检索结果-内蒙古大学图书馆

Hierarchical Reaction Logic Enables Computational Design of Complex Peptide syntheses

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 2025年第9期147卷 7644-7662页

作者： Molga, Karol Beker, Wiktor Roszak, Rafal Czerwinski, Andrzej Grzybowski, Bartosz A. Allchemy Inc Highland IN 46322 USA Polish Acad Sci Inst Organ Chem PL-01224 Warsaw Poland IBS Ctr Algorithm & Robotized Synth CARS Ulsan 689798 South Korea UNIST Dept Chem Ulsan 689798 South Korea

The prevalent assumption in computer-assisted synthesis planning has been to rely on the wealth of reaction data and on the consideration of this vast knowledge base at every stage of route planning. Yet even if equipped with all requisite knowledge of individual reaction transforms and state-of-the-art search algorithms, the existing programs struggle when confronted with advanced targets, such as the complex peptides this work considers. By contrast, when the searches are constrained by hierarchical logic, dictating which subsets of reactions to apply at different stages of synthesis planning, these algorithms are able to plan, within minutes, complete routes to clinically relevant targets as complex as vancomycin and as large as semaglutide. Despite not being trained on any literature precedents, the routes designed by the algorithm mimic the strategies used by human experts. The hierarchical planning we describe incorporates protecting-group strategies and realistic pathway pricing and can be performed in solid-state or solution modes, in the latter case using either C-to-N or N-to-C peptide extension strategies.

关键词： Computer aided logic design

来源：评论

学校读者我要写书评

暂无评论

ODSEI Chip: An Open 3D Microfluidic Platform for Studying Tumor Spheroid-Endothelial Interactions

引用

ADVANCED SCIENCE 2025年第13期12卷 e2410659页

作者： Ro, Jooyoung Kim, Junyoung Park, Juhee Choi, Yongjun Cho, Yoon-Kyoung Ulsan Natl Inst Sci & Technol UNIST Dept Biomed Engn Ulsan 44919 South Korea Inst Basic Sci IBS Ctr Algorithm & Robotized Synth Ulsan 44919 South Korea

Current in vitro models of 3D tumor spheroids within the microenvironment have emerged as promising tools for understanding tumor progression and potential drug responses. However, creating spheroids with functional vasculature remains challenging in a controlled and high-throughput manner. Herein, a novel open 3D-microarray platform is presented for a spheroid-endothelium interaction (ODSEI) chip, capable of arraying more than 1000 spheroids on top of the vasculature, compartmentalized for single spheroid-level analysis of drug resistance, and allows for the extraction of specific spheroids for further analysis. As proof of concept, the crosstalk between breast cancer spheroids and vasculature is monitored, validating the roles of endothelial cells in acquired tamoxifen resistance. Cancer spheroids exhibited reduced sensitivity to tamoxifen in the presence of vasculature. Further analysis through single-cell RNA sequencing of extracted spheroids and protein arrays elucidated gene expression profiles and cytokines associated with acquired tamoxifen resistance, particularly involving the TNF-alpha pathway via NF-kappa B and mTOR signaling. By targeting the highly expressed cytokines (IL-8, TIMP1) identified, tamoxifen resistance in cancer spheroid can be effectively reversed. In summary, the ODSEI chip allows to study spheroid and endothelial interaction in various contexts, leading to improved insights into tumor biology and therapeutic strategies.

关键词： co-culture drug-resistant mechanism study open microfluidics spheroids

来源：评论

学校读者我要写书评

暂无评论

Retro-forward synthesis design and experimental validation of potent structural analogs of known drugs

引用

CHEMICAL SCIENCE 2025年第19期16卷 8383-8393页

作者： Makkawi, Ahmad Beker, Wiktor Wolos, Agnieszka Manna, Sabyasachi Roszak, Rafal Szymkuc, Sara Moskal, Martyna Koshevarnikov, Aleksei Molga, Karol Zadlo-Dobrowolska, Anna Grzybowski, Bartosz A. Polish Acad Sci Inst Organ Chem Warsaw Poland Allchemy Inc Highland IN USA Inst Basic Sci IBS Ctr Algorithm & Robotized Synth CARS Ulsan 44919 South Korea UNIST Ulsan Inst Sci & Technol Dept Chem Ulsan 44919 South Korea

Generation of structural analogs to "parent" molecule(s) of interest remains one of the important elements of drug development. Ideally, such analogs should be synthesizable by concise and robust synthetic routes. The current work illustrates how this process can be facilitated by a computational pipeline spanning (i) diversification of the parent via substructure replacements aimed at enhancing biological activity, (ii) retrosynthesis of the thus generated "replicas" to identify substrates, (iii) forward syntheses originating from these substrates (and synthetically versatile "auxiliaries") and guided "towards" the parent, and (iv) evaluation of the candidates for target binding and other medicinal-chemical properties. This pipeline proposes syntheses of thousands of readily makeable analogs in a matter of minutes, and is deployed here to validate by experiment seven structural analogs of Ketoprofen and six analogs of Donepezil. The concise, computer-designed syntheses are confirmed in 12 out of 13 cases, offering access to several potent inhibitors. While the synthesis-design component is robust, binding affinities are predicted less accurately although still to the order-of-magnitude, which may be valuable in discerning promising from inadequate binders.

关键词： Bioactivity

来源：评论

学校读者我要写书评

暂无评论

Nanoplasmonic SERS on fidget spinner for digital bacterial identification

引用

MICROSYSTEMS & NANOENGINEERING 2025年第1期11卷 1-15页

作者： Karmacharya, Mamata Michael, Issac Han, Jiyun Clarissa, Elizabeth Maria Gulenko, Oleksandra Kumar, Sumit Cho, Yoon-Kyoung Inst Basic Sci IBS Ctr Algorithm & Robot Synth CARS Ulsan 44919 South Korea Ulsan Natl Inst Sci & Technol UNIST Dept Biomed Engn Ulsan 44919 South Korea

Raman spectroscopy offers non-destructive and highly sensitive molecular insights into bacterial species, making it a valuable tool for detection, identification, and antibiotic susceptibility testing. However, achieving clinically relevant accuracy, quantitative data, and reproducibility remains challenging due to the dominance of bulk signals and the uncontrollable heterogeneity of analytes. In this study, we introduce an innovative diagnostic tool: a plasmonic fidget spinner (P-FS) incorporating a nitrocellulose membrane integrated with a metallic feature, referred to as a nanoplasmonic-enhanced matrix, designed for simultaneous bacterial filtration and detection. We developed a method to fabricate a plasmonic array patterned nitrocellulose membrane using photolithography, which is then integrated with a customized fidget spinner. Testing the P-FS device with various bacterial species (E. coli 25922, S. aureus 25923, E. coli MG1655, Lactobacillus brevis, and S. mutans 3065) demonstrated successful identification based on their unique Raman fingerprints. The bacterial interface with regions within the plasmonic array, where the electromagnetic field is most intensely concentrated-called nanoplasmonic hotspots-on the P-FS significantly enhances sensitivity, enabling more precise detection. SERS intensity mappings from the Raman spectrometer are transformed into digital signals using a threshold-based approach to identify and quantify bacterial distribution. Given the P-FS's ability to enhance vibrational signatures and its scalable fabrication under routine conditions, we anticipate that nanoplasmonic-enhanced Raman spectroscopy-utilizing nanostructures made from metals (specifically gold and silver) deposited onto a nitrocellulose membrane to amplify Raman scattering signals-will become the preferred technology for reliable and ultrasensitive detection of various analytes, including those crucial to human health, with strong potential for transitioning from labora

关键词： Escherichia coli

来源：评论

学校读者我要写书评

暂无评论

Nature Inspired Delivery Vehicles for CRISPR-Based Genome Editing

引用

SMALL 2025年第0期 e2409353页

作者： Clarissa, Elizabeth Maria Karmacharya, Mamata Choi, Hyunmin Kumar, Sumit Cho, Yoon-Kyoung Inst Basic Sci IBS Ctr Algorithm & Robotized Synth UNIST Gil 50 Ulsan 44919 South Korea Ulsan Natl Inst Sci & Technol UNIST Dept Biomed Engn UNIST Gil 50 Ulsan 44919 South Korea

The advent of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-based genome editing technologies has opened up groundbreaking possibilities for treating a wide spectrum of genetic disorders and diseases. However, the success of these technologies relies heavily on the development of efficient and safe delivery systems. Among the most promising approaches are natural and synthetic nanocarrier-mediated delivery systems, including viral vectors, extracellular vesicles (EVs), engineered cellular membrane particles, liposomes, and various nanoparticles. These carriers enhance the efficacy of the CRISPR system by providing a unique combination of efficiency, specificity, and reduced immunogenicity. synthetic carriers such as liposomes and nanoparticles facilitate CRISPR delivery with high reproducibility and customizable functions. Viral vectors, renowned for their high transduction efficiency and broad tropism, serve as powerful vehicles for delivering CRISPR components to various cell types. EVs, as natural carriers of RNA and proteins, offer a stealth mechanism to evade immune detection, allowing for the targeted delivery of genome editors with minimal off-target effects. Engineered cellular membrane particles further improve delivery by simulating the cellular environment, enhancing uptake, and minimizing immune response. This review explores the innovative integration of CRISPR genome editors with various nanocarrier systems, focusing on recent advancements, applications, and future directions in therapeutic genome editing.

关键词： CRISPR delivery genome editing membrane vesicles precision therapy

来源：评论

学校读者我要写书评

暂无评论

Enzymes as viscoelastic catalytic machines

引用

NATURE PHYSICS 2025年第5期21卷 1-12页

作者： Weinreb, Eyal Mcbride, John M. Siek, Marta Rougemont, Jacques Renault, Renaud Peleg, Yoav Unger, Tamar Albeck, Shira Fridmann-Sirkis, Yael Lushchekina, Sofya Sussman, Joel L. Grzybowski, Bartosz A. Zocchi, Giovanni Eckmann, Jean-Pierre Moses, Elisha Tlusty, Tsvi Weizmann Inst Sci Dept Phys Complex Syst Rehovot Israel Inst Basic Sci IBS Ctr Soft & Living Matter Ulsan South Korea Inst Basic Sci IBS Ctr Algorithm & Robotized Synth Ulsan South Korea Univ Geneva DEPT PHYS THEOR GENEVA Switzerland Olfera San Francisco CA USA Weizmann Inst Sci Dept Life Sci Core Facil LSCF Struct Prote Unit SPU Rehovot Israel Weizmann Inst Sci Dept Life Sci Core Facil LSCF Rehovot Israel Weizmann Inst Sci Dept Biomol Sci Rehovot Israel Weizmann Inst Sci Dept Chem & Struct Biol Rehovot Israel Polish Acad Sci Inst Organ Chem Warsaw Poland Ulsan Natl Inst Sci & Technol Dept Chem Ulsan South Korea Univ Calif Los Angeles Dept Phys & Astron Los Angeles CA USA Univ Geneva Sect Math Geneva Switzerland Ulsan Natl Inst Sci & Technol UNIST Dept Phys Ulsan 689798 South Korea

The catalytic cycle involves internal motions and conformational changes that allow enzymes to specifically bind to substrates, reach the transition state and release the product. Such mechanical interactions and motions are often long ranged so that mutations of residues far from the active site can modulate the enzymatic cycle. In particular, regions that undergo high strain during the cycle give mechanical flexibility to the protein, which is crucial for protein motion. Here we directly probe the connection between strain, flexibility and functionality, and we quantify how distant high-strain residues modulate the catalytic function via long-ranged force transduction. We measure the rheological and catalytic properties of wild-type guanylate kinase and of its mutants with a single amino acid replacement in low-/high-strain regions and in binding/non-binding regions. The rheological response of the protein to an applied oscillating force fits a continuum model of a viscoelastic material whose mechanical properties are significantly affected by mutations in high-strain regions, as opposed to mutations in control regions. Furthermore, catalytic activity assays show that mutations in high-strain or binding regions tend to reduce activity, whereas mutations in low-strain, non-binding regions are neutral. These findings suggest that enzymes act as viscoelastic catalytic machines with sequence-encoded mechanical specifications.

关键词： Continuum mechanics

来源：评论

学校读者我要写书评

暂无评论

Recent advances in micro-physiological systems for investigating tumor metastasis and organotropism

引用

LAB ON A CHIP 2024年第5期24卷 1351-1366页

作者： Yoon, Heejeong Sabate del Rio, Jonathan Cho, Seung Woo Park, Tae-Eun Ulsan Natl Inst Sci & Technol UNIST Dept Biomed Engn Coll Informat & Biotechnol Ulsan 44919 South Korea Inst Basic Sci IBS Ctr Algorithm & Robotized Synth CARS Ulsan 44919 South Korea

Tumor metastasis involves complex processes that traditional 2D cultures and animal models struggle to fully replicate. Metastatic tumors undergo a multitude of transformations, including genetic diversification, adaptation to diverse microenvironments, and modified drug responses, contributing significantly to cancer-related mortality. Micro-physiological systems (MPS) technology emerges as a promising approach to emulate the metastatic process by integrating critical biochemical, biomechanical, and geometrical cues at a microscale. These systems are particularly advantageous simulating metastasis organotropism, the phenomenon where tumors exhibit a preference for metastasizing to particular organs. Organotropism is influenced by various factors, such as tumor cell characteristics, unique organ microenvironments, and organ-specific vascular conditions, all of which can be effectively examined using MPS. This review surveys the recent developments in MPS research from the past five years, with a specific focus on their applications in replicating tumor metastasis and organotropism. Furthermore, we discuss the current limitations in MPS-based studies of organotropism and propose strategies for more accurately replicating and analyzing the intricate aspects of organ-specific metastasis, which is pivotal in the development of targeted therapeutic approaches against metastatic cancers. MPS technology holds great potential for studying complex metastasis organotropism. It effectively simulates the dynamic interactions between distinct organ environments and the tumor cells, capturing both their inter- and intra-tumor heterogeneity.

关键词： Tumors

来源：评论

学校读者我要写书评

暂无评论

Computational synthesis design for controlled degradation and revalorization

NATURE SYNTHESIS

引用

NATURE synthESIS 2024年第5期3卷 643-654页

作者： Zadlo-Dobrowolska, Anna Molga, Karol Kolodiazhna, Olga O. Szymkuc, Sara Moskal, Martyna Roszak, Rafal Grzybowski, Bartosz A. Polish Acad Sci Inst Organ Chem Warsaw Poland Allchemy Highland IN USA IBS Ctr Algorithm & Robotized Synth CARS Ulsan South Korea UNIST Dept Chem Ulsan South Korea

Degradation of larger and undesired or harmful molecules into smaller and, ideally, value-added products is one of the most important facets of circular chemistry. However, this task may be cumbersome for chemists who are accustomed to planning syntheses using bond-forming, rather than bond-breaking, methodologies. This work describes a forward-synthesis algorithm that can guide such degradation-oriented analyses. This algorithm uses a broad knowledge-base of degradative and related reactions and applies them to arbitrary small-molecule feeds to generate large synthetic networks within which it then traces degradative pathways that are chemically sound and lead to value-added products. Predictions of the algorithm are validated by proof-of-concept experiments entailing degradation and revalorization of two biomass feeds, d-glucose and quinine. The controlled degradation of larger and potentially harmful molecules into smaller, and preferably valuable, products is a crucial step to close the waste-degradation-synthesis loop envisioned by circular chemistry. Now, a forward-synthesis algorithm is designed to facilitate such degradation-oriented analyses, and proof-of-concept experimental validation is provided.

关键词：

来源：评论

学校读者我要写书评

暂无评论

Systematic, computational discovery of multicomponent and one-pot reactions

引用

NATURE COMMUNICATIONS 2024年第1期15卷 10285页

作者： Roszak, Rafal Gadina, Louis Wolos, Agnieszka Makkawi, Ahmad Mikulak-Klucznik, Barbara Bilgi, Yasemin Molga, Karol Golebiowska, Patrycja Popik, Oskar Klucznik, Tomasz Szymkuc, Sara Moskal, Martyna Bas, Sebastian Frydrych, Rafal Mlynarski, Jacek Vakuliuk, Olena Gryko, Daniel T. Grzybowski, Bartosz A. Allchemy Inc Highland IN USA Polish Acad Sci Inst Organ Chem Warsaw Poland Inst Basic Sci IBS Ctr Algorithm & Robotized Synth CARS Ulsan 44919 South Korea Jagiellonian Univ Krakow Poland Ulsan Inst Sci & Technol Dept Chem UNIST Ulsan 44919 South Korea

Discovery of new types of reactions is essential to organic chemistry because it expands the scope of accessible molecular scaffolds and can enable more economical syntheses of existing structures. In this context, the so-called multicomponent reactions, MCRs, are of particular interest because they can build complex scaffolds from multiple starting materials in just one step, without purification of intermediates. However, for over a century of active research, MCRs have been discovered rather than designed, and their number remains limited to only several hundred. This work demonstrates that computers taught the essential knowledge of reaction mechanisms and rules of physical-organic chemistry can design - completely autonomously and in large numbers - mechanistically distinct MCRs. Moreover, when supplemented by models to approximate kinetic rates, the algorithm can predict reaction yields and identify reactions that have potential for organocatalysis. These predictions are validated by experiments spanning different modes of reactivity and diverse product scaffolds. Multi component reactions (MCRs) can build complex scaffolds from multiple starting materials in just one step without purification of intermediates but until now MCRs have been discovered rather than designed. Here, the authors demonstrate an algorithmic approach based in the knowledge of reaction mechanisms and rules of physical-organic chemistry to design autonomously MCRs in large numbers.

关键词：

来源：评论

学校读者我要写书评

暂无评论

Microfluidic Dielectrophoretic Purification of Extracellular Vesicles from Plasma Lipoproteins

引用

LANGMUIR 2024年第49期40卷 25772-25784页

作者： del Rio, Jonathan Sabate Son, Yeonzu Park, Juhee Sunkara, Vijaya Cho, Yoon-Kyoung Inst Basic Sci IBS Ctr Algorithm & Robotized Synth Ulsan 44919 South Korea Ulsan Natl Inst Sci & Technol UNIST Dept Biomed Engn Ulsan 44919 South Korea Korea Adv Inst Sci & Technol KAIST Program Brain & Cognit Engn Daejeon 34141 South Korea

Extracellular vesicles (EVs) are small lipid vesicles shed by cells, carrying proteins, nucleic acids, and other molecular fingerprints. EVs have emerged as crucial mediators of cell-to-cell communication and hold great promise as biomarkers for liquid biopsies, enabling disease screening, diagnosis, prognosis, and monitoring. However, conventional EV separation methods are hampered by the presence of lipoproteins (LPs) in plasma samples, which have comparable characteristics and significantly outnumber EVs. These LPs contaminants complicate downstream analysis, compromising the accuracy of EV-based liquid biopsies. In this study, we present a lab-on-a-chip device that utilizes dielectrophoretic (DEP) separation principles to achieve efficient separation of EVs from LPs. Our method starts with a lab-on-a-disc filtration of human blood plasma gathering similar-sized EVs and LPs, followed by on-disc buffer exchange and subsequent injection into a microfluidic chip containing slanted interdigitated microelectrodes. The DEP force is negative for all EV sizes and positive for all LP sizes at 104 Hz and thus EVs are pushed away and collected at the collection outlet, whereas LPs are flowed down to the waste outlet. This two-step EVs isolation method, size-based filtration followed by DEP-based purification, offers a promising solution for enhancing the quality and accuracy of EV-based liquid biopsies.

关键词： Lipoproteins

来源：评论

学校读者我要写书评

暂无评论

建议与咨询留下您的常用邮箱和电话号码，以便我们向您反馈解决方案和替代方法

时间限定

文献类型

馆藏选择

核心期刊

语言

文献类型

帮助

文字说明：

检索规则说明：

检索范例：

分类表

所选分类

限定检索结果

文献类型

馆藏范围

日期分布

学科分类号

主题

机构

作者

语言

请选择保存的检索档案：

请选择收藏分类：

通借通还

建议与咨询 留下您的常用邮箱和电话号码，以便我们向您反馈解决方案和替代方法

时间限定

文献类型

馆藏选择

核心期刊

语言

文献类型

帮助

文字说明：

检索规则说明：

检索范例：

分类表

所选分类

限定检索结果

文献类型

馆藏范围

日期分布

学科分类号

主题

机构

作者

语言

请选择保存的检索档案： 新增检索档案 确定 取消

请选择收藏分类： 新增自定义分类 确定 取消

通借通还

建议与咨询留下您的常用邮箱和电话号码，以便我们向您反馈解决方案和替代方法

请选择保存的检索档案：

请选择收藏分类：