Linlin Gu

Ministry of Agriculture and Rural Affairs

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Qiana L. Matthews

Alabama State University

Alexandre Krendelchtchikov

University of Alabama at Birmingham

Jennifer L. Larson‐Casey

University of Alabama at Birmingham

Ming Fang

Jimei University

A. Brent Carter

University of Alabama at Birmingham

Anitra L. Farrow

University of Alabama at Birmingham

Hualan Chen

Harbin Veterinary Research Institute

Valentina Krendelchtchikova

Czech Academy of Sciences, Institute of Microbiology

Dan Jiang

Peking University

Zhiyong Wang

Kunming Medical University

Cooperative Institutions

University of Alabama at Birmingham

Chinese Academy of Agricultural Sciences

Harbin Veterinary Research Institute

Ministry of Agriculture and Rural Affairs

Jimei University

University of Alabama

Chinese Academy of Sciences

Pulmonary and Allergy Associates

Birmingham VA Medical Center

Chinese Academy of Medical Sciences & Peking Union Medical College

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Cadmium-mediated lung injury is exacerbated by the persistence of classically activated macrophages

Journal of Biological Chemistry (2020)

Jennifer L. Larson‐Casey Linlin Gu Oliver Fiehn A. Brent Carter

Heavy metals released into the environment have a significant effect on respiratory health. Lung macrophages are important in mounting an inflammatory response to injury, but they are also involved in repair of injury. Macrophages develop mixed phenotypes in complex pathological conditions and polarize to a predominant phenotype depending on the duration and stage of injury and/or repair. Little is known about the reprogramming required for lung macrophages to switch between these divergent functions; therefore, understanding the mechanism(s) by which macrophages promote metabolic reprogramming to regulate lung injury is essential. Here, we show that lung macrophages polarize to a pro-inflammatory, classically activated phenotype after cadmium-mediated lung injury. Because metabolic adaptation provides energy for the diverse macrophage functions, these classically activated macrophages show metabolic reprogramming to glycolysis. RNA-Seq revealed up-regulation of glycolytic enzymes and transcription factors regulating glycolytic flux in lung macrophages from cadmium-exposed mice. Moreover, cadmium exposure promoted increased macrophage glycolytic function with enhanced extracellular acidification rate, glycolytic metabolites, and lactate excretion. These observations suggest that cadmium mediates the persistence of classically activated lung macrophages to exacerbate lung injury.

Persistence (discontinuity)

10.1074/jbc.ra120.013632

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Citations (28)

Rapid and accurate multi-phenotype imputation for millions of individuals

bioRxiv (Cold Spring Harbor Laboratory) (2023)

Linlin Gu Hong-Shan Wu Tianyi Liu Yongjie Zhang Jing-Cheng He

Deep phenotyping can enhance the power of genetic analysis, including genome-wide association studies (GWAS), but the occurrence of missing phenotypes compromises the potential of such resources. Although many phenotypic imputation methods have been developed, the accurate imputation of millions of individuals remains extremely challenging. In the present study, we developed a novel multi-phenotype imputation method based on mixed fast random forest (PIXANT) by leveraging efficient machine learning (ML)-based algorithms. We demonstrate that PIXANT runtime is faster and computer memory usage is less than that of other state-of-the-art methods when applied to the UK Biobank (UKB) data, suggesting that PIXANT is scalable to cohorts with millions of individuals. Our simulations with hundreds of individuals showed that PIXANT accuracy was superior to or comparable to the accuracy of the most advanced methods available. PIXANT was used to impute 425 phenotypes for the UKB data of 277,301 unrelated White British citizens. When GWAS was subsequently performed on the imputed phenotypes, 18.4% more GWAS loci were identified than before imputation (8,710 vs 7,355). The increased statistical power of GWAS identified novel positional candidate genes affecting heart rate, such as RNF220, SCN10A, and RGS6, suggesting that the use of imputed phenotype data from a large cohort may lead to the discovery of novel genes for complex traits.

Imputation (statistics)

10.1101/2023.06.25.546422

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Research progress on protein-energy wasting in patients with chronic kidney disease

Linlin Gu Yan Liu Rongshao Tan Daoyuan Zhou Xiao Xiao

Patients with chronic kidney disease often experience protein-energy wasting.The clinical manifestations performs include the abnormality of nutrient intake,biochemical index,body mass index,and muscle mass.Protein-energy wasting always results from decreased dietary intake,inflammation,metabolic acidosis,hormone level disorder,dialysis related factors,social psychological factors and so on,and seriously affects the prognosis and survival rates of patients with chronic kidney disease.Therefore,early detection,diagnosis and prevention and cure are very important.Nutritional evaluation should be included in daily diagnosis and treatment in patients with chronic kidney diseases.Contrasting diagnostic criteria,prevention and control of protein-energy wasting with early diagnosis and taking various measures will improve the prognosis and survival rate of patients with chronic kidney disease ultimately.Thus,the aim is to improve the patients' understanding of epidemiological characteristics,pathogenesis,assessment,treatment and intervention measures of protein-energy wasting in patients with chronic kidney disease. Key words: Protein-energy wasting; Chronic kidney disease

10.3760/cma.j.issn.1007-1245.2014.01.048

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Ensemble learning for integrative prediction of genetic values with genomic variants

BMC Bioinformatics (2024)

Linlin Gu Runqing Yang Zhiyong Wang Dan Jiang Ming Fang

Abstract Background Whole genome variants offer sufficient information for genetic prediction of human disease risk, and prediction of animal and plant breeding values. Many sophisticated statistical methods have been developed for enhancing the predictive ability. However, each method has its own advantages and disadvantages, so far, no one method can beat others. Results We herein propose an Ensemble Learning method for Prediction of Genetic Values (ELPGV), which assembles predictions from several basic methods such as GBLUP, BayesA, BayesB and BayesCπ, to produce more accurate predictions. We validated ELPGV with a variety of well-known datasets and a serious of simulated datasets. All revealed that ELPGV was able to significantly enhance the predictive ability than any basic methods, for instance, the comparison p -value of ELPGV over basic methods were varied from 4.853E−118 to 9.640E−20 for WTCCC dataset. Conclusions ELPGV is able to integrate the merit of each method together to produce significantly higher predictive ability than any basic methods and it is simple to implement, fast to run, without using genotype data. is promising for wide application in genetic predictions.

Ensemble Learning

Predictive modelling

10.1186/s12859-024-05720-x

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Macrophage Rac2 Is Required to Reduce the Severity of Cigarette Smoke–induced Pneumonia

American Journal of Respiratory and Critical Care Medicine (2018)

Jennifer L. Larson‐Casey Linlin Gu Patricia L. Jackson David E. Briles Joanetha Y. Hale

Cigarette smoking is prevalent in the United States and is the leading cause of preventable diseases. A prominent complication of smoking is an increase in lower respiratory tract infections (LRTIs). Although LRTIs are known to be increased in subjects that smoke, the mechanism(s) by which this occurs is poorly understood.Determine how cigarette smoke (CS) reduces reactive oxygen species (ROS) production by the phagocytic NOX2 (NADPH oxidase 2), which is essential for innate immunity in lung macrophages.NOX2-derived ROS and Rac2 (Ras-related C3 botulinum toxin substrate 2) activity were determined in BAL cells from wild-type and Rac2-/- mice exposed to CS or cadmium and in BAL cells from subjects that smoke. Host defense to respiratory pathogens was analyzed in mice infected with Streptococcus pneumoniae.NOX2-derived ROS in BAL cells was reduced in mice exposed to CS via inhibition of the small GTPase Rac2. These mice had greater bacterial burden and increased mortality compared with air-exposed mice. BAL fluid from CS-exposed mice had increased levels of cadmium, which mediated the effect on Rac2. Similar observations were seen in human subjects that smoke. To support the importance of Rac2 in the macrophage immune response, overexpression of constitutively active Rac2 by lentiviral administration increased NOX2-derived ROS, decreased bacterial burden in lung tissue, and increased survival compared with CS-exposed control mice.These observations suggest that therapies to maintain Rac2 activity in lung macrophages restore host defense against respiratory pathogens and diminish the prevalence of LRTIs in subjects that smoke.

Respiratory tract

10.1164/rccm.201712-2388oc

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Mitochondrial calcium uniporter regulates PGC-1α expression to mediate metabolic reprogramming in pulmonary fibrosis

Redox Biology (2019)

Linlin Gu Jennifer L. Larson‐Casey Shaida A. Andrabi Jun Hee Lee Selene Meza‐Perez

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with an increased mortality. Metabolic reprogramming has a critical role in multiple chronic diseases. Lung macrophages expressing the mitochondrial calcium uniporter (MCU) have a critical role in fibrotic repair, but the contribution of MCU in macrophage metabolism is not known. Here, we show that MCU regulates peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and metabolic reprogramming to fatty acid oxidation (FAO) in macrophages. MCU regulated PGC-1α expression by increasing the phosphorylation of ATF-2 by the p38 MAPK in a redox-dependent manner. The expression and activation of PGC-1α via the p38 MAPK was regulated by MCU-mediated mitochondrial calcium uptake, which is linked to increased mitochondrial ROS (mtROS) production. Mice harboring a conditional expression of dominant-negative MCU in macrophages had a marked reduction in mtROS and FAO and were protected from pulmonary fibrosis. Moreover, IPF lung macrophages had evidence of increased MCU and mitochondrial calcium, increased phosphorylation of ATF2 and p38, as well as increased expression of PGC-1α. These observations suggest that macrophage MCU-mediated metabolic reprogramming contributes to fibrotic repair after lung injury.

Reprogramming

Mitochondrial ROS

10.1016/j.redox.2019.101307

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Rapid Detection of Subtype H10N8 Influenza Virus by One-Step Reverse Transcription–Loop-Mediated Isothermal Amplification Methods

Journal of Clinical Microbiology (2015)

Hongmei Bao Xiaoxiao Feng Yong Ma Jianzhong Shi Yuhui Zhao

We developed hemagglutinin- and neuraminidase-specific one-step reverse transcription-loop-mediated isothermal amplification assays for detecting the H10N8 virus. The detection limit of the assays was 10 copies of H10N8 virus, and the assays did not amplify nonspecific RNA. The assays can detect H10N8 virus from chicken samples with high sensitivity and specificity, and they can serve as an effective tool for detecting and monitoring H10N8 virus in live poultry markets.

10.1128/jcm.02165-15

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NOX4 regulates macrophage apoptosis resistance to induce fibrotic progression

Journal of Biological Chemistry (2021)

Jennifer L. Larson‐Casey Linlin Gu Jungsoon Kang A. Dhyani A. Brent Carter

Pulmonary fibrosis is a progressive lung disease often occurring secondary to environmental exposure. Asbestos exposure is an important environmental mediator of lung fibrosis and remains a significant cause of disease despite strict regulations to limit exposure. Lung macrophages play an integral role in the pathogenesis of fibrosis induced by asbestos (asbestosis), in part by generating reactive oxygen species (ROS) and promoting resistance to apoptosis. However, the mechanism by which macrophages acquire apoptosis resistance is not known. Here, we confirm that macrophages isolated from asbestosis subjects are resistant to apoptosis and show they are associated with enhanced mitochondrial content of NADPH oxidase 4 (NOX4), which generates mitochondrial ROS generation. Similar results were seen in chrysotile-exposed WT mice, while macrophages from Nox4

NOX4

Pathogenesis

10.1016/j.jbc.2021.100810

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Viral Vectors for Vaccine Development

InTech eBooks (2013)

L. Qiana Linlin Gu Alexandre Krendelchtchikov Zan C.

Recombinant vectors can be used to deliver antigens and to stimulate immune responses in humans. Viral vectors possess various intrinsic properties which may lend to advantages and disadvantages for usage for a given therapeutic application [reviewed by Larocca and Schlom] [1]. The safety and flexibility of recombinant viral vectors have lead to their usage in gene therapy, virotherapy, and vaccine applications. In this chapter, we will discuss the utility and importance of recombinant vectors as vaccine agents. This chapter will highlight some of the uses of recombinant viral vectors for therapeutic vaccines; and will mostly focus on the application of a range of recombinant viral vectors for prophylactic vaccines against infectious agents. More specifically, this chapter will focus in depth on the use of recombinant adenovirus (Ad) for vaccine development against infectious agents.

10.5772/54700

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Post‐translational regulation of PGC‐1α modulates fibrotic repair

The FASEB Journal (2021)

Jennifer L. Larson‐Casey Linlin Gu Dana Davis Guoqiang Cai Qiang Ding

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease associated with mitochondrial oxidative stress. Mitochondrial reactive oxygen species (mtROS) are important for cell homeostasis by regulating mitochondrial dynamics. Here, we show that IPF BAL cells exhibited increased mitochondrial biogenesis that is, in part, due to increased nuclear expression of peroxisome proliferator-activated receptor-ɣ (PPARɣ) coactivator (PGC)-1α. Increased PPARGC1A mRNA expression directly correlated with reduced pulmonary function in IPF subjects. Oxidant-mediated activation of the p38 MAPK via Akt1 regulated PGC-1α activation to increase mitochondrial biogenesis in monocyte-derived macrophages. Demonstrating the importance of PGC-1α in fibrotic repair, mice harboring a conditional deletion of Ppargc1a in monocyte-derived macrophages or mice administered a chemical inhibitor of mitochondrial division had reduced biogenesis and increased apoptosis, and the mice were protected from pulmonary fibrosis. These observations suggest that Akt1-mediated regulation of PGC-1α maintains mitochondrial homeostasis in monocyte-derived macrophages to induce apoptosis resistance, which contributes to the pathogenesis of pulmonary fibrosis.

PPARGC1A

Mitochondrial ROS

10.1096/fj.202100339r

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