bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ragam Layanan Pendidikan Inklusif Dan Bentuk Pelibatan Orang Tua Anak Berkebutuhan Khusus
Authors: Nela Yunita Wa Ode , Diana Diana , Kurniawati Yuli 
Published: January 2025

Implementasi pendidikan inklusif di Indonesia masih bervariasi disetiap daerah, termasuk di Kota Kendari. Hal ini disebabkan beberapa kendala yang meliputi kebijakan, masih kurangnya ketersediaan tenaga pendidik yang terlatih, serta sarana dan prasarana guna mendukung kebutuhan peserta didik berkebutuhan khusus. Ketercapaian potensi anak di sekolah inklusif bukan hanya menjadi tanggung jawab guru saja tetapi juga menjadi tanggung jawab orang tua sebagai lingkungan pertama dan utama anak di rumah. Tujuan penelitian ini difokuskan pada ragam layanan pendidikan inklusif dalam model kelas sesuai tingkat kebutuhan peserta didik, bentuk pelibatan orang tua anak berkebutuhan khusus, serta faktor pendukung dan penghambat terlaksananya ragam layanan pendidikan inklusif dan bentuk pelibatan orang tua anak berkebutuhan khusus. Penelitian dilakukan dengan pendekatan kualitatif dengan jenis studi kasus. Sumber data primer penelitian ini adalah kepala sekolah guru kelas, shadow teacher, dan orang tua. Sumber data sekunder penelitian ini adalah dokumen-dokumen sekolah seperti kurikulum, fasilitas pendukung, dan program sekolah. Teknik analisis data penelitian ini menggunakan model analisis interaktif yaitu melakukan pengumpulan data, reduksi data, penyajian data, dan penarikan kesimpulan. Hasil penelitian ini menunjukkan bahwa: (1) pelaksanaan ragam layanan pendidikan inklusif di lembaga PAUD meliputi model kelas, pendekatan pembelajaran, layanan khusus, sarana dan prasarana serta pembiayaan. (2) bentuk pelibatan orang tua anak berkebutuhan khusus yaitu kontribusi dan kebutuhan. (3) faktor pendukung dan penghambat berupa dukungan dan tantangan yang muncul di lingkungan sekolah dan di rumah.
Breast Cancer Detection and Diagnosis Using Gabor Features and EfficientNetV2 Model
Authors: Ali Dihin Rasha 
Published: January 2025

Breast cancer is one of the most common diseases and the second most dangerous and fatal disease after skin cancer. The malignant masses begin to grow in the breast cells and develop in the breast tissue of women all over the world. Due to the necessity of early diagnosis to prevent the development of cancer and thus improve the chances of survival, many computer-aided methods are available to automate tissue classification to reduce the workload of the pathologist and improve accuracy. In this paper, a proposed method Gabor-EfficientNetV2 to extract deep features from a breast cancer dataset called “Breast cancer Histopathological dataset” (BreaKHis) to classify it as “benign” or “malignant” based on Gabor filter bank and EfficientNetV2 architecture. The proposed Gabor-EfficientNetV2 model offers significant advances in breast cancer detection and diagnosis by combining the texture analysis capabilities of Gabor filters with the efficiency and scalability of the EfficientNetV2 architecture. This hybrid approach enhances feature representation, resulting in improved classification accuracy and robustness compared to traditional models. Highest classification accuracy obtained with 400X magnification factor where the train accuracy of 97% and train loss of 0.13% while the test accuracy of 96.3% and the test loss of 0.135%, precision of 97.30% , recall of 90.30% , and F1-score obtained is 98.52%.
Analisis Manajemen Nilai Al Islam Kemuhammadiyahan dan Ke’aisyiyahan dalam Kurikulum Merdeka di TK ‘Aisyiyah Bustanul Athfal
Authors: Kusumastuti Vivi , Imron Imron 
Published: January 2025

Kurikulum Taman Kanak-kanak (TK) ‘Aisyiyah Bustanul Athfal memiliki ciri khas muatan lokal nilai-nilai Al Islam, Kemuhammadiyahan, dan Ke’aisyiyahan (AIK). Seiring pemberlakuan Kurikulum Merdeka, perlu penelitian terhadap manajemen nilai-nilai AIK beserta tantangan yang dihadapi guru dalam pembelajaran AIK. Tujuannya untuk memaparkan hasil analisis SWOT terhadap kurikulum muatan lokal AIK. Selain itu untuk melihat permasalahan serta alternatif pemecahan masalah dalam pembelajaran AIK. Menggunakan pendekatan deskriptif kualitatif. Lokasi penelitian di TK ‘Aisyiyah Bustanul Athfal. Subyek penelitian yakni kepala sekolah, dan guru. Hasil penelitian menunjukkan diagram analisis SWOT berada pada kuadran I dengan nilai positif, artinya TK ‘Aisyiyah Bustanul Athfal memiliki posisi yang prima, mantap, kuat secara organisasi dan memiliki banyak peluang. Permasalahan dalam pembelajaran adalah peserta didik yang sulit fokus dan rentang konsentrasi pendek. Untuk mengatasinya guru menerapkan disiplin positif dan segitiga resititusi untuk menjaga agar situasi kelas tetap teratur dan kondusif. Dengan demikian hal ini membuktikan bahwa pelaksanaan kurikulum muatan lokal AIK tetap relevan dalam Kurikulum Merdeka.
उत्तरवर्ती नेपाली उपन्यासमा आद्यस्वरूप
Authors: घर्ती Gharti दुर्गाबहादुर  Durga Bahadur 
Published: January 2025

प्रस्तुत लेख उत्तरवर्ती नेपाली उपन्यासमा प्रयुक्त आद्यस्वरूपको अध्ययनमा केन्द्रित छ । नेपाली उपन्यासमा परम्परागत प्रवृत्तिको परित्याग र नवीन प्रवृत्ति देखिन थालेपछि उत्तरवर्ती चरणको आरम्भ भएको मानिन्छ । प्रयोगवादी उपन्यासले परम्परागत लेखनबाट परिवर्तनको सङ्केत मिले पनि अर्थको केन्द्रीयता तिनले पनि त्याग्न सकेनन् । नेपाली उपन्यासमा वि.सं. २०३६ देखि बहुलवाद, अर्थको अनिर्धायता, केन्द्रभञ्जन, विधामिश्रण, विडम्बना, सापेक्षतावाद, विनिर्माण, आत्मसन्दर्भात्मकताजस्ता प्रवृत्ति देखापर्न थाल्दछन् । त्यो उत्तरार्ध चरणको आरम्भ हो । उत्तरवर्ती नेपाली उपन्यासमा मनोविश्लेषणको प्रयोग निकै फस्टाएको देखिन्छ । सिग्मन्ड फ्रायड, अल्फ्रेड एडलर र कार्ल गुस्ताभ युङ्गले मनोविश्लेषणात्मक सिद्धान्तको स्थापनामा महत्त्वपूर्ण योगदान रहेको छ । कार्ल गुस्ताभ युङ्गले विभिन्न पुराण, धर्मशास्त्र, संस्कृति आदिको अध्ययनबाट आद्यस्वरूप सिद्धान्तको प्रतिपादन गरेका छन् । त्यो उनको मौलिक योगदान हो । आद्यस्वरूपको अर्थ मूल ढाँचा वा मूल आकार भन्ने हुन्छ । साहित्यमा यसको प्रयोग आदिम बिम्ब, चरित्र वा परिस्थितिहरूको ढाँचा भन्ने अर्थमा गरिन्छ । युङ्गले आदिम अवशेषलाई आद्यस्वरूप वा आद्यबिम्ब भनेका छन् । आद्यस्वरूप मिथकीय बिम्ब वा अभिप्रायसँग सम्बन्धित हुन्छ । आद्यस्वरूप सामूहिक अचेतनसँग सम्बन्धित हुन्छ । युङ्गले 'एनिमा' (नारीपन), 'एनिमस' (पुरुषपन), 'स्याडो' (छाया), 'पर्सोना' (नकाब) र 'सेल्फ' (स्व) लगायत विभिन्न प्रकारका आद्यस्वरूपको उल्लेख गरेका छन् । उत्तरवर्ती नेपाली उपन्यासमा मिथकीय विषयवस्तु, सपना, पुरुषत्व र नारीत्व, नायकत्वको खोजी, मातृभूमिको आमा बिम्ब, जलवायु परिवर्तनको दुष्प्रभावलाई मानवजातिको मृत्युको छायाका रूपमा प्रस्तुत गरिएको पाइन्छ । प्रस्तुत अध्ययनका लागि सामग्री सङ्कलन पुस्तकालयकार्यद्वारा गरिएको छ । विश्लेष्य उपन्यास प्राथमिक सामग्री हुन् भने आद्यस्वरूपको सिद्धान्त र पूर्वकार्यसँग सम्बन्धित सामग्री द्वितीयक सामग्री हुन् । सङ्कलित सामग्रीको विश्लेषण गुणात्मक पद्धतिमा रहेर पाठात्मक विधिमा गरिएको छ । विविध आद्यस्वरूपको प्रयोग उत्तरवर्ती उपन्यासको विशेषता हो र त्यो उत्तरवर्ती नेपाली उपन्यासको प्राप्ति हो भन्ने यस अध्ययनको निष्कर्ष रहेको छ ।
‘स्त्रीको खेल’ लोककथामा वस्तुविधान
Authors: श्रेष्ठ Shrestha अर्जुनकुमार Arjun Kumar 
Published: January 2025

प्रस्तुत ‘स्त्रीको खेल’ लोककथा दिक्तेल–रूपाकोट–मझुवागढी क्षेत्रमा प्रचलित मझौला आयामको लोककथा हो । प्रस्तुत कथामा स्त्रीले आफ्नो श्रीमान्‌लाई मार्न दुःख दिएको कुरा देखाइएको छ । राक्षससँग मिलेर राजकुमारकी श्रीमतीले राजकुमारलाई धेरै दुख दिने गरेको र अन्त्यमा खाल्टो खनेर पासो थापी राजकुमारलाई मारेको घटनापछि कथा समापन तिर लाग्छ । लोककथाले समाजको सामाजिक आवरणलाई चित्रण गरेको हुन्छ । यस अध्ययनमा लोकसाहित्यभित्र पर्ने लोककथाको कथानक वा वस्तुविधानलाई चिनाइएको छ । अध्ययनका लागि छनोट गरिएको ‘स्त्रीको खेल’ कथालाई कथानक, पात्र, परिवेश, उद्देश्य र भाषाशैलीमध्ये कथानक वा वस्तुविधानको आधारमा सैद्धान्तिक र कथागत सामग्रीमा प्रयुक्त उद्धरणलाई लिएर विश्लेषण गरिएको छ । यस अध्ययनमा लोकसाहित्यका सिद्धान्त र लोककथाको विधातत्त्वभित्रको कथावस्तुपक्षलाई ध्यानमा राखेर त्यसमा व्यक्त भएको सन्दर्भलाई प्रस्तुत गरिएको छ । काल्पनिकतामा आधारित र मनोरञ्जनप्रधान विषयवस्तुलाई बोकेको यस कथाले समयअनुसार काम गर्न जान्नु पर्ने दर्शनलाई बोध गराएको छ । सत्यको विजय हुने भावलाई दर्शाउन सुखान्तक र दुःखान्तक दुवै कथावस्तुका आधारमा यो कथा पूर्वीय दर्शनको पूर्वजन्मको मान्यतामा आधारित छ । पुस्तकालयीय सामग्रीलाई आधार मानेर सम्पन्न गरिएको यस अध्ययनमा गुणात्मक अनुसन्धान विधिको उपयोग गरिएको छ । वस्तुविधानको मुख्य पक्ष कथानकको स्रोत, कथानकको गठन, कथानकको विकासक्रम, कौतूहल र कथानकको ढाँचाको आधारमा कथाको विश्लेषण गरी यस अध्ययनको निष्कर्षलाई प्रस्तुत गरिएको छ ।
शाह कालीन नेपाली मुद्राका विशेषताहरू
Authors: अधिकारी Adhikari सुशीलकुमार Sushil Kumar , ओझा Ojha केदार Kedar 
Published: January 2025

प्रस्तुत लेख शाह कालीन नेपाली मुद्राका विशेषताहरूको विश्लेषणमा केन्द्रित छ । गुणात्मक अनुसन्धान विधि तथा सङ्कलित सामग्रीमा उपलब्ध विषयवस्तुको विश्लेषणमा आधारित रहेकाले यो विषयवस्तु विश्लेषणकेन्द्री अध्ययन हो । यस लेखका सामग्रीको सङ्कलन पुस्तकालयबाट भएको छ । पुस्तकालयबाट सङ्कलित द्वितीयक स्रोतमा अधारित यस लेखमा आधुनिक नेपाली राजनीतिक इतिहासमा नेपाली मुद्राका विशेषताका विषयमा विमर्श भएको छ । नेपाली मुद्राको इतिहास दोलखाली राजा इन्द्रसिंहदेवको पालामा आरम्भ भई मल्लकालीन समयमा यसको राष्६रिय र अन्तर्राष्ट्रिय स्तरमा पहिचान स्थापित भएको हो । नेपाली मौद्रिक प्रणालीसँग सम्बन्धित ऐतिहिसक दस्तावेजका आधारमा हेर्दा तत्कालीन शासकको सर्वोच्च तहमा रहने राजा, राजपरिवारका अन्य विशिष्ट सदस्य तथा महासामन्तका नाममा टकमरी गर्ने प्रचलनको स्थापना र गतिशीलता पाइन्छ भने शाहकालीन मुद्रा राजाका नामबाट टकमरी भई प्रचलनमा आएका छन् । शाहकालीन नेपाली मुद्रा पूर्ववर्ती शासककै निरन्तरताका रूपमा धातुका मुद्राका साथै कागजी संरचनामा मुद्रित छन् । शाहकालीन नेपाली मुद्रा गोलाकार, राजाको नामाङ्कन,मुद्रा प्रकाशन भएको मिति, देवनागरी लिपिको प्रयोग, धार्मिक तथा इष्ट देवताको नामाङ्कन, राजा, नायबी, युवराज र राजमाता आदिको नाममा मुद्रा निष्कासन, प्रत्येक मुद्राको मूल्य अङ्कन, मुद्रा निष्कासनका लागि यन्त्रको उपयोग, आलङ्कारिक र कलाकारितापूर्ण मुद्रा ढाँचाको उपयोग, नेपाली भाषा विकासको ऐतिहासिक प्रभावजस्ता विशेषताका आधारमा पहिचान र अस्तित्वका साथ प्रचलनमा आएका छन् । यस लेखमा शाहकालीन नेपाली मुद्राका उपर्युक्त विशेषताका सम्बन्धमा विश्लेषण र संश्लेषण भएको छ ।
Regesty zaginionych dokumentów Bernarda, księcia opolskiego
Authors: Woźny Maciej 
Published: January 2025

W artykule przedstawiono regesty 43 zaginionych dokumentów Bernarda, księcia opolskiego, pana na Strzelcach i Niemodlinie. Połowa z nich została wpisana do kopiarza przechowywanego obecnie w Wiedniu. Część przechowywana była w archiwach prywatnych, w Szydłowcu Śląskim i Niemodlinie, oraz w archiwum miejskim w Strzelcach Opolskich. Przed drugą wojną światową sporządzono inwentarze, a dokumenty miejskie zostały wpisane do kroniki, obecnie zaginionej, a znanej z pracy Johanna Josepha Reichela oraz wypisów barona Friedricha von Schirndinga. Pozostałe dokumenty znane są z kopiarza przechowywanego we Wrocławiu, saalbuchów oraz katastru karolińskiego. Edycję źródeł przygotowano według zasad przyjętych przez wydawców Regestów dokumentów przechowywanych na Górnym Śląsku, starając się szerzej omówić, skąd znany jest dany dyplom oraz gdzie był przechowywany. W niniejszym artykule pokazano, jak wiele informacji o utraconych średniowiecznych dokumentach można odnaleźć w starych inwentarzach oraz w źródłach nowożytnych.
A potential exodus: what is behind dropping out intentions among university students?
Authors: Herrera Dora , Matos Lennia , Gargurevich Rafael , Gómez Marjhori , Lira Benjamín , Ferreyra Cecilia 
Published: January 2025

IntroductionThe alarming dropout rates among university students in Peru deplete the country’s human resources and reduce prospects for personal growth and societal development. Explaining those rates calls for a comprehensive and holistic approach beyond the students’ socio-economic characteristics. This study seeks to identify the socio-demographic, academic and psychological variables that predict dropout intention among university students in Peru.Materials and methodThe sample was composed of 768 students from nine universities, both public and private, across the coastal, highland and rainforest regions of Peru. Students completed questionnaires assessing factors that favor resilience, future orientation, and dropout intention.ResultsAs hypothesized, we found that students who scored higher on factors favoring resilience and future orientation subscales, with the exception of the exploration sub-dimension, were less likely to develop dropout intentions. We found differences by sex and type of university; then evaluated whether the model parameters varied by sex. Our findings show higher dropout intentions among male students. No significant relationships were found between grades, tutoring programme and future orientation.DiscussionResults contribute to support these university students as valuable human resources who, due to Peru’s characteristics, lack easy access to higher education and should be protected. Our findings also provide general guidelines for further interventions to counter the risk of increased dropout rates at the university level.
Drawing the future: gender and future occupational aspirations of young children in Sweden
Authors: Wamala-Andersson Sarah , Richardson Matt X. , Schölin Bywall Karin , Norgren Therese , Chambers Nick 
Published: January 2025

IntroductionResearch on young children’s occupational aspirations and the factors shaping them is still limited, especially in early interventions addressing gender disparities in high-status fields like STEM.MethodsThis is the first study in Sweden utilizing the Drawing the Future method, surveyed 1,832 children (aged 5–13) from 28 schools in Skåne region of southern, asking them to draw their dream jobs. This exercise was conducted in a classroom setting and facilitated by their class teacher.ResultsSignificant gender differences emerged, revealing distinct stereotypical patterns in children’s future occupational aspirations and influencing factors. Only three occupations—footballer, doctor, and police officer—were popular among both genders. Girls preferred people- or animal-centered roles, while boys leaned toward jobs involving “things” (p &lt; 0.001). Girls felt they could pursue similar careers as boys, but boys showed more skepticism (p &lt; 0.001). Influence patterns also varied by gender: 25% of girls were inspired by mothers, while 45% of boys were inspired by fathers (p = 0.02). Beyond immediate family, girls often sought career information from acquaintances, while boys turned to media (p &lt; 0.001). STEM interest was limited, with “game developer” being the only STEM job on boys’ lists. Additionally, a larger proportion of boys ranked STEM subjects among their top 10 favorite school subjects, while girls preferred crafts, art, and English (p &lt; 0.001).DiscussionThese findings highlight the need for early, unbiased, evidence-based career interventions and policies to broaden children’s awareness of diverse job options and opportunities in the labor market.
Association between chronic kidney disease and oxidative balance score: National Health and Nutrition Examination Survey (NHANES) 2005–2018
Authors: Liu Cong , Yang Jiju , Li Hongdian , Deng Yuanyuan , He Pengfei , Zhang Jiao , Zhang Mianzhi 
Published: January 2025

BackgroundThe oxidative balance score (OBS) is a comprehensive concept that includes 16 dietary components and four lifestyle factors to assess an individual's exposure to pro-oxidants and antioxidants. This study aims to explore the relationship between OBS and the risk of chronic kidney disease (CKD).MethodsThis cross-sectional study included nationally representative National Health and Nutrition Examination Survey (NHANES) participants aged 18 and above from 2005 to 2018. The OBS, a novel concept derived from multiple dietary (pro-oxidant and antioxidant nutrients) and lifestyle exposures (including smoking, alcohol consumption, obesity, and physical activity), serves as a useful tool for assessing an individual's oxidative stress status. The continuous variable OBS was converted into categorical variables by quartiles. Covariates included age, gender, race, education level, marital status, poverty-income ratio, sleep duration, depression, hypertension, diabetes, hyperlipidemia, cardiovascular disease, use of hypoglycemic medications, and use of antihypertensive medications. The relationship between OBS and CKD was explored using multiple logistic regression analysis and restricted cubic spline models. Additionally, subgroup analyses, interaction tests, and sensitivity analyses were conducted to validate the stability of the results.ResultsA total of 25,118 NHANES participants were included in this study. The weighted prevalence of CKD was 14.97%. In the fully adjusted model, compared to the lowest OBS quartile, participants in the highest quartile had a 26% reduced risk of CKD (OR = 0.74, 95%CI: 0.63–0.87, p &lt; 0.001). In restricted cubic spline regression, there was a linear association between OBS and CKD. The results of subgroup analysis and sensitivity analysis remain consistent. A significant interaction was found in the stratified analysis by age group (p for interaction = 0.012), suggesting that individuals older than 60 years may benefit more significantly from an increase in OBS scores compared to those aged 60 years or younger.ConclusionThis study demonstrates that higher OBS is associated with a lower risk of CKD, particularly among the elderly population, providing innovative insights and preliminary evidence for the development of preventive strategies against CKD.
Parental depression and emotional feeding practices are associated with a tendency towards overeating in preadolescents
Authors: Sarkkola Catharina , Leppänen Marja H. , Eloranta Aino-Maija , Räisänen Laura , Männistö Satu , Viljakainen Heli 
Published: January 2025

BackgroundChildren’s eating behaviors, including a tendency towards overeating, are strongly influenced by the family. Children prone to overeating are at a high risk of excessive weight gain, which can lead to further adverse health outcomes. Therefore, identifying factors that contribute to overeating is crucial for promoting healthy weight development. Given the inconsistencies in previous research, mostly involving young children, we investigated the child and parental characteristics associated with overeating in preadolescence.MethodsThe cross-sectional study included 5,973 preadolescents aged 9–12 years from the Finnish Health in Teens (Fin-HIT) cohort. A tendency towards overeating was based on a parent-reported question. We utilized extensive parent questionnaire and Medical Birth Register data, and used ordinal and stepwise logistic regression to identify the independent determinants of overeating.ResultsThe proportion of preadolescents with a parent-reported tendency towards overeating was 10% (n = 606). In the multivariable model, boys had higher odds of overeating (OR 1.30, 95% CI 1.06–1.58) compared with girls. Preadolescents with overweight and obesity had 9- and 30-fold odds (95% CI 7.31–11.29 and 20.07–44.54, respectively) of overeating compared with healthy-weight preadolescents. Furthermore, parental depression and emotional feeding increased the odds of overeating in the preadolescent (OR 1.48, 95% CI 1.08–2.02 and OR 1.27, 95% CI 1.03–1.57).ConclusionAlong with child weight status and sex, parental depression and emotional feeding were independently associated with overeating in preadolescence. Therefore, it is important to support parents’ mental health and their healthy feeding practices. Our findings can be targeted to manage overeating and prevent overweight in children and adolescents.
Synthesis, characterization, and computational evaluation of some synthesized xanthone derivatives: focus on kinase target network and biomedical properties
Authors: Muslim Wisam Taher , Mohammad Layth Jasim , Naji Munaf M. , Karimi Isaac , Al-Sabti Matheel D. , Jabir Majid , Najm Mazin A. A. , Schiöth Helgi B. 
Published: January 2025

BackgroundXanthones are dubbed as putative lead-like molecules for cancer drug design and discovery. This study was aimed at the synthesis, characterization, and in silico target fishing of novel xanthone derivatives.MethodsThe products of reactions of xanthydrol with urea, thiourea, and thiosemicarbazide reacted with α-haloketones to prepare the thiazolone compounds. Xanthydrol reacted sequentially with ethyl chloroacetate, hydrazine, carbon disulfide, and α-haloketones to prepare the dithiolane. The xanthydrol reacted with propargyl bromide and it submitted to click reaction with azide to prepare triazole ring.ResultsFinally, four novel xanthones derivatives including (E)-2-(2-(9H-xanthen-9-yl)hydrazono)-1,3-dithiolan-4-one (L3), 2-(2-(9H-xanthen-9-yl)hydrazinyl)thiazol-5(4H)-one (L5), 2-(9H-xanthen-9-ylamino)thiazol-5(4H)-one (L7), and 4-((9H-xanthen-9-yloxy)methyl)-1-(4-nitrophenyl)-1H-1,2,3-triazole (L9) were synthesized and characterized using thin layer chromatography, Fourier-transform infrared spectroscopy, and nuclear magnetic resonance (1H and 13C). ADMET, Pfizer filter, adverse drug reaction, toxicity, antitarget interaction profiles, target fishing, kinase target screening, molecular docking validation, and protein and gene network analysis were computed for derivatives. Ligands obeyed Pfizer filter for drug-likeness, while all ligands were categorized as toxic chemicals. Major targets of all ligands were predicted to be kinases including Haspin, WEE2, and PIM3. Mitogen-activated protein kinase 1 was the hub gene of target kinase network of all derivatives. All the ligands were predicted to show hepatotoxic potentials, while L7 presented cardiac toxicity.ConclusionAcute leukemic T-cells were one of the top predicted tumor cell lines for these ligands. The possible antileukemic effects of synthesized xanthone derivatives are potentially very interesting and warrant further studies.
Ceftriaxone-associated dysbiosis decreases voriconazole bioavailability by upregulating intestinal P-glycoprotein expression through activation of the Nrf2-mediated signalling pathway
Authors: Wang Xiaokang , Ye Chunxiao , Yang Xixiao , Yang Maoxun 
Published: January 2025

ObjectivesThe purpose of this study was to investigate the effect of intestinal dysbiosis on the bioavailability of voriconazole and to explore any underlying mechanisms.MethodSprague-Dawley rats were randomly divided into two groups: a normal control group and a ceftriaxone-associated dysbiotic group. The composition of the intestinal flora was examined using 16S rRNA sequencing analysis. Voriconazole concentrations were determined by high-performance liquid chromatography-tandem mass spectrometry. Outer membrane vesicles (OMVs) of microbes from the different groups were prepared for in vitro study in Caco-2 cells. The Nrf2 pathway and its related proteins involved in modifying P-glycoprotein (P-gp) expression were clarified by a series of immunoblot analyses.Key findingsThe diversity and richness of intestinal bacteria, especially the abundance of gram-negative bacteria, were significantly decreased after ceftriaxone treatment. The AUC(0-t) and Cmax of voriconazole were reduced, and greater voriconazole clearance were noted in the dysbiotic group. An in vivo study also indicated that the expression of P-glycoprotein was significantly increased after ceftriaxone treatment, which may be due to the absence of gram-negative bacteria in the intestine. Finally, in vitro findings in Caco-2 cells treated with OMVs from the ceftriaxone-associated dysbiotic group suggested that Nrf2 translocation into the nucleus induced high expression of P-gp.ConclusionOMVs from intestinal bacterial in the ceftriaxone-associated dysbiotic group induced high P-gp expression by regulating the Nrf2 signalling pathway, which led to an in vivo reduction in the bioavailability of voriconazole due to ceftriaxone-associated dysbiosis.