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Discovery of dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) inhibitors using an artificial intelligence model and their effects on tau and tubulin dynamics

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Biomedicine and Pharmacotherapy 2024年 181卷 117688-117688页

作者： Chen, Jun-Hong Tu, Huang-Ju Lin, Tony Eight Peng, Zhao-Xiang Wu, Yi-Wen Yen, Shih-Chung Sung, Tzu-Ying Hsieh, Jui-Hua Lee, Hsueh-Yun Pan, Shiow-Lin HuangFu, Wei-Chun Hsu, Kai-Cheng Graduate Institute of Cancer Biology and Drug Discovery College of Medical Science and Technology Taipei Medical University Taipei Taiwan Ph.D. Program for Cancer Molecular Biology and Drug Discovery College of Medical Science and Technology Taipei Medical University Taipei Taiwan Warshel Institute for Computational Biology The Chinese University of Hong Kong Guangdong Shenzhen China Division of Translational Toxicology National Institute of Environmental Health Sciences National Institutes of Health Durham NC United States School of Pharmacy College of Pharmacy Taipei Medical University Taipei Taiwan TMU Research Center of Cancer Translational Medicine Taipei Medical University Taipei Taiwan Cancer Center Wan Fang Hospital Taipei Medical University Taipei Taiwan

The dual-specificity tyrosine-phosphorylation-regulated kinase 1 A (DYRK1A) presents a promising therapeutic target for neurological diseases. However, current inhibitors lack selectivity, which can lead to unexpected side effects and increase the difficulty of studying DYRK1A. Therefore, identifying selective inhibitors targeting DYRK1A is essential for reducing side effects and facilitating neurological disease research. This study aimed to discover DYRK1A inhibitors through a screening pipeline incorporating a deep neural network (DNN) model. Herein, we report an optimized model with an accuracy of 0.93 on a testing set. The pipeline was then performed to identify potential DYRK1A inhibitors from the National Cancer Institute (NCI) library. Four novel DYRK1A inhibitors were identified, and compounds NSC657702 and NSC31059 were noteworthy for their potent inhibition, with IC₅₀ values of 50.9 and 39.5 nM, respectively. NSC31059 exhibited exceptional selectivity across 70 kinases. The compounds also significantly reduced DYRK1A-induced tau phosphorylation at key sites associated with the pathology of neurodegenerative diseases. Moreover, they promoted tubulin polymerization, suggesting a role in microtubule stabilization. Cytotoxicity assessments further confirmed the neuronal safety of the compounds. Together, the results demonstrated a promising screening pipeline and novel DYRK1A inhibitors as candidates for further optimization and development. © 2024 The Authors

关键词： Deep Learning DYRK1A Tau

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Cellucalst enzyme-assisted extraction of Sargassum horneri enhances the immunomodulation by regulating TLR4/MyD88/NF-kB pathway in murine splenocytes with or without Concanavalin A

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Biomedicine and Pharmacotherapy 2024年 181卷 117673-117673页

作者： Yang, Jiwon Kim, Hyo Jin Herath, Kalahe Hewage Iresha Nadeeka Madushani Jee, Youngheun Interdisciplinary Graduate Program in Advanced Convergence Technology & Science Jeju National University Jeju 63243 South Korea Department of Food Bioengineering Jeju National University Jeju 690-756 South Korea Department of Environmental Health Harvard T.H. Chan School of Public Health Harvard University Boston Massachusetts United States Department of Biosystems Engineering Faculty of Agriculture and Plantation Management Wayamba University Gonawila Makandura 60170 Sri Lanka Department of Veterinary Medicine and Veterinary Medical Research Institute Jeju National University Jeju 64243 South Korea

Sargassum horneri (S. horneri) is an edible species of large brown algae inhabiting along the coasts of northeastern Asia. The study focuses on the impact of celluclast enzyme extract of S. hoeneri (SHC) on various immune cell populations in splenocytes including granulocytes, macrophages, dendritic cells, and T lymphocytes. SHC alone increased the population of granulocytes and macrophages and the secretion of M1 macrophage-derived cytokines (TNF-α, IL-22), and M2 macrophage-derived cytokines (IL-4, IL-10). Interestingly, however, SHC suppressed the concanavalin A (Con A)-expanded populations of macrophages, dendritic cells, granulocytes, T and B cells, and Con A-promoted secretion of M1-macrophage derived cytokines (IFN-γ, IL-1β, TNF-α, IL-17, IL-22) and M2-macrophage derived cytokines (IL-4, IL-10, IL-13, TGF-β). SHC further restrained the Th1, Th2, and Th17 cell responses through attenuating the expression of respective transcription factors T-bet, Gata3, and Rorγt. The anti-inflammatory property of SHC is highlighted through its influence on cytokine production, particularly in the NF-κB pathway, and the attenuation of Toll-like receptor (TLR) signaling. The results reveal that SHC acts as both an immunostimulator and an inhibitor of hyperimmune reactions, showcasing its potential therapeutic applications in conditions involving dysregulated immune responses such as autoimmune diseases and inflammatory disorders. This positions SHC as a promising candidate for the development of functional ingredients with diverse applications encompassing the realms of food, pharmaceuticals, and cosmetics. © 2024

关键词： Celluclast Concanavalin A S. horneri Splenocytes

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Hatching performances of native chicken supplemented L-arginine in ration and in Ovo injection

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AIP Conference Proceedings 2023年第1期2628卷

作者： I. Muing W. Pakiding S. Purwanti Student of Animal Husbandry Science and Technology Study Program Post Graduate School Hasanuddin University Makassar Indonesia Department of Animal Production Faculty of Animal Husbandry Hasanuddin University Makassar Indonesia Department of Animal Nutrition Faculty of Animal Husbandry Hasanuddin University Makassar Indonesia

This study aims to determine the effect of supplemented by L-Arginine in ration and Treated by L-Arginine in-ovo injection on the hatching performance of native chickens. This study used 60 fertile eggs obtained from hens supplemented by 0% L-Arginine in ration and 60 fertile eggs obtained from hens supplemented by 0.25% L-Arginine in ration. Eggs are arranged by Randomized Block Design with 4 treatments and 3 groups. The treatment consists of P0 (Control=Ration+0% L-Arginine and no L-Arginine injection), P1 (Ration+0% L-Arginine and 2% L-Arginine injection), P2 (Ration+0.25% and without L-Arginine injection), and P3 (Ration+0.25% and injection 2% L-Arginine). The results showed that supplemented by L-Arginine in ration and Treated by L-Arginine in-ovo injection no significant (P>0.05) on the hatching performance of native chickens. We conclude that supplemented by L-Arginine in ration and Treated by L-Arginine in-ovo injection no significant on hatching performance of native chickens although there is a tendency that supplemented of the L-Arginine in ration and Treated by L-Arginine in-ovo injection shows a better trend.

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Preliminary study: Production and quality of signal grass (Brachiaria decumbens) on the post mining land

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AIP Conference Proceedings 2023年第1期2628卷

作者： N. A. A. Toputri R. A. Habibi E. Harri Sema R. F. Utamy S. Hasan Animal Husbandry and Technology Post-Graduate Program Hasanuddin University Makassar Indonesia Nursery PT. Vale Sorowako East Luwu South Sulawesi Indonesia Animal Nutrition and Feed Technology Faculty of Agriculture Puangrimaggalatung University Sengkang Indonesia Faculty of Animal Science Universitas Hasanuddin Makassar South Sulawesi Indonesia

The post-mining land decrease soil fertility. Soil fertility is required for plant growth. One way to minimize this soil fertility is by planting grass and legume in a mixed-cropping system. This preliminary study was aimed to evaluate the production and quality of signal grass and legume on the post-mining land of PT Vale Indonesia, Tbk. This study used a descriptive/survey method such as direct measurements and observations in the field. The results showed the average production of fresh weight (7.5 tons/Ha), dry matter (1.5 tons/Ha), chlorophyll (30 mg/g leaves), and leaf area (22.5 cm) of signal grass without legumes. Meanwhile, the average production of fresh weight (15.80 tons/Ha), dry matter (3.16 tons/Ha), chlorophyll (38 mg/g leaves), and leaf area (35.6 cm) of signal grass with legumes.

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Genetic diversity and relatedness of feline parvovirus in Vietnam and its potential implications for canine-feline transmission

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Archives of Virology 2024年第1期169卷 11-11页

作者： Minh, Hoang Son, Nguyen Vu Duc, Hoang Minh Lin, Chao-Nan Tyan, Yu-Chung Chuang, Kuo-Pin Department of Veterinary Medicine College of Veterinary Medicine National Pingtung University of Science and Technology Pingtung 912 Taiwan Department of Anatomy and Histology Faculty of Veterinary Medicine Vietnam National University of Agriculture Hanoi Viet Nam Department of Veterinary Pathology Faculty of Veterinary Medicine Vietnam National University of Agriculture Hanoi Viet Nam Department of Veterinary Public Health Faculty of Veterinary Medicine Vietnam National University of Agriculture Hanoi Viet Nam Animal Disease Diagnostic Center College of Veterinary Medicine National Pingtung University of Science and Technology Pingtung 912 Taiwan Department of Medical Imaging and Radiological Sciences Kaohsiung Medical University Kaohsiung 807 Taiwan Graduate Institute of Animal Vaccine Technology National Pingtung University of Science and Technology Pingtung 912 Taiwan School of Medicine Kaohsiung Medical University Kaohsiung 807 Taiwan Research Center for Precision Environmental Medicine Kaohsiung Medical University Kaohsiung 807 Taiwan Department of Medical Research Kaohsiung Medical University Hospital Kaohsiung 807 Taiwan Center for Tropical Medicine and Infectious Disease Research Kaohsiung Medical University Kaohsiung 807 Taiwan International Degree Program in Animal Vaccine Technology International College National Pingtung University of Science and Technology Pingtung 912 Taiwan

Feline panleukopenia, caused by feline parvovirus (FPV), has been studied worldwide, but there have been very few studies conducted in Vietnam. In this study, 19 rectal swab samples were collected from northern Vietnam in 2018–2019 and screened for the presence of FPV using PCR. Through sequence analysis of the full-length VP2 gene, it was found that the FPV strains detected in Vietnam were closely related to those obtained from dogs in Vietnam, Asia, Europe, and America. Moreover, the FPV strains found in Vietnam may constitute a distinct group, related to viruses sampled in China. Interestingly, most of the nucleotide changes identified were T-C substitutions. © 2023, The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.

关键词： Feline panleukopenia virus Parvoviridae Vietnam

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Assessment of sources and health risks of heavy metals in metropolitan household dust among preschool children: The LEAPP-HIT study

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Journal of environmental Management 2024年 352卷 120015页

作者： Kao, Chi-Sian Wang, Ying-Lin Jiang, Chuen-Bin Tai, Pei-Ju Chen, Yi-Hua Chao, Hsing-Jasmine Lo, Yu-Chun Hseu, Zeng-Yei Hsi, Hsing-Cheng Chien, Ling-Chu School of Public Health College of Public Health Taipei Medical University Taipei Taiwan Graduate Institute of Environmental Engineering National Taiwan University Taipei Taiwan Department of Pediatric Gastroenterology Hepatology and Nutrition MacKay Children's Hospital Taipei Taiwan Department of Medicine MacKay Medical College SanZhi District New Taipei City Taiwan Neuroscience Research Center Taipei Medical University Taipei Taiwan Ph.D. Program in Medical Neuroscience College of Medical Science and Technology Taipei Medical University Taipei Taiwan Department of Agricultural Chemistry National Taiwan University Taipei Taiwan Nutrition Research Center Taipei Medical University Hospital Taipei Taiwan

The most common construction material used in Taiwan is concrete, potentially contaminated by geologic heavy metals (HMs). Younger children spend much time indoors, increasing HM exposure risks from household dust owing to their behaviors. We evaluated arsenic (As), cadmium (Cd), and lead (Pb) concentrations in fingernails among 280 preschoolers between 2017 and 2023. We also analyzed HM concentrations, including As, Cd, Pb, chromium (Cr), nickel (Ni), copper (Cu), zinc (Zn), iron (Fe), and manganese (Mn), in 90 household dust and 50 road dust samples from a residential area where children lived between 2019 and 2021 to deepen the understanding of sources and health risks of exposure to HMs from household dust. The average As, Cd, and Pb concentrations in fingernails were 0.12 ± 0.06, 0.05 ± 0.05, and 0.95 ± 0.77 μg/g, respectively. Soil parent materials, indoor construction activities, vehicle emissions, and mixed indoor combustion were the pollution sources of HMs in household dust. Higher Cr and Pb levels in household dust may pose non-carcinogenic risks to preschoolers. Addressing indoor construction and soil parent materials sources is vital for children's health. The finding of the present survey can be used for indoor environmental management to reduce the risks of HM exposure and avoid potential adverse health effects for younger children. © 2024 Elsevier Ltd

关键词： Heavy metals

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Bangka Belitung Islands: Great Potencies of Massive environmental Impacts 4

Bangka Belitung Islands: Great Potencies of Massive Environm...

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4th International Conference on Energy, Environment, Epidemiology and Information System, ICENIS 2019

作者： Purnaweni, Hartuti Kismartini Prabawani, Bulan Roziqin, Ali Public Administration Department Faculty of Social and Political Sciences Universitas Diponegoro Indonesia Program of Environmental Science School of Post Graduate Undip Indonesia Business Administration Department Faculty of Social and Political Sciences Undip Indonesia Government Science Universitas Muhammadiyah Malang Indonesia

Mining is a very crucial activity of human being and is practiced everywhere in the world, including in Bangka Belitung Province which is rich in tin, making tin is the leading commodity in this area. This study aimed at analyzing the Bangka Belitung profile, tin mining activities in this area and its impact on an environmental conditions in Bangka Belitung Islands. The study applied a descriptive-qualitative method, using data from library study and previous researches dealing with the research topic, as well as data from field observation. It concluded that tin mining has been done since the Dutch era in Bangka Belitung, and is more active today. Therefore, it is concluded that massive environmental degradation will occur should the mining practices are not stopped. The study It is recommended that the government has to strengthen its policy in the form of local regulation on the tin mining activities for erecting a better public administration practices. © The Authors, published by EDP sciences, 2019.

关键词： environmental regulations

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Role of plant genetic resources in encountering climate change challenge 10

Role of plant genetic resources in encountering climate chan...

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10th Annual International Conference 2020 on environmental and Life sciences, AIC-ELS 2020

作者： Ichsan, C.N. Darusman Sulaiman, M.I. Andini, R. Doctoral Program in Agricultural Sciences Post Graduate School Universitas Syiah Kuala Jl. Tgk. Chik Pante Kulu No.3 Banda Aceh Indonesia Department of Soil Science Universitas Syiah Kuala Jl. Tgk. Hasan Krueng Kalee No. 3 Banda Aceh Indonesia Department of Agricultural Product Technology Universitas Syiah Kuala Jl. Tgk. Hasan Krueng Kalee No. 3 Banda Aceh Indonesia Department of Forestry Universitas Syiah Kuala Jl. Tgk. Hasan Krueng Kalee No. 3 Banda Aceh Indonesia

The world is encountering a global threat: Climate change. It is estimated that the average air temperature will raise 3.7-7.8 °C by 2100. The possible impacts will vary, however, agriculture will be adversely affected marked with yield loss of staple crops such as rice and maize and altered post-harvest quality of horticulture products. On the other hand, the world Food and Agriculture Organization (UN-FAO) has set a target 'zero hunger' by 2030', despite the five big challenges ahead: I) protracted conflict, ii) growing inequality, iii) rapid urbanization, iv) economic challenges, v) drought and natural disasters. The existing plant genetic resources, particularly the wild, neglected, and underutilized species has a great role and bears big potential to be exploited and targetted to achieve food and nutrition security, esp. in the densely populated regions with malnutrition problem e.g. in Asia and sub-Saharan regions. However, a key to future and sustainable crop production lies in the collection of crop and their wild relatives stored in ex-situ, or in-situ. This paper aims to explain the importance of plant genetic resources as well as the potential of some underutilized crops closely attributed with drought resistence, such as sorghum (Sorghum bicolor L. Moench), amaranth (Amaranthus sp.). These crops bear potential to support national food security program. © Published under licence by IOP Publishing Ltd.

关键词： Crops

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Phage display-derived alpaca nanobodies as potential therapeutics for Naja atra snake envenomation

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Applied and environmental Microbiology 2024年第8期90卷 e0012124页

作者： Wang, Wei-Chu Chang, Jungshan Lee, Chi-Hsin Chiang, Yu-Wei Leu, Sy-Jye Mao, Yan-Chiao Chiang, Jen-Ron Yang, Chun-Kai Wu, Chao-Jung Yang, Yi-Yuan Ph.D. Program in Medical Biotechnology College of Medical Science and Technology Taipei Medical University Taipei Taiwan Graduate Institute of Medical Sciences College of Medicine Taipei Medical University Taipei Taiwan International Master/Ph.D. Program in Medicine College of Medicine Taipei Medical University Taipei Taiwan International Ph.D. Program for Cell Therapy and Regeneration Medicine College of Medicine Taipei Medical University Taipei Taiwan School of Medical Laboratory Science and Biotechnology College of Medical Science and Technology Taipei Medical University Taipei Taiwan Core Laboratory of Antibody Generation and Research Taipei Medical University Taipei Taiwan Department of Medical Research Taipei Veterans General Hospital Taipei Taiwan Department of Biology and Anatomy National Defense Medical Center Taipei Taiwan Foundation for Poison Control Taipei Taiwan Department of Microbiology and Immunology School of Medicine College of Medicine Taipei Medical University Taipei Taiwan School of Medicine National Defense Medical Centre Taipei Taiwan Department of Post-Baccalaureate Medicine College of Medicine National Chung Hsing University Taichung Taiwan Division of Clinical Toxicology Department of Emergency Medicine Taichung Veterans General Hospital Taichung Taiwan Bioproduction Plants National Institute of Infectious Diseases and Vaccinology National Health Research Institutes Miaoli Taiwan Interdisciplinary Research on Ecology and Sustainability National Dong Hwa University Hualien Taiwan

Naja atra, the Chinese cobra, is a major cause of snake envenomation in Asia, causing hundreds of thousands of clinical incidents annually. The current treatment, horse serum-derived antivenom, has unpredictable side effects and presents manufacturing challenges. This study focused on developing new-generation snake venom antidotes by using microbial phage display technology to derive nanobodies from an alpaca immunized with attenuated N. atra venom. Following confirmation of the immune response in the alpaca, we amplified VHH genes from isolated peripheral blood mononuclear cells and constructed a phage display VHH library of 1.0 × 107 transformants. After four rounds of biopanning, the enriched phages exhibited increased binding activity to N. atra venom. Four nanobody clones with high binding affinities were selected: aNAH1, aNAH6, aNAH7, and aNAH9. Specificity testing against venom from various snake species, including two Southeast Asian cobra species, revealed nanobodies specific to the genus Naja. An in vivo mouse venom neutralization assay demonstrated that all nanobodies prolonged mouse survival and aNAH6 protected 66.6% of the mice from the lethal dosage. These findings highlight the potential of phage display-derived nanobodies as valuable antidotes for N. atra venom, laying the groundwork for future applications in snakebite treatment. Copyright © 2024 American Society for Microbiology. All Rights Reserved.

关键词： Mammals

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Multi Effect of Rain Harvesting in the Floating Village of Malahing on the Coast Bontang Developed by the CSR of PKT

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IOP Conference Series: Earth and environmental science 2020年第1期448卷

作者： S D Ekowati S P Hadi Doctoral Program in Environmental Science Post-Graduate Program Diponegoro University Semarang-Indonesia Graduate Program of Environmental Science Diponegoro University Semarang-Indonesia

The residents of the floating village of Malahing, Bontang, East Kalimantan, earn their living as fish catching fishermen and seaweed farming. Residents even experience a clean water crisis, every month they require a budget IDR 300, 000 until IDR 400, 000 to buy clean water at Tanjung Laut by ketinting. The PKT programmed rain harvesting for Malahing residents to supply clean water. The method used was field observations and surveys as well as simple calculations using the program of Office Excel. The PKT carried out gutter procurement for every resident's house, provided three plastic drums of 200 litres to collect rainwater, provided filters to filter rain water, train the residents to care for and repair the filters. As a result, the residents get clean water to meet their daily basic, grow vegetables for family needs and do greening in their yard and water them. They can also water communal latrines so that defecation is not carried out at sea. Malahing residents can save IDR. 356, 000 until IDR 456.000 per month, help save fossil fuels and reduce carbon dioxide emissions so they become healthier, prosperous and environmentally friendly.

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