Publications by authors named "Lisha Shen"

49 Publications

N-methyladenosine modification underlies messenger RNA metabolism and plant development.

Curr Opin Plant Biol 2021 May 6;63:102047. Epub 2021 May 6.

Temasek Life Sciences Laboratory, National University of Singapore, 1 Research Link, 117604, Singapore; Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, 117543, Singapore. Electronic address:

RNA modifications constitute an essential layer of gene regulation in living organisms. As the most prevalent internal modification on eukaryotic mRNAs, N-methyladenosine (mA) exists in many plant species and requires the evolutionarily conserved methyltransferases, demethylases, and mA binding proteins for writing, erasing, and reading mA, respectively. In plants, mA affects many aspects of mRNA metabolism, including alternative polyadenylation, secondary structure, translation, and decay, which underlies various plant developmental processes and stress responses. Here, we discuss the recent progress in understanding the roles of mA modification in mRNA metabolism and their mechanistic link with plant development and stress responses. We also highlight some outstanding questions and provide an outlook on future prospects of mA research in plants.
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http://dx.doi.org/10.1016/j.pbi.2021.102047DOI Listing
May 2021

The MYB family transcription factor TuODORANT1 from Triticum urartu and the homolog TaODORANT1 from Triticum aestivum inhibit seed storage protein synthesis in wheat.

Plant Biotechnol J 2021 May 5. Epub 2021 May 5.

State Key Laboratory of Plant Cell and Chromosome Engineering, National Center for Plant Gene Research, Institute of Genetics and Developmental Biology/Innovative Academy of Seed Design, Chinese Academy of Sciences, Beijing, China.

Seed storage proteins (SSPs) are determinants of wheat end-product quality. SSP synthesis is mainly regulated at the transcriptional level. Few transcriptional regulators of SSP synthesis have been identified in wheat and this study aims to identify novel SSP gene regulators. Here, the R2R3 MYB transcription factor TuODORANT1 from Triticum urartu was found to be preferentially expressed in the developing endosperm during grain filling. In common wheat (Triticum aestivum) overexpressing TuODORANT1, the transcription levels of all the SSP genes tested by RNA-Seq analysis were reduced by 49.71% throughout grain filling, which contributed to 13.38%-35.60% declines in the total SSP levels of mature grains. In in vitro assays, TuODORANT1 inhibited both the promoter activities and the transcription of SSP genes by 1- to 13-fold. The electrophoretic mobility shift assay (EMSA) and ChIP-qPCR analysis demonstrated that TuODORANT1 bound to the cis-elements 5'-T/CAACCA-3' and 5'-T/CAACT/AG-3' in SSP gene promoters both in vitro and in vivo. Similarly, the homolog TaODORANT1 in common wheat hindered both the promoter activities and the transcription of SSP genes by 1- to 112-fold in vitro. Knockdown of TaODORANT1 in common wheat led to 14.73%-232.78% increases in the transcription of the tested SSP genes, which contributed to 11.43%-19.35% elevation in the total SSP levels. Our data show that both TuODORANT1 and TaODORANT1 are repressors of SSP synthesis.
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http://dx.doi.org/10.1111/pbi.13604DOI Listing
May 2021

Clinical Characteristics of Chronic Lung Abscess Associated with Diagnosed Using Metagenomic Next-Generation Sequencing.

Infect Drug Resist 2021 23;14:1191-1198. Epub 2021 Mar 23.

Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People's Republic of China.

Purpose: () is a Gram-positive anaerobic bacterium distributed in the oral cavity, with a potential to become pathogenic causing lung abscess. Due to the lack of specificity of symptoms and the difficulty in culture, the diagnosis of lung abscess associated with is delayed. It is essential to elucidate the clinical characteristics of lung abscess associated with .

Methods: From January 2019 to July 2020, five patients with chronic lung abscess associated with diagnosed by pathological biopsy and metagenomic next-generation sequencing (mNGS) were analyzed in this retrospective study.

Results: Among the five patients, four had a history of smoking, three had periodontitis, and two had a history of drinking. The average course of the disease was 6.5 months. High-density flake-like or mass shadows with irregular boundaries were observed in the chest computed tomography (CT) images of the five patients, and liquefactive necrosis was detected in the middle of the lesions; however, no gas-liquid plane or cavity was noted, making it difficult to distinguish a lung cancer. The pathological biopsy of the five patients showed chronic inflammation of lung tissue, and was detected by mNGS in the biopsy or bronchoalveolar lavage fluid samples. Two patients were treated with amoxicillin-clavulanate, two had metronidazole, and one had moxifloxacin. Among them, four recovered after receiving antibiotic treatment, and the remaining one underwent surgical resection due to poor antibiotic treatment effect.

Conclusion: Chronic lung abscess associated with , common in elderly male smokers with poor oral hygiene, is often diagnosed in a delayed manner and misdiagnosed as lung cancer. The mNGS technology is beneficial to the rapid determination of
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http://dx.doi.org/10.2147/IDR.S304569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001108PMC
March 2021

Pregnancy after the diagnosis of lymphangioleiomyomatosis (LAM).

Orphanet J Rare Dis 2021 03 17;16(1):133. Epub 2021 Mar 17.

Department of Pulmonary and Critical Care Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.

Background: Lymphangioleiomyomatosis (LAM) is a rare disease that almost exclusively affects women of reproductive age. Patients are warned of the increased risks if they become pregnant. However, information on pregnancy in patients after the diagnosis of LAM is limited.

Methods: Patients were collected from the LAM registry study at Peking Union Medical College Hospital, Beijing, China. Patients with a history of pregnancy after the diagnosis of LAM were included. Medical records were reviewed, and baseline information and data during and after pregnancy were collected in May 2018.

Results: Thirty patients with a total of 34 pregnancies after the diagnosis of LAM were included. Livebirth, spontaneous abortion and induced abortion occurred in 10, 6 and 18 pregnancies, respectively. Sirolimus treatment was common (17/34). A total of 6/10, 5/6, and 6/18 patients with livebirths, spontaneous abortions, and induced abortions respectively, had a history of sirolimus treatment. Ten pregnancies (29.4%) had LAM-associated complications during pregnancy, including the exacerbation of dyspnea in 7 patients, pneumothorax in 3 patients (2 resulting in induced abortion and 1 successful parturition), and spontaneous bleeding of renal angiomyolipomas in 2 patients (both having successful parturition). No chylothorax was found during pregnancy. There were six pregnancies in six patients (17.6%) who had a history of livebirth after sirolimus treatment for LAM (all having successful parturition and healthy infants); two of these patients reported exacerbated dyspnea after parturition compared with before pregnancy.

Conclusions: Patients with LAM, especially those taking sirolimus before pregnancy, were at a higher risk of spontaneous abortion. Complications such as pneumothorax, bleeding of renal angiomyolipoma, and exacerbated dyspnea during pregnancy were common. In patients without spontaneous abortion, sirolimus discontinuation before or during pregnancy did not lead to increased adverse neonatal outcomes.
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http://dx.doi.org/10.1186/s13023-021-01776-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7972207PMC
March 2021

Circular RNA circEIF4G2 aggravates renal fibrosis in diabetic nephropathy by sponging miR-218.

J Cell Mol Med 2020 Dec 7. Epub 2020 Dec 7.

Department of Endocrinology, Tongren Hospital Affiliated to Shanghai Jiaotong University, Shanghai, China.

Circular RNAs play essential roles in the development of various human diseases. However, how circRNAs are involved in diabetic nephropathy (DN) are not fully understood. Our study aimed to investigate the effects of circRNA circEIF4G2 on DN. Experiments were performed in the db/db mouse model of type 2 diabetes and NRK-52E cells. We found that circEIF4G2 was significantly up-regulated in the kidneys of db/db mice and NRK-52E cells stimulated by high glucose. circEIF4G2 knockdown inhibited the expressions of TGF-β1, Collagen I and Fibronectin in high glucose-stimulated NRK-52E cells, which could be rescued by miR-218 inhibitor. Knockdown of SERBP1 reduced the expression of TGF-β1, Collagen I and Fibronectin in HG-stimulated NRK-52E cells. In summary, our findings suggested that circEIF4G2 promotes renal tubular epithelial cell fibrosis via the miR-218/SERBP1 pathway, presenting a novel insight for DN treatment.
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http://dx.doi.org/10.1111/jcmm.16129DOI Listing
December 2020

Effects of hydrological change on the risk of riverine algal blooms: case study in the mid-downstream of the Han River in China.

Environ Sci Pollut Res Int 2021 Apr 6;28(16):19851-19865. Epub 2021 Jan 6.

School of Water Conservancy Science and Engineering, Zhengzhou University, Zhengzhou, 450001, China.

Algal blooms usually occur in semi-closed water bodies such as lakes or estuaries; however, it has occurred frequently in the mid-downstream of the Han River (MSHR) in China since the 1990s. We made a comparative analysis of the hydrological conditions and identified the hydrological condition thresholds that induce algal blooms. From the hydrodynamic point of view, the changes and characteristics of the hydrological conditions in the MSHR were analyzed. Furthermore, the influence on the risk of algal blooms under different design water transfer schemes for the middle route of the South-to-North Water Diversion Project (SNWDP) was studied. The results indicated that (1) the flow in the MSHR less than 900 m/s and water level in the Yangtze River higher than 14 m provided a suitable hydrological environment for diatoms multiply. (2) The flow of the MSHR showed a downtrend, while the water level of the Yangtze River showed an uptrend. There were variations in hydrological processes. Through specific IHA index analysis, the fact of flow reduction in the MSHR was demonstrated, and further indicated that algal bloom outbreak was in low flow period. (3) The water transfer in the middle route of SNWDP affected the risk probability of algal blooms. The more the amount of water transfer, the greater the risk probability of algal blooms. It was the Water Diversion Project from Yangtze River to Han River (WDPYHR) that replenished flow of the MSHR and was conducive to the prevention and control of algal bloom risk.
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http://dx.doi.org/10.1007/s11356-020-11756-2DOI Listing
April 2021

Nucleoporin 160 Regulates Flowering through Anchoring HOS1 for Destabilizing CO in .

Plant Commun 2020 Mar 19;1(2):100033. Epub 2020 Feb 19.

Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore 117543, Singapore.

Nuclear pore complexes (NPCs), which comprise multiple copies of nucleoporins (Nups), are large protein assemblies embedded in the nuclear envelope connecting the nucleus and cytoplasm. Although it has been known that Nups affect flowering in , the underlying mechanisms are poorly understood. Here, we show that loss of function of () leads to increased abundance of CONSTANS (CO) protein and the resulting upregulation of () specifically in the morning. We demonstrate that Nup160 regulates CO protein stability through affecting NPC localization of an E3-ubiquitin ligase, HIGH EXPRESSION OF OSMOTICALLY RESPONSIVE GENES1 (HOS1), which destabilizes CO protein in the morning period. Taken together, these results provide a mechanistic understanding of Nup function in the transition from vegetative to reproductive growth, suggesting that deposition of HOS1 at NPCs by Nup160 is essential for preventing precocious flowering in response to photoperiod in .
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http://dx.doi.org/10.1016/j.xplc.2020.100033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7748013PMC
March 2020

A novel NAC family transcription factor SPR suppresses seed storage protein synthesis in wheat.

Plant Biotechnol J 2021 May 4;19(5):992-1007. Epub 2021 Jan 4.

State Key Laboratory of Plant Cell and Chromosome Engineering, National Center for Plant Gene Research, Institute of Genetics and Developmental Biology/Innovation Academy of Seed Design, Chinese Academy of Sciences, Beijing, China.

The synthesis of seed storage protein (SSP) is mainly regulated at the transcriptional level. However, few transcriptional regulators of SSP synthesis have been characterized in common wheat (Triticum aestivum) owing to the complex genome. As the A genome donor of common wheat, Triticum urartu could be an elite model in wheat research considering its simple genome. Here, a novel NAC family transcription factor TuSPR from T. urartu was found preferentially expressed in developing endosperm during grain-filling stages. In common wheat transgenically overexpressing TuSPR, the content of total SSPs was reduced by c. 15.97% attributed to the transcription declines of SSP genes. Both in vitro and in vivo assays showed that TuSPR bound to the cis-element 5'-CANNTG-3' distributed in SSP gene promoters and suppressed the transcription. The homolog in common wheat TaSPR shared a conserved function with TuSPR on SSP synthesis suppression. The knock-down of TaSPR in common wheat resulted in 7.07%-20.34% increases in the total SSPs. Both TuSPR and TaSPR could be superior targets in genetic engineering to manipulate SSP content in wheat, and this work undoubtedly expands our knowledge of SSP gene regulation.
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http://dx.doi.org/10.1111/pbi.13524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131056PMC
May 2021

Seawater-Associated Highly Pathogenic Francisella hispaniensis Infections Causing Multiple Organ Failure.

Emerg Infect Dis 2020 10;26(10):2424-2428

A rare case of Francisella hispaniensis infection associated with seawater exposure occurred in a deep-sea diving fisherman in Zhejiang, China. He had skin and soft tissue infection that progressed to bacteremia and multiple organ failure. Moxifloxacin treatment cleared the infections, but the patient suffered a sequela of heart damage.
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http://dx.doi.org/10.3201/eid2610.190844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510699PMC
October 2020

Characterization of C- and D-Class MADS-Box Genes in Orchids.

Plant Physiol 2020 11 8;184(3):1469-1481. Epub 2020 Sep 8.

Department of Biological Sciences, National University of Singapore, Singapore 117543

Orchids (members of the Orchidaceae family) possess unique flower morphology and adaptive reproduction strategies. Although the mechanisms underlying their perianth development have been intensively studied, the molecular basis of reproductive organ development in orchids remains largely unknown. Here, we report the identification and functional characterization of two ()-like MADS-box genes, 'Orchid' () and , which are putative C- and D-class genes, respectively, from the orchid 'Chao Praya Smile'. Both and are highly expressed in the reproductive organ, known as the column, compared to perianth organs, while expression gradually increases in pace with pollination-induced ovule development and is localized in ovule primordia. Ectopic expression of , but not , rescues floral defects in the Arabidopsis () mutant, including reiteration of stamenoid perianth organs in inner whorls and complete loss of carpels. Downregulation of and in orchids by artificial microRNA interference using l-Met sulfoximine selection-based gene transformation systems shows that both genes are essential for specifying reproductive organ identity, yet they, exert different roles in mediating floral meristem determinacy and ovule development, respectively, in spp. orchids. Notably, knockdown of and also affects perianth organ development in orchids. Our findings suggest that and not only act as evolutionarily conserved C- and D-class genes, respectively, in determining reproductive organ identity, but also play hitherto unknown roles in mediating perianth organ development in orchids.
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http://dx.doi.org/10.1104/pp.20.00487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608164PMC
November 2020

circ_0037128/miR-17-3p/AKT3 axis promotes the development of diabetic nephropathy.

Gene 2021 Jan 27;765:145076. Epub 2020 Aug 27.

Department of Endocrinology, Shanghai Tongren Hospital Affiliated to Shanghai Jiaotong University, Shanghai, China. Electronic address:

Circular RNAs (circRNAs) play vital roles in the development of diabetic nephropathy (DN). In this study, we investigated the function of circ_0037128 and molecular mechanism via which it regulates diabetic nephropathy development. It was found that expression of circ_0037128 was significantly increased in mouse DN model and high glucose treated mesangial cells (MCs), and circ_0037128 loss-of-function led to reduced cell proliferation and fibrosis in vitro. Moreover, miR-17-3p acts as competitive endogenous RNA (ceRNA) that directly interacts with circ_0037128 through its miRNA response elements (MREs). Consistently, expression of miR-17-3p was remarkably down-regulated in DN model, and negatively regulated cell proliferation and fibrosis. Further investigations revealed that AKT3 was the putative target of miR-17-3p, whose expression was elevated in DN model. In conclusion, we have characterized the function of a novel circ_0037128 and illustrated the significance of circ_0037128-miR-17-3p-AKT3 axis in DN pathogenesis.
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http://dx.doi.org/10.1016/j.gene.2020.145076DOI Listing
January 2021

First-in-Human Phase 1 Study of ES-072, an Oral Mutant-Selective EGFR T790M Inhibitor, in Non-Small-Cell Lung Cancer.

Clin Lung Cancer 2020 11 9;21(6):509-519.e1. Epub 2020 Jul 9.

Department of Respiratory Medicine, Thoracic Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.

Background: Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are rapidly being developed for treatment of non-small-cell lung cancer (NSCLC) in patients harboring EGFR T790M mutations. This first-in-human phase 1 study evaluated the maximum tolerated dose, recommended phase 2 dose (RP2D), safety, tolerability, and pharmacokinetics (PK), and preliminarily determined the antitumor activity of ES-072 in NSCLC patients with EGFR T790M mutations.

Patients And Methods: Dose escalation and expansion studies were performed using an accelerated titration method. Oral ES-072 doses (25-450 mg) were administrated once daily for single- and multiple-dose escalation trials. Characteristic PK parameters were assessed in the single-dose escalation phase and in the first cycle of the multiple-dose escalation phase. Tumor responses were assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 to evaluate ES-072 antitumor activity.

Results: Nineteen patients were enrolled onto this study, 16 to the dose-escalation phase and 3 to the dose-expansion phase. The most common adverse events were QT interval prolongation (11/19, 57.9%), anemia (5/19, 26.3%), mouth ulceration (4/19, 21.1%), keratosis (4/19, 21.1%), and cough (4/19, 21.1%). Safety and tolerability evaluation of ES-072 showed an maximum tolerated dose of 300 mg, and the RP2D dose was therefore 300 mg once daily. PK analysis showed an ES-072 half-life of 24.5 hours and a T of approximately 4 hours. The total objective response rate and disease control rate were 46.2% and 76.9%, respectively.

Conclusion: ES-072 was safe and well tolerated in NSCLC patients harboring EGFR T790M mutations, and adverse events were controllable and reversible. A RP2D of 300 mg once daily was determined, and preliminary investigations showed promising antitumor activity.
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http://dx.doi.org/10.1016/j.cllc.2020.07.001DOI Listing
November 2020

Bloodstream Infections due to Carbapenem-Resistant : A Single-Center Retrospective Study on Risk Factors and Therapy Options.

Microb Drug Resist 2021 Feb 23;27(2):227-233. Epub 2020 Jun 23.

Department of Respiratory Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

We aimed to compare efficacy of different patterns of antibiotics and explore the risk factors related to mortality in patients with bloodstream infections (BSIs) due to carbapenem-resistant (CRKP). This study retrospectively included 89 patients with BSIs due to CRKP with complete data during the year of 2018 in the First Affiliated Hospital of Zhejiang University School of Medicine. Overall, the 28-day mortality was 47.2% (42/89). Multivariate analysis of Cox regression revealed that hematological malignancy (hazard ratio [HR] 5.698; 95% confidence interval [CI], 2.405-13.504;  < 0.001) and Pitt bacteremia score (HR per unit increase, 1.303; 95% CI, 1.109-1.532;  = 0.001) were identified as independent predictors for 28-day mortality. Among 70 patients with appropriate therapy, 35 received tigecycline (TGC)-based therapy, 20 received polymyxin B (PMB)-based therapy, 9 received ceftazidime/avibactam-based therapy, and 6 patients had other kinds of antibiotics, including ciprofloxacin, amikacin, and cotrimoxazole. By adjusting variables selected by crude analysis, it showed that receiving PMB-based therapy provided a survival benefit comparing with TGC-based therapy (HR, 0.068; 95% CI, 0.018-0.260;  < 0.001). Hematological malignancy and Pitt bacteremia score were independent risk factors of death in patients with BSIs due to CRKP and PMB-based therapy improved survival rate compared with TGC-based therapy.
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http://dx.doi.org/10.1089/mdr.2019.0455DOI Listing
February 2021

SHAGGY-like kinase 12 regulates flowering through mediating CONSTANS stability in .

Sci Adv 2020 Jun 12;6(24):eaaw0413. Epub 2020 Jun 12.

Temasek Life Sciences Laboratory, National University of Singapore, Singapore 117604, Singapore.

Photoperiod is a major environmental cue that determines the floral transition from vegetative to reproductive development in flowering plants. responds to photoperiodic signals mainly through a central regulator CONSTANS (CO). Although it has been suggested that phosphorylation of CO contributes to its role in photoperiodic control of flowering, how this is regulated so far remains unknown. Here, we report that a glycogen synthase kinase-3 member, SHAGGY-like kinase 12 (SK12), plays an important role in preventing precocious flowering through phosphorylating CO. Loss of function of causes early flowering. expression in seedlings is decreased during the floral transition, and its expression in vascular tissues is required for repressing flowering. SK12 interacts with and phosphorylates CO at threonine 119, thus facilitating CO degradation. Our findings suggest that site-specific phosphorylation of CO by SK12 is critical for modulating the photoperiodic output for the floral induction in .
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http://dx.doi.org/10.1126/sciadv.aaw0413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292628PMC
June 2020

TubZIP28, a novel bZIP family transcription factor from Triticum urartu, and TabZIP28, its homologue from Triticum aestivum, enhance starch synthesis in wheat.

New Phytol 2020 06 8;226(5):1384-1398. Epub 2020 Feb 8.

Agronomy College, National Key Laboratory of Wheat and Maize Crop Science, Collaborative Innovation Center of Henan Grain Crops, Henan Agricultural University, 15 Longzihu College District, Zhengzhou, 450046, China.

Starch in wheat grain provides humans with carbohydrates and influences the quality of wheaten food. However, no transcriptional regulator of starch synthesis has been identified first in common wheat (Triticum aestivum) due to the complex genome. Here, a novel basic leucine zipper (bZIP) family transcription factor TubZIP28 was found to be preferentially expressed in the endosperm throughout grain-filling stages in Triticum urartu, the A genome donor of common wheat. When TubZIP28 was overexpressed in common wheat, the total starch content increased by c. 4%, which contributed to c. 5% increase in the thousand kernel weight. The grain weight per plant of overexpression wheat was also elevated by c. 9%. Both in vitro and in vivo assays showed that TubZIP28 bound to the promoter of cytosolic AGPase and enhanced both the transcription and activity of the latter. Knockout of the homologue TabZIP28 in common wheat resulted in declines of both the transcription and activity of cytosolic AGPase in developing endosperms and c. 4% reduction of the total starch in mature grains. To the best of our knowledge, TubZIP28 and TabZIP28 are transcriptional activators of starch synthesis first identified in wheat, and they could be superior targets to improve the starch content and yield potential of wheat.
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http://dx.doi.org/10.1111/nph.16435DOI Listing
June 2020

Genome and Transcriptome Provide Insights into the Origin and Evolution of Streptophyta.

Adv Sci (Weinh) 2020 Jan 24;7(1):1901850. Epub 2019 Oct 24.

Department of Biological Sciences National University of Singapore Singapore 117543 Singapore.

The Streptophyta include unicellular and multicellular charophyte green algae and land plants. Colonization of the terrestrial habitat by land plants is a major evolutionary event that has transformed the planet. So far, lack of genome information on unicellular charophyte algae hinders the understanding of the origin and the evolution from unicellular to multicellular life in Streptophyta. This work reports the high-quality reference genome and transcriptome of , a single-celled charophyte alga with a position at the base of Streptophyta. There are abundant segmental duplications and transposable elements in , which contribute to a relatively large genome with high gene content compared to other algae and early diverging land plants. This work identifies the origin of genetic tools that multicellular Streptophyta have inherited and key genetic innovations required for the evolution of land plants from unicellular aquatic ancestors. The findings shed light on the age-old questions of the evolution of multicellularity and the origin of land plants.
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http://dx.doi.org/10.1002/advs.201901850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6947507PMC
January 2020

Dissecting the Function of MADS-Box Transcription Factors in Orchid Reproductive Development.

Front Plant Sci 2019 15;10:1474. Epub 2019 Nov 15.

Temasek Life Sciences Laboratory, National University of Singapore, Singapore, Singapore.

The orchid family (Orchidaceae) represents the second largest angiosperm family, having over 900 genera and 27,000 species in almost all over the world. Orchids have evolved a myriad of intriguing ways in order to survive extreme weather conditions, acquire nutrients, and attract pollinators for reproduction. The family of MADS-box transcriptional factors have been shown to be involved in the control of many developmental processes and responses to environmental stresses in eukaryotes. Several findings in different orchid species have elucidated that MADS-box genes play critical roles in the orchid growth and development. An in-depth understanding of their ecological adaptation will help to generate more interest among breeders and produce novel varieties for the floriculture industry. In this review, we summarize recent findings of MADS-box transcription factors in regulating various growth and developmental processes in orchids, in particular, the floral transition and floral patterning. We further discuss the prospects for the future directions in light of new genome resources and gene editing technologies that could be applied in orchid research and breeding.
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http://dx.doi.org/10.3389/fpls.2019.01474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6872546PMC
November 2019

New insights into gibberellin signaling in regulating flowering in Arabidopsis.

J Integr Plant Biol 2020 Jan 8;62(1):118-131. Epub 2020 Jan 8.

Department of Biological Sciences, National University of Singapore, Singapore, 117543, Singapore.

In angiosperms, floral transition is a key developmental transition from the vegetative to reproductive growth, and requires precise regulation to maximize the reproductive success. A complex regulatory network governs this transition through integrating flowering pathways in response to multiple exogenous and endogenous cues. Phytohormones are essential for proper plant developmental regulation and have been extensively studied for their involvement in the floral transition. Among various phytohormones, gibberellin (GA) plays a major role in affecting flowering in the model plant Arabidopsis thaliana. The GA pathway interact with other flowering genetic pathways and phytohormone signaling pathways through either DELLA proteins or mediating GA homeostasis. In this review, we summarize the recent advances in understanding the mechanisms of DELLA-mediated GA pathway in flowering time control in Arabidopsis, and discuss its possible link with other phytohormone pathways during the floral transition.
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http://dx.doi.org/10.1111/jipb.12892DOI Listing
January 2020

Long noncoding RNA GAS5 inhibits cell proliferation and fibrosis in diabetic nephropathy by sponging miR-221 and modulating SIRT1 expression.

Aging (Albany NY) 2019 10 20;11(20):8745-8759. Epub 2019 Oct 20.

Department of Endocrinology, Tongren Hospital Affiliated to Shanghai Jiaotong University, Shanghai, China.

Diabetic nephropathy (DN) is one of the leading causes of end-stage renal diseases worldwide. This study is designed to investigate the underlying function and mechanism of a novel lncRNA GAS5 in the progression of DN. We found that lncRNA GAS5 expression level was decreased in type 2 diabetes (T2D) with DN compared with that in patients without DN. Moreover, lncRNA GAS5 expression level was negatively associated with the severity of DN-related complications. lncRNA GAS5 inhibited MCs proliferation and caused G0/1 phase arrest. lncRNA GAS5 overexpression alleviated the expression of fibrosis-related protein in mesangial cells (MCs). The dual-luciferase reporter assay and RNA binding protein immunoprecipitation (RIP) assay results revealed that lncRNA GAS5 functions as an endogenous sponge for miR-221 via both the directly targeting way and Ago2-dependent manner. Furthermore, SIRT1 was confirmed as a target gene of miR-221. lncRNA GAS5 upregulated SIRT1 expression and inhibited MCs proliferation and fibrosis by acting as an miR-221 sponge. Finally, we found that lncRNA GSA5 suppressed the development of DN in vivo. Thus, lncRNA GAS5 was involved in the progression of DN by sponging miR-221 and contributed to lncRNA-directed diagnostics and therapeutics in DN.
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http://dx.doi.org/10.18632/aging.102249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834398PMC
October 2019

Molecular Basis of Natural Variation in Photoperiodic Flowering Responses.

Dev Cell 2019 07 6;50(1):90-101.e3. Epub 2019 Jun 6.

Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore 117543, Singapore; Temasek Life Sciences Laboratory, National University of Singapore, Singapore 117604, Singapore. Electronic address:

Plants exhibit different flowering behaviors in response to variable photoperiods across a wide geographical range. Here, we identify MYC3, a bHLH transcription factor, and its cis-element form the long-sought regulatory module responsible for cis-regulatory changes at the florigen gene FLOWERING LOCUS T (FT) that mediate natural variation in photoperiodic flowering responses in Arabidopsis. MYC3 is stabilized by DELLAs in the gibberellin pathway to suppress FT through binding the ACGGAT motif and antagonizing CONSTANS (CO) activation. Changing photoperiods modulate the relative abundance of MYC3 and CO, thus determining either of them as the predominant regulator for FT expression under different day lengths. Cis-regulatory changes in the MYC3 binding site at FT are associated with natural variation in day-length requirement for flowering in Arabidopsis accessions. Our findings reveal that environmental and developmental signals converge at MYC3 suppression of FT, an elementary event underlying natural variation in photoperiodic flowering responses.
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http://dx.doi.org/10.1016/j.devcel.2019.05.018DOI Listing
July 2019

The mA pathway protects the transcriptome integrity by restricting RNA chimera formation in plants.

Life Sci Alliance 2019 06 29;2(3). Epub 2019 May 29.

Centre National de la Recherche Scientifique, Laboratoire Génome et Développement des Plantes, UMR 5096, Perpignan, France

Global, segmental, and gene duplication-related processes are driving genome size and complexity in plants. Despite their evolutionary potentials, those processes can also have adverse effects on genome regulation, thus implying the existence of specialized corrective mechanisms. Here, we report that an N6-methyladenosine (mA)-assisted polyadenylation (m-ASP) pathway ensures transcriptome integrity in Efficient m-ASP pathway activity requires the mA methyltransferase-associated factor FIP37 and CPSF30L, an mA reader corresponding to an YT512-B Homology Domain-containing protein (YTHDC)-type domain containing isoform of the 30-kD subunit of cleavage and polyadenylation specificity factor. Targets of the m-ASP pathway are enriched in recently rearranged gene pairs, displayed an atypical chromatin signature, and showed transcriptional readthrough and mRNA chimera formation in FIP37- and CPSF30L-deficient plants. Furthermore, we showed that the m-ASP pathway can also restrict the formation of chimeric gene/transposable-element transcript, suggesting a possible implication of this pathway in the control of transposable elements at specific locus. Taken together, our results point to selective recognition of 3'-UTR mA as a safeguard mechanism ensuring transcriptome integrity at rearranged genomic loci in plants.
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http://dx.doi.org/10.26508/lsa.201900393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545605PMC
June 2019

Long noncoding RNA NONHSAG053901 promotes diabetic nephropathy via stimulating Egr-1/TGF-β-mediated renal inflammation.

J Cell Physiol 2019 08 29;234(10):18492-18503. Epub 2019 Mar 29.

Endocrinology Department, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, People's Republic of China.

Diabetic nephropathy (DN) is an important factor leading to end-stage kidney disease that affects diabetes mellitus patients globally. Our previous transcriptome sequencing has identified a large group of differentially expressed long noncoding RNA (lncRNA) in early development of DN. On basis of this, we aimed to investigate the function of lncRNA NONHSAG053901 in DN pathogenesis. In this study, we revealed that the expression of NONHSAG053901 was drastically elevated in both DN mouse model and mesangial cells (MCs). It was found that overexpression of NONHSAG053901 remarkably promoted inflammation, fibrosis and proliferation in MCs. Consistently, further investigations suggested that the stimulation of NONHSAG053901 on proinflammatory cytokines via direct binding to early growth response protein 1 (Egr-1). Interaction between Egr-1 and transforming growth factor β (TGF-β) could augment TGF-β function in DN inflammation. Furthermore, the effects of NONHSAG053901 on stimulation of proinflammatory cytokines were abolished by knockdown of Egr-1. These results together suggested that NONHSAG053901 promoted proinflammatory cytokines via stimulating Egr-1/TGF-β mediated renal inflammation.
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http://dx.doi.org/10.1002/jcp.28485DOI Listing
August 2019

Messenger RNA Modifications in Plants.

Trends Plant Sci 2019 04 8;24(4):328-341. Epub 2019 Feb 8.

Temasek Life Sciences Laboratory, 1 Research Link, National University of Singapore, 117604, Singapore; Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, 117543, Singapore. Electronic address:

Over 160 distinct RNA modifications are known and collectively termed the epitranscriptome. Some of these modifications have been discovered in mRNA, uncovering a new layer of gene regulation. Transcriptome-wide mapping of epitranscriptomic codes and the discovery of their writers, erasers, and readers that dynamically install, remove, and interpret RNA modifications, respectively, are fundamental to understanding the epitranscriptome. Recent technologies have enabled the transcriptome-wide profiling of several mRNA modifications in Arabidopsis thaliana, providing key insights into regulating these modifications and their effects on plant development. Here we review technological innovations and recent progress in epitranscriptomics, with specific focus on N-methyladenosine (mA), 5-methylcytosine (mC), uridylation, and their roles in multiple aspects of plant development.
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http://dx.doi.org/10.1016/j.tplants.2019.01.005DOI Listing
April 2019

Long noncoding RNA NEAT1 accelerates the proliferation and fibrosis in diabetic nephropathy through activating Akt/mTOR signaling pathway.

J Cell Physiol 2019 07 4;234(7):11200-11207. Epub 2018 Dec 4.

Endocrinology Department, School of Medicine, Shanghai Tongren Hospital, Affiliated to Shanghai Jiao Tong University, Shanghai, China.

Accumulating evidence has indicated the significant roles of long noncoding RNAs (lncRNAs) in the pathophysiology of diabetic nephropathy (DN). LncRNA nuclear enriched abundant transcript 1 (NEAT1) has been reported to exert a key role in the progression of several diseases including diabetes. However, the role of NEAT1 in the regulation of DP progression remains barely known. Therefore, our study aimed to investigate the role of NEAT1 in a streptozotocin-induced diabetes model (DM) of rats and glucose-induced mouse mesangial cell models. Currently, we found that NEAT1 was greatly upregulated in DM rats and glucose-induced mice mesangial cells, in which a high activation of Akt/mTOR signaling was also observed. Then, it was shown that knockdown of NETA1 was able to reduce renal injury in DM rats obviously. In addition, cell counting kit-8 assay and 5-ethynyl-2'-deoxyuridine assay were carried out and we observed downregulation of NEAT1 significantly inhibited mesangial cell proliferation. Meanwhile, extracellular matrix proteins and messenger RNA (transforming growth factor β1, fibronectin, and collagen IV) expression was dramatically restrained by silencing of NEAT1 in the high glucose-induced mesangial cells. Finally, knockdown of NEAT1 greatly reduced the expression of the phosphorylation of Akt and mammalian target of rapamycin (mTOR) in vitro. These findings revealed that the decrease of NEAT1 repressed the proliferation and fibrosis in DN via activating the Akt/mTOR signaling pathway, which might represent a novel pathological mechanism of DN progression.
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http://dx.doi.org/10.1002/jcp.27770DOI Listing
July 2019

Whole-Genome Resequencing of a Worldwide Collection of Rapeseed Accessions Reveals the Genetic Basis of Ecotype Divergence.

Mol Plant 2019 01 22;12(1):30-43. Epub 2018 Nov 22.

Institute of Crop Science, Zhejiang University, Hangzhou 310058, China. Electronic address:

Rapeseed (Brassica napus), an important oilseed crop, has adapted to diverse climate zones and latitudes by forming three main ecotype groups, namely winter, semi-winter, and spring types. However, genetic variations underlying the divergence of these ecotypes are largely unknown. Here, we report the global pattern of genetic polymorphisms in rapeseed determined by resequencing a worldwide collection of 991 germplasm accessions. A total of 5.56 and 5.53 million single-nucleotide polymorphisms (SNPs) as well as 1.86 and 1.92 million InDels were identified by mapping reads to the reference genomes of "Darmor-bzh" and "Tapidor," respectively. We generated a map of allelic drift paths that shows splits and mixtures of the main populations, and revealed an asymmetric evolution of the two subgenomes of B. napus by calculating the genetic diversity and linkage disequilibrium parameters. Selective-sweep analysis revealed genetic changes in genes orthologous to those regulating various aspects of plant development and response to stresses. A genome-wide association study identified SNPs in the promoter regions of FLOWERING LOCUS T and FLOWERING LOCUS C orthologs that corresponded to the different rapeseed ecotype groups. Our study provides important insights into the genomic footprints of rapeseed evolution and flowering-time divergence among three ecotype groups, and will facilitate screening of molecular markers for accelerating rapeseed breeding.
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http://dx.doi.org/10.1016/j.molp.2018.11.007DOI Listing
January 2019

Low molecular weight glutenin subunit gene composition at Glu-D3 loci of Aegilops tauschii and common wheat and a further view of wheat evolution.

Theor Appl Genet 2018 Dec 17;131(12):2745-2763. Epub 2018 Sep 17.

State Key Laboratory of Plant Cell and Chromosome Engineering, National Center for Plant Gene Research, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 1 West Beichen Road, Chaoyang District, Beijing, 100101, China.

Key Message: A comprehensive comparison of LMW-GS genes between Ae. tauschii and its progeny common wheat. Low molecular weight glutenin subunits (LMW-GSs) are determinant of wheat flour processing quality. However, the LMW-GS gene composition in Aegilops tauschii, the wheat D genome progenitor, has not been comprehensively elucidated and the impact of allohexaploidization on the Glu-D3 locus remains elusive. In this work, using the LMW-GS gene molecular marker system and the full-length gene-cloning method, LMW-GS genes at the Glu-D3 loci of 218 Ae. tauschii and 173 common wheat (Triticum aestivum L.) were characterized. Each Ae. tauschii contained 11 LMW-GS genes, and the whole collection was divided into 25 haplotypes (AeH01-AeH25). The Glu-D3 locus in common wheat lacked the LMW-GS genes D3-417, D3-507 and D3-552, but shared eight genes of identical open reading frame (ORF) sequences when compared to that of Ae. tauschii. Therefore, the allohexaploidization induces deletions, but exerts no influence on LMW-GS gene coding sequences at the Glu-D3 locus. 92.17% Ae. tauschii had 7-9 LMW-GSs, more than the six subunits in common wheat. The haplotypes AeH16, AeH20 and AeH23 of Ae. tauschii ssp. strangulate distributed in southeastern Caspian Iran were the main putative D genome donor of common wheat. These results facilitate the utilization of the Ae. tauschii glutenin gene resources and the understanding of wheat evolution.
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http://dx.doi.org/10.1007/s00122-018-3188-1DOI Listing
December 2018

FTIP-Dependent STM Trafficking Regulates Shoot Meristem Development in Arabidopsis.

Cell Rep 2018 05;23(6):1879-1890

Temasek Life Sciences Laboratory and Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore. Electronic address:

Organogenesis in higher plants occurs in the shoot meristem, which contains pluripotent stem cells. Here, we show that two multiple C2 domain and transmembrane region proteins, FT INTERACTING PROTEIN 3 (FTIP3) and FTIP4, play an essential role in mediating proliferation and differentiation of shoot stem cells in Arabidopsis. FTIP3/4 prevent intracellular trafficking of a key regulator, SHOOTMERISTEMLESS (STM), to the plasma membrane in cells in the peripheral shoot meristem region. This facilitates STM recycling to the nucleus to maintain stem cells. Without FTIP3/4, STM localizes substantially to the plasma membrane, which promotes intercellular trafficking but compromises nuclear localization of STM. This accelerates stem cell differentiation, causing early termination of shoot apices and resulting in dwarf and bushy phenotypes. Our findings reveal a molecular framework that determines the fate of shoot stem cells and the resulting aboveground plant body.
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http://dx.doi.org/10.1016/j.celrep.2018.04.033DOI Listing
May 2018

Mechanisms, origin and heredity of Glu-1Ay silencing in wheat evolution and domestication.

Theor Appl Genet 2018 Jul 25;131(7):1561-1575. Epub 2018 Apr 25.

State Key Laboratory of Plant Cell and Chromosome Engineering, National Center for Plant Gene Research, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 1 West Beichen Road, Chaoyang District, Beijing, 100101, China.

Key Message: Allotetraploidization drives Glu-1Ay silencing in polyploid wheat. The high-molecular-weight glutenin subunit gene, Glu-1Ay, is always silenced in common wheat via elusive mechanisms. To investigate its silencing and heredity during wheat polyploidization and domestication, the Glu-1Ay gene was characterized in 1246 accessions containing diploid and polyploid wheat worldwide. Eight expressed Glu-1Ay alleles (in 71.81% accessions) and five silenced alleles with a premature termination codon (PTC) were identified in Triticum urartu; 4 expressed alleles (in 41.21% accessions), 13 alleles with PTCs and 1 allele with a WIS 2-1A retrotransposon were present in wild tetraploid wheat; and only silenced alleles with PTC or WIS 2-1A were in cultivated tetra- and hexaploid wheat. Both the PTC number and position in T. urartu Glu-1Ay alleles (one in the N-terminal region) differed from its progeny wild tetraploid wheat (1-5 PTCs mainly in the repetitive domain). The WIS 2-1A insertion occurred ~ 0.13 million years ago in wild tetraploid wheat, much later than the allotetraploidization event. The Glu-1Ay alleles with PTCs or WIS 2-1A that arose in wild tetraploid wheat were fully succeeded to cultivated tetraploid and hexaploid wheat. In addition, the Glu-1Ay gene in wild einkorn inherited to cultivated einkorn. Our data demonstrated that the silencing of Glu-1Ay in tetraploid and hexaploid wheat was attributed to the new PTCs and WIS 2-1A insertion in wild tetraploid wheat, and most silenced alleles were delivered to the cultivated tetraploid and hexaploid wheat, providing a clear evolutionary history of the Glu-1Ay gene in the wheat polyploidization and domestication processes.
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http://dx.doi.org/10.1007/s00122-018-3098-2DOI Listing
July 2018

DNA N-Adenine Methylation in Arabidopsis thaliana.

Dev Cell 2018 05 12;45(3):406-416.e3. Epub 2018 Apr 12.

Department of Biological Sciences and Temasek Life Sciences Laboratory, National University of Singapore, Singapore 117543, Singapore. Electronic address:

DNA methylation on N-adenine (6mA) has recently been found to be a potentially epigenetic mark in several unicellular and multicellular eukaryotes. However, its distribution patterns and potential functions in land plants, which are primary producers for most ecosystems, remain largely unknown. Here we report global profiling of 6mA sites at single-nucleotide resolution in the genome of Arabidopsis thaliana at different developmental stages using single-molecule real-time sequencing. 6mA sites are widely distributed across the Arabidopsis genome and enriched over the pericentromeric heterochromatin regions. 6mA occurs more frequently in gene bodies than intergenic regions. Analysis of 6mA methylomes and RNA sequencing data demonstrates that 6mA frequency positively correlates with the gene expression level and the transition from vegetative to reproductive growth in Arabidopsis. Our results uncover 6mA as a DNA mark associated with actively expressed genes in Arabidopsis, suggesting that 6mA serves as a hitherto unknown epigenetic mark in land plants.
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http://dx.doi.org/10.1016/j.devcel.2018.03.012DOI Listing
May 2018

Functional improvements in patients with lymphangioleiomyomatosis after sirolimus: an observational study.

Orphanet J Rare Dis 2018 02 20;13(1):34. Epub 2018 Feb 20.

Department of Respiratory Medicine, Peking Union Medical College Hospital, Beijing, China.

Background: Sirolimus has been shown to be effective in patients with lymphangioleiomyomatosis (LAM). We wish to summarize our experience using sirolimus and its effectiveness in LAM patients.

Methods: We analyzed data from 98 patients who were diagnosed with definite or probable sporadic LAM based on the European Respiratory Society diagnosis criteria for LAM in 2010 at Peking Union Medical College Hospital and who had received sirolimus during January 2007 to June 2015. The data before and after the initiation of sirolimus therapy included pulmonary function tests, arterial blood gas analysis, 6-min walking distance (6MWD), size of chylous effusion and renal angiomyolipomas (AML), St. George's Respiratory Questionnaires (SGRQ) and vascular endothelial growth factor-D (VEGF-D) levels. Serum levels of sirolimus and adverse events were collected.

Results: Median follow-up was 2.5 years. Most patients had forced expiratory volume in 1 s (FEV) values less than 70% predicted or symptomatic chylothorax. The mean changes before and after the initiation of sirolimus were - 31.12 ± 30.78 mL/month and 16.11 ± 36.00 mL/month (n = 18,p = 0.002) for FEV change, and - 0.55 ± 0.60 mmHg/month and 0.30 ± 1.19 mmHg/month (n = 17, p = 0.018) for PO change. 6MWD improved from 358.8 ± 114.4 m to 415.6 ± 118.6 m (n = 46, p = 0.004) and SGRQ total score from 57.2 ± 21.0 to 47.5 ± 22.8 (n = 50, p < 0.001). The median VEGF-D concentration decreased to 1609.4 pg/mL from 3075.6 pg/mL after sirolimus therapy (n = 41, p < 0.001). Patients with sirolimus trough levels of 5-9.9 ng/mL had an increase in FEV (p < 0.05). Sixty-five percent of patients (13/20) had almost complete resolution of chylous effusions. The most frequent adverse events were mouth ulcers, menstrual disorder, hyperlipidemia and acneiform rash, all were mild.

Conclusion: Long-term use of sirolimus is safe in patients with LAM. LAM patients with FEV less than 70% predicted and symptomatic chylothorax are suitable for receiving sirolimus therapy. The maintaining serum trough levels of sirolimus are recommended between 5 to 9.99 ng/mL.
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http://dx.doi.org/10.1186/s13023-018-0775-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5819088PMC
February 2018