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9. Dual domestications and origin of traits in grapevine evolution

Author

Yang Dong, Shengchang Duan, Qiuju Xia, Zhenchang Liang, Xiao Dong, Kristine Margaryan, Mirza Musayev, Svitlana Goryslavets, Goran Zdunić, Pierre-François Bert, Thierry Lacombe, Erika Maul, Peter Nick, Kakha Bitskinashvili, György Dénes Bisztray, Elyashiv Drori, Gabriella De Lorenzis, Jorge Cunha, Carmen Florentina Popescu, Rosa Arroyo-Garcia, Claire Arnold, Ali Ergül, Yifan Zhu, Chao Ma, Shufen Wang, Siqi Liu, Liu Tang, Chunping Wang, Dawei Li, Yunbing Pan, Jingxian Li, Ling Yang, Xuzhen Li, Guisheng Xiang, Zijiang Yang, Baozheng Chen, Zhanwu Dai, Yi Wang, Arsen Arakelyan, Varis Kuliyev, Gennady Spotar, Nabil Girollet, Serge Delrot, Nathalie Ollat, Patrice This, Cécile Marchal, Gautier Sarah, Valérie Laucou, Roberto Bacilieri, Franco Röckel, Pingyin Guan, Andreas Jung, Michael Riemann, Levan Ujmajuridze, Tekle Zakalashvili, David Maghradze, Maria Höhn, Gizella Jahnke, Erzsébet Kiss, Tamás Deák, Oshrit Rahimi, Sariel Hübner, Fabrizio Grassi, Francesco Mercati, Francesco Sunseri, José Eiras-Dias, Anamaria Mirabela Dumitru, David Carrasco, Alberto Rodriguez-Izquierdo, Gregorio Muñoz, Tamer Uysal, Cengiz Özer, Kemal Kazan, Meilong Xu, Yunyue Wang, Shusheng Zhu, Jiang Lu, Maoxiang Zhao, Lei Wang, Songtao Jiu, Ying Zhang, Lei Sun, Huanming Yang, Ehud Weiss, Shiping Wang, Youyong Zhu, Shaohua Li, Jun Sheng, Wei Chen, Duan, Shengchang, Xia, Qiuju, Liang, Zhenchang, Margaryan, Kristine, Musayev, Mirza, Goryslavets, Svitlana, Zdunić, Goran, Bert, Pierre-François, Lacombe, Thierry, Maul, Erika, Bitskinashvili, Kakha, Bisztray, György Dénes, Drori, Elyashiv, De Lorenzis, Gabriella, Popescu, Carmen Florentina, Arroyo García, Rosa Adela, Chen, Baozheng, Dai, Zhanwu, Spotar, Gennady, Girollet, Nabil, Delrot, Serge, Ollat, Nathalie, This, Patrice, Sarah, Gautier, Laucou, Valérie, Bacilieri, Roberto, Röckel, Franco, Guan, Pingyin, Riemann, Michael, Ujmajuridze, Levan, Zakalashvili, Tekle, Höhn, Maria, Jahnke, Gizella, Kiss, Erzsébet, Deák, Tamás, Rahimi, Oshrit, Hübner, Sariel, Grassi, Fabrizio, Mercati, Francesco, Eiras-Dias, José, Dumitru, Anamaria Mirabela, Carrasco, David, Rodriguez-Izquierdo, Alberto, Muñoz, Gregorio, Uysal, Tamer, Özer, Cengiz, Kazan, Kemal, Wang, Yunyue, Zhao, Maoxiang, Weiss, Ehud, Dong, Y, Duan, S, Xia, Q, Liang, Z, Dong, X, Margaryan, K, Musayev, M, Goryslavets, S, Zdunić, G, Bert, P, Lacombe, T, Maul, E, Nick, P, Bitskinashvili, K, Bisztray, G, Drori, E, De Lorenzis, G, Cunha, J, Popescu, C, Arroyo-Garcia, R, Arnold, C, Ergül, A, Zhu, Y, Ma, C, Wang, S, Liu, S, Tang, L, Wang, C, Li, D, Pan, Y, Li, J, Yang, L, Li, X, Xiang, G, Yang, Z, Chen, B, Dai, Z, Wang, Y, Arakelyan, A, Kuliyev, V, Spotar, G, Girollet, N, Delrot, S, Ollat, N, This, P, Marchal, C, Sarah, G, Laucou, V, Bacilieri, R, Röckel, F, Guan, P, Jung, A, Riemann, M, Ujmajuridze, L, Zakalashvili, T, Maghradze, D, Höhn, M, Jahnke, G, Kiss, E, Deák, T, Rahimi, O, Hübner, S, Grassi, F, Mercati, F, Sunseri, F, Eiras-Dias, J, Dumitru, A, Carrasco, D, Rodriguez-Izquierdo, A, Muñoz, G, Uysal, T, Özer, C, Kazan, K, Xu, M, Zhu, S, Lu, J, Zhao, M, Wang, L, Jiu, S, Zhang, Y, Sun, L, Yang, H, Weiss, E, Li, S, Sheng, J, and Chen, W

Subjects
Domestication, Ecotype, Phenotype, Multidisciplinary, Acclimatization, Grapes, domestication, origin, Genetics, Humans, genetic diversity, genomic history, accessions, holocene, insights, Agriculture, Vitis, Asia Western, Biological Evolution
Abstract

We elucidate grapevine evolution and domestication histories with 3525 cultivated and wild accessions worldwide. In the Pleistocene, harsh climate drove the separation of wild grape ecotypes caused by continuous habitat fragmentation. Then, domestication occurred concurrently about 11,000 years ago in Western Asia and the Caucasus to yield table and wine grapevines. The Western Asia domesticates dispersed into Europe with early farmers, introgressed with ancient wild western ecotypes, and subsequently diversified along human migration trails into muscat and unique western wine grape ancestries by the late Neolithic. Analyses of domestication traits also reveal new insights into selection for berry palatability, hermaphroditism, muscat flavor, and berry skin color. These data demonstrate the role of the grapevines in the early inception of agriculture across Eurasia.

Published
2023
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16. Exoskeleton-Assisted Anthropomorphic Movement Training for the Upper Limb After Stroke: The EAMT Randomized Trial

Author

Ze-Jian Chen, Chang He, Jiang Xu, Chan-Juan Zheng, Jing Wu, Nan Xia, Qiang Hua, Wen-Guang Xia, Cai-Hua Xiong, and Xiao-Lin Huang

Subjects
Advanced and Specialized Nursing, Neurology (clinical), Cardiology and Cardiovascular Medicine
Abstract

Background: Robot-assisted arm training is generally delivered in the robot-like manner of planar or mechanical 3-dimensional movements. It remains unclear whether integrating upper extremity (UE) natural coordinated patterns into a robotic exoskeleton can improve outcomes. The study aimed to compare conventional therapist-mediated training to the practice of human-like gross movements derived from 5 typical UE functional activities managed with exoskeletal assistance as needed for patients after stroke. Methods: In this randomized, single-blind, noninferiority trial, patients with moderate-to-severe UE motor impairment due to subacute stroke were randomly assigned (1:1) to receive 20 sessions of 45-minute exoskeleton-assisted anthropomorphic movement training or conventional therapy. Treatment allocation was masked from independent assessors, but not from patients or investigators. The primary outcome was the change in the Fugl-Meyer Assessment for Upper Extremity from baseline to 4 weeks against a prespecified noninferiority margin of 4 points. Superiority would be tested if noninferiority was demonstrated. Post hoc subgroup analyses of baseline characteristics were performed for the primary outcome. Results: Between June 2020 and August 2021, totally 80 inpatients (67 [83.8%] males; age, 51.9±9.9 years; days since stroke onset, 54.6±38.0) were enrolled, randomly assigned to the intervention, and included in the intention-to-treat analysis. The mean Fugl-Meyer Assessment for Upper Extremity change in exoskeleton-assisted anthropomorphic movement training (14.73 points; [95% CI, 11.43–18.02]) was higher than that of conventional therapy (9.90 points; [95% CI, 8.15–11.65]) at 4 weeks (adjusted difference, 4.51 points [95% CI, 1.13–7.90]). Moreover, post hoc analysis favored the patient subgroup (Fugl-Meyer Assessment for Upper Extremity score, 23–38 points) with moderately severe motor impairment. Conclusions: Exoskeleton-assisted anthropomorphic movement training appears to be effective for patients with subacute stroke through repetitive practice of human-like movements. Although the results indicate a positive sign for exoskeleton-assisted anthropomorphic movement training, further investigations into the long-term effects and paradigm optimization are warranted. Registration: URL: https://www.chictr.org.cn ; Unique identifier: ChiCTR2100044078.

Published
2023
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19. Search for gamma-ray spectral lines with the DArk Matter Particle Explorer

Author

Yun-Feng Liang, Francesca Alemanno, Qi An, Philipp Azzarello, Felicia Carla Tiziana Barbato, Paolo Bernardini, Xiao-Jun Bi, Ming-Sheng Cai, Elisabetta Casilli, Enrico Catanzani, Jin Chang, Deng-Yi Chen, Jun-Ling Chen, Zhan-Fang Chen, Ming-Yang Cui, Tian-Shu Cui, Yu-Xing Cui, Hao-Ting Dai, Antonio De Benedittis, Ivan De Mitri, Francesco de Palma, Maksym Deliyergiyev, Margherita Di Santo, Qi Ding, Tie-Kuang Dong, Zhen-Xing Dong, Giacinto Donvito, David Droz, Jing-Lai Duan, Kai-Kai Duan, Domenico D’Urso, Rui-Rui Fan, Yi-Zhong Fan, Fang Fang, Kun Fang, Chang-Qing Feng, Lei Feng, Piergiorgio Fusco, Min Gao, Fabio Gargano, Ke Gong, Yi-Zhong Gong, Dong-Ya Guo, Jian-Hua Guo, Shuang-Xue Han, Yi-Ming Hu, Guang-Shun Huang, Xiao-Yuan Huang, Yong-Yi Huang, Maria Ionica, Wei Jiang, Jie Kong, Andrii Kotenko, Dimitrios Kyratzis, Shi-Jun Lei, Shang Li, Wen-Hao Li, Wei-Liang Li, Xiang Li, Xian-Qiang Li, Yao-Ming Liang, Cheng-Ming Liu, Hao Liu, Jie Liu, Shu-Bin Liu, Yang Liu, Francesco Loparco, Chuan-Ning Luo, Miao Ma, Peng-Xiong Ma, Tao Ma, Xiao-Yong Ma, Giovanni Marsella, Mario Nicola Mazziotta, Dan Mo, Maria Muñoz Salinas, Xiao-Yang Niu, Xu Pan, Andrea Parenti, Wen-Xi Peng, Xiao-Yan Peng, Chiara Perrina, Rui Qiao, Jia-Ning Rao, Arshia Ruina, Zhi Shangguan, Wei-Hua Shen, Zhao-Qiang Shen, Zhong-Tao Shen, Leandro Silveri, Jing-Xing Song, Mikhail Stolpovskiy, Hong Su, Meng Su, Hao-Ran Sun, Zhi-Yu Sun, Antonio Surdo, Xue-Jian Teng, Andrii Tykhonov, Jin-Zhou Wang, Lian-Guo Wang, Shen Wang, Shu-Xin Wang, Xiao-Lian Wang, Ying Wang, Yan-Fang Wang, Yuan-Zhu Wang, Da-Ming Wei, Jia-Ju Wei, Yi-Feng Wei, Di Wu, Jian Wu, Li-Bo Wu, Sha-Sha Wu, Xin Wu, Zi-Qing Xia, En-Heng Xu, Hai-Tao Xu, Zhi-Hui Xu, Zun-Lei Xu, Zi-Zong Xu, Guo-Feng Xue, Hai-Bo Yang, Peng Yang, Ya-Qing Yang, Hui-Jun Yao, Yu-Hong Yu, Guan-Wen Yuan, Qiang Yuan, Chuan Yue, Jing-Jing Zang, Sheng-Xia Zhang, Wen-Zhang Zhang, Yan Zhang, Yi Zhang, Yong-Jie Zhang, Yun-Long Zhang, Ya-Peng Zhang, Yong-Qiang Zhang, Zhe Zhang, Zhi-Yong Zhang, Cong Zhao, Hong-Yun Zhao, Xun-Feng Zhao, Chang-Yi Zhou, Yan Zhu, Francesca Alemanno, Qi An, Philipp Azzarello, Felicia Carla Tiziana Barbato , Paolo Bernardini , Xiao-Jun Bi , Ming-Sheng Cai , Elisabetta Casilli , Enrico Catanzani , Jin Chang , Deng-Yi Chenj , Jun-Ling Chen , Zhan-Fang Chen , Ming-Yang Cui , Tian- Shu Cuin , Yu-Xin Cui , Hao-Ting Dai , Antonio De Benedittis , Ivan De Mitri , Francesco de Palma , Maksym Deliyergiyev Margherita Di Santo , Qi Ding , Tie-Kuan Dong , Zhen-Xing Dong , Giacinto Donvito , David Droz, Jing-Lai Duan , Kai-Kai Duan , Domenico D’Urso , Rui-Rui Fan , Yi-Zhong Fan , Fan Fang , Kun Fang, Chang-Qin Feng , Lei Feng , Piergiorgio Fusco, Min Gao , Fabio Gargano , Ke Gong , Yi-Zhong Gong , Dong- Ya Guo , Jian-Hua Guo , Shuang-Xue Han, Yi-Ming Hu , Guang- Shun Huang , Xiao-Yuan Huang , Yong-Yi Huang , Maria Ionica , Wei Jiang , Jie Kong , Andrii Kotenko , Dimitrios Kyratzis , Shi- Jun Lei, Shang Li , Wen-Hao Li , Wei-Liang Li , Xiang Li , Xian Qiang Li , Yao-Ming Lian , Cheng-Ming Liu , Hao Liu , Jie Liu , Shu-Bin Liu , Yang Liu , Francesco Loparco , Chuan-Ning Luo , Miao Ma , Peng-Xiong Ma , Tao Ma , Xiao-Yong Ma, Giovanni Marsella, Mario Nicola Mazziotta , Dan Mo , Maria Muñoz Salinas , Xiao-Yang Niu , Xu Pan , Andrea Parenti , Wen-Xi Peng , Xiao- Yan Peng , Chiara Perrina , Rui Qiao , Jia-Ning Rao , Arshia Ruina , Zhi Shangguan , Wei-Hua Shen , Zhao-Qiang Shen , Zhong-Tao Shen , Leandro Silveri, Jing-Xing Song , Mikhail Stolpovskiy Hong Su , Meng Su , Hao-Ra Sun , Zhi-Yu Sun , Antonio Surdo , Xue-Jian Teng , Andrii Tykhonov , Jin-Zhou Wang , Lian-Guo Wang , Shen Wang , Shu-Xin Wang , Xiao-Lian Wang , Ying Wang , Yan-Fang Wang , Yuan-Zhu Wang , Da-Ming Wei , Jia-Ju Wei , Yi-Feng Wei , Di Wu , Jian Wu , Li-Bo Wu , Sha-Sha Wun , Xin Wu , Zi-Qing Xi , En-Heng Xu , Hai-Tao Xu , Zhi-Hui Xu , Zun-Lei Xu , Zi-Zong Xu , Guo-Feng Xuen , Hai-Bo Yang , Peng Yang , Ya-Qing Yang , Hui-Jun Yao , Yu-Hong Yu , Guan-Wen Yuan , Qiang Yuan , Chuan Yue , JingJing Zang Sheng-Xi Zhang , Wen-Zhang Zhang , Yan Zhang, Yi Zhangj, Yong-Jie Zhang , Yun-Long Zhang , Ya-Peng Zhang , Yong-Qiang Zhang , Zhe Zhang , Zhi-Yong Zhang , Cong Zhao , Hong-Yun Zhao , Xun-Feng Zhao , Chang-Yi Zhou , and Yan Zhu, Alemanno, Francesca, An, Qi, Azzarello, Philipp, Carla Tiziana Barbato, Felicia, Bernardini, Paolo, Bi, Xiao-Jun, Cai, Ming-Sheng, Casilli, Elisabetta, Catanzani, Enrico, Chang, Jin, Chen, Deng-Yi, Chen, Jun-Ling, Chen, Zhan-Fang, Cui, Ming-Yang, Cui, Tian-Shu, Cui, Yu-Xin, Dai, Hao-Ting, De Benedittis, Antonio, De Mitri, Ivan, DE PALMA, Francesco, Deliyergiyev, Maksym, Di Santo, Margherita, Ding, Qi, Dong, Tie-Kuang, Dong, Zhen-Xing, Donvito, Giacinto, Droz, David, Duan, Jing-Lai, Duan, Kai-Kai, D’Urso, Domenico, Fan, Rui-Rui, Fan, Yi-Zhong, Fang, Fang, Fang, Kun, Feng, Chang-Qing, Feng, Lei, Fusco, Piergiorgio, Gao, Min, Gargano, Fabio, Gong, Ke, Gong, Yi-Zhong, Guo, Dong-Ya, Guo, Jian-Hua, Han, Shuang-Xue, Hu, Yi-Ming, Huang, Guang-Shun, Huang, Xiao-Yuan, Huang, Yong-Yi, Ionica, Maria, Jiang, Wei, Kong, Jie, Kotenko, Andrii, Kyratzis, Dimitrio, Lei, Shi-Jun, Li, Shang, Li, Wen-Hao, Li, Wei-Liang, Li, Xiang, Li, Xian-Qiang, Lian, Yao-Ming, Liu, Cheng-Min, Liu, Hao, Liu, Jie, Liu, Shu-Bin, Liu, Yang, Loparco, Francesco, Luo, Chuan-Ning, Ma, Miao, Ma, Peng-Xiong, Ma, Tao, Ma, Xiao-Yong, Marsella, Giovanni, Nicola Mazziotta, Mario, Mo, Dan, Muñoz Salinas, Maria, Niu, Xiao-Yang, Pan, Xu, Parenti, Andrea, Peng, Wen-Xi, Peng, Xiao-Yan, Perrina, Chiara, Qiao, Rui, Ra, Jia-Ning, Ruina, Arshia, Shangguan, Zhi, Shen, Wei-Hua, Shen, Zhao-Qiang, Shen, Zhong-Tao, Silveri, Leandro, Song, Jing-Xing, Stolpovskiy, Mikhail, Su, Hong, Su, Meng, Sun, Hao-Ran, Sun, Zhi-Yu, Surdo, Antonio, Teng, Xue-Jian, Tykhonov, Andrii, Wang, Jin-Zhou, Wang, Lian-Guo, Wang, Shen, Wang, Shu-Xin, Wang, Xiao-Lian, Wang, Ying, Wang, Yan-Fang, Wang, Yuan-Zhu, Wei, Da-Ming, Wei, Jia-Ju, Wei, Yi-Feng, Wu, Di, Wu, Jian, Wu, Li-Bo, Wu, Sha-Sha, Wu, Xin, Xia, Zi-Qing, Xu, En-Heng, Xu, Hai-Tao, Xu, Zhi-Hui, Xu, Zun-Lei, Xu, Zi-Zong, Xue, Guo-Feng, Yang, Hai-Bo, Yang, Peng, Yang, Ya-Qing, Yao, Hui-Jun, Yu, Yu-Hong, Yuan, Guan-Wen, Yuan, Qiang, Yue, Chuan, Zann, Jing-Jing, Zhan, Sheng-Xia, Zhan, Wen-Zhang, Zhan, Yan, Zhan, Yi, Zhang, Yong-Jie, Zhang, Yun-Long, Zhang, Ya-Peng, Zhang, Yong-Qiang, Zhang, Zhe, Zhang, Zhi-Yong, Zhao, Cong, Zhao, Hong-Yun, Zhao, Xun-Feng, Zhou, Chang-Yi, and Yan Zhu, And

Subjects
High Energy Astrophysical Phenomena (astro-ph.HE), Line-like structure, High Energy Physics - Experiment (hep-ex), Multidisciplinary, Astrophysics::High Energy Astrophysical Phenomena, DAMPE, Dark matter, Gamma-ray, Line-like structure, Settore FIS/01 - Fisica Sperimentale, DAMPE, Dark matter, FOS: Physical sciences, Astrophysics - High Energy Astrophysical Phenomena, Gamma-ray, High Energy Physics - Experiment
Abstract

The DArk Matter Particle Explorer (DAMPE) is well suitable for searching for monochromatic and sharp $\gamma$-ray structures in the GeV$-$TeV range thanks to its unprecedented high energy resolution. In this work, we search for $\gamma$-ray line structures using five years of DAMPE data. To improve the sensitivity, we develop two types of dedicated data sets (including the BgoOnly data which is the first time to be used in the data analysis for the calorimeter-based gamma-ray observatories) and adopt the signal-to-noise ratio optimized regions of interest (ROIs) for different DM density profiles. No line signals or candidates are found between 10 and 300 GeV in the Galaxy. The constraints on the velocity-averaged cross section for $\chi\chi \to \gamma\gamma$ and the decay lifetime for $\chi \to \gamma\nu$, both at 95% confidence level, have been calculated and the systematic uncertainties have been taken into account. Comparing to the previous Fermi-LAT results, though DAMPE has an acceptance smaller by a factor of $\sim 10$, similar constraints on the DM parameters are achieved and below 100 GeV the lower limits on the decay lifetime are even stronger by a factor of a few. Our results demonstrate the potential of high-energy-resolution observations on dark matter detection., Comment: 14 pages, 8 figures. Update the content to keep up with the published version

Published
2022
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21. The Protective Effect of the Asystasia chelonoides Extracts on Hypertensive Nephropathy Rats

Author

Junzheng Yang, Zhenghai Li, Tingting Duan, Minyi Li, Beifeng Lie, Ziyang Lin, Mengqiu Li, Tao Xia, Guixuan Lin, Lanqing Meng, and Xiuqing Lu

Subjects
Pharmaceutical Science, Biotechnology
Abstract

Background: Hypertensive nephropathy (HN) is one kind of kidney disorders caused by long-term uncontrolled hypertension, usually resulting in severe kidney damage, including inflammation and oxidative stress, no matter in cells or tissues, from patients with nephropathy. In recent years, nephropathy accompanied by hypertension is becoming one of the main causes for kidney replacement therapy, but few effective treatments have been reported for HN treatment. Asystasia chelonoides (AC) is a kind of plant with the effects of anti-inflammation, lowering blood pressure, and anti-oxidative stress. Still, the therapeutic effect of AC in HN rats is not clear. Methods: To establish HN model by feeding high sugar and high fat diet spontaneously hypertensive rats. Blood measurement, HE staining, PAS staining and biochemical analysis and were used to assess the therapeutic effects of AC extracts and western blotting analyzed the underlying mechanisms of AC extracts treatment in the HN rat model. Results: AC extracts could significantly lower systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean blood pressure (MBP) in HN rats; and reduce the expression of total protein (TP), blood urea nitrogen (BUN), microalbuminuria (MALB), creatinine (Cr), total cholesterol (TC), triglyceride (TG), and low-density lipoprotein-cholesterol (LDL-C) concentrations, and also could down-regulate expression of IL-6, MDA and AGEs, up-regulate the expression of SOD in HN rats; HE staining and PAS staining demonstrated that AC extracts could alleviate the histopathological changes in HN rats; western blotting demonstrated that AC extracts could up-regulate the expression of PPARγ and down-regulate the expression of TGFβ1 and NF-кB in HN rats. Conclusion: The finding of the article demonstrated that AC extracts had the better therapeutic effect for HN, and provided the pharmacological evidences for AC extracts treatment for HN.

Published
2023
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22. Prediction and Experimental Evaluation of the hERG Blocking Potential of Drugs Showing Clinical Signs of Cardiotoxicity

Author

Svetoslav Slavov, Jinghua Zhao, Ruili Huang, Menghang Xia, and Richard Beger

Subjects
Drug Discovery, Pharmaceutical Science, Molecular Medicine
Abstract

Background: A large scale experimental validation conducted at the National Center for Advancing Translational Sciences (NCATS/NIH, USA) confirmed the predictions of our 3D-SDAR model of hERG blockage and phospholipidosis induction. It was demonstrated that both hERG blockage and phospholipidosis induction are driven by a common three-center toxicophore composed of two aromatic rings and an amino group. This work extends our earlier efforts by predicting the hERG blocking potential of pharmaceuticals from two additional datasets: i) one comprised of 106 drugs with reported clinical signs of cardiotoxicity from the AZCERT database and ii) a dataset of 54 FDA-approved tyrosine kinase inhibitors (TKIs). Methods: A bagging-like 3D-SDAR algorithm aggregating predictions from 100 randomized models was used to predict the hERG blocking potential of all 160 drugs. All 106 drugs from the AZCERT dataset were further evaluated for their hERG inhibition at NCATS using a thallium flux assay. Results: Comparison of the predicted hERG class against the results of the thallium flux qHTS assay resulted in an overall predictive accuracy of 0.736 and the area under the ROC curve of 0.780. Factors such as the generation of false negatives by the thallium flux assay, proximity to the cut-off, use of conformations that may differ from the biologically relevant ones, and the lack of structurally similar compounds in the modeling set could explain the somewhat reduced predictive performance compared to that of the original model. The original 3D-SDAR model was also used to evaluate the TKIs ability to block hERG. Comparing our predictions to class assignments based on IC50 values with a 30 μM cut-off, an accuracy of 0.850, sensitivity of 0.906, and specificity of 0.625 were achieved. Conclusion: 3D-SDAR provides a reliable platform for the prediction of hERG blockage. Particular attention should be paid to all investigational new drugs containing our three-center hERG toxicophore, especially those having highly flexible molecules. Particular scrutiny should be given to the tyrosine kinase inhibitors, which represent a therapeutic class possessing all structural characteristics previously associated with an increased potential to block hERG.

Published
2023
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28. Research Progress in Competitive Purine Antagonists

Author

Guo-Wu Rao, Dan-Xia Ying, Peng-Cheng Zhao, and Wen Zhang

Subjects
Pharmacology, Drug Discovery, Organic Chemistry, Molecular Medicine, Biochemistry
Abstract

Abstract: Purine, one of the nucleotides, is an important substance for the metabolism and regulation of the body. Purine plays a key role not only in the composition of coenzymes but also in the supply of energy. Since purine was artificially synthesized, it has always been an important scaffold for respiratory diseases, cardiovascular diseases, and anti- tumor and anti-viral drugs. In addition to being widely used as competitive antagonists in the treatment of diseases, purines can be used in combination with other drugs and as precursors to benefit human life. Unfortunately, few new discoveries have been made in recent years. In this article, purine drugs in the market have been classified according to their different targets. In addition, their mechanism of action and structure-activity relationship have also been introduced. This paper provides details of the signaling pathways through which purine drugs can bind to the respective receptors on the surface of cells and cause consequent reactions within the cell, which finally affect the targeted diseases. The various receptors and biological reactions involved in the signaling for respective disease targets within the cells are discussed in detail.

Published
2023
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46. Hub Genes and Immune Cell Infiltration in Hypoxia-Induced Pulmonary Hypertension: Bioinformatics Analysis and In Vivo Validation

Author

Shengqing Li, Chengwei Li, Jingwen Xia, Ruzetuoheti Yiminniyaze, and Liang Dong

Subjects
Organic Chemistry, Drug Discovery, General Medicine, Computer Science Applications
Abstract

Background: Hypoxia-induced pulmonary hypertension (HPH) represents a severe pulmonary disorder with high morbidity and mortality, which necessitates identifying the critical molecular mechanisms underlying HPH pathogenesis. Method: The mRNA expression microarray GSE15197 (containing 8 pulmonary tissues from HPH and 13 normal controls) was downloaded from Gene Expression Omnibus (GEO). Gene ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) were executed by RStudio software. The Protein-Protein Interaction (PPI) network was visualized and established using Cytoscape, and the cytoHubba app from Cytoscape was used to pick out the hub modules. The infiltration of immune cells in HPH was analyzed using the CIBERSORTx. To confirm the potential hub genes, real-time quantitative reverse transcription PCR (qRT-PCR) was conducted using lung tissues of rat HPH models and controls. Results: A total of 852 upregulated and 547 downregulated genes were identified. The top terms in biological processes were apoptosis, proliferation, and regulation of the MAPK cascade, including ERK1/2. Cytoplasm, cytosol, and membrane were enriched in cellular component groups. Molecular functions mainly focus on protein binding, protein serine/threonine kinase activity and identical protein binding. KEGG analysis identified pathways in cancer, regulation of actin cytoskeleton and rap1 signaling pathway. There was significantly different immune cell infiltration between HPH and normal control samples. High proportions of the memory subsets of B cells and CD4 cells, Macrophages M2 subtype, and resting Dendritic cells were found in HPH samples, while high proportions of naive CD4 cells and resting mast cells were found in normal control samples. The qRTPCR results showed that among the ten identified hub modules, FBXL3, FBXL13 and XCL1 mRNA levels were upregulated, while NEDD4L, NPFFR2 and EDN3 were downregulated in HPH rats compared with control rats. Conclusion: Our study revealed the key genes and the involvement of immune cell infiltration in HPH, thus providing new insight into the pathogenesis of HPH and potential treatment targets for patients with HPH.

Published
2023
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