Article
Biochemistry & Molecular Biology
Xiaoli An, Qifeng Bai, Zhitong Bing, Huanxiang Liu, Xiaojun Yao
Summary: This study elucidates the mechanism of conformational coupling between different sites of the protein, highlighting the crucial role of flexibility in certain regions for agonist binding and action. The results provide important structural information for the design of novel GPR40 agonists.
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
(2021)
Article
Chemistry, Organic
Yong-Li Zhong, Yining Ji, Heather Wang, Xiao Wang, Donald R. Gauthier
Summary: A highly efficient enantioselective synthesis method was developed for the synthesis of potent G-protein-coupled receptor 40 agonist MK-2305. The key tetrasubstituted olefin was prepared through a stereoselective chemical reaction, followed by highly enantioselective rhodium-catalyzed transfer hydrogenation to obtain the target compound MK-2305 in high purity. The tethered catalysts used in the reaction showed superior reactivity, as revealed by NMR studies.
Article
Chemistry, Physical
Hongliu Zhang, Xi Chen, Tong Lv, Qian Li, Weidong Liu, Jinhui Feng, Xiangtao Liu, Peiyuan Yao, Qiaqing Wu, Dunming Zhu
Summary: In this study, a mutant M242F/Q245T of the carbonyl reductase from Sporobolomyces salmonicolor was found to enhance its activity toward both methyl 2-phthalimidomethyl-3-oxobutanoate(1a) and isopropanol, enabling the dynamic kinetic asymmetric reduction of 1a to a single stereoisomer of the product by hydrogen transfer from isopropanol. Structural and computational analysis suggested that the synergic effect of 242F and 245T reshaped the substrate entrance tunnel and enzyme active site. This study demonstrated that a carbonyl reductase can be engineered to improve its activity toward bulky ketones and isopropanol, and enable efficient preparation of the target chiral alcohol via substrate-coupled cofactor regeneration.
Article
Pharmacology & Pharmacy
Sergio Hidalgo-Figueroa, Ana Rodriguez-Luevano, Julio C. Almanza-Perez, Abraham Giacoman-Martinez, Rolffy Ortiz-Andrade, Ismael Leon-Rivera, Gabriel Navarrete-Vazquez
Summary: The manuscript describes the design of two molecules targeting PPAR gamma and GPR40 receptors, with compound 1 showing strong activity in increasing mRNA expression levels of PPAR gamma, GLUT4, and GPR40. Additionally, compound 1 exhibited a moderate increase in insulin secretion and calcium mobilization. These findings suggest that compound 1 acts as a dual PPAR gamma and GPR40 agonist, offering better glycemic control than current treatments.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2021)
Article
Chemistry, Multidisciplinary
Chengjie Wang, Hairong Zhao, Zhongsheng Ge, Lizhuang Dong, Xiao Han, Avula Balakrishna, Praveen Kumar Balguri, Yixi Wang, Udayabhaskararao Thumu
Summary: By systematically studying the reaction steps, we have optimized the synthesis method of Au18SG14 nanoclusters, enabling large-scale production under different laboratory conditions.
Article
Chemistry, Applied
Zubair-ul Islam, Nisar A. Mir, Adil Gani
Summary: The present study examined the effects of enzymatic treatment on high-intensity ultrasound modified album proteins. The results showed that enzymatic treatment induced structural changes and improved the physiochemical and functional characteristics of album proteins. Enzymatic treatment decreased particle size, poly-dispersibility index, turbidity, and total SH content, while increasing DPPH radical scavenging activity, total phenolic content, solubility, surface hydrophobicity, and free SH groups. Enzymatic treatment also led to a decrease in molecular weight, crystallinity, and improved thermal characteristics of album proteins.
FOOD HYDROCOLLOIDS
(2023)
Article
Computer Science, Software Engineering
Elvira Albert, Maria Garcia de la Banda, Miguel Gomez-Zamalloa, Miguel Isabel, Peter Stuckey
Summary: Dynamic Partial Order Reduction (DPOR) algorithms are used in stateless model checking of concurrent programs to avoid the exploration of equivalent execution sequences. Our work introduces a new algorithm, Optimal Context-Sensitive DPOR with Observers, that combines conditional notions of independence and goes beyond them by exploiting their synergies. Experimental evaluation shows that our algorithm effectively combines the benefits of both context-sensitive and observers-based independence and produces exponential reductions.
JOURNAL OF SYSTEMS AND SOFTWARE
(2023)
Article
Engineering, Marine
Shuai Sun, Shijie Qin, Hezhen Fang, Ximin Feng, Dazhuan Wu
Summary: The paper investigates the evolution of cavity shape and internal cavity pressure oscillation under different gust waves using the RANS coupled VOF method. Two types of cavity closure modes are found due to the presence of gust waves. A strong correlation between internal pressure variation and cavity oscillation behavior is revealed by time-frequency analysis. Additionally, the natural frequency of the cavity leads to an additional pressure fluctuation independent of waves.
Article
Engineering, Marine
Qiang Zheng, Hai-Chao Chang, Zu-Yuan Liu, Bai-Wei Feng
Summary: A dynamic space reduction method based on partial correlation analysis is proposed in this study to improve the efficiency of hull optimization design. This method analyzes and reduces the range of values for relevant design variables dynamically, significantly improving the optimization efficiency.
JOURNAL OF SHIP RESEARCH
(2021)
Article
Computer Science, Software Engineering
Quan Zhang, Chijin Zhou, Yiwen Xu, Zijing Yin, Mingzhe Wang, Zhuo Su, Chengnian Sun, Yu Jiang, Jiaguang Sun
Summary: Attack surface reduction is a security technique that protects the operating system by removing unnecessary code or features. By restricting the system calls that programs can use, the attack surface is reduced and prevents damage from vulnerable programs. This paper proposes DYNBOX, which dynamically disables unnecessary system calls throughout program execution using partial order analysis. Evaluation shows that DYNBOX outperforms existing techniques in terms of the number of restricted system calls and mitigating malicious exploits.
PROCEEDINGS OF THE ACM ON PROGRAMMING LANGUAGES-PACMPL
(2023)
Proceedings Paper
Automation & Control Systems
Jie Su, Cong Tian, Zuchao Yang, Jiyu Yang, Bin Yu, Zhenhua Duan
Summary: This paper proposes a symbolic approach, PC-DPOR, to reduce redundant traces in concurrent program verification. The approach utilizes a constrained dependency graph to refine dependencies between transitions and prioritizes the exploration of isolated transitions. Experimental results show that PC-DPOR can effectively reduce time and memory consumption in verifying concurrent programs.
PROCEEDINGS OF THE 37TH IEEE/ACM INTERNATIONAL CONFERENCE ON AUTOMATED SOFTWARE ENGINEERING, ASE 2022
(2022)
Article
Computer Science, Software Engineering
Michalis Kokologiannakis, Iason Marmanis, Vladimir Gladstein, Viktor Vafeiadis
Summary: This paper introduces an algorithm called TruSt for dynamic partial order reduction (DPOR) that is able to explore exactly one interleaving per equivalence class with linear memory consumption in weak memory models. TruSt is also embarrassingly parallelizable, leading to improved memory and time performance.
PROCEEDINGS OF THE ACM ON PROGRAMMING LANGUAGES-PACMPL
(2022)
Article
Chemistry, Multidisciplinary
Liangyan Zhu, Yunfeng Cui, Xi Chen, Hongliu Zhang, Jinhui Feng, Qiaqing Wu, Dunming Zhu
Summary: Two enzymes were discovered to catalyze the desymmetric reduction of 2-benzyl-2methyl-1,3-cylcohexanedione analogues, yielding 3-hydroxycyclohexane-1ones with excellent enantioselectivity and diastereoselectivity. Further studies are necessary to identify more enzymes for expanding the substrate scope and stereo-preference.
GREEN SYNTHESIS AND CATALYSIS
(2021)
Article
Computer Science, Software Engineering
Ahmed Bouajjani, Constantin Enea, Enrique Roman-Calvo
Summary: Modern applications rely on large-scale databases for data storage and retrieval, with weaker isolation levels for improved performance. In this research, we propose stateless model checking algorithms to study the correctness of such applications. These algorithms work with various weak isolation levels and have shown completeness, soundness, and optimal performance with polynomial memory consumption. Our implementation in Java Pathfinder has been applied to challenging applications from distributed systems and databases.
PROCEEDINGS OF THE ACM ON PROGRAMMING LANGUAGES-PACMPL
(2023)
Article
Biochemistry & Molecular Biology
Julie A. Zorn, Dennis W. Wolan, Nicholas J. Agard, James A. Wells
JOURNAL OF BIOLOGICAL CHEMISTRY
(2012)
Article
Medicine, Research & Experimental
Danielle M. DiCara, Nisana Andersen, Ruby Chan, James A. Ernst, Gai Ayalon, Greg A. Lazar, Nicholas J. Agard, Amy Hilderbrand, Isidro Hotzel
Article
Biochemical Research Methods
Nicholas J. Agard, David Maltby, James A. Wells
MOLECULAR & CELLULAR PROTEOMICS
(2010)
Article
Biochemical Research Methods
Emily D. Crawford, Julia E. Seaman, Nick Agard, Gerald W. Hsu, Olivier Julien, Sami Mahrus, Huy Nguyen, Kazutaka Shimbo, Hikari A. I. Yoshihara, Min Zhuang, Robert J. Chalkley, James A. Wells
MOLECULAR & CELLULAR PROTEOMICS
(2013)
Article
Biochemistry & Molecular Biology
Olivier Julien, Martin Kampmann, Michael C. Bassik, Julie A. Zorn, Vincent J. Venditto, Kazutaka Shimbo', Nicholas J. Agard, Kenichi Shimada, Arnold L. Rheingold, Brent R. Stockwell, Jonathan S. Weissman, James A. Wells
NATURE CHEMICAL BIOLOGY
(2014)
Article
Multidisciplinary Sciences
Nicholas J. Agard, Sami Mahrus, Jonathan C. Trinidad, Aenoch Lynn, Alma L. Burlingame, James A. Wells
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2012)
Article
Medicine, Research & Experimental
Josefa Dela Cruz Chuh, MaryAnn Go, Yvonne Chen, Jun Guo, Hanine Rafidi, Danielle Mandikian, Yonglian Sun, Zhonghua Lin, Kellen Schneider, Pamela Zhang, Rajesh Vij, Danielle Sharpnack, Pamela Chan, Cecile de la Cruz, Jack Sadowsky, Dhaya Seshasayee, James T. Koerber, Thomas H. Pillow, Gail D. Phillips, Rebecca K. Rowntree, C. Andrew Boswell, Katherine R. Kozak, Andrew G. Polson, Paul Polakis, Shang-Fan Yu, Peter S. Dragovich, Nicholas J. Agard
Summary: Early success with brentuximab vedotin in treating classical Hodgkin lymphoma led to the development of multiple MMAE antibody-drug conjugates, but most of these have not been successful in clinical trials. This study describes the development of second-generation therapeutic ADCs targeting Ly6E, with a focus on using DNA-damaging agents to improve durability of response. The new ADCs showed promising preclinical efficacy in driving tumor regression and reducing the likelihood of resistance compared to traditional MMAE-based conjugates.
Article
Hematology
Karen P. Fong, Kathleen S. Molnar, Nicholas Agard, Rustem Litvinov, Oleg Kim, James A. Wells, John W. Weisel, William F. DeGrado, Joel S. Bennett
Summary: Blood clot contraction is driven by traction forces generated by the platelet cytoskeleton and regulated by integrin alpha IIb beta 3. Proteolytically cleaved platelet proteins, particularly talin and vinculin, play crucial roles in clot contraction. Calpain-mediated cleavage of these proteins occurs independent of cytoskeletal-generated tensile forces, suggesting calpain's involvement in later stages of clot retraction through focal adhesion disassembly.
Article
Medicine, Research & Experimental
Robert F. Kelley, Devin B. Tesar, Yue Wang, Nicholas J. Agard, Patrick G. Holder, Joyce Chan, Laetitia Comps-Agrar, Judit Horvath, Joshua D. Horvath, Susan R. Crowell
Summary: Researchers have successfully developed a stable surrogate molecule for testing ocular drug delivery systems in a porcine model, which has low porcine immunogenicity and can continuously release the drug.
MOLECULAR PHARMACEUTICS
(2022)
Article
Medicine, Research & Experimental
Danielle M. Dicara, Sunil Bhakta, Mary Ann Go, James Ziai, Ron Firestein, Bill Forrest, Chen Gu, Steven R. Leong, Genee Lee, Shang-Fan Yu, Andrew G. Polson, Nicholas J. Agard
Summary: T cell-engaging bispecific antibodies (TCEs) have shown clinical effectiveness in treating hematological cancers, but their use in solid tumors can cause toxicity in normal tissues. This study developed TCEs that preferentially induce T cell-mediated death in target cells co-expressing two tumor-associated antigens, aiming to improve safety and efficacy.
Article
Multidisciplinary Sciences
Hadir Marei, Wen-Ting K. Tsai, Yee-Seir Kee, Karen Ruiz, Jieyan He, Chris Cox, Tao Sun, Sai Penikalapati, Pankaj Dwivedi, Meena Choi, David Kan, Pablo Saenz-Lopez, Kristel Dorighi, Pamela Zhang, Yvonne T. Kschonsak, Noelyn Kljavin, Dhara Amin, Ingrid Kim, Andrew G. Mancini, Thao Nguyen, Chunling Wang, Eric Janezic, Alexander Doan, Elaine Mai, Hongkang Xi, Chen Gu, Melanie Heinlein, Brian Biehs, Jia Wu, Isabelle Lehoux, Seth Harris, Laetitia Comps-Agrar, Dhaya Seshasayee, Frederic J. de Sauvage, Matthew Grimmer, Jing Li, Nicholas J. Agard, Felipe de Sousa e Melo
Summary: The study presents a strategy utilizing PROTABs technology to achieve target degradation advantages, enabling tissue-selective degradation of cell-surface receptors. By optimizing antibody formats, this technology can facilitate 'on-demand' degradation.
Article
Ophthalmology
Nicholas J. Agard, Gu Zhang, John Ridgeway, Danielle M. Dicara, Phillip Y. Chu, Rachana Ohri, Sarah Sanowar, Jean-Michel Vernes, Hannah Chi, Jiameng Zhang, Emily Holz, Maciej Paluch, Guannan He, Yingjia Benson, Jianhuan Zhang, Pamela Chan, Nga Tang, Prachi Javale, Blair Wilson, Kathy Barrett, Rebecca K. Rowntree, Julie Hang, Y. Gloria Meng, Phil Hass, Germaine Fuh, Robert Piskol, Vladimir Bantseev, Kelly M. Loyet, John C. Tran, Cong Wu, Vahan B. Indjeian, Vittal Shivva, Minhong Yan
Summary: This study explores a potential therapeutic approach for the treatment of DME by directly activating the Tie2 pathway to reduce vascular leakage, leading to the reduction of edema and improvement of vision.
TRANSLATIONAL VISION SCIENCE & TECHNOLOGY
(2022)
Article
Multidisciplinary Sciences
William C. Hallows, Kristen Skvorak, Nick Agard, Nikki Kruse, Xiyun Zhang, Yu Zhu, Rachel C. Botham, Chinping Chng, Charu Shukla, Jessica Lao, Mathew Miller, Antoinette Sero, Judy Viduya, Moulay Hicham Alaoui Ismaili, Kerryn McCluskie, Raphael Schiffmann, Adam P. Silverman, Jin-Song Shen, Gjalt W. Huisman
Summary: Fabry disease is caused by a deficiency of α-galactosidase A (GLA), resulting in the accumulation of glycosphingolipids. Directed evolution was used to generate more stable GLA variants, such as GLAv05 and GLAv09, which showed improved stability, enzyme activity, and pharmacokinetics. These findings hold promise for more effective treatments of lysosomal storage diseases.
SCIENTIFIC REPORTS
(2023)
Article
Medicine, Research & Experimental
Yvonne Chen, Maciej Paluch, Julie A. Zorn, Sharmila Rajan, Brandon Leonard, Alberto Estevez, John Brady, Henry Chiu, Wilson Phung, Amin Famili, Minhong Yan, Claudio Ciferri, Marissa L. Matsumoto, Greg A. Lazar, Susan Crowell, Phil Hass, Nicholas J. Agard