{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T19:24:01Z","timestamp":1782761041140,"version":"3.54.5"},"reference-count":49,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2018,1,15]],"date-time":"2018-01-15T00:00:00Z","timestamp":1515974400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003246","name":"Nederlandse Organisatie voor Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["2013DFG32630"],"award-info":[{"award-number":["2013DFG32630"]}],"id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Microbial Biotechnology"],"published-print":{"date-parts":[[2018,5]]},"abstract":"<jats:title>Summary<\/jats:title>\n                  <jats:p>\n                    In a 54\u00a0m\n                    <jats:sup>3<\/jats:sup>\n                    large\u2010scale penicillin fermentor, the cells experience substrate gradient cycles at the timescales of global mixing time about 20\u201340\u00a0s. Here, we used an intermittent feeding regime (\n                    <jats:styled-content style=\"fixed-case\">IFR<\/jats:styled-content>\n                    ) and a two\u2010compartment reactor (\n                    <jats:styled-content style=\"fixed-case\">TCR<\/jats:styled-content>\n                    ) to mimic these substrate gradients at laboratory\u2010scale continuous cultures. The\n                    <jats:styled-content style=\"fixed-case\">IFR<\/jats:styled-content>\n                    was applied to simulate substrate dynamics experienced by the cells at full scale at timescales of tens of seconds to minutes (30\u00a0s, 3\u00a0min and 6\u00a0min), while the\n                    <jats:styled-content style=\"fixed-case\">TCR<\/jats:styled-content>\n                    was designed to simulate substrate gradients at an applied mean residence time (\n                    <jats:inline-graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"graphic\/mbt213046-math-0001.png\" xlink:title=\"urn:x-wiley:17517915:media:mbt213046:mbt213046-math-0001\"\/>\n                    ) of 6\u00a0min. A biological systems analysis of the response of an industrial high\u2010yielding\n                    <jats:italic>P.\u00a0chrysogenum<\/jats:italic>\n                    strain has been performed in these continuous cultures. Compared to an undisturbed continuous feeding regime in a single reactor, the penicillin productivity (q\n                    <jats:sub>PenG<\/jats:sub>\n                    ) was reduced in all scale\u2010down simulators. The dynamic metabolomics data indicated that in the\n                    <jats:styled-content style=\"fixed-case\">IFR<\/jats:styled-content>\n                    s, the cells accumulated high levels of the central metabolites during the feast phase to actively cope with external substrate deprivation during the famine phase. In contrast, in the\n                    <jats:styled-content style=\"fixed-case\">TCR<\/jats:styled-content>\n                    system, the storage pool (e.g. mannitol and arabitol) constituted a large contribution of carbon supply in the non\u2010feed compartment. Further, transcript analysis revealed that all scale\u2010down simulators gave different expression levels of the glucose\/hexose transporter genes and the penicillin gene clusters. The results showed that q\n                    <jats:sub>PenG<\/jats:sub>\n                    did not correlate well with exposure to the substrate regimes (excess, limitation and starvation), but there was a clear inverse relation between q\n                    <jats:sub>PenG<\/jats:sub>\n                    and the intracellular glucose level.\n                  <\/jats:p>","DOI":"10.1111\/1751-7915.13046","type":"journal-article","created":{"date-parts":[[2018,1,15]],"date-time":"2018-01-15T04:51:14Z","timestamp":1515991874000},"page":"486-497","source":"Crossref","is-referenced-by-count":32,"title":["Comparative performance of different scale\u2010down simulators of substrate gradients in\n                    <i>Penicillium chrysogenum<\/i>\n                    cultures: the need of a biological systems response analysis"],"prefix":"10.1111","volume":"11","author":[{"given":"Guan","family":"Wang","sequence":"first","affiliation":[{"name":"State key laboratory of Bioreactor Engineering East China University of Science and Technology (ECUST) Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junfei","family":"Zhao","sequence":"additional","affiliation":[{"name":"State key laboratory of Bioreactor Engineering East China University of Science and Technology (ECUST) Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cees","family":"Haringa","sequence":"additional","affiliation":[{"name":"Transport Phenomena Chemical Engineering Department Delft University of Technology Delft The\u00a0Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjun","family":"Tang","sequence":"additional","affiliation":[{"name":"State key laboratory of Bioreactor Engineering East China University of Science and Technology (ECUST) Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianye","family":"Xia","sequence":"additional","affiliation":[{"name":"State key laboratory of Bioreactor Engineering East China University of Science and Technology (ECUST) Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ju","family":"Chu","sequence":"additional","affiliation":[{"name":"State key laboratory of Bioreactor Engineering East China University of Science and Technology (ECUST) Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingping","family":"Zhuang","sequence":"additional","affiliation":[{"name":"State key laboratory of Bioreactor Engineering East China University of Science and Technology (ECUST) Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siliang","family":"Zhang","sequence":"additional","affiliation":[{"name":"State key laboratory of Bioreactor Engineering East China University of Science and Technology (ECUST) Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amit 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