<?xml version="1.0" encoding="UTF-8"?>
<!DOCTYPE root>
<article xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xmlns:ali="http://www.niso.org/schemas/ali/1.0/" article-type="other" dtd-version="1.2" xml:lang="en"><front><journal-meta><journal-id journal-id-type="publisher-id">Journal of microbiology, epidemiology and immunobiology</journal-id><journal-title-group><journal-title xml:lang="en">Journal of microbiology, epidemiology and immunobiology</journal-title><trans-title-group xml:lang="ru"><trans-title>Журнал микробиологии, эпидемиологии и иммунобиологии</trans-title></trans-title-group></journal-title-group><issn publication-format="print">0372-9311</issn><issn publication-format="electronic">2686-7613</issn><publisher><publisher-name xml:lang="en">Central Research Institute for Epidemiology</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="publisher-id">990</article-id><article-id pub-id-type="doi">10.36233/0372-9311-33</article-id><article-categories><subj-group subj-group-type="toc-heading" xml:lang="en"><subject>REVIEWS</subject></subj-group><subj-group subj-group-type="toc-heading" xml:lang="ru"><subject>ОБЗОРЫ</subject></subj-group><subj-group subj-group-type="article-type"><subject>Unknown</subject></subj-group></article-categories><title-group><article-title xml:lang="en">Heterogeneity in isogenic bacteria populations and modern technologies of cell phenotyping</article-title><trans-title-group xml:lang="ru"><trans-title>Гетерогенность в изогенных популяциях бактерий и современные технологии клеточного фенотипирования</trans-title></trans-title-group></title-group><contrib-group><contrib contrib-type="author"><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0003-4456-808X</contrib-id><name-alternatives><name xml:lang="en"><surname>Andryukov</surname><given-names>B. G.</given-names></name><name xml:lang="ru"><surname>Андрюков</surname><given-names>Б. Г.</given-names></name></name-alternatives><address><country country="RU">Russian Federation</country></address><bio xml:lang="en"><p>Boris G. Andryukov — D. Sci. (Med.), leading researcher, Laboratory of molecular microbiology</p><p>Vladivostok</p></bio><bio xml:lang="ru"><p>Андрюков Борис Георгиевич — д.м.н., в.н.с. лаб. молекулярной микробиологии</p><p>Владивосток</p></bio><email>andrukov_bg@mail.ru</email><xref ref-type="aff" rid="aff1"/></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0001-6051-292X</contrib-id><name-alternatives><name xml:lang="en"><surname>Timchenko</surname><given-names>N. F.</given-names></name><name xml:lang="ru"><surname>Тимченко</surname><given-names>Н. Ф.</given-names></name></name-alternatives><address><country country="RU">Russian Federation</country></address><bio xml:lang="en"><p>Nelly F. Timchenko — D. Sci. (Med.), leading researcher, Laboratory of molecular microbiology</p><p>Vladivostok</p></bio><bio xml:lang="ru"><p>Тимченко Нелли Фёдоровна — д.м.н., в.н.с. лаб.молекулярной микробиологии</p><p>Владивосток</p></bio><xref ref-type="aff" rid="aff1"/></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0002-5290-3864</contrib-id><name-alternatives><name xml:lang="en"><surname>Lyapun</surname><given-names>I. N.</given-names></name><name xml:lang="ru"><surname>Ляпун</surname><given-names>И. Н.</given-names></name></name-alternatives><address><country country="RU">Russian Federation</country></address><bio xml:lang="en"><p>Irina N. Lyapun — Cand. Sci. (Biol.), senior researcher, Laboratory of molecular microbiology</p><p>Vladivostok</p></bio><bio xml:lang="ru"><p>Ляпун Ирина Николаевна — к.б.н., c.н.с. лаб. молекулярной микробиологии</p><p>Владивосток</p></bio><xref ref-type="aff" rid="aff1"/></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0001-8255-328X</contrib-id><name-alternatives><name xml:lang="en"><surname>Bynina</surname><given-names>M. P.</given-names></name><name xml:lang="ru"><surname>Бынина</surname><given-names>М. П.</given-names></name></name-alternatives><address><country country="RU">Russian Federation</country></address><bio xml:lang="en"><p>Marina P. Bynina — junior researcher, Laboratory of molecular microbiology</p><p>Vladivostok</p></bio><bio xml:lang="ru"><p>Бынина Марина Павловна — м.н.с. лаб. молекулярной микробиологии</p><p>Владивосток</p></bio><xref ref-type="aff" rid="aff1"/></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0001-9968-3347</contrib-id><name-alternatives><name xml:lang="en"><surname>Matosova</surname><given-names>E. V.</given-names></name><name xml:lang="ru"><surname>Матосова</surname><given-names>Е. В.</given-names></name></name-alternatives><address><country country="RU">Russian Federation</country></address><bio xml:lang="en"><p>Ekaterina V. Matosova — junior researcher, Laboratory of molecular microbiology</p><p>Vladivostok</p></bio><bio xml:lang="ru"><p>Матосова Екатерина Владимировна — м.н.с. лаб. молекулярной микробиологии</p><p>Владивосток</p></bio><xref ref-type="aff" rid="aff1"/></contrib></contrib-group><aff-alternatives id="aff1"><aff><institution xml:lang="en">Somov Research Institute of Epidemiology and Microbiology</institution></aff><aff><institution xml:lang="ru">НИИ эпидемиологии и микробиологии имени Г.П. Сомова</institution></aff></aff-alternatives><pub-date date-type="pub" iso-8601-date="2021-03-04" publication-format="electronic"><day>04</day><month>03</month><year>2021</year></pub-date><volume>98</volume><issue>1</issue><issue-title xml:lang="en"/><issue-title xml:lang="ru"/><fpage>73</fpage><lpage>83</lpage><history><date date-type="received" iso-8601-date="2021-03-04"><day>04</day><month>03</month><year>2021</year></date><date date-type="accepted" iso-8601-date="2021-03-04"><day>04</day><month>03</month><year>2021</year></date></history><permissions><copyright-statement xml:lang="en">Copyright ©; 2021, Andryukov B.G., Timchenko N.F., Lyapun I.N., Bynina M.P., Matosova E.V.</copyright-statement><copyright-statement xml:lang="ru">Copyright ©; 2021, Андрюков Б.Г., Тимченко Н.Ф., Ляпун И.Н., Бынина М.П., Матосова Е.В.</copyright-statement><copyright-year>2021</copyright-year><copyright-holder xml:lang="en">Andryukov B.G., Timchenko N.F., Lyapun I.N., Bynina M.P., Matosova E.V.</copyright-holder><copyright-holder xml:lang="ru">Андрюков Б.Г., Тимченко Н.Ф., Ляпун И.Н., Бынина М.П., Матосова Е.В.</copyright-holder><ali:free_to_read xmlns:ali="http://www.niso.org/schemas/ali/1.0/"/><license><ali:license_ref xmlns:ali="http://www.niso.org/schemas/ali/1.0/">https://creativecommons.org/licenses/by/4.0</ali:license_ref></license></permissions><self-uri xlink:href="https://microbiol.crie.ru/jour/article/view/990">https://microbiol.crie.ru/jour/article/view/990</self-uri><abstract xml:lang="en"><p>In the framework of the modern microbiological paradigm, colonies of genetically identical microorganisms are considered as biosocial systems consisting of several heterogeneous clonal cell clusters (bacterial phenotypes) that respond differently to changes in the environment. Phenotypic heterogeneity was found in recent decades in all isogenic populations of pathogenic bacteria. Such heterogeneity provides a selective advantage of cellular phenotypes with changes in the physicochemical parameters of the environment and competitive interaction with other microorganisms. Heterogeneity in bacterial communities is of great importance for the survival of pathogenic bacteria in the host organism, the progression and persistence of infections, as well as the decrease in the effectiveness of antibiotic therapy. The modern spectrum of analytical tools for studying cellular phenotyping is presented both by optical imaging methods and qualitative structural characteristics of single cells, and by omix technologies of quantitative analysis and monitoring of molecular intracellular processes. These diverse tools make it possible not only to identify and modulate phenotypic heterogeneity in isogenic bacterial populations, but also to evaluate the functional significance of cellular phenotypes in the development of the infectious process. The aim of the review is the integration of modern concepts of heterogeneity in isogenic bacterial populations, with an emphasis on the presentation of modern analytical technologies for assessing and monitoring phenotypic typing of single cells.</p></abstract><trans-abstract xml:lang="ru"><p>В рамках современной микробиологической парадигмы колонии генетически идентичных микроорганизмов рассматриваются как биосоциальные системы, состоящие из нескольких гетерогенных клональных кластеров клеток (фенотипов бактерий), которые по-разному реагируют на изменения в окружающей среде. За последние десятилетия фенотипическая гетерогенность обнаружена во всех изогенных популяциях патогенных бактерий. Она обеспечивает избирательное преимущество клеточных фенотипов при изменениях физико-химических параметров среды обитания и конкурентном взаимодействии с другими микроорганизмами. Установлено, что данной адаптационной стратегией бактерий управляют разнообразные механизмы вне- и внутриклеточного генеза. Гетерогенность в бактериальных сообществах имеет большое значение для выживания патогенных бактерий в организме-хозяине, прогрессирования и персистенции инфекций, а также снижения эффективности антибиотикотерапии. Современный спектр аналитических инструментов для изучения клеточного фенотипирования представлен как методами оптической визуализации и качественной структурной характеристики одиночных клеток, так и омиксными технологиями количественного анализа и мониторинга молекулярных внутриклеточных процессов. Эти разнообразные инструменты позволяют не только выявлять и модулировать фенотипическую гетерогенность в изогенных популяциях бактерий, но и оценивать функциональную значимость клеточных фенотипов для развития инфекционного процесса. Целью обзора является интеграция современных представлений о гетерогенности в изогенных популяциях бактерий с акцентом на представлении современных аналитических технологий оценки и мониторинга фенотипирования одиночных клеток.</p></trans-abstract><kwd-group xml:lang="en"><kwd>bacteria</kwd><kwd>isogenic populations</kwd><kwd>phenotypic heterogeneity</kwd><kwd>cell phenotyping</kwd><kwd>modern technologies</kwd><kwd>single cells</kwd></kwd-group><kwd-group xml:lang="ru"><kwd>бактерии</kwd><kwd>изогенные популяции</kwd><kwd>фенотипическая гетерогенность</kwd><kwd>клеточное фенотипирование</kwd><kwd>современные технологии</kwd><kwd>одиночные клетки</kwd></kwd-group><funding-group><funding-statement xml:lang="en">The work was carried out within the framework of the state assignment on the topic of research work No. 0545-2019-0007 "Molecular mechanisms of the formation of stable uncultivated forms of bacteria."</funding-statement><funding-statement xml:lang="ru">Работа выполнена в рамках государственного задания по теме НИР № 0545-2019-0007 «Молекулярные механизмы образования устойчивых некультивируемых форм бактерий».</funding-statement></funding-group></article-meta></front><body></body><back><ref-list><ref id="B1"><label>1.</label><mixed-citation>Oleskin A.V., Botvinko I.V., Tsavkelova E.A. Colonial organization and intercellular communication in microorganisms. Microbiology (Mikrobiologiya). 2000; 69(3): 249–65. https://doi.org/10.1007/BF02756730</mixed-citation></ref><ref id="B2"><label>2.</label><mixed-citation>Магданова Л.А., Голясная Н.В. Гетерогенность как адаптивное свойство бактериальной популяции. Микробиология. 2013; 82(1): 3–13. https://doi.org/10.7868/S0026365613010072</mixed-citation></ref><ref id="B3"><label>3.</label><mixed-citation>Sánchez-Romero M.A., Casadesús J. Contribution of phenotypic heterogeneity to adaptive antibiotic resistance. Proc. Natl. Acad. Sci. USA. 2014; 111(1): 355–60. https://doi.org/10.1073/pnas.1316084111</mixed-citation></ref><ref id="B4"><label>4.</label><mixed-citation>Heyse J., Buysschaert B., Props R., Rubbens P., Skirtach A.G., Waegeman W., et al. Coculturing bacteria leads to reduced phenotypic heterogeneities. Appl. Environ. Microbiol. 2019; 85(8): e02814–18. https://doi.org/10.1128/AEM.02814-18</mixed-citation></ref><ref id="B5"><label>5.</label><mixed-citation>Jeanson S., Floury J., Gagnaire V., Lortal S., Thierry A. Bacterial colonies in solid media and foods: a review on their growth and interactions with the micro-environment. Front. Microbiol. 2015; 6: 1284. https://doi.org/10.3389/fmicb.2015.01284</mixed-citation></ref><ref id="B6"><label>6.</label><mixed-citation>Ryall B., Eydallin G., Ferenci T. Culture history and population heterogeneity as determinants of bacterial adaptation: the adaptomics of a single environmental transition. Microbiol. Mol. Biol. Rev. 2012; 76(3): 597–25. https://doi.org/10.1128/MMBR.05028-11</mixed-citation></ref><ref id="B7"><label>7.</label><mixed-citation>Dhar N., McKinney J.D. Microbial phenotypic heterogeneity and antibiotic tolerance. Curr. Opin. Microbiol. 2007; 10(1): 30–8. https://doi.org/10.1016/J.MIB.2006.12.007</mixed-citation></ref><ref id="B8"><label>8.</label><mixed-citation>Ackermann M. A functional perspective on phenotypic heterogeneity in microorganisms. Nat. Rev. Microbiol. 2015; 13(8): 497–08. https://doi.org/10.1038/nrmicro3491</mixed-citation></ref><ref id="B9"><label>9.</label><mixed-citation>Davis K.M., Isberg R.R. Defining heterogeneity within bacterial populations via single cell approaches. Bioessays. 2016; 38(8): 782–90. https://doi.org/10.1002/bies.201500121</mixed-citation></ref><ref id="B10"><label>10.</label><mixed-citation>González-Cabaleiro R., Mitchell A.M., Smith W., Wipat A., Ofiteru I.D. Heterogeneity in pure microbial systems: experimental measurements and modeling. Front. Microbiol. 2017; 8: 1813. https://doi.org/10.3389/fmicb.2017.01813</mixed-citation></ref><ref id="B11"><label>11.</label><mixed-citation>Tsimring L.S. Noise in biology. Reports. Prog. Phys. 2014; 77(2): 26601. https://doi.org/10.1093/nar/gkw273</mixed-citation></ref><ref id="B12"><label>12.</label><mixed-citation>Li G.W., Xie X.S. Central dogma at the single-molecule level in living cells. Nature. 2011; 475(7356): 308–15. https://doi.org/10.1038/nature10315</mixed-citation></ref><ref id="B13"><label>13.</label><mixed-citation>Govers S.K., Adam A., Blockeel H., Aertsen A. Rapid phenotypic individualization of bacterial sister cells. Sci. Rep. 2017; 7(1): 1–9. https://doi.org/10.1038/s41598-017-08660-0</mixed-citation></ref><ref id="B14"><label>14.</label><mixed-citation>Heins A.L., Johanson T., Han S., Lundin L., Carlquist M., Gernaey K.V., et al. A quantitative flow cytometry to understand population heterogeneity in response to changes in substrate availability in Escherichia coli and Saccharomyces cerevisiae chemostats. Front. Bioeng. Biotechnol. 2019; 7: 187. https://doi.org/10.3389/fbioe.2019.00187</mixed-citation></ref><ref id="B15"><label>15.</label><mixed-citation>Lewis K. Persister cells. Annu. Rev. Microbiol. 2010; 64: 357–72. https://doi.org/10.1146/annurev.micro.112408.134306</mixed-citation></ref><ref id="B16"><label>16.</label><mixed-citation>Dorobantu L.S., Bhattacharjee S., Foght J.M., Gray M.R. Atomic force microscopy measurement of heterogeneity in bacterial surface hydrophobicity. Langmuir. 2008; 24(9): 4944–51. https://doi.org/10.1021/la7035295</mixed-citation></ref><ref id="B17"><label>17.</label><mixed-citation>Cao H., Kuipers O.P. Influence of global gene regulatory networks on single cell heterogeneity of green fluorescent protein production in Bacillus subtilis. Microb. Cell. Fact. 2018; 17(1): 134. https://doi.org/10.1186/s12934-018-0985-9</mixed-citation></ref><ref id="B18"><label>18.</label><mixed-citation>Stracy M., Uphoff S., Garza de Leon F., Kapanidis A.N. In vivo single-molecule imaging of bacterial DNA replication, transcription, and repair. FEBS Lett. 2014; 588(19): 3585–94. https://doi.org/10.1016/j.febslet.2014.05.026</mixed-citation></ref><ref id="B19"><label>19.</label><mixed-citation>Helaine S., Cheverton A.M., Watson K.G., Faure L.M., Matthews S.A., Holden D.W. Internalization of Salmonella by macrophages induces formation of nonreplicating persisters. Science. 2014; 343(6167): 204–08. https://doi.org/10.1126/science.1244705</mixed-citation></ref><ref id="B20"><label>20.</label><mixed-citation>Ambriz-Avina V., Contreras-Garduno J.A., Pedraza-Reyes M. Applications of flow cytometry to characterize bacterial physiological responses. Biomed. Res. Int. 2014; 2014: 461941. https://doi.org/10.1155/2014/461941</mixed-citation></ref><ref id="B21"><label>21.</label><mixed-citation>Burdikova Z., Svindrych Z., Pala J., Hickey C.D., Wilkinson M.G., Panek J., et al. Measurement of pH micro-heterogeneity in natural cheese matrices by fluorescence lifetime imaging. Front. Microbiol. 2015; 6: 183. https://doi.org/10.3389/fmicb.2015.00183</mixed-citation></ref><ref id="B22"><label>22.</label><mixed-citation>Han Y., Zhang F. Heterogeneity coordinates bacterial multigene expression in single cells. PLoS Comput. Biol. 2020; 16(1): e1007643. https://doi.org/10.1371/journal.pcbi.1007643</mixed-citation></ref><ref id="B23"><label>23.</label><mixed-citation>Casadesús J., Low D.A. Programmed heterogeneity: epigenetic mechanisms in bacteria. J. Biol. Chem. 2013; 288(20): 13929–35. https://doi.org/10.1074/jbc.R113.472274</mixed-citation></ref><ref id="B24"><label>24.</label><mixed-citation>Андрюков Б.Г., Сомова Л.М., Матосова Е.В., Ляпун И.Н. Фенотипическая пластичность бактерий как стратегия резистентности и объект современных антимикробных технологий (обзор). Современные технологии в медицине. 2019; 11(2): 164–82. http://doi.org/10.17691/stm2019.11.2.22</mixed-citation></ref><ref id="B25"><label>25.</label><mixed-citation>Brehm-Stecher B.F., Johnson E.A. Single-cell microbiology: tools, technologies, and applications. Microbiol. Mol. Biol. Rev. 2004; 68(3): 538–59. https://doi.org/10.1128/MMBR.68.3.538-559.2004</mixed-citation></ref><ref id="B26"><label>26.</label><mixed-citation>Fritzsch F.S., Dusny C., Frick O., Schmid A. Single-cell analysis in biotechnology, systems biology, and biocatalysis. Annu. Rev. Chem. Biomol. Eng. 2012; 3: 129–55. https://doi.org/10.1146/annurev-chembioeng-062011-081056</mixed-citation></ref><ref id="B27"><label>27.</label><mixed-citation>García-Timermans C., Rubbens P., Heyse J., Kerckhof F.M., Props R., Skirtach A.G., et al. Discriminating bacterial phenotypes at the population and single-cell level: a comparison of flow cytometry and raman spectroscopy fingerprinting. Cytometry A. 2020; 97(7): 713–26. https://doi.org/10.1002/cyto.a.23952</mixed-citation></ref><ref id="B28"><label>28.</label><mixed-citation>Ceuppens S., Boon N., Uyttendaele M. Diversity of Bacillus cereus group strains is reflected in their broad range of pathogenicity and diverse ecological lifestyles. FEMS Microbiol. Ecol. 2013; 84(3): 433–50. https://doi.org/10.1111/1574-6941.12110</mixed-citation></ref><ref id="B29"><label>29.</label><mixed-citation>Stewart M.K., Cummings L.A., Johnson M.L., Berezow A.B., Cookson B.T. Regulation of phenotypic heterogeneity permits Salmonella evasion of the host caspase-1 inflammatory response. Proc. Natl. Acad. Sci. USA. 2011; 108(51): 20742–7. https://doi.org/10.1073/pnas.1108963108</mixed-citation></ref><ref id="B30"><label>30.</label><mixed-citation>Heins A.L., Weuster-Botz D. Population heterogeneity in microbial bioprocesses: origin, analysis, mechanisms, and future perspectives. Bioprocess. Biosyst. Eng. 2018; 41(7): 889–16. https://doi.org/10.1007/s00449-018-1922-3</mixed-citation></ref><ref id="B31"><label>31.</label><mixed-citation>Xie X.S., Choi P.J., Li G.W., Lee N.K., Lia G. Single-molecule approach to molecular biology in living bacterial cells. Annu. Rev. Biophys. 2008; 37: 417–44. https://doi.org/10.1146/annurev.biophys.37.092607.174640</mixed-citation></ref><ref id="B32"><label>32.</label><mixed-citation>Hinterdorfer P., Garcia-Parajo M.F., Dufrêne Y.F. Single-molecule imaging of cell surfaces using near-field nanoscopy. Acc. Chem. Res. 2012; 45(3): 327–36. https://doi.org/10.1021/ar2001167</mixed-citation></ref><ref id="B33"><label>33.</label><mixed-citation>Skinner S.O., Sepúlveda L.A., Xu H., Golding I. Measuring mRNA copy number in individual Escherichia coli cells using single-molecule fluorescent in situ hybridization. Nat. Protoc. 2013; 8(6): 1100–13. https://doi.org/10.1038/nprot.2013.066</mixed-citation></ref><ref id="B34"><label>34.</label><mixed-citation>Manina G., Dhar N., McKinney J.D. Stress and host immunity amplify Мycobacterium tuberculosis phenotypic heterogeneity and induce nongrowing metabolically active forms. Cell. Host. Microbe. 2015; 17(1): 32–46. https://doi.org/10.1016/j.chom.2014.11.016</mixed-citation></ref><ref id="B35"><label>35.</label><mixed-citation>Arbel-Goren R., Shapira Y., Stavans J. Method for labeling transcripts in individual Escherichia coli cells for single-molecule fluorescence in situ hybridization experiments. J. Vis. Exp. 2017; (130): 56600. https://doi.org/10.3791/56600</mixed-citation></ref><ref id="B36"><label>36.</label><mixed-citation>Read D.S., Woodcock D.J., Strachan N.J.C., Forbes K.J., Colles F.M., Maiden M.C.J., et al. Evidence for phenotypic plasticity among multihost Campylobacter jejuni and C. coli lineages, obtained using ribosomal multilocus sequence typing and Raman spectroscopy. Appl. Environ. Microbiol. 2013; 79(3): 965–73. https://doi.org/10.1128/AEM.02521-12</mixed-citation></ref><ref id="B37"><label>37.</label><mixed-citation>van de Vossenberg J., Tervahauta H., Maquelin K., Blokker-Koopmans C.H.W., Uytewaal-Aarts M., van der Kooij D., et al. Identification of bacteria in drinking water with Raman. Anal. Methods. 2013; 5(11): 2679–87. https://doi.org/10.1039/c3ay40289d</mixed-citation></ref><ref id="B38"><label>38.</label><mixed-citation>Davey H.M. Prospects for the automation of analysis and interpretation of flow cytometric data. Cytometry A. 2010; 77(1): 3–5. https://doi.org/10.1002/cyto.a.20835</mixed-citation></ref><ref id="B39"><label>39.</label><mixed-citation>Davey H.M. Flow cytometric techniques for the detection of microorganisms. Methods. Cell. Sci. 2002; 24(1-3): 91–7. https://doi.org/10.1023/A:1024106317540</mixed-citation></ref><ref id="B40"><label>40.</label><mixed-citation>Андрюков Б.Г., Карпенко А.А., Матосова Е.В., Ляпун И.Н. Рамановская спектроскопия — современная диагностическая технология для изучения и индикации возбудителей инфекций (обзор). Современные технологии в медицине. 2019; 11(4): 161–74. http://doi.org/10.17691/stm2019.11.4.19</mixed-citation></ref><ref id="B41"><label>41.</label><mixed-citation>Wharfe E.S., Jarvis R.M., Winder C.L., Whiteley A.S., Goodacre R. Fourier transform infrared spectroscopy as a metabolite fingerprinting tool for monitoring the phenotypic changes in complex bacterial communities capable of degrading phenol. Environ. Microbiol. 2010; 12(12): 3253–63. https://doi.org/10.1111/j.1462-2920.2010.02300.x</mixed-citation></ref><ref id="B42"><label>42.</label><mixed-citation>Shukla S., Bajpai V.K. Visual demonstration of transmission electron microscopy for intracellular observation of a single bacterial cell. Bangladesh J. Pharmacol. 2017; 12(1): 23–7. https://doi.org/10.3329/bjp.v12i1.31390</mixed-citation></ref><ref id="B43"><label>43.</label><mixed-citation>Syal K., Wang W., Shan X., Wang S., Chen H.Y., Tao N. Plasmonic imaging of protein interactions with single bacterial cells. Biosens. Bioelectron. 2015; 63: 131–7. https://doi.org/10.1016/j.bios.2014.06.069</mixed-citation></ref><ref id="B44"><label>44.</label><mixed-citation>Peterson A.W., Halter M., Tona A., Plant A.L., Elliott J.T. Mass measurements of focal adhesions in single cells using high resolution surface plasmon resonance microscopy. Proc. SPIE Int. Soc. Opt. Eng. 2018; 10509: 1050905. https://doi.org/10.1117/12.2290776</mixed-citation></ref><ref id="B45"><label>45.</label><mixed-citation>Righi V., Constantinou C., Kesarwani M., Rahme L.G., Tzika A.A. Effects of a small, volatile bacterial molecule on Pseudomonas aeruginosa bacteria using whole cell high-resolution magic angle spinning nuclear magnetic resonance spectroscopy and genomics. Int. J. Mol. Med. 2018; 42(4): 2129–36. https://doi.org/10.3892/ijmm.2018.3760</mixed-citation></ref><ref id="B46"><label>46.</label><mixed-citation>Zhou X.L., Yang Y., Wang S., Liu X.W. Surface plasmon resonance microscopy: from single molecule sensing to single cell imaging. Angew. Chem. Int. Ed. Engl. 2020; 59(5): 1776–85. https://doi.org/10.1002/anie.201908806</mixed-citation></ref><ref id="B47"><label>47.</label><mixed-citation>Elowitz M.B., Levine A.J., Siggia E.D., Swain P.S. Stochastic gene expression in a single cell. Science. 2002; 297(5584): 1183–6. https://doi.org/10.1126/science.1070919</mixed-citation></ref><ref id="B48"><label>48.</label><mixed-citation>Liu Y., Singh A.K. Microfluidic platforms for single cell protein analysis. J. Lab. Autom. 2013; 18(6): 446–54. https://doi.org/10.1177/22110-68213-494389</mixed-citation></ref><ref id="B49"><label>49.</label><mixed-citation>Cho S., Cho Y., Lee S., Kim J., Yum H., Kim S.C., et al. Current challenges in bacterial transcriptomics. Genomics. Inform. 2013; 11(2): 76–82. https://doi.org/10.5808/GI.2013.11.2.76</mixed-citation></ref><ref id="B50"><label>50.</label><mixed-citation>Shahrezaei V., Marguerat S. Connecting growth with gene expression: of noise and numbers. Curr. Opin. Microbiol. 2015; 25: 127–35. https://doi.org/10.1016/j.mib.2015.05.012</mixed-citation></ref><ref id="B51"><label>51.</label><mixed-citation>Schröter L., Dersch P. Phenotypic diversification of microbial pathogens ‒ cooperating and preparing for the future. J. Mol. Biol. 2019; 431(23): 4645–55. https://doi.org/10.1016/j.jmb.2019.06.024</mixed-citation></ref><ref id="B52"><label>52.</label><mixed-citation>Weigel W.A., Dersch P. Phenotypic heterogeneity: a bacterial virulence strategy. Microbes Infect. 2018; 20(9-10): 570–7. https://doi.org/10.1016/j.micinf.2018.01.008</mixed-citation></ref><ref id="B53"><label>53.</label><mixed-citation>Mortier J., Tadesse W., Govers S.K., Aertsen A. Stress-induced protein aggregates shape population heterogeneity in bacteria. Curr. Genet. 2019; 65(4): 865–9. https://doi.org/10.1007/s00294-019-00947-1</mixed-citation></ref><ref id="B54"><label>54.</label><mixed-citation>Henry T.C., Brynildsen M.P. Development of Persister-FACSeq: a method to massively parallelize quantification of persister physiology and its heterogeneity. Sci. Rep. 2016; 6: 25100. https://doi.org/10.1038/srep25100</mixed-citation></ref><ref id="B55"><label>55.</label><mixed-citation>Binder D., Drepper T., Jaeger K.E., Delvigne F., Wiechert W., Kohlheyer D., et al. Homogenizing bacterial cell factories: analysis and engineering of phenotypic heterogeneity. Metab. Eng. 2017; 42: 145–56. https://doi.org/10.1016/j.ymben.2017.06.009</mixed-citation></ref></ref-list></back></article>
