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Automated and miniaturized screening of antibiotic combinations via robotic-printed combinatorial droplet platform

Acta Pharmaceutica Sinica B 2024年第4期14卷 1801-1813页

作者： Fangchi Shao Hui Li Kuangwen Hsieh Pengfei Zhang Sixuan Li Tza-Huei Wang Department of Biomedical Engineering Johns Hopkins UniversityBaltimoreMD 21218USA Department of Mechanical Engineering Johns Hopkins UniversityBaltimoreMD 21218USA

Antimicrobial resistance(AMR)has become a global health crisis in need of novel *** this end,antibiotic combination therapies,which combine multiple antibiotics for treatment,have at-tracted significant attention as a potential approach for combating *** facilitate advances in anti-biotic combination therapies,most notably in investigating antibiotic interactions and identifying synergistic antibiotic combinations however,there remains a need for automated high-throughput plat-forms that can create and examine antibiotic combinations on-demand,at scale,and with minimal reagent *** address these challenges,we have developed a Robotic-Printed Combinatorial Droplet(RoboDrop)platform by integrating a programmable droplet microfuidic device that generates antibiotic combinations in nanoliter droplets in automation,a robotic arm that arranges the droplets in an array,and a camera that images the array of thousands of droplets in *** further implement a resazurin-based bacterial viability assay to accelerate our antibiotic combination *** a demonstration,we use RoboDrop to corroborate two pairs of antibiotics with known interactions and subsequently identify a new synergistic combination of cefsulodin,penicillin,and oxacillin against a model *** *** therefore envision RoboDrop becoming a useful tool to efficiently identify new synergistic antibiotic combinations toward combating AMR.

关键词： Droplet microfluidics Antimicrobial resistance Antibiotic combinatorial screening Contact printing Robotics Pharmaceutical analysis High-throughput Antibiotic interactions

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Precise genome-editing in human diseases:mechanisms,strategies and applications

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Signal Transduction and Targeted Therapy 2024年第3期9卷 1065-1085页

作者： Yanjiang Zheng Yifei Li Kaiyu Zhou Tiange Li Nathan J.VanDusen Yimin Hua Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE Department of PediatricsWest China Second University HospitalSichuan UniversityChengduSichuan 610041China Department of Cardiovascular Surgery West China HospitalSichuan UniversityChengduSichuan 610041China Department of Pediatrics Herman B Wells Center for Pediatric ResearchIndiana University School of MedicineIndianapolisIN 46202USA

Precise genome-editing platforms are versatile tools for generating specific,site-directed DNA insertions,deletions,and *** continuous enhancement of these tools has led to a revolution in the life sciences,which promises to deliver novel therapies for genetic *** genome-editing can be traced back to the 1950s with the discovery of DNA’s doublehelix and,after 70 years of development,has evolved from crude in vitro applications to a wide range of sophisticated capabilities,including in vivo ***,precise genome-editing faces constraints such as modest efficiency,delivery challenges,and off-target *** this review,we explore precise genome-editing,with a focus on introduction of the landmark events in its history,various platforms,delivery systems,and ***,we discuss the landmark events in the history of precise ***,we describe the current state of precise genome-editing strategies and explain how these techniques offer unprecedented precision and versatility for modifying the human ***,we introduce the current delivery systems used to deploy precise genome-editing components through DNA,RNA,and ***,we summarize the current applications of precise genome-editing in labeling endogenous genes,screening genetic variants,molecular recording,generating disease models,and gene therapy,including ex vivo therapy and in vivo therapy,and discuss potential future advances.

关键词： precise generating editing

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APIR:Aggregating Universal Proteomics Database Search Algorithms for Peptide Identification with FDR Control

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Genomics, Proteomics & Bioinformatics 2024年第2期22卷 171-187页

作者： Yiling Elaine Chen Xinzhou Ge Kyla Woyshner MeiLu McDermott Antigoni Manousopoulou Scott B.Ficarro Jarrod A.Marto Kexin Li Leo David Wang Jingyi Jessica Li Department of Statistics and Data Science University of CaliforniaLos AngelesCA 90095USA Department of Immuno-Oncology Beckman Research InstituteCity of Hope National Medical CenterDuarteCA 91010USA Department of Quantitative and Computational Biology University of Southern CaliforniaLos AngelesCA 90089USA Department of Cancer Biology and Blais Proteomics Center Dana-Farber Cancer InstituteDepartment of PathologyBrigham and Women’s Hospital and Harvard Medical SchoolBostonMA 02215USA Department of Pediatrics City of Hope National Medical CenterDuarteCA 91010USA Bioinformatics Interdepartmental Program University of CaliforniaLos AngelesCA 90095USA Department of Human Genetics University of CaliforniaLos AngelesCA 90095USA Department of Computational Medicine University of CaliforniaLos AngelesCA 90095USA Department of Biostatistics University of CaliforniaLos AngelesCA 90095USA

Advances in mass spectrometry(MS)have enabled high-throughput analysis of proteomes in biological *** state-of-the-art MS data analysis relies on database search algorithms to quantify proteins by identifying peptide–spectrum matches(PSMs),which convert mass spectra to peptide *** database search algorithms use distinct search strategies and thus may identify unique ***,no existing approaches can aggregate all user-specified database search algorithms with a guaranteed increase in the number of identified peptides and a control on the false discovery rate(FDR).To fill in this gap,we proposed a statistical framework,Aggregation of Peptide Identification Results(APIR),that is universally compatible with all database search ***,under an FDR threshold,APIR is guaranteed to identify at least as many,if not more,peptides as individual database search algorithms *** of APIR on a complex proteomics standard dataset showed that APIR outpowers individual database search algorithms and empirically controls the *** data studies showed that APIR can identify disease-related proteins and post-translational modifications missed by some individual database search *** APIR framework is easily extendable to aggregating discoveries made by multiple algorithms in other high-throughput biomedical data analysis,e.g.,differential gene expression analysis on RNA sequencing *** APIR R package is available at https://***/yiling0210/APIR.

关键词： Shotgun proteomics Peptide–spectrum match Peptide identification Aggregation of lists FDR control

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Honey vesicle-like nanoparticles protect aged liver from non-alcoholic steatohepatitis

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Acta Pharmaceutica Sinica B 2024年第8期14卷 3661-3679页

作者： Baolong Liu Phuong Linh Nguyen Han Yu Xingzhi Li Huiren Wang Tram Gia Bao Nguyen Prakash Kumar Sahoo Meghna Sur Jay Reddy Sarah Sillman Stephen D.Kachman Bara Altartouri Guoqing Lu Sathish Kumar Natarajan Mahesh Pattabiraman Jiujiu Yu Department of Nutrition and health Sciences University of Nebraska-LincolnLincolnNE 68583USA Shaanxi Key Laboratory of Molecular Biology for Agriculture College of Animal Science and TechnologyNorthwest A&F UniversityYangling 712100China Department of Nutrition Case Western Reserve UniversityClevelandOH 44106USA School of Veterinary Medicine and Biomedical Sciences University of Nebraska-LincolnLincolnNE 68583USA Department of Statistics University of Nebraska-LincolnLincolnNE 68583USA Center for Biotechnology University of Nebraska-LincolnLincolnNE 68588USA Department of Biology University of Nebraska OmahaOmahaNE 68182USA Department of Chemistry University of Nebraska-KearneyKearneyNE 68849USA

Non-alcoholic steatohepatitis(NASH),an advanced form of non-alcoholic fatty liver disease(NAFLD),has emerged as the leading cause of liver failure and related ***,no medication is specifically approved to treat NAFLD or *** we report that oral administration of honey vesiclelike nanoparticles(H-VLNs)to naturally aged mice protects the liver from NASH development.H-VLNs are dominantly taken up by Kupffer cells in the liver and suppress hepatic chronic inflammation and further development of fibrosis and nodule formation in aged *** their reported antiinflammasome function,H-VLNs are found to inhibit the transcriptional activities of C-JUN and nuclear factor-kappa B(NF-κB).MicroRNAs miR5119 and miR5108 and phenolic compound luteolin in H-VLNs are identified in suppressing both the C-JUN and NF-kB ***,oral intake of H-VLNs represents a promising new user-friendly modality to prevent the development of NASH.

关键词： Honey Extracellular vesicles Exosomes Nanoparticles microRNAs Aging Inflammation Non-alcoholic steatohepatitis

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Syrosingopine,an anti-hypertensive drug and lactate transporter(MCT1/4)inhibitor,activates hepatic stellate cells and exacerbates liver fibrosis in a mouse model

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Genes & Diseases 2024年第4期11卷 28-30页

作者： Meichun Guo Yannian Gou Xiangyu Dong Jiamin Zhong Aohua Li Ailing Hao Tongchuan He Jiaming Fan Ministry of Education Key Laboratory of Diagnostic Medicine and the School of Laboratory Diagnostic MedicineChongqing Medical UniversityChongqing 400016China Molecular Oncology Laboratory Department of Orthopaedic Surgery and Rehabilitation MedicineThe University of Chicago Medical CenterChicagoIL 60637USA

Syrosingopine is an anti-hypertensive drug and can cause high intracellular lactate levels and end-product inhibition of lactate dehydrogenase by inhibiting the lactate transporters MCT1 and *** studies have shown that syrosingopine plays an essential role in the process of glycolytic blockade,ATP depletion,and cell death in cancer due to high intracellular levels of lactate.

关键词： hypertensive MCT1 drug

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Cancer immunotherapy with envelopedself-amplifying mRNA CARG-2020 thatmodulates IL-12,IL-17 and PD-L1 pathways toprevent tumor recurrence

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Acta Pharmaceutica Sinica B 2024年第1期14卷 335-349页

作者： Ju Chen Bhaskara Reddy Madina Elham Ahmadi Timur Olegovich Yarovinsky Marie Marthe Krady Eileen Victoria Meehan Isabella China Wang Xiaoyang Ye Elise Pitmon Xian-Yong Ma Bijan Almassian Valerian Nakaar Kepeng Wang Department of Immunology School of MedicineUniversity of Connecticut Health CenterFarmingtonCT 06030USA CaroGen Corporation FarmingtonCT 06030USA The Eighth Clinical Medical College of Guangzhou University of Chinese Medicine Foshan Hospital of Traditional Chinese MedicineFoshan 528000China The Loomis Chaffee School WindsorCT 06095USA

Targeting multiple immune mechanisms may overcome therapy resistance and further improve cancer immunotherapy for ***,we describe the application of virus-like vesicles(VLV)for delivery of three immunomodulators alone and in combination,as a promising approach for cancer *** vectors were designed to deliver single chain interleukin(IL)-12,shorthairpin RNA(shRNA)targeting programmed death ligand 1(PD-L1),and a dominant-negative form of IL-17 receptor A(dn-IL17RA)as a single payload or as a combination *** delivery of the VLV vector expressing IL-12 alone,as well as the trivalent vector(designated CARG-2020)eradicated large established ***,only CARG-2020 prevented tumor recurrence and provided long-term survival benefit to the tumor-bearing mice,indicating a benefit of the combined *** abscopal effects of CARG-2020 on the non-injected contralateral tumors,as well as protection from the tumor cell re-challenge,suggest immune-mediated mechanism of protection and establishment of immunological ***,CARG-2020 potently activates Th1 immune mechanisms and inhibits expression of genes related to T cell exhaustion and cancer-promoting *** ability of CARG-2020 to prevent tumor recurrence and to provide survival benefit makes it a promising candidate for its development for human cancer immunotherapy.

关键词： Virus-like vesicles Oncolytic virus IL-12 IL-17 PD-L1 T cell exhaustion Combination therapy Cancer immunotherapy

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Epigenetic modification in liver fibrosis:Promising therapeutic direction with significant challenges ahead

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1009-1029页

作者： Runping Liu Yajing Li Qi Zheng Mingning Ding Huiping Zhou Xiaojiaoyang Li School of Chinese Materia Medica Beijing University of Chinese MedicineBeijing 102400China School of Life Sciences Beijing University of Chinese MedicineBeijing 102400China Department of Microbiology and Immunology Virginia Commonwealth UniversityRichmondVA 22460USA

Liver fibrosis,characterized by scar tissue formation,can ultimately result in liver ***’s a major cause of morbidity and mortality globally,often associated with chronic liver diseases like hepatitis or alcoholic and non-alcoholic fatty liver ***,current treatment options are limited,highlighting the urgent need for the development of new *** a reversible regulatory mechanism,epigenetic modification is implicated in many biological processes,including liver *** the epigenetic mechanisms involved in liver fibrosis could provide valuable insights into developing new treatments for chronic liver diseases,although the current evidence is still *** review provides a comprehensive summary of the regulatory mechanisms and critical targets of epigenetic modifications,including DNA methylation,histone modification,and RNA modification,in liver fibrotic *** potential cooperation of different epigenetic modifications in promoting fibrogenesis was also ***,available agonists or inhibitors regulating these epigenetic mechanisms and their potential application in preventing liver fibrosis were *** summary,elucidating specific druggable epigenetic targets and developing more selective and specific candidate medicines may represent a promising approach with bright prospects for the treatment of chronic liver diseases.

关键词： Liver fibrosis Epigenetics regulation DNA methylation Histone acetylation Histone methylation mRNA methylation Non-coding RNA Drug development

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Targeting stroma and tumor,silencing galectin 1 treats orthotopic mouse hepatocellular carcinoma

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Acta Pharmaceutica Sinica B 2024年第1期14卷 292-303页

作者： Tahereh Setayesh Ying Hu Farzam Vaziri Xin Chen Jinping Lai Dongguang Wei Yu-Jui Yvonne Wan Department of Medical Pathology and Laboratory Medicine University of CaliforniaDavisSacramentoCA 95817USA Cancer Biology Program the University of Hawaii Cancer CenterHonoluluHI 96813USA Department of Pathology and Laboratory Medicine Kaiser Permanente Sacramento Medical CenterSacramentoCA 95825USA

This study examines inhibiting galectin 1(Gal1)as a treatment option for hepatocellular carcinoma(HCC).Gal1 has immunosuppressive and cancer-promoting *** data showed that Gal1 was highly expressed in human and mouse *** levels of Gal1 positively correlated with the stages of human HCC and negatively with *** roles of Gal1 in HCC were studied using overexpression(OE)or silencing using Igals1 siRNA delivered by *** to HCC initiation induced by RAS and AKT mutations,lgals1-OE and silencing had opposite impacts on tumor *** treatment effect of lgals1 siRNAwas further demonstrated by intersecting HCC at different time points when the tumor load had already reached 9%or even 42%of the body *** spatial transcriptomic profiles of Gal1 silenced and OE HCC,inhibiting matrix formation and recognition of foreign antigen in CD45t cell-enriched areas located at tumor-margin likely contributed to the anti-HCC effects of Gal1 *** the tumors,silencing Gal1 inhibited translational initiation,elongation,and ***,Gal1 silencing increased immune cells as well as expanded cytotoxic T cells within the tumor,and the anti-HCC effect of lgals1 siRNAwas ***,Gal1 silencing has a promising potential for HCC treatment.

关键词： Liver Hepatocellular carcinoma Carbohydrate-binding lectin Galectin 1 Extracellular matrix Translation Spatial transcriptomics Tumor-margin

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NKT cell subsets as key participants in liver physiology and pathology

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Cellular & Molecular Immunology 2016年第3期13卷 337-346页

作者： Keya Bandyopadhyay Idania Marrero Vipin Kumar Department of Medicine University of California San Diego La Jolla CA 92037 USA

Natural killer T （NKT） cells are innate-like lymphocytes that generally recognize lipid antigens and are enriched in microvascular compartments of the liver. NKT cells can be activated by self- or microbial-lipid antigens and by signaling through toll-like receptors. Following activation, NKT cells rapidly secrete pro-inflammatory or anti- inflammatory cytokines and chemokines, and thereby determine the milieu for subsequent immunity or tolerance. It is becoming clear that two different subsets of NKT cells-type I and type II--have different modes of antigen recognition and have opposing roles in inflammatory liver diseases. Here we focus mainly on the roles of both NKT cell subsets in the maintenance of immune tolerance and inflammatory diseases in liver. Furthermore, how the differential activation of type I and type II NKT cells influences other innate cells and adaptive immune cells to result in important consequences for tissue integrity is discussed. It is crucial that better reagents, including CDld tetramers, be used in clinical studies to define the roles of NKT cells in liver diseases in patients.

关键词： CDld lipids liver disease NKT cells

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Genetic studies of schizophrenia:an update

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Neuroscience Bulletin 2015年第1期31卷 87-98页

作者： Jingchun Chen Fei Cao Lanfen Liu Lina Wang Xiangning Chen Virginia Institute for Psychiatric and Behavioral Genetics Virginia Commonwealth University Department of Neurology Union HospitalTongji Medical CollegeHuazhong University of Science and Technology Department of Psychiatry Shandong Mental Health Center

Schizophrenia（SCZ） is a complex and heterogeneous mental disorder that affects about 1% of global population. In recent years,considerable progress has been made in genetic studies of SCZ. A number of common variants with small effects and rare variants with relatively larger effects have been identifi ed. These variants include risk loci identifi ed by genome-wide association studies,rare copy-number variants identifi ed by comparative genomic analyses,and de novo mutations identified by high-throughput DNA sequencing. Collectively,they contribute to the heterogeneity of the disease. In this review,we update recent discoveries in the fi eld of SCZ genetics,and outline the perspectives of future directions.

关键词： schizophrenia genome-wide association study copy-number variant de novo mutation sequencing genetics

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