• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

增殖的肿瘤细胞模拟成熟人类红细胞的葡萄糖代谢。

Proliferating tumor cells mimick glucose metabolism of mature human erythrocytes.

机构信息

a Department of Dermatology , University Medical Center Schleswig-Holstein, Campus Kiel , Kiel , Germany.

b Klinik und Poliklinik für Dermatologie und Allergologie, Fakultät für Medizin , Technische Universität München , Munich , Germany.

出版信息

Cell Cycle. 2019 Jun;18(12):1316-1334. doi: 10.1080/15384101.2019.1618125. Epub 2019 Jun 3.

DOI:10.1080/15384101.2019.1618125
PMID:31154896
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6592250/
Abstract

Mature human erythrocytes are dependent on anerobic glycolysis, i.e. catabolism (oxidation) of one glucose molecule to produce two ATP and two lactate molecules. Proliferating tumor cells mimick mature human erythrocytes to glycolytically generate two ATP molecules. They deliberately avoid or switch off their respiration, i.e. tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) machinery and consequently dispense with the production of additional 36 ATP molecules from one glucose molecule. This phenomenon is named aerobic glycolysis or Warburg effect. The present review deals with the fate of a glucose molecule after entering a mature human erythrocyte or a proliferating tumor cell and describes why it is useful for a proliferating tumor cell to imitate a mature erythrocyte. Blood consisting of plasma and cellular components (99% of the cells are erythrocytes) may be regarded as a mobile organ, constantly exercising a direct interaction with other organs. Therefore, the use of drugs, which influences the biological activity of erythrocytes, has an immediate effect on the entire organism. : TCA: tricarboxylic acid cycle; OXPHOS: oxidative phosphorylation; GSH: reduced state of glutathione; NFκB: Nuclear factor of kappa B; PKB (Akt): protein kinase B; NOS: nitric oxide synthase; IgG: immune globulin G; HS: hydrogen sulfide; slanDCs: Human 6-sulfo LacNAc-expressing dendritic cells; IL-8: interleukin-8; LPS: lipopolysaccharide; ROS: reactive oxygen species; PPP: pentose phosphate pathway; NADPH: nicotinamide adenine dinucleotide phosphate hydrogen; R5P: ribose-5-phophate; NAD: nicotinamide adenine dinucleotide; FAD: flavin adenine dinucleotide; O: superoxide anion; G6P: glucose 6-phosphate; HbO: Oxyhemoglobin; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GAP: glyceraldehyde-3-phosphate; 1,3-BPG: 1,3-bis-phosphoglycerate; 2,3-BPG: 2,3-bisphosphoglycerte; PGAM1: phosphoglycerate mutase 1; 3-PG: 3-phosphoglycerate; 2-PG: 2-phosphoglycerate; MIPP1: Multiple inositol polyphosphate phosphatase; mTORC1: mammalian target of rapamycin complex 1; Ru5P: ribulose 5-phosphate; ox-PPP: oxidative branch of pentose phosphate pathway; PGK: phosphoglycerate kinase; IFN-γ: interferon-γ; LDH: lactate dehydrogenase; STAT3: signal transducer and activator of transcription 3; Rheb: Ras homolog enriched in Brain; HO: hydrogen peroxide; ROOH: lipid peroxide; SOD: superoxide dismutase; MRC: mitochondrial respiratory chain; MbFe-O: methmyoglobin; RNR: ribonucleotide reductase; PRPP: phosphoribosylpyrophosphate; PP: pyrophosphate; GSSG: oxidized state of glutathione; non-ox-PPP: non-oxidative branch of pentose phosphate pathway; RPI: ribose-5-phosphate isomerase; RPE: ribulose 5-phosphate 3-epimerase; X5P: xylulose 5-phosphate; TK: transketolase; TA: transaldolase; F6P: fructose-6-phosphate; AR2: aldose reductase 2; SD: sorbitol dehydrogenase; HK: hexokinase; MG: mehtylglyoxal; DHAP: dihydroxyacetone phosphate; TILs: tumor-infiltrating lymphocytes; MCTs: monocarboxylate transporters; pHi: intracellular pH; Hif-1α: hypoxia-induced factor 1; NHE1: sodium/H (Na/H) antiporter 1; V-ATPase: vacuolar-type proton ATPase; CAIX: carbonic anhydrase; CO: carbon dioxide; HCO: bicarbonate; NBC: sodium/bicarbonate (Na/HCO) symporter; pHe: extracellular pH; GLUT-1: glucose transporter 1; PGK-1: phosphoglycerate kinase 1.

摘要

成熟的人类红细胞依赖于无氧糖酵解，即一个葡萄糖分子的分解（氧化）产生两个 ATP 和两个乳酸分子。增殖的肿瘤细胞模仿成熟的人类红细胞，通过糖酵解产生两个 ATP 分子。它们故意避免或关闭呼吸作用，即三羧酸 (TCA) 循环和氧化磷酸化 (OXPHOS) 机制，因此从一个葡萄糖分子中不再产生额外的 36 个 ATP 分子。这种现象被称为有氧糖酵解或瓦伯格效应。本综述涉及葡萄糖分子进入成熟的人类红细胞或增殖的肿瘤细胞后的命运，并描述了为什么增殖的肿瘤细胞模仿成熟的红细胞是有益的。由血浆和细胞成分组成的血液（99%的细胞是红细胞）可被视为一个移动的器官，它与其他器官不断进行直接的相互作用。因此，影响红细胞生物活性的药物的使用会对整个机体立即产生影响。: TCA: 三羧酸循环; OXPHOS: 氧化磷酸化; GSH: 还原型谷胱甘肽; NFκB: 核因子 κB; PKB (Akt): 蛋白激酶 B; NOS: 一氧化氮合酶; IgG: 免疫球蛋白 G; HS: 硫化氢; slanDCs: 表达 6-硫酸唾液酸的人类树突细胞; IL-8: 白细胞介素-8; LPS: 脂多糖; ROS: 活性氧; PPP: 戊糖磷酸途径; NADPH: 烟酰胺腺嘌呤二核苷酸磷酸氢; R5P: 核糖-5-磷酸; NAD: 烟酰胺腺嘌呤二核苷酸; FAD: 黄素腺嘌呤二核苷酸; O: 超氧阴离子; G6P: 葡萄糖 6-磷酸; HbO: 氧合血红蛋白; GAPDH: 甘油醛-3-磷酸脱氢酶; GAP: 甘油醛-3-磷酸; 1,3-BPG: 1,3-双磷酸甘油酸; 2,3-BPG: 2,3-双磷酸甘油酯; PGAM1: 磷酸甘油酸变位酶 1; 3-PG: 3-磷酸甘油酸; 2-PG: 2-磷酸甘油酸; MIPP1: 多磷酸肌醇多磷酸酶; mTORC1: 雷帕霉素靶蛋白复合体 1; Ru5P: 核酮糖 5-磷酸; ox-PPP: 戊糖磷酸途径的氧化分支; PGK: 磷酸甘油酸激酶; IFN-γ: 干扰素-γ; LDH: 乳酸脱氢酶; STAT3: 信号转导和转录激活因子 3; Rheb: 富含脑的 Ras 同源物; HO: 过氧化氢; ROOH: 脂质过氧化物; SOD: 超氧化物歧化酶; MRC: 线粒体呼吸链; MbFe-O: 甲硫血红蛋白; RNR: 核糖核苷酸还原酶; PRPP: 磷酸核糖焦磷酸; PP: 焦磷酸; GSSG: 氧化型谷胱甘肽; non-ox-PPP: 戊糖磷酸途径的非氧化分支; RPI: 核糖-5-磷酸异构酶; RPE: 核酮糖 5-磷酸 3-差向异构酶; X5P: 木酮糖 5-磷酸; TK: 转酮醇酶; TA: 转醛醇酶; F6P: 果糖-6-磷酸; AR2: 醛糖还原酶 2; SD: 山梨醇脱氢酶; HK: 己糖激酶; MG: 甲基乙二醛; DHAP: 二羟丙酮磷酸; TILs: 肿瘤浸润淋巴细胞; MCTs: 单羧酸转运蛋白; pHi: 细胞内 pH; Hif-1α: 缺氧诱导因子 1; NHE1: 钠/H (Na/H) 反向转运体 1; V-ATPase: 液泡型质子 ATP 酶; CAIX: 碳酸酐酶; CO: 二氧化碳; HCO: 碳酸氢盐; NBC: 钠/碳酸氢盐 (Na/HCO) 转运体; pHe: 细胞外 pH; GLUT-1: 葡萄糖转运蛋白 1; PGK-1: 磷酸甘油激酶 1。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/daf1/6592250/7683b88be957/kccy-18-12-1618125-g016.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/daf1/6592250/b8922150612d/kccy-18-12-1618125-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/daf1/6592250/1564f16fe918/kccy-18-12-1618125-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/daf1/6592250/bfce6dfbe9fb/kccy-18-12-1618125-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/daf1/6592250/0dcfb625a170/kccy-18-12-1618125-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/daf1/6592250/eb0aa1b70671/kccy-18-12-1618125-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/daf1/6592250/cebc42047b19/kccy-18-12-1618125-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/daf1/6592250/2feb4a0abba6/kccy-18-12-1618125-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/daf1/6592250/ff3d1e99edee/kccy-18-12-1618125-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/daf1/6592250/6382a206e4a8/kccy-18-12-1618125-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/daf1/6592250/2322a74e0b2b/kccy-18-12-1618125-g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/daf1/6592250/64c100f47e61/kccy-18-12-1618125-g012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/daf1/6592250/2c4e31373ff4/kccy-18-12-1618125-g013.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/daf1/6592250/13f00a2a88d1/kccy-18-12-1618125-g014.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/daf1/6592250/3e21aad59788/kccy-18-12-1618125-g015.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/daf1/6592250/7683b88be957/kccy-18-12-1618125-g016.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/daf1/6592250/b8922150612d/kccy-18-12-1618125-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/daf1/6592250/1564f16fe918/kccy-18-12-1618125-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/daf1/6592250/bfce6dfbe9fb/kccy-18-12-1618125-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/daf1/6592250/0dcfb625a170/kccy-18-12-1618125-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/daf1/6592250/eb0aa1b70671/kccy-18-12-1618125-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/daf1/6592250/cebc42047b19/kccy-18-12-1618125-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/daf1/6592250/2feb4a0abba6/kccy-18-12-1618125-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/daf1/6592250/ff3d1e99edee/kccy-18-12-1618125-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/daf1/6592250/6382a206e4a8/kccy-18-12-1618125-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/daf1/6592250/2322a74e0b2b/kccy-18-12-1618125-g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/daf1/6592250/64c100f47e61/kccy-18-12-1618125-g012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/daf1/6592250/2c4e31373ff4/kccy-18-12-1618125-g013.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/daf1/6592250/13f00a2a88d1/kccy-18-12-1618125-g014.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/daf1/6592250/3e21aad59788/kccy-18-12-1618125-g015.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/daf1/6592250/7683b88be957/kccy-18-12-1618125-g016.jpg

相似文献

1
Proliferating tumor cells mimick glucose metabolism of mature human erythrocytes.增殖的肿瘤细胞模拟成熟人类红细胞的葡萄糖代谢。
Cell Cycle. 2019 Jun;18(12):1316-1334. doi: 10.1080/15384101.2019.1618125. Epub 2019 Jun 3.
2
Metabolic dysregulation and emerging therapeutical targets for hepatocellular carcinoma.肝细胞癌的代谢失调与新兴治疗靶点
Acta Pharm Sin B. 2022 Feb;12(2):558-580. doi: 10.1016/j.apsb.2021.09.019. Epub 2021 Sep 25.
3
Solute carrier transporters: the metabolic gatekeepers of immune cells.溶质载体转运蛋白：免疫细胞的代谢守门人。
Acta Pharm Sin B. 2020 Jan;10(1):61-78. doi: 10.1016/j.apsb.2019.12.006. Epub 2019 Dec 14.
4
Catabolite regulation analysis of Escherichia coli for acetate overflow mechanism and co-consumption of multiple sugars based on systems biology approach using computer simulation.基于系统生物学方法利用计算机模拟对大肠杆菌的分解代谢物调节分析，以了解乙酸溢出机制和多种糖的共消耗。
J Biotechnol. 2013 Oct 20;168(2):155-73. doi: 10.1016/j.jbiotec.2013.06.023. Epub 2013 Jul 10.
5
Interaction of storage carbohydrates and other cyclic fluxes with central metabolism: A quantitative approach by non-stationary C metabolic flux analysis.储存碳水化合物及其他循环通量与中心代谢的相互作用：基于非稳态碳代谢通量分析的定量方法
Metab Eng Commun. 2016 Jan 22;3:52-63. doi: 10.1016/j.meteno.2016.01.001. eCollection 2016 Dec.
6
Vanadium: Risks and possible benefits in the light of a comprehensive overview of its pharmacotoxicological mechanisms and multi-applications with a summary of further research trends.钒：综合其药理毒理机制和多方面应用的全面概述，以及对进一步研究趋势的总结，探讨其风险和可能的益处。
J Trace Elem Med Biol. 2020 Sep;61:126508. doi: 10.1016/j.jtemb.2020.126508. Epub 2020 Apr 12.
7
Naringin prevents cyclophosphamide-induced erythrocytotoxicity in rats by abrogating oxidative stress.柚皮苷通过消除氧化应激来预防环磷酰胺诱导的大鼠红细胞毒性。
Toxicol Rep. 2021 Oct 25;8:1803-1813. doi: 10.1016/j.toxrep.2021.10.011. eCollection 2021.
8
Revisited Metabolic Control and Reprogramming Cancers by Means of the Warburg Effect in Tumor Cells.重新审视肿瘤细胞中的瓦博格效应对代谢控制和癌症重编程的影响。
Int J Mol Sci. 2022 Sep 2;23(17):10037. doi: 10.3390/ijms231710037.
9
Glycolytic pathway, redox state of NAD(P)-couples and energy metabolism in lens in galactose-fed rats: effect of an aldose reductase inhibitor.半乳糖喂养大鼠晶状体中的糖酵解途径、NAD(P) 偶联的氧化还原状态及能量代谢：醛糖还原酶抑制剂的作用
Curr Eye Res. 1997 Jan;16(1):34-43. doi: 10.1076/ceyr.16.1.34.5113.
10
Cellular metabolic and autophagic pathways: traffic control by redox signaling.细胞代谢和自噬途径：氧化还原信号对交通的控制。
Free Radic Biol Med. 2013 Oct;63:207-21. doi: 10.1016/j.freeradbiomed.2013.05.014. Epub 2013 May 20.

引用本文的文献

1
Fructose Metabolism in Cancer: Molecular Mechanisms and Therapeutic Implications.癌症中的果糖代谢：分子机制与治疗意义
Int J Med Sci. 2025 Jun 9;22(11):2852-2876. doi: 10.7150/ijms.108549. eCollection 2025.
2
Energy metabolism in health and diseases.健康与疾病中的能量代谢。
Signal Transduct Target Ther. 2025 Feb 18;10(1):69. doi: 10.1038/s41392-025-02141-x.
3
Metabolic reprogramming and therapeutic resistance in primary and metastatic breast cancer.原发性和转移性乳腺癌中的代谢重编程和治疗抵抗。

本文引用的文献

1
Comparing Electron Leak in Vertebrate Muscle Mitochondria.比较脊椎动物肌肉线粒体中的电子泄漏
Integr Comp Biol. 2018 Sep 1;58(3):495-505. doi: 10.1093/icb/icy095.
2
Lactic acid induces lactate transport and glycolysis/OXPHOS interconversion in glioblastoma.乳酸诱导脑胶质瘤中乳酸转运和糖酵解/氧化磷酸化的转换。
Biochem Biophys Res Commun. 2018 Sep 5;503(2):888-894. doi: 10.1016/j.bbrc.2018.06.092. Epub 2018 Jun 21.
3
Inhibition of Glycolysis and Glutaminolysis: An Emerging Drug Discovery Approach to Combat Cancer.抑制糖酵解和谷氨酰胺分解：一种新兴的药物发现方法，用于对抗癌症。
Mol Cancer. 2024 Nov 21;23(1):261. doi: 10.1186/s12943-024-02165-x.
4
Mitochondrial Plasticity and Glucose Metabolic Alterations in Human Cancer under Oxidative Stress-From Viewpoints of Chronic Inflammation and Neutrophil Extracellular Traps (NETs).线粒体可塑性和氧化应激下人癌症中的葡萄糖代谢改变——从慢性炎症和中性粒细胞胞外陷阱 (NETs) 的角度来看。
Int J Mol Sci. 2024 Aug 30;25(17):9458. doi: 10.3390/ijms25179458.
5
Vitamin C-Dependent Uptake of Non-Heme Iron by Enterocytes, Its Impact on Erythropoiesis and Redox Capacity of Human Erythrocytes.肠细胞对非血红素铁的维生素C依赖性摄取及其对人体红细胞生成和氧化还原能力的影响。
Antioxidants (Basel). 2024 Aug 9;13(8):968. doi: 10.3390/antiox13080968.
6
Increase in GPIHBP1 expression in advanced stage colorectal cancer indicates poor immune surveillance.晚期结直肠癌中GPIHBP1表达增加表明免疫监视功能不佳。
Transl Cancer Res. 2024 Jun 30;13(6):2691-2703. doi: 10.21037/tcr-23-1766. Epub 2024 Jun 11.
7
Analysis of non-physiological shear stress-induced red blood cell trauma across different clinical support conditions of the blood pump.分析不同临床血液泵支持条件下非生理切应力诱导的红细胞损伤。
Med Biol Eng Comput. 2024 Oct;62(10):3209-3223. doi: 10.1007/s11517-024-03121-z. Epub 2024 May 28.
8
New Insights in ATP Synthesis as Therapeutic Target in Cancer and Angiogenic Ocular Diseases.ATP 合成的新见解——作为癌症和血管生成性眼病治疗靶点。
J Histochem Cytochem. 2024 May;72(5):329-352. doi: 10.1369/00221554241249515. Epub 2024 May 11.
9
O-GlcNAcylation of TRIM29 and OGT translation forms a feedback loop to promote adaptive response of PDAC cells to glucose deficiency.TRIM29 和 OGT 的 O-GlcNAcylation 形成反馈环，以促进胰腺导管腺癌（PDAC）细胞对葡萄糖缺乏的适应性反应。
Cell Oncol (Dordr). 2024 Jun;47(3):1025-1041. doi: 10.1007/s13402-023-00915-5. Epub 2024 Feb 12.
10
Aberrant LETM1 elevation dysregulates mitochondrial functions and energy metabolism and promotes lung metastasis in osteosarcoma.异常的LETM1升高会失调线粒体功能和能量代谢，并促进骨肉瘤的肺转移。
Genes Dis. 2023 Jun 23;11(3):100988. doi: 10.1016/j.gendis.2023.05.005. eCollection 2024 May.
Curr Top Med Chem. 2018;18(6):494-504. doi: 10.2174/1568026618666180523111351.
4
Pathogen clearance and immune adherence "revisited": Immuno-regulatory roles for CRIg.病原体清除和免疫黏附“再探”：CRIg 的免疫调节作用。
Semin Immunol. 2018 Jun;37:4-11. doi: 10.1016/j.smim.2018.02.007. Epub 2018 Mar 21.
5
Metabolic heterogeneity and plasticity of glioma stem cells in a mouse glioblastoma model.在小鼠脑胶质瘤模型中胶质瘤干细胞的代谢异质性和可塑性。
Neuro Oncol. 2018 Feb 19;20(3):343-354. doi: 10.1093/neuonc/nox170.
6
Bisphosphoglycerate mutase controls serine pathway flux via 3-phosphoglycerate.二磷酸甘油酸变位酶通过3-磷酸甘油酸控制丝氨酸途径通量。
Nat Chem Biol. 2017 Oct;13(10):1081-1087. doi: 10.1038/nchembio.2453. Epub 2017 Aug 7.
7
Trifluoperazine-Induced Suicidal Erythrocyte Death and S-Nitrosylation Inhibition, Reversed by the Nitric Oxide Donor Sodium Nitroprusside.三氟拉嗪诱导的自杀性红细胞死亡及S-亚硝基化抑制，可被一氧化氮供体硝普钠逆转。
Cell Physiol Biochem. 2017;42(5):1985-1998. doi: 10.1159/000479838. Epub 2017 Aug 9.
8
Eryptosis in health and disease: A paradigm shift towards understanding the (patho)physiological implications of programmed cell death of erythrocytes.红细胞程序性细胞死亡的健康与疾病中的发生：理解（病理）生理影响的范式转变
Blood Rev. 2017 Nov;31(6):349-361. doi: 10.1016/j.blre.2017.06.001. Epub 2017 Jun 17.
9
The Link Between Angiogenesis and Endothelial Metabolism.血管生成与内皮代谢之间的联系。
Annu Rev Physiol. 2017 Feb 10;79:43-66. doi: 10.1146/annurev-physiol-021115-105134. Epub 2016 Dec 15.
10
Revised Estimates for the Number of Human and Bacteria Cells in the Body.人体和细菌细胞数量的修订估计值。
PLoS Biol. 2016 Aug 19;14(8):e1002533. doi: 10.1371/journal.pbio.1002533. eCollection 2016 Aug.