Takeshi , Takagi Kikuko
Published: October 2023

As a cognitive state that impedes idea generation, fixation has been well studied across various domains in relation to the cultivation of creativity. With the aim of contributing to the development of an effective approach to overcoming fixation in order to enhance creativity, a systematic review is conducted of 53 experimental studies concerning the source of fixation and the problem type, which are two critical factors influencing the effectiveness of defixation approaches. Based on the results, it is indicated that an enhancement of the search beyond the frame, constructed by either information that is externally provided or memory that is internally activated by information about the problem, is essential in overcoming fixation. Further, the elimination of fixation leads to an increase in solution rates of closed-ended problems. However, in open-ended problem solving, defixation does not necessarily lead to an improvement in the performance of problem solving, and an advancement can still be achieved by enhancing the search within the constructed frame even when there is no search beyond the frame. Accordingly, an examination of both beyond-frame searches and within-frame searches is essential for an effective defixation approach to enhance creativity in open-ended problem solving.
Novel mutations in the SGCA gene in unrelated Vietnamese patients with limb-girdle muscular dystrophies disease
Authors: Chung Tran Nam , Lien Nguyen Thi Kim , Ta Thanh Dat , Nguyen Van Hung , Tran Huy Thinh , Van Tung Nguyen , Xuan Nguyen Thi , Huy Hoang Nguyen , Tran Van Khanh
Published: October 2023

Background: Limb-girdle muscular dystrophy (LGMD) is a group of inherited neuromuscular disorders characterized by atrophy and weakness in the shoulders and hips. Over 30 subtypes have been described in five dominant (LGMD type 1 or LGMDD) and 27 recessive (LGMD type 2 or LGMDR). Each subtype involves a mutation in a single gene and has high heterogeneity in age of onset, expression, progression, and prognosis. In addition, the lack of understanding of the disease and the vague, nonspecific symptoms of LGMD subtypes make diagnosis difficult. Even as next-generation sequencing (NGS) genetic testing has become commonplace, some patients remain undiagnosed for many years.

Methods: To identify LGMD-associated mutations, Targeted sequencing was performed in the patients and Sanger sequencing was performed in patients and family members. The in silico analysis tools such as Fathmm, M-CAP, Mutation Taster, PolyPhen 2, PROVEAN, REVEL, SIFT, MaxEntScan, Spliceailookup, Human Splicing Finder, NetGene2, and Fruitfly were used to predict the influence of the novel mutations. The pathogenicity of the mutation was interpreted according to the ACMG guidelines.

Results: In this study, six patients from four different Vietnamese families were collected for genetic analysis at The Center for Gene and Protein Research and The Department of Molecular Pathology Faculty of Medical Technology, Hanoi Medical University, Hanoi, Vietnam. Based on clinical symptoms and serum creatine kinase (CK) levels, the patients were diagnosed with limb-girdle muscular dystrophies. Five mutations, including four (c.229C>T, p.Arg77Cys; exon one to three deletion; c.983 + 5G>C; and c.257_258insTGGCT, p.Phe88Leufs*125) in the SGCA gene and one (c.946-4_946-1delACAG) in the CAPN3 gene, were detected in six LGMD patients from four unrelated Vietnamese families. Two homozygous mutations (c.983 + 5G>C and c.257_258insTGGCT) in the SGCA gene were novel. These mutations were identified as the cause of the disease in the patients.

Conclusion: Our results contribute to the general understanding of the etiology of the disease and provide the basis for definitive diagnosis and support genetic counseling and prenatal screening.
Tolerogenic dendritic cells generated in vitro using a novel protocol mimicking mucosal tolerance mechanisms represent a potential therapeutic cell platform for induction of immune tolerance
Authors: Dao Nyesiga Gillian , Pool Lieneke , Englezou Pavlos C. , Hylander Terese , Ohlsson Lars , Appelgren Daniel , Sundstedt Anette , Tillerkvist Kristina , Romedahl Hanne R. , Wigren Maria
Published: October 2023

Dendritic cells (DCs) are mediators between innate and adaptive immunity and vital in initiating and modulating antigen-specific immune responses. The most important site for induction of tolerance is the gut mucosa, where TGF-β, retinoic acid, and aryl hydrocarbon receptors collaborate in DCs to induce a tolerogenic phenotype. To mimic this, a novel combination of compounds – the synthetic aryl hydrocarbon receptor (AhR) agonist IGN-512 together with TGF-β and retinoic acid – was developed to create a platform technology for induction of tolerogenic DCs intended for treatment of several conditions caused by unwanted immune activation. These in vitro-generated cells, designated ItolDCs, are phenotypically characterized by their low expression of co-stimulatory and activating molecules along with high expression of tolerance-associated markers such as ILT3, CD103, and LAP, and a weak pro-inflammatory cytokine profile. When co-cultured with T cells and/or B cells, ItolDC-cultures contain higher frequencies of CD25+Foxp3+ regulatory T cells (Tregs), CD49b+LAG3+ ‘type 1 regulatory (Tr1) T cells, and IL-10-producing B cells and are less T cell stimulatory compared to cultures with matured DCs. Factor VIII (FVIII) and tetanus toxoid (TT) were used as model antigens to study ItolDC antigen-loading. ItolDCs can take up FVIII, process, and present FVIII peptides on HLA-DR. By loading both ItolDCs and mDCs with TT, antigen-specific T cell proliferation was observed. Cryo-preserved ItolDCs showed a stable tolerogenic phenotype that was maintained after stimulation with LPS, CD40L, or a pro-inflammatory cocktail. Moreover, exposure to other immune cells did not negatively impact ItolDCs’ expression of tolerogenic markers. In summary, a novel protocol was developed supporting the generation of a stable population of human DCs in vitro that exhibited a tolerogenic phenotype with an ability to increase proportions of induced regulatory T and B cells in mixed cultures. This protocol has the potential to constitute the base of a tolDC platform for inducing antigen-specific tolerance in disorders caused by undesired antigen-specific immune cell activation.
Extracellular proteins as potential biomarkers in Sepsis-related cerebral injury
Authors: Dong Jinlan , Wang Shuang , Hu Zhonghua , Gong Li
Published: October 2023

Background

Sepsis can cause brain damage known as septic encephalopathy (SAE), which is linked to higher mortality and poorer outcomes. Objective clinical markers for SAE diagnosis and prognosis are lacking. This study aimed to identify biomarkers of SAE by investigating genes and extracellular proteins involved in sepsis-induced brain injury.

Methods

Extracellular protein differentially expressed genes (EP-DEGs) from sepsis patients’ brain tissue (GSE135838) were obtained from Gene Expression Omnibus (GEO) and evaluated by protein annotation database. The function and pathways of EP-DEGs were examined using GO and KEGG. Protein-protein interaction (PPI) networks were built and crucial EP-DEGs were screened using STRING, Cytoscape, MCODE, and Cytohubba. The diagnostic and prognostic accuracy of key EP-DEGs was assessed in 31 sepsis patients’ blood samples and a rat cecal ligation and puncture (CLP)-induced sepsis model. Cognitive and spatial memory impairment was evaluated 7-11 days post-CLP using behavioral tests. Blood and cerebrospinal fluid from 26 rats (SHAM n=14, CLP n=12) were collected 6 days after CLP to analyze key EP-DEGs.

Results

Thirty-one EP-DEGs from DEGs were examined. Bone marrow leukocytes, neutrophil movement, leukocyte migration, and reactions to molecules with bacterial origin were all enhanced in EP-DEGs. In comparison to the sham-operated group, sepsis rats had higher levels of MMP8 and S100A8 proteins in their venous blood (both p<0.05) and cerebrospinal fluid (p=0.0506, p<0.0001, respectively). Four important extracellular proteins, MMP8, CSF3, IL-6, and S100A8, were identified in clinical peripheral blood samples. MMP8 and S100A8 levels in the peripheral blood of sepsis patients were higher in SAE than in non-SAE. In comparison to MMP8, S100A8 had a higher area under the curve (AUC: 0.962, p<0.05) and a higher sensitivity and specificity (80% and 100%, respectively) than MMP8 (AUC: 0.790, p<0.05). High levels of S100A8 strongly correlated with 28-day mortality and the Glasgow Coma Scale (GCS) scores.

Conclusion

The extracellular proteins MMP8, CSF3, IL-6, and S100A8 may be crucial in the pathophysiology of SAE. S100A8 and MMP8 are possible biomarkers for SAE’s onset and progression. This research may help to clarify the pathogenesis of SAE and improve the diagnosis and prognosis of the disease.
Efficacy and safety of immunosuppressive agents for adults with lupus nephritis: a systematic review and network meta-analysis
Authors: Jiang Nan , Jin Shangyi , Yu Chen , Zhao Jiuliang , Wang Qian , Tian Xinping , Li Mengtao , Zeng Xiaofeng
Published: October 2023

Introduction

Various immunosuppressive regimens have been developed for the treatment of lupus nephritis (LN). This study aimed to compare the efficacy and safety of immunosuppressive regimens in adults with LN.

Methods

We systematically searched the PubMed, Embase, and Cochrane Central Register of Controlled Trials databases, including conference proceedings, trial registries, and reference lists, from inception until July 10, 2022. The effects of treatment were compared and ranked using the surface under the cumulative ranking curve (SUCRA). The primary endpoint was total remission. The secondary endpoints were complete remission, systemic lupus erythematosus disease activity index (SLEDAI), relapse, all-cause mortality, end-stage renal disease (ESRD), infection, herpes zoster, ovarian failure, myelosuppression, and cancer.

Results

Sixty-two trials reported in 172 studies involving 6,936 patients were included in the network meta-analysis. The combination of tacrolimus (TAC), mycophenolate mofetil (MMF), and glucocorticoid (GC) provided the best result for the total remission rate (SUCRA, 86.63%) and SLEDAI (SUCRA, 91.00%), while the combination of voclosporin (VCS) , MMF and GC gave the best improvement in the complete remission rate (SUCRA, 90.71%). The combination of cyclophosphamide (CYC), MMF and GC was associated with the lowest risk of relapse (SUCRA, 85.57%) and cancer (SUCRA, 85.14%), while the combination of obinutuzumab (OTB), MMF and GC was associated with the lowest risk of all-cause mortality (SUCRA, 84.07%). Rituximab (RTX) plus MMF plus GC was associated with the lowest risk of ESRD (SUCRA, 83.11%), while the risk of infection was lowest in patients treated with azathioprine (AZA) plus CYC plus GC (SUCRA, 68.59%). TAC plus GC was associated with the lowest risk of herpes zoster (SUCRA, 87.67%) and ovarian failure (SUCRA, 73.60%). Cyclosporine (CsA) plus GC was associated with the lowest risk of myelosuppression (SUCRA, 79.50%), while AZA plus GC was associated with the highest risk of myelosuppression (SUCRA, 16.25%).

Discussion

This study showed that a combination of TAC, MMF and GC was the best regimen for improving the total remission rate. The optimal regimen for specific outcomes should be highlighted for high-risk patients.
Single-cell mass cytometric analysis of peripheral immunity and multiplex plasma marker profiling of non-small cell lung cancer patients receiving PD-1 targeting immune checkpoint inhibitors in comparison with platinum-based chemotherapy
Authors: Neuperger Patrícia , Szalontai Klára , Gémes Nikolett , Balog József Á. , Tiszlavicz László , Furák József , Lázár György , Puskás László G. , Szebeni Gábor J.
Published: October 2023

Introduction

The effect of platinum-based chemotherapy (Chem.) and second- or multiple- line immune checkpoint PD-1 blocking therapy by Nivolumab or Pembrolizumab (ICI) was assayed in the peripheral blood of non-small cell lung cancer (NSCLC) patients.

Methods

Flow cytometry was used to detect NSCLC-related antigen binding IgG antibodies. The Luminex MagPix multiplex bead-based cytokine/chemokine detecting system was used to quantitatively measure 17 soluble markers in the plasma samples. Single-cell mass cytometry was applied for the immunophenotyping of peripheral leukocytes.

Results

The incubation of patient derived plasma with human NSCLC tumor cell lines, such as A549, H1975, and H1650, detected NSCLC-specific antibodies reaching a maximum of up to 32% reactive IgG-positive NSCLC cells. The following markers were detected in significantly higher concentration in the plasma of Chem. group versus healthy non-smoker and smoker controls: BTLA, CD27, CD28, CD40, CD80, CD86, GITRL, ICOS, LAG-3, PD-1, PD-L1, and TLR-2. The following markers were detected in significantly higher concentration in the plasma of ICI group versus healthy non-smoker and smoker controls: CD27, CD28, CD40, GITRL, LAG-3, PD-1, PD-L1, and TLR-2. We showed the induction of CD69 and IL-2R on CD4+ CD25+ T-cells upon chemotherapy; the exhaustion of one CD8+ T-cell population was detected by the loss of CD127 and a decrease in CD27. CD19+CD20+, CD79B+, or activated B-cell subtypes showed CD69 increase and downregulation of BTLA, CD27, and IL-2R in NSCLC patients following chemotherapy or ICI.

Discussion

Peripheral immunophenotype caused by chemotherapy or PD-1 blocking was shown in the context of advanced NSCLC.