tag:blogger.com,1999:blog-371841002024-02-18T05:50:11.298-08:00The Toxoplasma BlogUp to date information and news regarding the protozoan parasite <i>Toxoplasma gondii</i>Unknownnoreply@blogger.comBlogger2632125tag:blogger.com,1999:blog-37184100.post-32698116188645166542017-09-27T10:59:00.003-07:002017-09-27T10:59:46.694-07:00Translational Control in the Latency of Apicomplexan Parasites<div class="cit">
<span role="menubar"><a abstractlink="yes" alsec="jour" alterm="Trends Parasitol." aria-expanded="false" aria-haspopup="true" href="https://www.ncbi.nlm.nih.gov/pubmed/28942109?dopt=Abstract#" role="menuitem" title="Trends in parasitology.">Trends Parasitol.</a></span> 2017 Sep 20. pii: S1471-4922(17)30211-8. doi: 10.1016/j.pt.2017.08.006. [Epub ahead of print]</div>
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<a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Holmes%20MJ%5BAuthor%5D&cauthor=true&cauthor_uid=28942109">Holmes MJ</a><sup>1</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Augusto%20LDS%5BAuthor%5D&cauthor=true&cauthor_uid=28942109">Augusto LDS</a><sup>1</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Zhang%20M%5BAuthor%5D&cauthor=true&cauthor_uid=28942109">Zhang M</a><sup>2</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Wek%20RC%5BAuthor%5D&cauthor=true&cauthor_uid=28942109">Wek RC</a><sup>3</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Sullivan%20WJ%20Jr%5BAuthor%5D&cauthor=true&cauthor_uid=28942109">Sullivan WJ Jr</a><sup>4</sup>.</div>
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<abstracttext>Apicomplexan parasites Toxoplasma gondii and Plasmodium spp. use latent stages to persist in the host, facilitate transmission, and thwart treatment of infected patients. Therefore, it is important to understand the processes driving parasite differentiation to and from quiescent stages. Here, we discuss how a family of protein kinases that phosphorylate the eukaryotic initiation factor-2 (eIF2) function in translational control and drive differentiation. This translational control culminates in reprogramming of the transcriptome to facilitate parasite transition towards latency. We also discuss how eIF2 phosphorylation contributes to the maintenance of latency and provides a crucial role in the timing of reactivation of latent parasites towards proliferative stages.</abstracttext><br />
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Copyright © 2017 Elsevier Ltd. All rights reserved.</div>
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KEYWORDS: </h4>
Plasmodium; Toxoplasma; eIF2; latency; translational control</div>
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<dd>28942109</dd>
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<dd><a href="https://doi.org/10.1016/j.pt.2017.08.006" ref="aid_type=doi">10.1016/j.pt.2017.08.006</a></dd> </dl>
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Unknownnoreply@blogger.com4tag:blogger.com,1999:blog-37184100.post-56650346726449583092017-09-27T10:59:00.001-07:002017-09-27T10:59:20.815-07:00Apicomplexan actin polymerization depends on nucleation<div class="cit">
<span role="menubar"><a abstractlink="yes" alsec="jour" alterm="Sci Rep." aria-expanded="false" aria-haspopup="true" href="https://www.ncbi.nlm.nih.gov/pubmed/28939886?dopt=Abstract#" role="menuitem" title="Scientific reports.">Sci Rep.</a></span> 2017 Sep 22;7(1):12137. doi: 10.1038/s41598-017-11330-w.</div>
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<a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Kumpula%20EP%5BAuthor%5D&cauthor=true&cauthor_uid=28939886">Kumpula EP</a><sup>1</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Pires%20I%5BAuthor%5D&cauthor=true&cauthor_uid=28939886">Pires I</a><sup>1</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Lasiwa%20D%5BAuthor%5D&cauthor=true&cauthor_uid=28939886">Lasiwa D</a><sup>1</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Piirainen%20H%5BAuthor%5D&cauthor=true&cauthor_uid=28939886">Piirainen H</a><sup>1</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Bergmann%20U%5BAuthor%5D&cauthor=true&cauthor_uid=28939886">Bergmann U</a><sup>1</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Vahokoski%20J%5BAuthor%5D&cauthor=true&cauthor_uid=28939886">Vahokoski J</a><sup>1,</sup><sup>2</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Kursula%20I%5BAuthor%5D&cauthor=true&cauthor_uid=28939886">Kursula I</a><sup>3,</sup><sup>4</sup>.</div>
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<abstracttext>Filamentous actin is critical for apicomplexan motility and host cell invasion. Yet, parasite actin filaments are short and unstable. Their kinetic characterization has been hampered by the lack of robust quantitative methods. Using a modified labeling method, we carried out thorough biochemical characterization of malaria parasite actin. In contrast to the isodesmic polymerization mechanism suggested for Toxoplasma gondii actin, Plasmodium falciparum actin I polymerizes via the classical nucleation-elongation pathway, with kinetics similar to canonical actins. A high fragmentation rate, governed by weak lateral contacts within the filament, is likely the main reason for the short filament length. At steady state, Plasmodium actin is present in equal amounts of short filaments and dimers, with a small proportion of monomers, representing the apparent critical concentration of ~0.1 µM. The dimers polymerize but do not serve as nuclei. Our work enhances understanding of actin evolution and the mechanistic details of parasite motility, serving as a basis for exploring parasite actin and actin nucleators as drug targets against malaria and other apicomplexan parasitic diseases.</abstracttext></div>
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<dd>28939886</dd>
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<dd><a href="https://doi.org/10.1038/s41598-017-11330-w" ref="aid_type=doi">10.1038/s41598-017-11330-w</a></dd> </dl>
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Unknownnoreply@blogger.com0tag:blogger.com,1999:blog-37184100.post-50053171122423409192017-09-22T10:44:00.001-07:002017-09-22T10:44:01.210-07:00Inhibition of calcium dependent protein kinase 1 (CDPK1) by pyrazolopyrimidine analogs decreases establishment and reoccurrence of central nervous system disease by Toxoplasma gondii<div class="cit">
<span role="menubar"><a abstractlink="yes" alsec="jour" alterm="J Med Chem." aria-expanded="false" aria-haspopup="true" href="https://www.ncbi.nlm.nih.gov/pubmed/28933846?dopt=Abstract#" role="menuitem" title="Journal of medicinal chemistry.">J Med Chem.</a></span> 2017 Sep 21. doi: 10.1021/acs.jmedchem.7b01192. [Epub ahead of print]</div>
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<a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Rutaganira%20FU%5BAuthor%5D&cauthor=true&cauthor_uid=28933846">Rutaganira FU</a>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Barks%20J%5BAuthor%5D&cauthor=true&cauthor_uid=28933846">Barks J</a>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Dhason%20MS%5BAuthor%5D&cauthor=true&cauthor_uid=28933846">Dhason MS</a>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Wang%20Q%5BAuthor%5D&cauthor=true&cauthor_uid=28933846">Wang Q</a>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Lopez%20MS%5BAuthor%5D&cauthor=true&cauthor_uid=28933846">Lopez MS</a>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Long%20S%5BAuthor%5D&cauthor=true&cauthor_uid=28933846">Long S</a>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Radke%20JB%5BAuthor%5D&cauthor=true&cauthor_uid=28933846">Radke JB</a>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Jones%20NG%5BAuthor%5D&cauthor=true&cauthor_uid=28933846">Jones NG</a>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Maddirala%20AR%5BAuthor%5D&cauthor=true&cauthor_uid=28933846">Maddirala AR</a>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Janetka%20JW%5BAuthor%5D&cauthor=true&cauthor_uid=28933846">Janetka JW</a>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=El%20Bakkouri%20M%5BAuthor%5D&cauthor=true&cauthor_uid=28933846">El Bakkouri M</a>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Hui%20R%5BAuthor%5D&cauthor=true&cauthor_uid=28933846">Hui R</a>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Shokat%20KM%5BAuthor%5D&cauthor=true&cauthor_uid=28933846">Shokat KM</a>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Sibley%20LD%5BAuthor%5D&cauthor=true&cauthor_uid=28933846">Sibley LD</a>.</div>
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Abstract</h3>
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<abstracttext>Calcium dependent protein kinase 1 (CDPK1) is an essential enzyme in the opportunistic pathogen Toxoplasma gondii. CDPK1 controls multiple processes that are essential to the intracellular replicative cycle of T. gondii including secretion of adhesins, motility, invasion, and egress. Remarkably, CDPK1 contains a small glycine gatekeeper residue in the ATP binding pocket making it sensitive to ATP-competitive inhibitors with bulky substituents that complement this expanded binding pocket. Here we explored structure-activity relationships of a series of pyrazolopyrimidine inhibitors of CDPK1 with the goals of increasing selectivity over host enzymes, improving anti-parasite potency, and improving metabolic stability. The resulting lead compound 24 exhibits excellent enzyme inhibition and selectivity for CDPK1 and potently inhibited parasite growth in vitro. Compound 24 was also effective at treating acute toxoplasmosis in the mouse, reducing dissemination to the central nervous system, decreasing reactivation of chronic infection in severely immunocompromised mice. These findings provide proof of concept for the development of small molecule inhibitors of CDPK1 for treatment of CNS toxoplasmosis.</abstracttext></div>
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<dt>PMID:</dt>
<dd>28933846</dd>
<dt>DOI:</dt>
<dd><a href="https://doi.org/10.1021/acs.jmedchem.7b01192" ref="aid_type=doi">10.1021/acs.jmedchem.7b01192</a></dd> </dl>
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Unknownnoreply@blogger.com3tag:blogger.com,1999:blog-37184100.post-47940496172720664962017-09-21T08:44:00.001-07:002017-09-21T08:44:42.869-07:00Characterization of a cytoplasmic glucosyltransferase that extends the core trisaccharide of the Toxoplasma Skp1 E3 ubiquitin ligase subunit<div class="cit">
<span role="menubar"><a abstractlink="yes" alsec="jour" alterm="J Biol Chem." aria-expanded="false" aria-haspopup="true" href="https://www.ncbi.nlm.nih.gov/pubmed/28928220?dopt=Abstract#" role="menuitem" title="The Journal of biological chemistry.">J Biol Chem.</a></span> 2017 Sep 19. pii: jbc.M117.809301. doi: 10.1074/jbc.M117.809301. [Epub ahead of print]</div>
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<a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Rahman%20K%5BAuthor%5D&cauthor=true&cauthor_uid=28928220">Rahman K</a><sup>1</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Mandalasi%20M%5BAuthor%5D&cauthor=true&cauthor_uid=28928220">Mandalasi M</a><sup>1</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Zhao%20P%5BAuthor%5D&cauthor=true&cauthor_uid=28928220">Zhao P</a><sup>1</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Sheikh%20MO%5BAuthor%5D&cauthor=true&cauthor_uid=28928220">Sheikh MO</a><sup>1</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Taujale%20R%5BAuthor%5D&cauthor=true&cauthor_uid=28928220">Taujale R</a><sup>1</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Kim%20HW%5BAuthor%5D&cauthor=true&cauthor_uid=28928220">Kim HW</a><sup>1</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=van%20der%20Wel%20H%5BAuthor%5D&cauthor=true&cauthor_uid=28928220">van der Wel H</a><sup>1</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Matta%20K%5BAuthor%5D&cauthor=true&cauthor_uid=28928220">Matta K</a><sup>2</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Kannan%20N%5BAuthor%5D&cauthor=true&cauthor_uid=28928220">Kannan N</a><sup>1</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Glushka%20JN%5BAuthor%5D&cauthor=true&cauthor_uid=28928220">Glushka JN</a><sup>1</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Wells%20L%5BAuthor%5D&cauthor=true&cauthor_uid=28928220">Wells L</a><sup>1</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=West%20CM%5BAuthor%5D&cauthor=true&cauthor_uid=28928220">West CM</a><sup>3</sup>.</div>
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<abstracttext>Skp1 is a subunit of the SCF (Skp1/Cullin-1/F-box protein) class of E3 ubiquitin ligases that are important for eukaryotic protein degradation. Unlike its animal counterparts, Skp1 from Toxoplasma gondii is hydroxylated by an O2-dependent prolyl-4-hydroxylase (PhyA), and the resulting hydroxyproline can subsequently be modified by a five-sugar chain. A similar modification is found in the social amoeba Dictyostelium, where it regulates SCF assembly and O2-dependent development. Homologous glycosyltransferases assemble a similar core trisaccharide in both organisms, and a bifunctional α-galactosyltransferase from CAZy family GT77 mediates addition of the final two sugars in Dictyostelium, generating Galα1,3Galα1,3Fucα1,2Galβ1,3GlcNAcα1-. Here, we found that Toxoplasma utilizes a cytoplasmic glycosyltransferase from an ancient clade of CAZy family GT32 to catalyze transfer of the fourth sugar. Catalytically active Glt1 was required for addition of the terminal disaccharide in cells, and cytosolic extracts catalyzed transfer of [3H]glucose from UDP-[3H]glucose to the trisaccharide form of Skp1 in a glt1-dependent fashion. Recombinant Glt1 catalyzed the same reaction, confirming that it directly mediates Skp1 glucosylation, and NMR demonstrated formation of a Glcα1,3Fuc linkage. Recombinant Glt1 strongly preferred the full core trisaccharide attached to Skp1, and labeled only Skp1 in glt1Δ extracts, suggesting specificity for Skp1. glt1-knockout parasites exhibited a growth defect not rescued by catalytically inactive Glt1, indicating that the glycan acts in concert with the first enzyme in the pathway, PhyA, in cells. A genomic bioinformatics survey suggested that Glt1 belongs to the ancestral Skp1 glycosylation pathway in protists and evolved separately from related Golgi-resident GT32 glycosyltransferases.</abstracttext><br />
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Copyright © 2017, The American Society for Biochemistry and Molecular Biology.</div>
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KEYWORDS: </h4>
E3 ubiquitin ligase; Toxoplasma gondii; carbohydrate structure; cytoplasmic glycosylation; evolution; glycobiology; glycosyltransferase; mass spectrometry (MS)</div>
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<dd>28928220</dd>
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<dd><a href="https://doi.org/10.1074/jbc.M117.809301" ref="aid_type=doi">10.1074/jbc.M117.809301</a></dd> </dl>
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Unknownnoreply@blogger.com2tag:blogger.com,1999:blog-37184100.post-37469536138941751512017-09-15T05:06:00.003-07:002017-09-15T05:06:56.919-07:00NLRP3 and Potassium Efflux Drive Rapid IL-1β Release from Primary Human Monocytes during Toxoplasma gondii Infection<div class="cit">
<span role="menubar"><a abstractlink="yes" alsec="jour" alterm="J Immunol." aria-expanded="false" aria-haspopup="true" href="https://www.ncbi.nlm.nih.gov/pubmed/28904126?dopt=Abstract#" role="menuitem" title="Journal of immunology (Baltimore, Md. : 1950).">J Immunol.</a></span> 2017 Sep 13. pii: ji1700245. doi: 10.4049/jimmunol.1700245. [Epub ahead of print]</div>
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<a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Gov%20L%5BAuthor%5D&cauthor=true&cauthor_uid=28904126">Gov L</a><sup>1</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Schneider%20CA%5BAuthor%5D&cauthor=true&cauthor_uid=28904126">Schneider CA</a><sup>1</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Lima%20TS%5BAuthor%5D&cauthor=true&cauthor_uid=28904126">Lima TS</a><sup>1</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Pandori%20W%5BAuthor%5D&cauthor=true&cauthor_uid=28904126">Pandori W</a><sup>1</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Lodoen%20MB%5BAuthor%5D&cauthor=true&cauthor_uid=28904126">Lodoen MB</a><sup>2</sup>.</div>
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<abstracttext>IL-1β is produced by myeloid cells and acts as a critical mediator of host defense during infection and injury. We found that the intracellular protozoan parasite <i>Toxoplasma gondii</i> induced an early IL-1β response (within 4 h) in primary human peripheral blood monocytes isolated from healthy donors. This process involved upregulation of <i>IL-1β</i>, <i>IL-1RN</i> (IL-1R antagonist), and <i>NLRP3</i> transcripts, de novo protein synthesis, and the release of pro- and mature IL-1β from infected primary monocytes. The released pro-IL-1β was cleavable to mature bioactive IL-1β in the extracellular space by the protease caspase-1. Treatment of primary monocytes with the NLRP3 inhibitor MCC950 or with extracellular potassium significantly reduced IL-1β cleavage and release in response to <i>T. gondii</i> infection, without affecting the release of TNF-α, and indicated a role for the inflammasome sensor NLRP3 and for potassium efflux in <i>T. gondii</i>-induced IL-1β production. Interestingly, <i>T. gondii</i> infection did not induce an IL-1β response in primary human macrophages derived from the same blood donors as the monocytes. Consistent with this finding, <i>NLRP3</i> was downregulated during the differentiation of monocytes to macrophages and was not induced in macrophages during <i>T. gondii</i> infection. To our knowledge, these findings are the first to identify NLRP3 as an inflammasome sensor for <i>T. gondii</i> in primary human peripheral blood cells and to define an upstream regulator of its activation through the release of intracellular potassium.</abstracttext><br />
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Copyright © 2017 by The American Association of Immunologists, Inc.</div>
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<dd>28904126</dd>
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<dd><a href="https://doi.org/10.4049/jimmunol.1700245" ref="aid_type=doi">10.4049/jimmunol.1700245</a></dd> </dl>
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Unknownnoreply@blogger.com0tag:blogger.com,1999:blog-37184100.post-34784157159239533372017-09-15T05:06:00.001-07:002017-09-15T05:06:29.472-07:00Toxoplasma Modulates Signature Pathways of Human Epilepsy, Neurodegeneration & Cancer<br />
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<span role="menubar"><a abstractlink="yes" alsec="jour" alterm="Sci Rep." aria-expanded="false" aria-haspopup="true" href="https://www.ncbi.nlm.nih.gov/pubmed/28904337?dopt=Abstract#" role="menuitem" title="Scientific reports.">Sci Rep.</a></span> 2017 Sep 13;7(1):11496. doi: 10.1038/s41598-017-10675-6.</div>
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<a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Ng%C3%B4%20HM%5BAuthor%5D&cauthor=true&cauthor_uid=28904337">Ngô HM</a><sup>1,</sup><sup>2,</sup><sup>3</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Zhou%20Y%5BAuthor%5D&cauthor=true&cauthor_uid=28904337">Zhou Y</a><sup>1</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Lorenzi%20H%5BAuthor%5D&cauthor=true&cauthor_uid=28904337">Lorenzi H</a><sup>4</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Wang%20K%5BAuthor%5D&cauthor=true&cauthor_uid=28904337">Wang K</a><sup>5</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Kim%20TK%5BAuthor%5D&cauthor=true&cauthor_uid=28904337">Kim TK</a><sup>5</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Zhou%20Y%5BAuthor%5D&cauthor=true&cauthor_uid=28904337">Zhou Y</a><sup>5</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Bissati%20KE%5BAuthor%5D&cauthor=true&cauthor_uid=28904337">Bissati KE</a><sup>1</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Mui%20E%5BAuthor%5D&cauthor=true&cauthor_uid=28904337">Mui E</a><sup>1</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Fraczek%20L%5BAuthor%5D&cauthor=true&cauthor_uid=28904337">Fraczek L</a><sup>1</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Rajagopala%20SV%5BAuthor%5D&cauthor=true&cauthor_uid=28904337">Rajagopala SV</a><sup>4</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Roberts%20CW%5BAuthor%5D&cauthor=true&cauthor_uid=28904337">Roberts CW</a><sup>6</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Henriquez%20FL%5BAuthor%5D&cauthor=true&cauthor_uid=28904337">Henriquez FL</a><sup>1,</sup><sup>7</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Montpetit%20A%5BAuthor%5D&cauthor=true&cauthor_uid=28904337">Montpetit A</a><sup>8</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Blackwell%20JM%5BAuthor%5D&cauthor=true&cauthor_uid=28904337">Blackwell JM</a><sup>9,</sup><sup>10</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Jamieson%20SE%5BAuthor%5D&cauthor=true&cauthor_uid=28904337">Jamieson SE</a><sup>10</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Wheeler%20K%5BAuthor%5D&cauthor=true&cauthor_uid=28904337">Wheeler K</a><sup>1</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Begeman%20IJ%5BAuthor%5D&cauthor=true&cauthor_uid=28904337">Begeman IJ</a><sup>1</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Naranjo-Galvis%20C%5BAuthor%5D&cauthor=true&cauthor_uid=28904337">Naranjo-Galvis C</a><sup>1</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Alliey-Rodriguez%20N%5BAuthor%5D&cauthor=true&cauthor_uid=28904337">Alliey-Rodriguez N</a><sup>1</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Davis%20RG%5BAuthor%5D&cauthor=true&cauthor_uid=28904337">Davis RG</a><sup>11</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Soroceanu%20L%5BAuthor%5D&cauthor=true&cauthor_uid=28904337">Soroceanu L</a><sup>12</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Cobbs%20C%5BAuthor%5D&cauthor=true&cauthor_uid=28904337">Cobbs C</a><sup>12</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Steindler%20DA%5BAuthor%5D&cauthor=true&cauthor_uid=28904337">Steindler DA</a><sup>13</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Boyer%20K%5BAuthor%5D&cauthor=true&cauthor_uid=28904337">Boyer K</a><sup>14</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Noble%20AG%5BAuthor%5D&cauthor=true&cauthor_uid=28904337">Noble AG</a><sup>2</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Swisher%20CN%5BAuthor%5D&cauthor=true&cauthor_uid=28904337">Swisher CN</a><sup>2</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Heydemann%20PT%5BAuthor%5D&cauthor=true&cauthor_uid=28904337">Heydemann PT</a><sup>14</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Rabiah%20P%5BAuthor%5D&cauthor=true&cauthor_uid=28904337">Rabiah P</a><sup>15</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Withers%20S%5BAuthor%5D&cauthor=true&cauthor_uid=28904337">Withers S</a><sup>1</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Soteropoulos%20P%5BAuthor%5D&cauthor=true&cauthor_uid=28904337">Soteropoulos P</a><sup>16</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Hood%20L%5BAuthor%5D&cauthor=true&cauthor_uid=28904337">Hood L</a><sup>5</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=McLeod%20R%5BAuthor%5D&cauthor=true&cauthor_uid=28904337">McLeod R</a><sup>17</sup>.</div>
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<div>
<abstracttext>One third of humans are infected lifelong with the brain-dwelling, protozoan parasite, Toxoplasma gondii. Approximately fifteen million of these have congenital toxoplasmosis. Although neurobehavioral disease is associated with seropositivity, causality is unproven. To better understand what this parasite does to human brains, we performed a comprehensive systems analysis of the infected brain: We identified susceptibility genes for congenital toxoplasmosis in our cohort of infected humans and found these genes are expressed in human brain. Transcriptomic and quantitative proteomic analyses of infected human, primary, neuronal stem and monocytic cells revealed effects on neurodevelopment and plasticity in neural, immune, and endocrine networks. These findings were supported by identification of protein and miRNA biomarkers in sera of ill children reflecting brain damage and T. gondii infection. These data were deconvoluted using three systems biology approaches: "Orbital-deconvolution" elucidated upstream, regulatory pathways interconnecting human susceptibility genes, biomarkers, proteomes, and transcriptomes. "Cluster-deconvolution" revealed visual protein-protein interaction clusters involved in processes affecting brain functions and circuitry, including lipid metabolism, leukocyte migration and olfaction. Finally, "disease-deconvolution" identified associations between the parasite-brain interactions and epilepsy, movement disorders, Alzheimer's disease, and cancer. This "reconstruction-deconvolution" logic provides templates of progenitor cells' potentiating effects, and components affecting human brain parasitism and diseases.</abstracttext></div>
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<dl class="rprtid">
<dt>PMID:</dt>
<dd>28904337</dd>
<dt>DOI:</dt>
<dd><a href="https://doi.org/10.1038/s41598-017-10675-6" ref="aid_type=doi">10.1038/s41598-017-10675-6</a></dd> </dl>
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Unknownnoreply@blogger.com0tag:blogger.com,1999:blog-37184100.post-29901419549480277682017-09-14T04:16:00.003-07:002017-09-14T04:16:44.029-07:00A druggable secretory protein maturase of Toxoplasma essential for invasion and egress<div class="cit" style="font-family: arial, helvetica, clean, sans-serif; font-size: 0.8465em; line-height: 1.45em;">
<span role="menubar"><a abstractlink="yes" alsec="jour" alterm="Elife." aria-expanded="false" aria-haspopup="true" href="https://www.ncbi.nlm.nih.gov/pubmed/28898199?dopt=Abstract#" role="menuitem" style="border-bottom-width: 0px; color: #660066;" title="eLife.">Elife.</a></span> 2017 Sep 12;6. pii: e27480. doi: 10.7554/eLife.27480.</div>
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<div class="auths" style="font-family: arial, helvetica, clean, sans-serif; font-size: 0.923em;">
<a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Dogga%20SK%5BAuthor%5D&cauthor=true&cauthor_uid=28898199" style="border-bottom-width: 0px; color: #660066;">Dogga SK</a><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">1</span>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Mukherjee%20B%5BAuthor%5D&cauthor=true&cauthor_uid=28898199" style="border-bottom-width: 0px; color: #660066;">Mukherjee B</a><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">1</span>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Jacot%20D%5BAuthor%5D&cauthor=true&cauthor_uid=28898199" style="border-bottom-width: 0px; color: #660066;">Jacot D</a><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">1</span>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Kockmann%20T%5BAuthor%5D&cauthor=true&cauthor_uid=28898199" style="border-bottom-width: 0px; color: #660066;">Kockmann T</a><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">2</span>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Molino%20L%5BAuthor%5D&cauthor=true&cauthor_uid=28898199" style="border-bottom-width: 0px; color: #660066;">Molino L</a><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">1</span>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Hammoudi%20PM%5BAuthor%5D&cauthor=true&cauthor_uid=28898199" style="border-bottom-width: 0px; color: #660066;">Hammoudi PM</a><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">1</span>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Hartkoorn%20RC%5BAuthor%5D&cauthor=true&cauthor_uid=28898199" style="border-bottom-width: 0px; color: #660066;">Hartkoorn RC</a><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">1,</span><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">3</span>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Hehl%20AB%5BAuthor%5D&cauthor=true&cauthor_uid=28898199" style="border-bottom-width: 0px; color: #660066;">Hehl AB</a><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">4</span>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Soldati-Favre%20D%5BAuthor%5D&cauthor=true&cauthor_uid=28898199" style="border-bottom-width: 0px; color: #660066;">Soldati-Favre D</a><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">1</span>.</div>
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<h3 style="color: #724128; font-size: 1.0769em; line-height: 1.2857; margin: 0.5em 0em; zoom: 1;">
<a aria-expanded="false" class="jig-ncbitoggler ui-widget ui-ncbitoggler" href="https://www.ncbi.nlm.nih.gov/pubmed/28898199?dopt=Abstract#" id="ui-ncbitoggler-2" role="button" style="border-bottom-width: 0px; color: #660066; display: block; font-family: arial, sans-serif !important; outline: none; padding-left: 16px; position: relative; text-decoration: none !important;" title="Open/close author information list"><span class="ui-ncbitoggler-master-text">Author information</span><span class="ui-icon ui-icon-triangle-1-e" style="background-attachment: scroll; background-image: url(https://static.pubmed.gov/portal/portal3rc.fcgi/4166260/img/3974597); background-position: 0px -21px; background-repeat: no-repeat no-repeat; border-bottom-left-radius: 3px; border-bottom-right-radius: 3px; border: none; display: inline; height: 16px; left: 0px; margin: 0px; overflow: hidden; padding: 0px; position: absolute; right: 0px; text-indent: -99999px; top: 0px; width: 16px;"></span></a></h3>
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Abstract</h3>
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<abstracttext>Micronemes and rhoptries are specialized secretory organelles that deploy their contents at the apical tip of apicomplexan parasites in a regulated manner. The secretory proteins participate in motility, invasion, and egress and are subjected to proteolytic maturation prior to organellar storage and discharge. Here we establish that <i>Toxoplasma gondii</i> aspartyl protease 3 (ASP3) resides in the endosomal-like compartment and is crucially associated to rhoptry discharge during invasion and to host cell plasma membrane lysis during egress. A comparison of the N-terminome, by terminal amine isotopic labelling of substrates between wild type and ASP3 depleted parasites identified microneme and rhoptry proteins as repertoire of ASP3 substrates. The role of ASP3 as a maturase for previously described and newly identified secretory proteins is confirmed <i>in vivo</i> and <i>in vitro</i>. An antimalarial compound based on a hydroxyethylamine scaffold interrupts the lytic cycle of <i>T. gondii</i> at submicromolar concentration by targeting ASP3.</abstracttext></div>
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KEYWORDS: </h4>
<div style="margin-bottom: 0.5em; margin-top: 0.5em;">
Apicomplexa; Toxoplasma gondii; aspartyl protease; infectious disease; invasion and egress; microbiology; micronemes and rhoptries; peptidomimetic inhibitor</div>
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<dl class="rprtid" style="display: inline; font-size: 0.8465em; line-height: 1.4em; margin: 0px 15px 0px 0px;">
<dt style="display: inline; margin-bottom: 0px; margin-left: 0px !important; margin-right: 0px; margin-top: 0px; padding: 0px; white-space: nowrap;">PMID:</dt>
<dd style="display: inline; margin: 0px; padding: 0px; white-space: nowrap;">28898199</dd>
<dt style="display: inline; margin-bottom: 0px; margin-left: 10px !important; margin-right: 0px; margin-top: 0px; padding: 0px; white-space: nowrap;">DOI:</dt>
<dd style="display: inline; margin: 0px; padding: 0px; white-space: nowrap;"><a href="https://doi.org/10.7554/eLife.27480" ref="aid_type=doi" style="border-bottom-width: 0px; color: #333333;">10.7554/eLife.27480</a></dd></dl>
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Unknownnoreply@blogger.com0tag:blogger.com,1999:blog-37184100.post-10698283397400343472017-09-14T04:16:00.000-07:002017-09-14T04:16:10.736-07:00Influence of indigenous microbiota on experimental toxoplasmosis in conventional and germ-free mice<div class="cit" style="font-family: arial, helvetica, clean, sans-serif; font-size: 0.8465em; line-height: 1.45em;">
<span role="menubar"><a abstractlink="yes" alsec="jour" alterm="Int J Exp Pathol." aria-expanded="false" aria-haspopup="true" href="https://www.ncbi.nlm.nih.gov/pubmed/28895246?dopt=Abstract#" role="menuitem" style="border-bottom-width: 0px; color: #660066;" title="International journal of experimental pathology.">Int J Exp Pathol.</a></span> 2017 Sep 11. doi: 10.1111/iep.12236. [Epub ahead of print]</div>
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<div class="auths" style="font-family: arial, helvetica, clean, sans-serif; font-size: 0.923em;">
<a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Nascimento%20BB%5BAuthor%5D&cauthor=true&cauthor_uid=28895246" style="border-bottom-width: 0px; color: #660066;">Nascimento BB</a><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">1</span>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Cartelle%20CT%5BAuthor%5D&cauthor=true&cauthor_uid=28895246" style="border-bottom-width: 0px; color: #660066;">Cartelle CT</a><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">1</span>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Noviello%20ML%5BAuthor%5D&cauthor=true&cauthor_uid=28895246" style="border-bottom-width: 0px; color: #660066;">Noviello ML</a><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">1</span>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Pinheiro%20BV%5BAuthor%5D&cauthor=true&cauthor_uid=28895246" style="border-bottom-width: 0px; color: #660066;">Pinheiro BV</a><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">2</span>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=de%20Almeida%20Vitor%20RW%5BAuthor%5D&cauthor=true&cauthor_uid=28895246" style="border-bottom-width: 0px; color: #660066;">de Almeida Vitor RW</a><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">2</span>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Souza%20DDG%5BAuthor%5D&cauthor=true&cauthor_uid=28895246" style="border-bottom-width: 0px; color: #660066;">Souza DDG</a><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">3</span>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=de%20Vasconcelos%20Generoso%20S%5BAuthor%5D&cauthor=true&cauthor_uid=28895246" style="border-bottom-width: 0px; color: #660066;">de Vasconcelos Generoso S</a><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">4</span>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Cardoso%20VN%5BAuthor%5D&cauthor=true&cauthor_uid=28895246" style="border-bottom-width: 0px; color: #660066;">Cardoso VN</a><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">4</span>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Martins%20FDS%5BAuthor%5D&cauthor=true&cauthor_uid=28895246" style="border-bottom-width: 0px; color: #660066;">Martins FDS</a><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">3</span>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Nicoli%20JR%5BAuthor%5D&cauthor=true&cauthor_uid=28895246" style="border-bottom-width: 0px; color: #660066;">Nicoli JR</a><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">3</span>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Arantes%20RME%5BAuthor%5D&cauthor=true&cauthor_uid=28895246" style="border-bottom-width: 0px; color: #660066;">Arantes RME</a><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">1</span>.</div>
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<a aria-expanded="false" class="jig-ncbitoggler ui-widget ui-ncbitoggler" href="https://www.ncbi.nlm.nih.gov/pubmed/28895246?dopt=Abstract#" id="ui-ncbitoggler-2" role="button" style="border-bottom-width: 0px; color: #660066; display: block; font-family: arial, sans-serif !important; outline: none; padding-left: 16px; position: relative; text-decoration: none !important;" title="Open/close author information list"><span class="ui-ncbitoggler-master-text">Author information</span><span class="ui-icon ui-icon-triangle-1-e" style="background-attachment: scroll; background-image: url(https://static.pubmed.gov/portal/portal3rc.fcgi/4166260/img/3974597); background-position: 0px -21px; background-repeat: no-repeat no-repeat; border-bottom-left-radius: 3px; border-bottom-right-radius: 3px; border: none; display: inline; height: 16px; left: 0px; margin: 0px; overflow: hidden; padding: 0px; position: absolute; right: 0px; text-indent: -99999px; top: 0px; width: 16px;"></span></a></h3>
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<h3 style="color: #985735; display: inline; font-size: 1.0769em; line-height: 1.2857; margin: 0px;">
Abstract</h3>
<div class="">
<div style="font-size: 1.04em; margin-bottom: 0.5em;">
<abstracttext>Toxoplasmosis represents one of the most common zoonosis worldwide. Its agent, Toxoplasma gondii, causes a severe innate pro-inflammatory response. The indigenous intestinal microbiota promotes host animal homoeostasis and may protect the host against pathogens. Germ-free (GF) animals provide an important tool for the study of interactions between host and microbiota. In this study, we assessed the role of indigenous microorganisms in disease development utilizing a murine toxoplasmosis model, which includes conventional (CV) and GF NIH Swiss mice. CV and GF mice orally inoculated with T. gondii had similar survival curves. However, disease developed differently in the two animal groups. In CV mice, intestinal permeability increased and levels of intestinal pro-inflammatory cytokines were altered. In GF animals, there were discrete epithelial degenerative changes and mucosal oedema, but the liver and lungs displayed significant lesions. We conclude that, despite similar survival curves, CV animals succumb to an exaggerated inflammatory response, whereas GF mice fail to produce an adequate systemic response.</abstracttext></div>
<div class="copyright" style="font-size: 0.93em; margin-bottom: 0.5em;">
© 2017 The Authors. International Journal of Experimental Pathology © 2017 International Journal of Experimental Pathology.</div>
</div>
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<div class="keywords" style="font-family: arial, helvetica, clean, sans-serif; font-size: 0.923em; margin: 1.8em auto auto;">
<h4 style="float: left; font-size: 1em; margin: 0px 0.35em 0px 0px; text-transform: uppercase;">
KEYWORDS: </h4>
<div style="margin-bottom: 0.5em; margin-top: 0.5em;">
Toxoplasma gondii ; germ-free mice; gut inflammation; microbiota; toxoplasmosis</div>
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<dd style="display: inline; margin: 0px; padding: 0px; white-space: nowrap;">28895246</dd>
<dt style="display: inline; margin-bottom: 0px; margin-left: 10px !important; margin-right: 0px; margin-top: 0px; padding: 0px; white-space: nowrap;">DOI:</dt>
<dd style="display: inline; margin: 0px; padding: 0px; white-space: nowrap;"><a href="https://doi.org/10.1111/iep.12236" ref="aid_type=doi" style="border-bottom-width: 0px; color: #333333;">10.1111/iep.12236</a></dd></dl>
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Unknownnoreply@blogger.com0tag:blogger.com,1999:blog-37184100.post-29597374413652366222017-09-14T04:15:00.001-07:002017-09-14T04:15:04.093-07:00IL17A-deficient mice are highly susceptible to Toxoplasma gondii infection due to excessively induced T. gondii HSP70 and IFN-γ production<div class="cit" style="font-family: arial, helvetica, clean, sans-serif; font-size: 0.8465em; line-height: 1.45em;">
<span role="menubar"><a abstractlink="yes" alsec="jour" alterm="Infect Immun." aria-expanded="false" aria-haspopup="true" href="https://www.ncbi.nlm.nih.gov/pubmed/28893913?dopt=Abstract#" role="menuitem" style="border-bottom-width: 0px; color: #660066;" title="Infection and immunity.">Infect Immun.</a></span> 2017 Sep 11. pii: IAI.00399-17. doi: 10.1128/IAI.00399-17. [Epub ahead of print]</div>
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<a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Moroda%20M%5BAuthor%5D&cauthor=true&cauthor_uid=28893913" style="border-bottom-width: 0px; color: #660066;">Moroda M</a><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">1</span>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Takamoto%20M%5BAuthor%5D&cauthor=true&cauthor_uid=28893913" style="border-bottom-width: 0px; color: #660066;">Takamoto M</a><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">2</span>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Iwakura%20Y%5BAuthor%5D&cauthor=true&cauthor_uid=28893913" style="border-bottom-width: 0px; color: #660066;">Iwakura Y</a><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">3</span>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Nakayama%20J%5BAuthor%5D&cauthor=true&cauthor_uid=28893913" style="border-bottom-width: 0px; color: #660066;">Nakayama J</a><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">2</span>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Aosai%20F%5BAuthor%5D&cauthor=true&cauthor_uid=28893913" style="border-bottom-width: 0px; color: #660066;">Aosai F</a><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">4,</span><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">2</span>.</div>
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<a aria-expanded="false" class="jig-ncbitoggler ui-widget ui-ncbitoggler" href="https://www.ncbi.nlm.nih.gov/pubmed/28893913?dopt=Abstract#" id="ui-ncbitoggler-2" role="button" style="border-bottom-width: 0px; color: #660066; display: block; font-family: arial, sans-serif !important; outline: none; padding-left: 16px; position: relative; text-decoration: none !important;" title="Open/close author information list"><span class="ui-ncbitoggler-master-text">Author information</span><span class="ui-icon ui-icon-triangle-1-e" style="background-attachment: scroll; background-image: url(https://static.pubmed.gov/portal/portal3rc.fcgi/4166260/img/3974597); background-position: 0px -21px; background-repeat: no-repeat no-repeat; border-bottom-left-radius: 3px; border-bottom-right-radius: 3px; border: none; display: inline; height: 16px; left: 0px; margin: 0px; overflow: hidden; padding: 0px; position: absolute; right: 0px; text-indent: -99999px; top: 0px; width: 16px;"></span></a></h3>
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Abstract</h3>
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<abstracttext>IL-17A is known to be involved in the host defense against pathogens and pathogenesis of autoimmune diseases. Previously, we showed that excessive IFN-γ plays an important role in the pathogenesis of lethal effect of <i>Toxoplasma gondii</i> (<i>T. gondii</i>) by inducing anaphylactic responses. In this report, we examine the effects of an IL-17A deficiency on murine host defense against oral <i>T. gondii</i>infection. IL-17A-deficient C57BL/6 (B6) mice exhibited higher mortality than wild type (WT) mice to <i>T. gondii</i> at the acute phase of infection. CD4<span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">+</span> T cells in mesenteric lymph nodes (mLNs) and ileum of <i>T. gondii</i>-infected IL-17A-deficient mice produced higher levels of IFN-γ than did those in WT mice. In addition, <i>T. gondii</i> HSP70 (<i>T.g.</i>HSP70) expression was also significantly increased in the ileum, mLNs, liver and spleen of infected IL-17A-deficient mice as compared with WT mice. These elevated expressions of <i>T.g.</i>HSP70 and IFN-γ in infected IL-17A-deficient mice were presumably linked to the IL-17A defect since they decreased to WT levels after treatment with recombinant IL-17A. Furthermore, IL-17A-deficient mice were highly susceptible to anaphylactic effect of <i>T.g.</i>HSP70, and acute phase survival of IL-17A-deficient mice was improved by the treatment with anti-<i>T.g.</i>HSP70 monoclonal antibody. These results suggest that IL-17A plays an important role in host survival against <i>T. gondii</i> infection by protecting host from anaphylactic reaction via downregulating <i>T.g.</i>HSP70 and IFN-γ production.</abstracttext></div>
<div class="copyright" style="font-size: 0.93em; margin-bottom: 0.5em;">
Copyright © 2017 American Society for Microbiology.</div>
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<dt style="display: inline; margin-bottom: 0px; margin-left: 0px !important; margin-right: 0px; margin-top: 0px; padding: 0px; white-space: nowrap;">PMID:</dt>
<dd style="display: inline; margin: 0px; padding: 0px; white-space: nowrap;">28893913</dd>
<dt style="display: inline; margin-bottom: 0px; margin-left: 10px !important; margin-right: 0px; margin-top: 0px; padding: 0px; white-space: nowrap;">DOI:</dt>
<dd style="display: inline; margin: 0px; padding: 0px; white-space: nowrap;"><a href="https://doi.org/10.1128/IAI.00399-17" ref="aid_type=doi" style="border-bottom-width: 0px; color: #333333;">10.1128/IAI.00399-17</a></dd></dl>
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Unknownnoreply@blogger.com0tag:blogger.com,1999:blog-37184100.post-18957724885177717582017-09-14T04:14:00.001-07:002017-09-14T04:14:40.152-07:00Advances in the application of genetic manipulation methods to Apicomplexan parasites<div class="cit" style="font-family: arial, helvetica, clean, sans-serif; font-size: 0.8465em; line-height: 1.45em;">
<span role="menubar"><a abstractlink="yes" alsec="jour" alterm="Int J Parasitol." aria-expanded="false" aria-haspopup="true" href="https://www.ncbi.nlm.nih.gov/pubmed/28893636?dopt=Abstract#" role="menuitem" style="border-bottom-width: 0px; color: #660066;" title="International journal for parasitology.">Int J Parasitol.</a></span> 2017 Sep 8. pii: S0020-7519(17)30246-1. doi: 10.1016/j.ijpara.2017.08.002. [Epub ahead of print]</div>
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<a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Suarez%20CE%5BAuthor%5D&cauthor=true&cauthor_uid=28893636" style="border-bottom-width: 0px; color: #660066;">Suarez CE</a><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">1</span>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Bishop%20RP%5BAuthor%5D&cauthor=true&cauthor_uid=28893636" style="border-bottom-width: 0px; color: #660066;">Bishop RP</a><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">2</span>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Alzan%20HF%5BAuthor%5D&cauthor=true&cauthor_uid=28893636" style="border-bottom-width: 0px; color: #660066;">Alzan HF</a><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">3</span>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Poole%20WA%5BAuthor%5D&cauthor=true&cauthor_uid=28893636" style="border-bottom-width: 0px; color: #660066;">Poole WA</a><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">4</span>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Cooke%20BM%5BAuthor%5D&cauthor=true&cauthor_uid=28893636" style="border-bottom-width: 0px; color: #660066;">Cooke BM</a><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">5</span>.</div>
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<a aria-expanded="false" class="jig-ncbitoggler ui-widget ui-ncbitoggler" href="https://www.ncbi.nlm.nih.gov/pubmed/28893636?dopt=Abstract#" id="ui-ncbitoggler-2" role="button" style="border-bottom-width: 0px; color: #660066; display: block; font-family: arial, sans-serif !important; outline: none; padding-left: 16px; position: relative; text-decoration: none !important;" title="Open/close author information list"><span class="ui-ncbitoggler-master-text">Author information</span><span class="ui-icon ui-icon-triangle-1-e" style="background-attachment: scroll; background-image: url(https://static.pubmed.gov/portal/portal3rc.fcgi/4166260/img/3974597); background-position: 0px -21px; background-repeat: no-repeat no-repeat; border-bottom-left-radius: 3px; border-bottom-right-radius: 3px; border: none; display: inline; height: 16px; left: 0px; margin: 0px; overflow: hidden; padding: 0px; position: absolute; right: 0px; text-indent: -99999px; top: 0px; width: 16px;"></span></a></h3>
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Abstract</h3>
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<abstracttext>Apicomplexan parasites such as Babesia, Theileria, Eimeria, Cryptosporidium and Toxoplasma greatly impact animal health globally, and improved, cost-effective measures to control them are urgently required. These parasites have complex multi-stage life cycles including obligate intracellular stages. Major gaps in our understanding of the biology of these relatively poorly characterized parasites and the diseases they cause severely limit options for designing novel control methods. Here we review potentially important shared aspects of the biology of these parasites, such as cell invasion, host cell modification, and asexual and sexual reproduction, and explore the potential of the application of relatively well-established or newly emerging genetic manipulation methods (GMMs), such as classical transfection or gene editing, respectively, for closing important gaps in our knowledge of the function of specific genes and proteins, and the biology of these parasites. In addition, GMMs impact the development of novel methods of control of the diseases caused by these economically important parasites. Transient and stable transfection methods, in conjunction with whole and deep genome sequencing, were initially instrumental in improving our understanding of the molecular biology of apicomplexan parasites and paved the way for the application of the more recently developed gene editing methods. The increasingly efficient and more recently developed gene editing methods, in particular those based on the CRISPR/Cas9 system and previous conceptually similar techniques, are already contributing to additional gene function discovery using reverse genetics and related approaches. However, gene editing methods are only possible due to the increasing availability of in vitro culture, transfection, and genome sequencing and analysis techniques. We envisage that rapid progress in the development of novel gene editing techniques applied to apicomplexan parasites of veterinary interest will ultimately lead to the development of novel and more efficient methods for disease control.</abstracttext></div>
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Published by Elsevier Ltd.</div>
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KEYWORDS: </h4>
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Apicomplexan; CRISPR/Cas9; Gene editing; Genetic manipulation; Transfection</div>
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<dt style="display: inline; margin-bottom: 0px; margin-left: 0px !important; margin-right: 0px; margin-top: 0px; padding: 0px; white-space: nowrap;">PMID:</dt>
<dd style="display: inline; margin: 0px; padding: 0px; white-space: nowrap;">28893636</dd>
<dt style="display: inline; margin-bottom: 0px; margin-left: 10px !important; margin-right: 0px; margin-top: 0px; padding: 0px; white-space: nowrap;">DOI:</dt>
<dd style="display: inline; margin: 0px; padding: 0px; white-space: nowrap;"><a href="https://doi.org/10.1016/j.ijpara.2017.08.002" ref="aid_type=doi" style="border-bottom-width: 0px; color: #333333;">10.1016/j.ijpara.2017.08.002</a></dd></dl>
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Unknownnoreply@blogger.com0tag:blogger.com,1999:blog-37184100.post-69700361467649852282017-09-09T09:30:00.001-07:002017-09-09T09:30:03.922-07:00Toxoplasma gondii seroprevalence varies by cat breed<div class="cit" style="font-family: arial, helvetica, clean, sans-serif; font-size: 0.8465em; line-height: 1.45em;">
<span role="menubar"><a abstractlink="yes" alsec="jour" alterm="PLoS One." aria-expanded="false" aria-haspopup="true" href="https://www.ncbi.nlm.nih.gov/pubmed/28886182?dopt=Abstract#" role="menuitem" style="border-bottom-width: 0px; color: #660066;" title="PloS one.">PLoS One.</a></span> 2017 Sep 8;12(9):e0184659. doi: 10.1371/journal.pone.0184659. eCollection 2017.</div>
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<a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Must%20K%5BAuthor%5D&cauthor=true&cauthor_uid=28886182" style="border-bottom-width: 0px; color: #660066;">Must K</a><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">1</span>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Hyt%C3%B6nen%20MK%5BAuthor%5D&cauthor=true&cauthor_uid=28886182" style="border-bottom-width: 0px; color: #660066;">Hytönen MK</a><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">2,</span><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">3,</span><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">4</span>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Orro%20T%5BAuthor%5D&cauthor=true&cauthor_uid=28886182" style="border-bottom-width: 0px; color: #660066;">Orro T</a><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">1</span>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Lohi%20H%5BAuthor%5D&cauthor=true&cauthor_uid=28886182" style="border-bottom-width: 0px; color: #660066;">Lohi H</a><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">2,</span><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">3,</span><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">4</span>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Jokelainen%20P%5BAuthor%5D&cauthor=true&cauthor_uid=28886182" style="border-bottom-width: 0px; color: #660066;">Jokelainen P</a><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">1,</span><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">4,</span><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">5</span>.</div>
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<a aria-expanded="false" class="jig-ncbitoggler ui-widget ui-ncbitoggler" href="https://www.ncbi.nlm.nih.gov/pubmed/28886182?dopt=Abstract#" id="ui-ncbitoggler-1" role="button" style="border-bottom-width: 0px; color: #660066; display: block; font-family: arial, sans-serif !important; outline: none; padding-left: 16px; position: relative; text-decoration: none !important;" title="Open/close author information list"><span class="ui-ncbitoggler-master-text">Author information</span><span class="ui-icon ui-icon-triangle-1-e" style="background-attachment: scroll; background-image: url(https://static.pubmed.gov/portal/portal3rc.fcgi/4166260/img/3974597); background-position: 0px -21px; background-repeat: no-repeat no-repeat; border-bottom-left-radius: 3px; border-bottom-right-radius: 3px; border: none; display: inline; height: 16px; left: 0px; margin: 0px; overflow: hidden; padding: 0px; position: absolute; right: 0px; text-indent: -99999px; top: 0px; width: 16px;"></span></a></h3>
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Abstract</h3>
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<abstracttext>Toxoplasma gondii is a widespread zoonotic parasite that is relevant for veterinary and public health. The domestic cat, the definitive host species with the largest worldwide population, has become evolutionarily and epidemiologically the most important host of T. gondii. The outcome of T. gondii infection is influenced by congenital and acquired host characteristics. We detected differences in T. gondii seroprevalence by cat breed in our previous studies. The aims of this study were to estimate T. gondii seroprevalence in selected domestic cat breeds, and to evaluate whether being of a certain breed is associated with T. gondii seropositivity, when the age and lifestyle of the cat are taken into account. The studied breeds were the Birman, British Shorthair, Burmese, Korat, Norwegian Forest Cat, Ocicat, Persian, and Siamese. Plasma samples were analyzed for the presence of immunoglobulin G antibodies against T. gondii with a commercial direct agglutination test at dilution 1:40. The samples were accompanied by owner-completed questionnaires that provided background data on the cats. Overall, 41.12% of the 1121 cats tested seropositive, and the seroprevalence increased with age. The Burmese had the lowest seroprevalence (18.82%) and the Persian had the highest (60.00%). According to the final multivariable logistic regression model, the odds to test seropositive were four to seven times higher in Birmans, Ocicats, Norwegian Forest Cats, and Persians when compared with the Burmese, while older age and receiving raw meat were also risk factors for T. gondii seropositivity. This study showed that T. gondii seroprevalence varies by cat breed and identified being of certain breeds, older age, and receiving raw meat as risk factors for seropositivity.</abstracttext></div>
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<dd style="display: inline; margin: 0px; padding: 0px; white-space: nowrap;">28886182</dd>
<dt style="display: inline; margin-bottom: 0px; margin-left: 10px !important; margin-right: 0px; margin-top: 0px; padding: 0px; white-space: nowrap;">DOI:</dt>
<dd style="display: inline; margin: 0px; padding: 0px; white-space: nowrap;"><a href="https://doi.org/10.1371/journal.pone.0184659" ref="aid_type=doi" style="border-bottom-width: 0px; color: #333333;">10.1371/journal.pone.0184659</a></dd></dl>
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Unknownnoreply@blogger.com0tag:blogger.com,1999:blog-37184100.post-90601396308391606572017-09-09T09:29:00.001-07:002017-09-09T09:29:40.686-07:00Endoplasmic reticulum stress and unfolded protein response in infection by intracellular parasites<div class="cit" style="font-family: arial, helvetica, clean, sans-serif; font-size: 0.8465em; line-height: 1.45em;">
<span role="menubar"><a abstractlink="yes" alsec="jour" alterm="Future Sci OA." aria-expanded="false" aria-haspopup="true" href="https://www.ncbi.nlm.nih.gov/pubmed/28883998?dopt=Abstract#" role="menuitem" style="border-bottom-width: 0px; color: #660066;" title="Future science OA.">Future Sci OA.</a></span> 2017 May 12;3(3):FSO198. doi: 10.4155/fsoa-2017-0020. eCollection 2017 Aug.</div>
<div class="cit" style="font-family: arial, helvetica, clean, sans-serif; font-size: 0.8465em; line-height: 1.45em;">
<br /></div>
<div class="auths" style="font-family: arial, helvetica, clean, sans-serif; font-size: 0.923em;">
<a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Galluzzi%20L%5BAuthor%5D&cauthor=true&cauthor_uid=28883998" style="border-bottom-width: 0px; color: #660066;">Galluzzi L</a><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">1</span>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Diotallevi%20A%5BAuthor%5D&cauthor=true&cauthor_uid=28883998" style="border-bottom-width: 0px; color: #660066;">Diotallevi A</a><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">1</span>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Magnani%20M%5BAuthor%5D&cauthor=true&cauthor_uid=28883998" style="border-bottom-width: 0px; color: #660066;">Magnani M</a><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">1</span>.</div>
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<a aria-expanded="false" class="jig-ncbitoggler ui-widget ui-ncbitoggler" href="https://www.ncbi.nlm.nih.gov/pubmed/28883998?dopt=Abstract#" id="ui-ncbitoggler-1" role="button" style="border-bottom-width: 0px; color: #660066; display: block; font-family: arial, sans-serif !important; outline: none; padding-left: 16px; position: relative; text-decoration: none !important;" title="Open/close author information list"><span class="ui-ncbitoggler-master-text">Author information</span><span class="ui-icon ui-icon-triangle-1-e" style="background-attachment: scroll; background-image: url(https://static.pubmed.gov/portal/portal3rc.fcgi/4166260/img/3974597); background-position: 0px -21px; background-repeat: no-repeat no-repeat; border-bottom-left-radius: 3px; border-bottom-right-radius: 3px; border: none; display: inline; height: 16px; left: 0px; margin: 0px; overflow: hidden; padding: 0px; position: absolute; right: 0px; text-indent: -99999px; top: 0px; width: 16px;"></span></a></h3>
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Abstract</h3>
<div class="">
<div style="font-size: 1.04em; margin-bottom: 0.5em;">
<abstracttext>Perturbations of the physiological status of the endoplasmic reticulum (ER) trigger a specific response known as the ER stress response or unfolded protein response (UPR). In mammalian cells, the UPR is mediated by three ER transmembrane proteins (IRE1, PERK and ATF6) which activate three signaling cascades to restore ER homeostasis. In recent years, a cross-talk between UPR, inflammatory and microbial sensing pathways has been elucidated. Pathogen infection can lead to UPR activation; moreover, several pathogens subvert the UPR to promote their survival and replication. While the UPR in viral and bacterial infection has been characterized, little is known about the role of UPR in intracellular parasite infection. Here, we review recent findings on UPR induction/modulation by intracellular parasites in host cells.</abstracttext></div>
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<h4 style="float: left; font-size: 1em; margin: 0px 0.35em 0px 0px; text-transform: uppercase;">
KEYWORDS: </h4>
<div style="margin-bottom: 0.5em; margin-top: 0.5em;">
Cryptosporidium; ER stress; Leishmania; Plasmodium; Toxoplasma; immunity; protozoan parasites; unfolded protein response</div>
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<dt style="display: inline; margin-bottom: 0px; margin-left: 0px !important; margin-right: 0px; margin-top: 0px; padding: 0px; white-space: nowrap;">PMID:</dt>
<dd style="display: inline; margin: 0px; padding: 0px; white-space: nowrap;">28883998</dd>
<dt style="display: inline; margin-bottom: 0px; margin-left: 10px !important; margin-right: 0px; margin-top: 0px; padding: 0px; white-space: nowrap;">PMCID:</dt>
<dd style="display: inline; margin: 0px; padding: 0px; white-space: nowrap;"><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5583660/" ref="aid_type=pmcid" style="border-bottom-width: 0px; color: #333333;">PMC5583660</a></dd>
<dt style="display: inline; margin-bottom: 0px; margin-left: 10px !important; margin-right: 0px; margin-top: 0px; padding: 0px; white-space: nowrap;">DOI:</dt>
<dd style="display: inline; margin: 0px; padding: 0px; white-space: nowrap;"><a href="https://doi.org/10.4155/fsoa-2017-0020" ref="aid_type=doi" style="border-bottom-width: 0px; color: #333333;">10.4155/fsoa-2017-0020</a></dd></dl>
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Unknownnoreply@blogger.com0tag:blogger.com,1999:blog-37184100.post-18586341438410663252017-09-06T07:41:00.001-07:002017-09-06T07:41:23.589-07:00Resistance towards monensin is proposed to be acquired in a Toxoplasma gondii model by reduced invasion and egress activities, in addition to increased intracellular replication<div class="cit">
<span role="menubar"><a abstractlink="yes" alsec="jour" alterm="Parasitology." aria-expanded="false" aria-haspopup="true" href="https://www.ncbi.nlm.nih.gov/pubmed/28870270?dopt=Abstract#" role="menuitem" title="Parasitology.">Parasitology.</a></span> 2017 Sep 5:1-13. doi: 10.1017/S0031182017001512. [Epub ahead of print]</div>
<div class="cit">
<br /></div>
<div class="auths">
<a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Thabet%20A%5BAuthor%5D&cauthor=true&cauthor_uid=28870270">Thabet A</a><sup>1</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Schmidt%20J%5BAuthor%5D&cauthor=true&cauthor_uid=28870270">Schmidt J</a><sup>2</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Baumann%20S%5BAuthor%5D&cauthor=true&cauthor_uid=28870270">Baumann S</a><sup>2</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Honscha%20W%5BAuthor%5D&cauthor=true&cauthor_uid=28870270">Honscha W</a><sup>3</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=VON%20Bergen%20M%5BAuthor%5D&cauthor=true&cauthor_uid=28870270">VON Bergen M</a><sup>2</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Daugschies%20A%5BAuthor%5D&cauthor=true&cauthor_uid=28870270">Daugschies A</a><sup>1</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Bangoura%20B%5BAuthor%5D&cauthor=true&cauthor_uid=28870270">Bangoura B</a><sup>1</sup>.</div>
<div class="auths">
<br /></div>
<div class="abstr">
<div>
<abstracttext>Monensin (Mon) is an anticoccidial polyether ionophore widely used to control coccidiosis. The extensive use of polyether ionophores on poultry farms resulted in widespread resistance, but the underlying resistance mechanisms are unknown in detail. For analysing the mode of action by which resistance against polyether ionophores is obtained, we induced in vitro Mon resistance in Toxoplasma gondii-RH strain (MonR-RH) and compared it with the sensitive parental strain (Sen-RH). The proteome assessment of MonR-RH and Sen-RH strains was obtained after isotopic labelling using stable isotope labelling by amino acid in cell culture. Relative proteomic quantification between resistant and sensitive strains was performed using liquid chromatography-mass spectrometry/mass spectrometry. Overall, 1024 proteins were quantified and 52 proteins of them were regulated. The bioinformatic analysis revealed regulation of cytoskeletal and transmembrane proteins being involved in transport mechanisms, metal ion-binding and invasion. During invasion, actin and microneme protein 8 (MIC8) are seem to be important for conoid extrusion and forming moving junction with host cells, respectively. Actin was significantly upregulated, while MIC8 was downregulated, which indicate an invasion reduction in the resistant strain. Resistance against Mon is not a simple process but it involves reduced invasion and egress activity of T. gondii tachyzoites while intracellular replication is enhanced.</abstracttext></div>
</div>
<div class="keywords">
<h4>
KEYWORDS: </h4>
Toxoplasma gondii ; SILAC; monensin; resistance mechanism; stable isotope labelling by amino acid in cell culture</div>
<div class="aux">
<div class="resc">
<dl class="rprtid">
<dt>PMID:</dt>
<dd>28870270</dd>
<dt>DOI:</dt>
<dd><a href="https://doi.org/10.1017/S0031182017001512" ref="aid_type=doi">10.1017/S0031182017001512</a></dd> </dl>
</div>
</div>
Unknownnoreply@blogger.com0tag:blogger.com,1999:blog-37184100.post-84012668570757685622017-09-05T05:59:00.001-07:002017-09-05T05:59:23.539-07:00Gliding motility powers invasion and egress in Apicomplexa<div class="cit">
<span role="menubar"><a abstractlink="yes" alsec="jour" alterm="Nat Rev Microbiol." aria-expanded="false" aria-haspopup="true" href="https://www.ncbi.nlm.nih.gov/pubmed/28867819?dopt=Abstract#" role="menuitem" title="Nature reviews. Microbiology.">Nat Rev Microbiol.</a></span> 2017 Sep 4. doi: 10.1038/nrmicro.2017.86. [Epub ahead of print]</div>
<div class="cit">
<br /></div>
<div class="auths">
<a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Fr%C3%A9nal%20K%5BAuthor%5D&cauthor=true&cauthor_uid=28867819">Frénal K</a><sup>1</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Dubremetz%20JF%5BAuthor%5D&cauthor=true&cauthor_uid=28867819">Dubremetz JF</a><sup>2</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Lebrun%20M%5BAuthor%5D&cauthor=true&cauthor_uid=28867819">Lebrun M</a><sup>2</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Soldati-Favre%20D%5BAuthor%5D&cauthor=true&cauthor_uid=28867819">Soldati-Favre D</a><sup>1</sup>.</div>
<div class="auths">
<br /></div>
<div class="abstr">
<div>
<abstracttext>Protozoan parasites have developed elaborate motility systems that facilitate infection and dissemination. For example, amoebae use actin-rich membrane extensions called pseudopodia, whereas Kinetoplastida are propelled by microtubule-containing flagella. By contrast, the motile and invasive stages of the Apicomplexa - a phylum that contains the important human pathogens Plasmodium falciparum (which causes malaria) and Toxoplasma gondii (which causes toxoplasmosis) - have a unique machinery called the glideosome, which is composed of an actomyosin system that underlies the plasma membrane. The glideosome promotes substrate-dependent gliding motility, which powers migration across biological barriers, as well as active host cell entry and egress from infected cells. In this Review, we discuss the discovery of the principles that govern gliding motility, the characterization of the molecular machinery involved, and its impact on parasite invasion and egress from infected cells.</abstracttext></div>
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<div class="aux">
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<dl class="rprtid">
<dt>PMID:</dt>
<dd>28867819</dd>
<dt>DOI:</dt>
<dd><a href="https://doi.org/10.1038/nrmicro.2017.86" ref="aid_type=doi">10.1038/nrmicro.2017.86</a></dd> </dl>
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</div>
Unknownnoreply@blogger.com0tag:blogger.com,1999:blog-37184100.post-40001286863418284422017-09-05T05:57:00.002-07:002017-09-05T05:57:46.646-07:00Targeting Prolyl-tRNA Synthetase <div class="cit">
<span role="menubar"><a abstractlink="yes" alsec="jour" alterm="Structure." aria-expanded="false" aria-haspopup="true" href="https://www.ncbi.nlm.nih.gov/pubmed/28867614?dopt=Abstract#" role="menuitem" title="Structure (London, England : 1993).">Structure.</a></span> 2017 Aug 24. pii: S0969-2126(17)30249-6. doi: 10.1016/j.str.2017.07.015. [Epub ahead of print]</div>
<h1>
Targeting Prolyl-tRNA Synthetase to Accelerate Drug Discovery against Malaria, Leishmaniasis, Toxoplasmosis, Cryptosporidiosis, and Coccidiosis</h1>
<div class="auths">
<a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Jain%20V%5BAuthor%5D&cauthor=true&cauthor_uid=28867614">Jain V</a><sup>1</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Yogavel%20M%5BAuthor%5D&cauthor=true&cauthor_uid=28867614">Yogavel M</a><sup>1</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Kikuchi%20H%5BAuthor%5D&cauthor=true&cauthor_uid=28867614">Kikuchi H</a><sup>2</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Oshima%20Y%5BAuthor%5D&cauthor=true&cauthor_uid=28867614">Oshima Y</a><sup>2</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Hariguchi%20N%5BAuthor%5D&cauthor=true&cauthor_uid=28867614">Hariguchi N</a><sup>3</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Matsumoto%20M%5BAuthor%5D&cauthor=true&cauthor_uid=28867614">Matsumoto M</a><sup>4</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Goel%20P%5BAuthor%5D&cauthor=true&cauthor_uid=28867614">Goel P</a><sup>1</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Touquet%20B%5BAuthor%5D&cauthor=true&cauthor_uid=28867614">Touquet B</a><sup>5</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Jumani%20RS%5BAuthor%5D&cauthor=true&cauthor_uid=28867614">Jumani RS</a><sup>6</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Tacchini-Cottier%20F%5BAuthor%5D&cauthor=true&cauthor_uid=28867614">Tacchini-Cottier F</a><sup>7</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Harlos%20K%5BAuthor%5D&cauthor=true&cauthor_uid=28867614">Harlos K</a><sup>8</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Huston%20CD%5BAuthor%5D&cauthor=true&cauthor_uid=28867614">Huston CD</a><sup>6</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Hakimi%20MA%5BAuthor%5D&cauthor=true&cauthor_uid=28867614">Hakimi MA</a><sup>5</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Sharma%20A%5BAuthor%5D&cauthor=true&cauthor_uid=28867614">Sharma A</a><sup>9</sup>.</div>
<dd><strong><br /></strong></dd><div class="abstr">
<div>
<abstracttext>Developing anti-parasitic lead compounds that act on key vulnerabilities are necessary for new anti-infectives. Malaria, leishmaniasis, toxoplasmosis, cryptosporidiosis and coccidiosis together kill >500,000 humans annually. Their causative parasites Plasmodium, Leishmania, Toxoplasma, Cryptosporidium and Eimeria display high conservation in many housekeeping genes, suggesting that these parasites can be attacked by targeting invariant essential proteins. Here, we describe selective and potent inhibition of prolyl-tRNA synthetases (PRSs) from the above parasites using a series of quinazolinone-scaffold compounds. Our PRS-drug co-crystal structures reveal remarkable active site plasticity that accommodates diversely substituted compounds, an enzymatic feature that can be leveraged for refining drug-like properties of quinazolinones on a per parasite basis. A compound we termed In-5 exhibited a unique double conformation, enhanced drug-like properties, and cleared malaria in mice. It thus represents a new lead for optimization. Collectively, our data offer insights into the structure-guided optimization of quinazolinone-based compounds for drug development against multiple human eukaryotic pathogens.</abstracttext><br />
<div class="copyright">
Copyright © 2017 Elsevier Ltd. All rights reserved.</div>
</div>
</div>
<div class="keywords">
<h4>
KEYWORDS: </h4>
X-ray crystallography; coccidiosis; cryptosporidiosis; drug discovery; leishmaniasis; malaria; prolyl-tRNA synthetase; toxoplasmosis</div>
<div class="aux">
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<dl class="rprtid">
<dt>PMID:</dt>
<dd>28867614</dd>
<dt>DOI:</dt>
<dd><a href="https://doi.org/10.1016/j.str.2017.07.015" ref="aid_type=doi">10.1016/j.str.2017.07.015</a></dd> </dl>
</div>
</div>
Unknownnoreply@blogger.com0tag:blogger.com,1999:blog-37184100.post-40107524321651398222017-09-04T11:41:00.003-07:002017-09-04T11:41:40.658-07:00Autophagy participates in the unfolded protein response in Toxoplasma gondii<div class="cit" style="font-family: arial, helvetica, clean, sans-serif; font-size: 0.8465em; line-height: 1.45em;">
<span role="menubar"><a abstractlink="yes" alsec="jour" alterm="FEMS Microbiol Lett." aria-expanded="false" aria-haspopup="true" href="https://www.ncbi.nlm.nih.gov/pubmed/28859319?dopt=Abstract#" role="menuitem" style="border-bottom-width: 0px; color: #660066;" title="FEMS microbiology letters.">FEMS Microbiol Lett.</a></span> 2017 Aug 15;364(15). doi: 10.1093/femsle/fnx153.</div>
<div class="cit" style="font-family: arial, helvetica, clean, sans-serif; font-size: 0.8465em; line-height: 1.45em;">
<br /></div>
<div class="auths" style="font-family: arial, helvetica, clean, sans-serif; font-size: 0.923em;">
<a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Nguyen%20HM%5BAuthor%5D&cauthor=true&cauthor_uid=28859319" style="border-bottom-width: 0px; color: #660066;">Nguyen HM</a><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">1</span>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Berry%20L%5BAuthor%5D&cauthor=true&cauthor_uid=28859319" style="border-bottom-width: 0px; color: #660066;">Berry L</a><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">1</span>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Sullivan%20WJ%20Jr%5BAuthor%5D&cauthor=true&cauthor_uid=28859319" style="border-bottom-width: 0px; color: #660066;">Sullivan WJ Jr</a><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">2</span>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Besteiro%20S%5BAuthor%5D&cauthor=true&cauthor_uid=28859319" style="border-bottom-width: 0px; color: #660066;">Besteiro S</a><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">1</span>.</div>
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<h3 style="color: #724128; font-size: 1.0769em; line-height: 1.2857; margin: 0.5em 0em; zoom: 1;">
<a aria-expanded="false" class="jig-ncbitoggler ui-widget ui-ncbitoggler" href="https://www.ncbi.nlm.nih.gov/pubmed/28859319?dopt=Abstract#" id="ui-ncbitoggler-2" role="button" style="border-bottom-width: 0px; color: #660066; display: block; font-family: arial, sans-serif !important; outline: none; padding-left: 16px; position: relative; text-decoration: none !important;" title="Open/close author information list"><span class="ui-ncbitoggler-master-text">Author information</span><span class="ui-icon ui-icon-triangle-1-e" style="background-attachment: scroll; background-image: url(https://static.pubmed.gov/portal/portal3rc.fcgi/4166260/img/3974597); background-position: 0px -21px; background-repeat: no-repeat no-repeat; border-bottom-left-radius: 3px; border-bottom-right-radius: 3px; border: none; display: inline; height: 16px; left: 0px; margin: 0px; overflow: hidden; padding: 0px; position: absolute; right: 0px; text-indent: -99999px; top: 0px; width: 16px;"></span></a></h3>
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<h3 style="color: #985735; display: inline; font-size: 1.0769em; line-height: 1.2857; margin: 0px;">
Abstract</h3>
<div class="">
<div style="font-size: 1.04em; margin-bottom: 0.5em;">
<abstracttext>Environmental and genetic perturbations of endoplasmic reticulum (ER) function can lead to the accumulation of unfolded proteins. In these conditions, eukaryotic cells can activate a complex signaling network called the unfolded protein response (UPR) to reduce ER stress and restore cellular homeostasis. Autophagy, a degradation and recycling process, is part of this response. The parasitic protist Toxoplasma gondii is known to be able to activate the UPR upon ER stress, and we now show that this pathway leads to autophagy activation, supporting the idea of a regulated function for canonical autophagy as part of an integrated stress response in the parasites.</abstracttext></div>
<div class="copyright" style="font-size: 0.93em; margin-bottom: 0.5em;">
© FEMS 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.</div>
</div>
</div>
<div class="keywords" style="font-family: arial, helvetica, clean, sans-serif; font-size: 0.923em; margin: 1.8em auto auto;">
<h4 style="float: left; font-size: 1em; margin: 0px 0.35em 0px 0px; text-transform: uppercase;">
KEYWORDS: </h4>
<div style="margin-bottom: 0.5em; margin-top: 0.5em;">
Autophagy; eIF2α; endoplasmic reticulum stress; integrated stress response; Toxoplasma; unfolded protein response</div>
</div>
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<dl class="rprtid" style="display: inline; font-size: 0.8465em; line-height: 1.4em; margin: 0px 15px 0px 0px;">
<dt style="display: inline; margin-bottom: 0px; margin-left: 0px !important; margin-right: 0px; margin-top: 0px; padding: 0px; white-space: nowrap;">PMID:</dt>
<dd style="display: inline; margin: 0px; padding: 0px; white-space: nowrap;">28859319</dd>
<dt style="display: inline; margin-bottom: 0px; margin-left: 10px !important; margin-right: 0px; margin-top: 0px; padding: 0px; white-space: nowrap;">DOI:</dt>
<dd style="display: inline; margin: 0px; padding: 0px; white-space: nowrap;"><a href="https://doi.org/10.1093/femsle/fnx153" ref="aid_type=doi" style="border-bottom-width: 0px; color: #333333;">10.1093/femsle/fnx153</a></dd></dl>
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Unknownnoreply@blogger.com0tag:blogger.com,1999:blog-37184100.post-35388249149039627962017-09-04T11:41:00.001-07:002017-09-04T11:41:13.096-07:00Humans with latent toxoplasmosis display altered reward modulation of cognitive control<div class="cit" style="font-family: arial, helvetica, clean, sans-serif; font-size: 0.8465em; line-height: 1.45em;">
<span role="menubar"><a abstractlink="yes" alsec="jour" alterm="Sci Rep." aria-expanded="false" aria-haspopup="true" href="https://www.ncbi.nlm.nih.gov/pubmed/28860577?dopt=Abstract#" role="menuitem" style="border-bottom-width: 0px; color: #660066;" title="Scientific reports.">Sci Rep.</a></span> 2017 Aug 31;7(1):10170. doi: 10.1038/s41598-017-10926-6.</div>
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<a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Stock%20AK%5BAuthor%5D&cauthor=true&cauthor_uid=28860577" style="border-bottom-width: 0px; color: #660066;">Stock AK</a><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">1</span>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Dajkic%20D%5BAuthor%5D&cauthor=true&cauthor_uid=28860577" style="border-bottom-width: 0px; color: #660066;">Dajkic D</a><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">2</span>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=K%C3%B6hling%20HL%5BAuthor%5D&cauthor=true&cauthor_uid=28860577" style="border-bottom-width: 0px; color: #660066;">Köhling HL</a><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">3</span>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=von%20Heinegg%20EH%5BAuthor%5D&cauthor=true&cauthor_uid=28860577" style="border-bottom-width: 0px; color: #660066;">von Heinegg EH</a><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">3</span>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Fiedler%20M%5BAuthor%5D&cauthor=true&cauthor_uid=28860577" style="border-bottom-width: 0px; color: #660066;">Fiedler M</a><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">4</span>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Beste%20C%5BAuthor%5D&cauthor=true&cauthor_uid=28860577" style="border-bottom-width: 0px; color: #660066;">Beste C</a><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">2,</span><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">5</span>.</div>
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<a aria-expanded="false" class="jig-ncbitoggler ui-widget ui-ncbitoggler" href="https://www.ncbi.nlm.nih.gov/pubmed/28860577?dopt=Abstract#" id="ui-ncbitoggler-2" role="button" style="border-bottom-width: 0px; color: #660066; display: block; font-family: arial, sans-serif !important; outline: none; padding-left: 16px; position: relative; text-decoration: none !important;" title="Open/close author information list"><span class="ui-ncbitoggler-master-text">Author information</span><span class="ui-icon ui-icon-triangle-1-e" style="background-attachment: scroll; background-image: url(https://static.pubmed.gov/portal/portal3rc.fcgi/4166260/img/3974597); background-position: 0px -21px; background-repeat: no-repeat no-repeat; border-bottom-left-radius: 3px; border-bottom-right-radius: 3px; border: none; display: inline; height: 16px; left: 0px; margin: 0px; overflow: hidden; padding: 0px; position: absolute; right: 0px; text-indent: -99999px; top: 0px; width: 16px;"></span></a></h3>
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Abstract</h3>
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<abstracttext>Latent infection with Toxoplasma gondii has repeatedly been shown to be associated with behavioral changes that are commonly attributed to a presumed increase in dopaminergic signaling. Yet, virtually nothing is known about its effects on dopamine-driven reward processing. We therefore assessed behavior and event-related potentials in individuals with vs. without latent toxoplasmosis performing a rewarded control task. The data show that otherwise healthy young adults with latent toxoplasmosis show a greatly diminished response to monetary rewards as compared to their non-infected counterparts. While this selective effect eliminated a toxoplasmosis-induced speed advantage previously observed for non-rewarded behavior, Toxo-positive subjects could still be demonstrated to be superior to Toxo-negative subjects with respect to response accuracy. Event-related potential (ERP) and source localization analyses revealed that this advantage during rewarded behavior was based on increased allocation of processing resources reflected by larger visual late positive component (LPC) amplitudes and associated activity changes in the right temporo-parietal junction (BA40) and left auditory cortex (BA41). Taken together, individuals with latent toxoplasmosis show superior behavioral performance in challenging cognitive control situations but may at the same time have a reduced sensitivity towards motivational effects of rewards, which might be explained by the presumed increase in dopamine.</abstracttext></div>
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<dt style="display: inline; margin-bottom: 0px; margin-left: 0px !important; margin-right: 0px; margin-top: 0px; padding: 0px; white-space: nowrap;">PMID:</dt>
<dd style="display: inline; margin: 0px; padding: 0px; white-space: nowrap;">28860577</dd>
<dt style="display: inline; margin-bottom: 0px; margin-left: 10px !important; margin-right: 0px; margin-top: 0px; padding: 0px; white-space: nowrap;">DOI:</dt>
<dd style="display: inline; margin: 0px; padding: 0px; white-space: nowrap;"><a href="https://doi.org/10.1038/s41598-017-10926-6" ref="aid_type=doi" style="border-bottom-width: 0px; color: #333333;">10.1038/s41598-017-10926-6</a></dd></dl>
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Unknownnoreply@blogger.com0tag:blogger.com,1999:blog-37184100.post-90142969253050455352017-08-31T05:11:00.002-07:002017-08-31T05:11:28.423-07:00Toxoplasma gondii Requires Glycogen Phosphorylase for Balancing Amylopectin Storage and for Efficient Production of Brain Cysts<div class="cit">
<span role="menubar"><a abstractlink="yes" alsec="jour" alterm="MBio." aria-expanded="false" aria-haspopup="true" href="https://www.ncbi.nlm.nih.gov/pubmed/28851850?dopt=Abstract#" role="menuitem" title="mBio.">MBio.</a></span> 2017 Aug 29;8(4). pii: e01289-17. doi: 10.1128/mBio.01289-17.</div>
<div class="cit">
<br /></div>
<div class="auths">
<a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Sugi%20T%5BAuthor%5D&cauthor=true&cauthor_uid=28851850">Sugi T</a><sup>1</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Tu%20V%5BAuthor%5D&cauthor=true&cauthor_uid=28851850">Tu V</a><sup>1</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Ma%20Y%5BAuthor%5D&cauthor=true&cauthor_uid=28851850">Ma Y</a><sup>1</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Tomita%20T%5BAuthor%5D&cauthor=true&cauthor_uid=28851850">Tomita T</a><sup>1</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Weiss%20LM%5BAuthor%5D&cauthor=true&cauthor_uid=28851850">Weiss LM</a><sup>2,</sup><sup>3</sup>.</div>
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<div class="abstr">
<div>
<abstracttext>In immunocompromised hosts, latent infection with <i>Toxoplasma gondii</i> can reactivate from tissue cysts, leading to encephalitis. A characteristic of <i>T. gondii</i> bradyzoites in tissue cysts is the presence of amylopectin granules. The regulatory mechanisms and role of amylopectin accumulation in this organism are not fully understood. The <i>T. gondii</i> genome encodes a putative glycogen phosphorylase (TgGP), and mutants were constructed to manipulate the activity of TgGP and to evaluate the function of TgGP in amylopectin storage. Both a stop codon mutant (Pru/TgGP<sup>S25stop</sup> [expressing a Ser-to-stop codon change at position 25 in TgGP]) and a phosphorylation null mutant (Pru/TgGP<sup>S25A</sup> [expressing a Ser-to-Ala change at position 25 in TgGp]) mutated at Ser25 displayed amylopectin accumulation, while the phosphorylation-mimetic mutant (Pru/TgGP<sup>S25E</sup> [expressing a Ser-to-Glu change at position 25 in TgGp]) had minimal amylopectin accumulation under both tachyzoite and bradyzoite growth conditions. The expression of active TgGP<sup>S25S</sup> or TgGP<sup>S25E</sup> restored amylopectin catabolism in Pru/TgGP<sup>S25A</sup> To understand the relation between GP and calcium-dependent protein kinase 2 (CDPK2), which was recently reported to regulate amylopectin consumption, we knocked out CDPK2 in these mutants. Pru<i>Δcdpk2</i>/TgGP<sup>S25E</sup> had minimal amylopectin accumulation, whereas the <i>Δcdpk2</i> phenotype in the other GP mutants and parental lines displayed amylopectin accumulation. Both the inactive S25A and hyperactive S25E mutant produced brain cysts in infected mice, but the numbers of cysts produced were significantly less than the number produced by the S25S wild-type GP parasite. Complementation that restored amylopectin regulation restored brain cyst production to the control levels seen in infected mice. These data suggest that <i>T. gondii</i> requires tight regulation of amylopectin expression for efficient production of cysts and persistent infections and that GP phosphorylation is a regulatory mechanism involved in amylopectin storage and utilization.</abstracttext><br />
<abstracttext><br /></abstracttext><br />
<abstracttext><b>IMPORTANCE</b><i>Toxoplasma gondii</i> is an obligate intracellular parasite that causes disease in immune-suppressed individuals, as well as a fetopathy in pregnant women who acquire infection for the first time during pregnancy. This parasite can differentiate between tachyzoites (seen in acute infection) and bradyzoites (seen in latent infection), and this differentiation is associated with disease relapse. A characteristic of bradyzoites is that they contain cytoplasmic amylopectin granules. The regulatory mechanisms and the roles of amylopectin granules during latent infection remain to be elucidated. We have identified a role of <i>T. gondii</i> glycogen phosphorylase (TgGP) in the regulation of starch digestion and a role of posttranslational modification of TgGP, i.e., phosphorylation of Ser25, in the regulation of amylopectin digestion. By manipulating TgGP activity in the parasite with genome editing, we found that the digestion and storage of amylopectin due to TgGP activity are both important for latency in the brain.</abstracttext><br />
<div class="copyright">
Copyright © 2017 Sugi et al.</div>
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<div class="keywords">
<h4>
KEYWORDS: </h4>
Toxoplasma gondii; amylopectin; bradyzoite; energy utilization; glycogen metabolism; glycogen phosphorylase; latency; metabolism; posttranslational modification; protein phosphorylation</div>
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<dl class="rprtid">
<dt>PMID:</dt>
<dd>28851850</dd>
<dt>DOI:</dt>
<dd><a href="https://doi.org/10.1128/mBio.01289-17" ref="aid_type=doi">10.1128/mBio.01289-17</a></dd> </dl>
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Unknownnoreply@blogger.com0tag:blogger.com,1999:blog-37184100.post-39579268702572697892017-08-31T05:10:00.001-07:002017-08-31T05:10:55.285-07:00mRNA pseudouridylation affects RNA metabolism in the parasite Toxoplasma gondii<div class="cit">
<span role="menubar"><a abstractlink="yes" alsec="jour" alterm="RNA." aria-expanded="false" aria-haspopup="true" href="https://www.ncbi.nlm.nih.gov/pubmed/28851751?dopt=Abstract#" role="menuitem" title="RNA (New York, N.Y.).">RNA.</a></span> 2017 Aug 29. pii: rna.062794.117. doi: 10.1261/rna.062794.117. [Epub ahead of print]</div>
<div class="cit">
<br /></div>
<div class="auths">
<a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Nakamoto%20MA%5BAuthor%5D&cauthor=true&cauthor_uid=28851751">Nakamoto MA</a><sup>1</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Lovejoy%20AF%5BAuthor%5D&cauthor=true&cauthor_uid=28851751">Lovejoy AF</a><sup>2</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Cygan%20AM%5BAuthor%5D&cauthor=true&cauthor_uid=28851751">Cygan AM</a><sup>1</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Boothroyd%20JC%5BAuthor%5D&cauthor=true&cauthor_uid=28851751">Boothroyd JC</a><sup>3</sup>.</div>
<div class="auths">
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<div class="abstr">
<div>
<abstracttext>RNA contains over 100 modified nucleotides that are created post-transcriptionally, among which pseudouridine (Ψ) is one of the most abundant. Although it was one of the first modifications discovered, the biological role of this modification is still not fully understood. Recently, we reported that a pseudouridine synthase (TgPUS1) is necessary for differentiation of the single-celled eukaryotic parasite Toxoplasma gondii from active to chronic infection. To better understand the biological role of pseudouridylation we report here gel-based and deep-sequencing methods to identify TgPUS1-dependent Ψs in Toxoplasma RNA, and the use of TgPUS1 mutants to examine the effect of this modification on mRNAs. In addition to identifying conserved sites of pseudouridylation in Toxoplasma rRNA, tRNA, and snRNA, we also report extensive pseudouridylation of Toxoplasma mRNAs, with the Ψs being relatively depleted in the 3'-UTR but enriched at position 1 of codons. We show that many of the Ψs in tRNA and mRNA are dependent on the action of TgPUS1 and that TgPUS1-dependent mRNA Ψs are enriched in developmentally regulated transcripts. RNA-Seq data obtained from wild-type and TgPUS1-mutant parasites shows that genes containing a TgPUS1-dependent Ψ are relatively more abundant in mutant parasites while pulse/chase labeling of RNA with 4-thiouracil shows that mRNAs containing TgPUS1-dependent Ψ have a modest but statistically significant increase in half-life in the mutant parasites. These data are some of the first evidence suggesting that mRNA Ψs play an important biological role.</abstracttext><br />
<div class="copyright">
Published by Cold Spring Harbor Laboratory Press for the RNA Society.</div>
</div>
</div>
<div class="keywords">
<h4>
KEYWORDS: </h4>
Pseudouridine; RNA Modification; Toxoplasma gondii</div>
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<dl class="rprtid">
<dt>PMID:</dt>
<dd>28851751</dd>
<dt>DOI:</dt>
<dd><a href="https://doi.org/10.1261/rna.062794.117" ref="aid_type=doi">10.1261/rna.062794.117</a></dd> </dl>
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Unknownnoreply@blogger.com0tag:blogger.com,1999:blog-37184100.post-91336697300001481822017-08-30T07:32:00.001-07:002017-08-30T07:32:47.338-07:00Efficient invasion by Toxoplasma depends on the subversion of host protein networks<div class="cit">
<span role="menubar"><a abstractlink="yes" alsec="jour" alterm="Nat Microbiol." aria-expanded="false" aria-haspopup="true" href="https://www.ncbi.nlm.nih.gov/pubmed/28848228?dopt=Abstract#" role="menuitem" title="Nature microbiology.">Nat Microbiol.</a></span> 2017 Aug 28. doi: 10.1038/s41564-017-0018-1. [Epub ahead of print]</div>
<div class="cit">
<br /></div>
<div class="auths">
<a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Gu%C3%A9rin%20A%5BAuthor%5D&cauthor=true&cauthor_uid=28848228">Guérin A</a><sup>1</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Corrales%20RM%5BAuthor%5D&cauthor=true&cauthor_uid=28848228">Corrales RM</a><sup>1</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Parker%20ML%5BAuthor%5D&cauthor=true&cauthor_uid=28848228">Parker ML</a><sup>2</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Lamarque%20MH%5BAuthor%5D&cauthor=true&cauthor_uid=28848228">Lamarque MH</a><sup>1</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Jacot%20D%5BAuthor%5D&cauthor=true&cauthor_uid=28848228">Jacot D</a><sup>3</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=El%20Hajj%20H%5BAuthor%5D&cauthor=true&cauthor_uid=28848228">El Hajj H</a><sup>4</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Soldati-Favre%20D%5BAuthor%5D&cauthor=true&cauthor_uid=28848228">Soldati-Favre D</a><sup>3</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Boulanger%20MJ%5BAuthor%5D&cauthor=true&cauthor_uid=28848228">Boulanger MJ</a><sup>2</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Lebrun%20M%5BAuthor%5D&cauthor=true&cauthor_uid=28848228">Lebrun M</a><sup>5</sup>.</div>
<div class="auths">
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<div class="abstr">
<div>
<abstracttext>Apicomplexan parasites are important pathogens of humans and domestic animals, including Plasmodium species (the agents of malaria) and Toxoplasma gondii, which is responsible for toxoplasmosis. They replicate within the cells of their animal hosts, to which they gain access using a unique parasite-driven invasion process. At the core of the invasion machine is a structure at the interface between the invading parasite and host cell called the moving junction (MJ) <sup>1</sup> . The MJ serves as both a molecular doorway to the host cell and an anchor point enabling the parasite to engage its motility machinery to drive the penetration of the host cell <sup>2</sup> , ultimately yielding a protective vacuole <sup>3</sup> . The MJ is established through self-assembly of parasite proteins at the parasite-host interface <sup>4</sup> . However, it is unknown whether host proteins are subverted for MJ formation. Here, we show that Toxoplasma parasite rhoptry neck proteins (RON2, RON4 and RON5) cooperate to actively recruit the host CIN85, CD2AP and the ESCRT-I components ALIX and TSG101 to the MJ during invasion. We map the interactions in detail and demonstrate that the parasite mimics and subverts conserved binding interfaces with remarkable specificity. Parasite mutants unable to recruit these host proteins show inefficient host cell invasion in culture and attenuated virulence in mice. This study reveals molecular mechanisms by which parasites subvert widely conserved host machinery to force highly efficient host cell access. Toxoplasma gondii uses its proteins RON2, RON4 and RON5 to recruit host proteins, including the ESCRT-I components ALIX and TSG101 to the moving junction, a multimolecular structure that enables invasion.</abstracttext></div>
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<dl class="rprtid">
<dt>PMID:</dt>
<dd>28848228</dd>
<dt>DOI:</dt>
<dd><a href="https://doi.org/10.1038/s41564-017-0018-1" ref="aid_type=doi">10.1038/s41564-017-0018-1</a></dd> </dl>
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Unknownnoreply@blogger.com0tag:blogger.com,1999:blog-37184100.post-76961819789312010382017-08-29T06:41:00.001-07:002017-08-29T06:41:52.697-07:00The Lymphotoxin β Receptor Is Essential for Upregulation of IFN-Induced Guanylate-Binding Proteins and Survival after Toxoplasma gondii Infection<br />
<div class="cit">
<span role="menubar"><a abstractlink="yes" alsec="jour" alterm="Mediators Inflamm." aria-expanded="false" aria-haspopup="true" href="https://www.ncbi.nlm.nih.gov/pubmed/28845089?dopt=Abstract#" role="menuitem" title="Mediators of inflammation.">Mediators Inflamm.</a></span> 2017;2017:7375818. doi: 10.1155/2017/7375818. Epub 2017 Aug 6.</div>
<div class="cit">
<br /></div>
<div class="auths">
<a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Behnke%20K%5BAuthor%5D&cauthor=true&cauthor_uid=28845089">Behnke K</a><sup>1,</sup><sup>2</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Sorg%20UR%5BAuthor%5D&cauthor=true&cauthor_uid=28845089">Sorg UR</a><sup>1</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Gabbert%20HE%5BAuthor%5D&cauthor=true&cauthor_uid=28845089">Gabbert HE</a><sup>3</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Pfeffer%20K%5BAuthor%5D&cauthor=true&cauthor_uid=28845089">Pfeffer K</a><sup>1</sup>.</div>
<div class="auths">
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<div class="abstr">
<div>
<abstracttext>Lymphotoxin <i>β</i> receptor (LT<i>β</i>R) signaling plays an important role in efficient initiation of host responses to a variety of pathogens, encompassing viruses, bacteria, and protozoans via induction of the type I interferon response. The present study reveals that after <i>Toxoplasma gondii</i> infection, LT<i>β</i>R<sup>-/-</sup> mice show a substantially reduced survival rate when compared to wild-type mice. LT<i>β</i>R<sup>-/-</sup> mice exhibit an increased parasite load and a more pronounced organ pathology. Also, a delayed increase of serum IL-12p40 and a failure of the protective IFN<i>γ</i> response in LT<i>β</i>R<sup>-/-</sup> mice were observed. Serum NO levels in LT<i>β</i>R<sup>-/-</sup> animals rose later and were markedly decreased compared to wild-type animals. At the transcriptional level, LT<i>β</i>R<sup>-/-</sup> animals exhibited a deregulated expression profile of several cytokines known to play a role in activation of innate immunity in <i>T. gondii</i> infection. Importantly, expression of the IFN<i>γ</i>-regulated murine guanylate-binding protein (mGBP) genes was virtually absent in the lungs of LT<i>β</i>R<sup>-/-</sup> mice. This demonstrates clearly that the LT<i>β</i>R is essential for the induction of a type II IFN-mediated immune response against <i>T. gondii</i>. The pronounced inability to effectively upregulate host defense effector molecules such as GBPs explains the high mortality rates of LT<i>β</i>R<sup>-/-</sup> animals after <i>T. gondii</i> infection.</abstracttext></div>
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<dl class="rprtid">
<dt>PMID:</dt>
<dd>28845089</dd>
<dt>PMCID:</dt>
<dd><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5563413/" ref="aid_type=pmcid">PMC5563413</a></dd>
<dt>DOI:</dt>
<dd><a href="https://doi.org/10.1155/2017/7375818" ref="aid_type=doi">10.1155/2017/7375818</a></dd> </dl>
</div>
</div>
Unknownnoreply@blogger.com0tag:blogger.com,1999:blog-37184100.post-91258857431050520592017-08-25T06:18:00.001-07:002017-08-25T06:18:15.924-07:00The Toxoplasma Centrocone Houses Cell Cycle Regulatory Factors<br />
<div class="cit">
<span role="menubar"><a abstractlink="yes" alsec="jour" alterm="MBio." aria-expanded="false" aria-haspopup="true" href="https://www.ncbi.nlm.nih.gov/pubmed/28830940?dopt=Abstract#" role="menuitem" title="mBio.">MBio.</a></span> 2017 Aug 22;8(4). pii: e00579-17. doi: 10.1128/mBio.00579-17.</div>
<div class="cit">
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<div class="auths">
<a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Naumov%20A%5BAuthor%5D&cauthor=true&cauthor_uid=28830940">Naumov A</a><sup>1</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Kratzer%20S%5BAuthor%5D&cauthor=true&cauthor_uid=28830940">Kratzer S</a><sup>1</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Ting%20LM%5BAuthor%5D&cauthor=true&cauthor_uid=28830940">Ting LM</a><sup>2</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Kim%20K%5BAuthor%5D&cauthor=true&cauthor_uid=28830940">Kim K</a><sup>2</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Suvorova%20ES%5BAuthor%5D&cauthor=true&cauthor_uid=28830940">Suvorova ES</a><sup>1</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=White%20MW%5BAuthor%5D&cauthor=true&cauthor_uid=28830940">White MW</a><sup>3</sup>.</div>
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<abstracttext>Our knowledge of cell cycle regulatory mechanisms in apicomplexan parasites is very limited. In this study, we describe a novel <i>Toxoplasma gondii</i> factor that has a vital role in chromosome replication and the regulation of cytoplasmic and nuclear mitotic structures, and we named this factor ECR1 for essential for chromosome replication 1. ECR1 was discovered by complementation of a temperature-sensitive (ts) mutant that suffers lethal, uncontrolled chromosome replication at 40°C similar to a ts mutant carrying a defect in topoisomerase. ECR1 is a 52-kDa protein containing divergent RING and TRAF-Sina-like zinc binding domains that are dynamically expressed in the tachyzoite cell cycle. ECR1 first appears in the unique spindle compartment of the <i>Apicomplexa</i> (centrocone) of the nuclear envelope in early S phase and then in the nucleus in late S phase where it reaches maximum expression. Following nuclear division, but before daughter parasites separate from the mother parasite, ECR1 is downregulated and is absent in new daughter parasites. The proteomics of ECR1 identified interactions with the ubiquitin-mediated protein degradation machinery and the minichromosome maintenance complex, and the loss of ECR1 led to increased stability of a key member of this complex, MCM2. ECR1 also forms a stable complex with the cyclin-dependent kinase (CDK)-related kinase, <i>T</i><i>gondii</i> Crk5 (TgCrk5), which displays a similar cell cycle expression and localization during tachyzoite replication. Importantly, the localization of ECR1/TgCrk5 in the centrocone indicates that this <i>Apicomplexa</i>-specific spindle compartment houses important regulatory factors that control the parasite cell cycle.</abstracttext><br />
<abstracttext><br /></abstracttext><br />
<abstracttext><b>IMPORTANCE</b> Parasites of the apicomplexan family are important causes of human disease, including malaria, toxoplasmosis, and cryptosporidiosis. Parasite growth is the underlying cause of pathogenesis, yet despite this importance, the molecular basis for parasite replication is poorly understood. Filling this knowledge gap cannot be accomplished by mining recent whole-genome sequencing data because apicomplexan cell cycles differ substantially and lack many of the key regulatory factors of well-studied yeast and mammalian cell division models. We have utilized forward genetics to discover essential factors that regulate cell division in these parasites using the <i>Toxoplasma gondii</i> model. An example of this approach is described here with the discovery of a putative E3 ligase/protein kinase mechanism involved in regulating chromosome replication and mitotic processes of asexual stage parasites.</abstracttext><br />
<div class="copyright">
Copyright © 2017 Naumov et al.</div>
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<div class="keywords">
<h4>
KEYWORDS: </h4>
E3 ligase; Toxoplasma gondii; apicomplexan parasites; cell cycle; chromosome replication; cyclin-dependent kinases</div>
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<dl class="rprtid">
<dt>PMID:</dt>
<dd>28830940</dd>
<dt>DOI:</dt>
<dd><a href="https://doi.org/10.1128/mBio.00579-17" ref="aid_type=doi">10.1128/mBio.00579-17</a></dd> </dl>
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Unknownnoreply@blogger.com0tag:blogger.com,1999:blog-37184100.post-32652353137918173222017-08-25T06:17:00.001-07:002017-08-25T06:17:48.016-07:00Evaluation of gene expression levels for cytokines in ocular toxoplasmosis<div class="cit">
<span role="menubar"><a abstractlink="yes" alsec="jour" alterm="Parasite Immunol." aria-expanded="false" aria-haspopup="true" href="https://www.ncbi.nlm.nih.gov/pubmed/28836673?dopt=Abstract#" role="menuitem" title="Parasite immunology.">Parasite Immunol.</a></span> 2017 Aug 24. doi: 10.1111/pim.12462. [Epub ahead of print]</div>
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<div class="auths">
<a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Maia%20MM%5BAuthor%5D&cauthor=true&cauthor_uid=28836673">Maia MM</a><sup>1</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Meira-Strejevitch%20CS%5BAuthor%5D&cauthor=true&cauthor_uid=28836673">Meira-Strejevitch CS</a><sup>1</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Pereira-Chioccola%20VL%5BAuthor%5D&cauthor=true&cauthor_uid=28836673">Pereira-Chioccola VL</a><sup>1</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=de%20Hipp%C3%B3lito%20DDC%5BAuthor%5D&cauthor=true&cauthor_uid=28836673">de Hippólito DDC</a><sup>1</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Silva%20VO%5BAuthor%5D&cauthor=true&cauthor_uid=28836673">Silva VO</a><sup>1</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Brand%C3%A3o%20de%20Mattos%20CC%5BAuthor%5D&cauthor=true&cauthor_uid=28836673">Brandão de Mattos CC</a><sup>2</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Frederico%20FB%5BAuthor%5D&cauthor=true&cauthor_uid=28836673">Frederico FB</a><sup>3</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Siqueira%20RC%5BAuthor%5D&cauthor=true&cauthor_uid=28836673">Siqueira RC</a><sup>2</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=de%20Mattos%20LC%5BAuthor%5D&cauthor=true&cauthor_uid=28836673">de Mattos LC</a><sup>2</sup>; <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=FAMERP%20and%20IAL%20Toxoplasma%20Research%20Group%5BCorporate%20Author%5D">FAMERP and IAL Toxoplasma Research Group</a>.</div>
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<abstracttext>This study evaluated levels for mRNA expression of 7 cytokines in ocular toxoplasmosis. Peripheral blood mononuclear cells (PBMC) of ocular toxoplasmosis patients (OT Group, n= 23) and chronic toxoplasmosis individuals (CHR Group, n= 9) were isolated and stimulated in vitro with T. gondii antigen. Negative controls (NC) were constituted of 7 PBMC samples from individuals seronegative for toxoplasmosis. mRNA expression for cytokines was determined by qPCR. Results showed a significant increase of mRNA levels from antigen stimulated PBMCs derived from OT Group for expressing IL-6 (at p0.005 and p 0.0005 for CHR and NC groups, respectively), IL-10 (at p0.0005 and p 0.005 for CHR and NC groups, respectively) and TGF-β (at p 0.005) for NC group. mRNA levels for TNF-α and IL-12 were also up-regulated in OT patients compared to CHR and NC individuals, although without statistical significance. Additionally, mRNA levels for IL-27 and IFN-γ in PBMC of OT patients were up-regulated in comparison with NC individuals. Differences between OT and NC groups were statistically significant at p0.05 and p 0.0005, respectively. This article is protected by copyright. All rights reserved.</abstracttext><br />
<div class="copyright">
This article is protected by copyright. All rights reserved.</div>
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<div class="keywords">
<h4>
KEYWORDS: </h4>
PBMC ; Cytokines; Gene expression; Ocular toxoplasmosis</div>
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<dl class="rprtid">
<dt>PMID:</dt>
<dd>28836673</dd>
<dt>DOI:</dt>
<dd><a href="https://doi.org/10.1111/pim.12462" ref="aid_type=doi">10.1111/pim.12462</a></dd> </dl>
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Unknownnoreply@blogger.com0tag:blogger.com,1999:blog-37184100.post-18601636852364288862017-08-23T06:26:00.001-07:002017-08-23T06:26:45.653-07:00Small molecule inhibition of apicomplexan FtsH1 disrupts plastid biogenesis in human pathogens<br />
<div class="cit">
<span role="menubar"><a abstractlink="yes" alsec="jour" alterm="Elife." aria-expanded="false" aria-haspopup="true" href="https://www.ncbi.nlm.nih.gov/pubmed/28826494?dopt=Abstract#" role="menuitem" title="eLife.">Elife.</a></span> 2017 Aug 18;6. pii: e29865. doi: 10.7554/eLife.29865. [Epub ahead of print]</div>
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<div class="auths">
<a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Amberg-Johnson%20K%5BAuthor%5D&cauthor=true&cauthor_uid=28826494">Amberg-Johnson K</a><sup>1</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Hari%20SB%5BAuthor%5D&cauthor=true&cauthor_uid=28826494">Hari SB</a><sup>2</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Ganesan%20SM%5BAuthor%5D&cauthor=true&cauthor_uid=28826494">Ganesan SM</a><sup>3</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Lorenzi%20HA%5BAuthor%5D&cauthor=true&cauthor_uid=28826494">Lorenzi HA</a><sup>4</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Sauer%20RT%5BAuthor%5D&cauthor=true&cauthor_uid=28826494">Sauer RT</a><sup>2</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Niles%20JC%5BAuthor%5D&cauthor=true&cauthor_uid=28826494">Niles JC</a><sup>3</sup>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Yeh%20E%5BAuthor%5D&cauthor=true&cauthor_uid=28826494">Yeh E</a><sup>1</sup>.</div>
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<abstracttext>The malaria parasite <i>Plasmodium falciparum</i> and related apicomplexan pathogens contain an essential plastid organelle, the apicoplast, which is a key anti-parasitic target. Derived from secondary endosymbiosis, the apicoplast depends on novel, but largely cryptic, mechanisms for protein/lipid import and organelle inheritance during parasite replication. These critical biogenesis pathways present untapped opportunities to discover new parasite-specific drug targets. We used an innovative screen to identify actinonin as having a novel mechanism-of-action inhibiting apicoplast biogenesis. Resistant mutation, chemical-genetic interaction, and biochemical inhibition demonstrate that the unexpected target of actinonin in <i>P. falciparum</i> and <i>Toxoplasma gondii</i> is FtsH1, a homolog of a bacterial membrane AAA+ metalloprotease. <i>Pf</i>FtsH1 is the first novel factor required for apicoplast biogenesis identified in a phenotypic screen. Our findings demonstrate that FtsH1 is a novel and, importantly, druggable antimalarial target. Development of FtsH1 inhibitors will have significant advantages with improved drug kinetics and multistage efficacy against multiple human parasites.</abstracttext></div>
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KEYWORDS: </h4>
P. falciparum; biochemistry; infectious disease; microbiology</div>
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<dl class="rprtid">
<dt>PMID:</dt>
<dd>28826494</dd>
<dt>DOI:</dt>
<dd><a href="https://doi.org/10.7554/eLife.29865" ref="aid_type=doi">10.7554/eLife.29865</a></dd> </dl>
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Unknownnoreply@blogger.com0tag:blogger.com,1999:blog-37184100.post-60364320954942286342017-08-19T09:53:00.002-07:002017-08-19T09:53:18.662-07:00Dissecting Amyloid Beta Deposition Using Distinct Strains of the Neurotropic Parasite Toxoplasma gondii as a Novel Tool<div class="cit" style="font-family: arial, helvetica, clean, sans-serif; font-size: 0.8465em; line-height: 1.45em;">
<span role="menubar"><a abstractlink="yes" alsec="jour" alterm="ASN Neuro." aria-expanded="false" aria-haspopup="true" href="https://www.ncbi.nlm.nih.gov/pubmed/28817954?dopt=Abstract#" role="menuitem" style="border-bottom-width: 0px; color: #660066;" title="ASN neuro.">ASN Neuro.</a></span> 2017 Jul-Aug;9(4):1759091417724915. doi: 10.1177/1759091417724915.</div>
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<a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Cabral%20CM%5BAuthor%5D&cauthor=true&cauthor_uid=28817954" style="border-bottom-width: 0px; color: #660066;">Cabral CM</a><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">1</span>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=McGovern%20KE%5BAuthor%5D&cauthor=true&cauthor_uid=28817954" style="border-bottom-width: 0px; color: #660066;">McGovern KE</a><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">1</span>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=MacDonald%20WR%5BAuthor%5D&cauthor=true&cauthor_uid=28817954" style="border-bottom-width: 0px; color: #660066;">MacDonald WR</a><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">2</span>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Franco%20J%5BAuthor%5D&cauthor=true&cauthor_uid=28817954" style="border-bottom-width: 0px; color: #660066;">Franco J</a><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">1</span>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Koshy%20AA%5BAuthor%5D&cauthor=true&cauthor_uid=28817954" style="border-bottom-width: 0px; color: #660066;">Koshy AA</a><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">1,</span><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">3,</span><span style="font-size: 0.8461em; line-height: 1.6363em; position: relative; top: -0.5em; vertical-align: baseline;">4</span>.</div>
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<a aria-expanded="false" class="jig-ncbitoggler ui-widget ui-ncbitoggler" href="https://www.ncbi.nlm.nih.gov/pubmed/28817954?dopt=Abstract#" id="ui-ncbitoggler-1" role="button" style="border-bottom-width: 0px; color: #660066; display: block; font-family: arial, sans-serif !important; outline: none; padding-left: 16px; position: relative; text-decoration: none !important;" title="Open/close author information list"><span class="ui-ncbitoggler-master-text">Author information</span><span class="ui-icon ui-icon-triangle-1-e" style="background-attachment: scroll; background-image: url(https://static.pubmed.gov/portal/portal3rc.fcgi/4165709/img/3974597); background-position: 0px -21px; background-repeat: no-repeat no-repeat; border-bottom-left-radius: 3px; border-bottom-right-radius: 3px; border: none; display: inline; height: 16px; left: 0px; margin: 0px; overflow: hidden; padding: 0px; position: absolute; right: 0px; text-indent: -99999px; top: 0px; width: 16px;"></span></a></h3>
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Abstract</h3>
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<abstracttext>Genetic and pathologic data suggest that amyloid beta (Aβ), produced by processing of the amyloid precursor protein, is a major initiator of Alzheimer's disease (AD). To gain new insights into Aβ modulation, we sought to harness the power of the coevolution between the neurotropic parasite Toxoplasma gondii and the mammalian brain. Two prior studies attributed Toxoplasma-associated protection against Aβ to increases in anti-inflammatory cytokines (TGF-β and IL-10) and infiltrating phagocytic monocytes. These studies only used one Toxoplasma strain making it difficult to determine if the noted changes were associated with Aβ protection or simply infection. To address this limitation, we infected a third human amyloid precursor protein AD mouse model (J20) with each of the genetically distinct, canonical strains of Toxoplasma (Type I, Type II, or Type III). We then evaluated the central nervous system (CNS) for Aβ deposition, immune cell responses, global cytokine environment, and parasite burden. We found that only Type II infection was protective against Aβ deposition despite both Type II and Type III strains establishing a chronic CNS infection and inflammatory response. Compared with uninfected and Type I-infected mice, both Type II- and Type III-infected mice showed increased numbers of CNS T cells and microglia and elevated pro-inflammatory cytokines, but neither group showed a >2-fold elevation of TGF-β or IL-10. These data suggest that we can now use our identification of protective (Type II) and nonprotective (Type III) Toxoplasma strains to determine what parasite and host factors are linked to decreased Aβ burden rather than simply with infection.</abstracttext></div>
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<h4 style="float: left; font-size: 1em; margin: 0px 0.35em 0px 0px; text-transform: uppercase;">
KEYWORDS: </h4>
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Alzheimer’s disease; Toxoplasma; amyloid beta; neurodegeneration; neuroprotection</div>
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<dt style="display: inline; margin-bottom: 0px; margin-left: 0px !important; margin-right: 0px; margin-top: 0px; padding: 0px; white-space: nowrap;">PMID:</dt>
<dd style="display: inline; margin: 0px; padding: 0px; white-space: nowrap;">28817954</dd>
<dt style="display: inline; margin-bottom: 0px; margin-left: 10px !important; margin-right: 0px; margin-top: 0px; padding: 0px; white-space: nowrap;">DOI:</dt>
<dd style="display: inline; margin: 0px; padding: 0px; white-space: nowrap;"><a href="https://doi.org/10.1177/1759091417724915" ref="aid_type=doi" style="border-bottom-width: 0px; color: #333333;">10.1177/1759091417724915</a></dd></dl>
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Unknownnoreply@blogger.com0