{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T04:24:23Z","timestamp":1793075063565,"version":"4.5.0"},"reference-count":22,"publisher":"American Society for Microbiology","issue":"8","license":[{"start":{"date-parts":[[2015,7,16]],"date-time":"2015-07-16T00:00:00Z","timestamp":1437004800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/3.0\/"},{"start":{"date-parts":[[2015,8,1]],"date-time":"2015-08-01T00:00:00Z","timestamp":1438387200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2015,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            The echinocandin antifungal drug caspofungin at high concentrations reverses the growth inhibition of\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Aspergillus fumigatus<\/jats:named-content>\n            , a phenomenon known as the \u201cparadoxical effect,\u201d which is not consistently observed with other echinocandins (micafungin and anidulafungin). Previous studies of\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">A. fumigatus<\/jats:named-content>\n            revealed the loss of the paradoxical effect following pharmacological or genetic inhibition of calcineurin, yet the underlying mechanism is poorly understood. Here, we utilized a codon-optimized bioluminescent Ca\n            <jats:sup>2+<\/jats:sup>\n            reporter aequorin expression system in\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">A. fumigatus<\/jats:named-content>\n            and showed that caspofungin elicits a transient increase in cytosolic free Ca\n            <jats:sup>2+<\/jats:sup>\n            ([Ca\n            <jats:sup>2+<\/jats:sup>\n            ]\n            <jats:sub>c<\/jats:sub>\n            ) in the fungus that acts as the initial trigger of the paradoxical effect by activating calmodulin-calcineurin signaling. While the increase in [Ca\n            <jats:sup>2+<\/jats:sup>\n            ]\n            <jats:sub>c<\/jats:sub>\n            was also observed upon treatment with micafungin, another echinocandin without the paradoxical effect, a higher [Ca\n            <jats:sup>2+<\/jats:sup>\n            ]\n            <jats:sub>c<\/jats:sub>\n            increase was noted with the paradoxical-growth concentration of caspofungin. Treatments with a Ca\n            <jats:sup>2+<\/jats:sup>\n            -selective chelator, BAPTA [1,2-bis(\n            <jats:italic>o<\/jats:italic>\n            -aminophenoxy)ethane-\n            <jats:italic>N<\/jats:italic>\n            ,\n            <jats:italic>N<\/jats:italic>\n            ,\n            <jats:italic>N<\/jats:italic>\n            \u2032,\n            <jats:italic>N<\/jats:italic>\n            \u2032-tetraacetic acid], or the L-type Ca\n            <jats:sup>2+<\/jats:sup>\n            channel blocker verapamil abolished caspofungin-mediated paradoxical growth in both the wild-type and the echinocandin-resistant (EMFR-S678P) strains. Concomitant with increased [Ca\n            <jats:sup>2+<\/jats:sup>\n            ]\n            <jats:sub>c<\/jats:sub>\n            levels at higher concentrations of caspofungin, calmodulin and calcineurin gene expression was enhanced. Phosphoproteomic analysis revealed that calcineurin is activated through phosphorylation at its serine-proline-rich region (SPRR), a domain previously shown to be essential for regulation of hyphal growth, only at a paradoxical-growth concentration of caspofungin. Our results indicate that as opposed to micafungin, the increased [Ca\n            <jats:sup>2+<\/jats:sup>\n            ]\n            <jats:sub>c<\/jats:sub>\n            at high concentrations of caspofungin activates calmodulin-calcineurin signaling at both a transcriptional and a posttranslational level and ultimately leads to paradoxical fungal growth.\n          <\/jats:p>","DOI":"10.1128\/aac.00263-15","type":"journal-article","created":{"date-parts":[[2015,6,10]],"date-time":"2015-06-10T19:10:15Z","timestamp":1433963415000},"page":"4946-4955","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":48,"title":["Calcium-Mediated Induction of Paradoxical Growth following Caspofungin Treatment Is Associated with Calcineurin Activation and Phosphorylation in Aspergillus fumigatus"],"prefix":"10.1128","volume":"59","author":[{"given":"Praveen R.","family":"Juvvadi","sequence":"first","affiliation":[{"name":"Division of Pediatric Infectious Diseases, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Mu\u00f1oz","sequence":"additional","affiliation":[{"name":"Manchester Fungal Infection Group, Institute of Inflammation and Repair, University of Manchester, Manchester, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fr\u00e9d\u00e9ric","family":"Lamoth","sequence":"additional","affiliation":[{"name":"Division of Pediatric Infectious Diseases, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA"},{"name":"Infectious Diseases Service, Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland"},{"name":"Institute of Microbiology, Lausanne University Hospital, Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik J.","family":"Soderblom","sequence":"additional","affiliation":[{"name":"Duke Proteomics Facility, Institute for Genome Sciences and Policy, Duke University, Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Arthur","family":"Moseley","sequence":"additional","affiliation":[{"name":"Duke Proteomics Facility, Institute for Genome Sciences and Policy, Duke University, Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nick D.","family":"Read","sequence":"additional","affiliation":[{"name":"Manchester Fungal Infection Group, Institute of Inflammation and Repair, University of Manchester, Manchester, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William J.","family":"Steinbach","sequence":"additional","affiliation":[{"name":"Division of Pediatric Infectious Diseases, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA"},{"name":"Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1086\/525258"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.48.9.3407-3411.2004"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01154-08"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00563-06"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00854-09"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.15.1.707"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.13.7.798"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1111\/mmi.12294"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature07292"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1111\/mmi.12634"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1006\/meth.2001.1262"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2013.01.020"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00917-07"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1104\/pp.104.040873"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1099\/mic.0.2008\/021089-0"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1128\/EC.00050-10"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1003564"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2004.04066.x"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/0014-2999(82)90315-6"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0167-4889(97)00021-9"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.fgb.2012.07.007"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2012.08091.x"}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.00263-15","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.00263-15","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,21]],"date-time":"2022-02-21T23:06:10Z","timestamp":1645484770000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/AAC.00263-15"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,8]]},"references-count":22,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2015,8]]}},"alternative-id":["10.1128\/AAC.00263-15"],"URL":"https:\/\/doi.org\/10.1128\/aac.00263-15","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,8]]},"assertion":[{"value":"2015-02-02","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2015-06-01","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2015-07-16","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}