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  • 1
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    Online Resource
    The newly discovered role of endocytosis in artemisinin resistance
    Wiley ; 2021
    In:  Medicinal Research Reviews Vol. 41, No. 6 ( 2021-11), p. 2998-3022
    Details
    In: Medicinal Research Reviews, Wiley, Vol. 41, No. 6 ( 2021-11), p. 2998-3022
    Abstract: Artemisinin and its derivatives (ART) are the cornerstone of malaria treatment as part of artemisinin combination therapy (ACT). However, reduced susceptibility to artemisinin as well as its partner drugs threatens the usefulness of ACTs. Single point mutations in the parasite protein Kelch13 (K13) are necessary and sufficient for the reduced sensitivity of malaria parasites to ART but several alternative mechanisms for this resistance have been proposed. Recent work found that K13 is involved in the endocytosis of host cell cytosol and indicated that this is the process responsible for resistance in parasites with mutated K13. These studies also identified a series of further proteins that act together with K13 in the same pathway, including previously suspected resistance proteins such as UBP1 and AP‐2μ. Here, we give a brief overview of artemisinin resistance, present the recent evidence of the role of endocytosis in ART resistance and discuss previous hypotheses in light of this new evidence. We also give an outlook on how the new insights might affect future research.
    Type of Medium: Online Resource
    ISSN: 0198-6325 , 1098-1128
    URL: Issue
    URL: Article
    DOI: 10.1002/med.v41.6
    DOI: 10.1002/med.21848
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2001841-1
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  • 2
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    Insulin‐like growth factor‐1 gene therapy and cell transplantation in diabetic wounds
    Wiley ; 2008
    In:  The Journal of Gene Medicine Vol. 10, No. 11 ( 2008-11), p. 1247-1252
    Details
    In: The Journal of Gene Medicine, Wiley, Vol. 10, No. 11 ( 2008-11), p. 1247-1252
    Abstract: Impaired wound healing is a frequent phenomenon in diabetes mellitus. However, little is known of the fundamental cause of this pathology. The present study examined the effect of human insulin‐like growth factor (hIGF)‐1 overexpression in combination with autologous cell transplantation to diabetic wounds in a preclinical large‐animal model. Methods Diabetes was induced in Yorkshire pigs with streptozotocin. Keratinocytes were cultured and transfected with hIGF‐1 or LacZ transgene. Plasmids were lipoplexed with either Lipofectin or Lipofectamin 2000. Transgene expression was assessed by enzyme‐linked immunosorbent assay or X‐gal staining. For in vivo studies, full‐thickness wounds were created and dressed with a sealed chamber. Transfected cells were transplanted into the wounds. Wound contraction was monitored and biopsies were obtained for measurement of re‐epithelialization. Wound fluid was collected and analysed for IGF‐1 concentrations. Results Quantification showed up to 740 ng/ml IGF‐1 in vitro and significantly higher concentrations over 14 days compared to controls for the Lipofectamin 2000 group. Lipofectin‐mediated gene transfer showed peak expression on day 2 with 68.5 ng/ml. In vivo , transfected cells showed peak expression of 457 ng/ml at day 1, followed by subsequent decline to 5 ng/ml on day 12 with Lipofectamin 2000. For Lipofectin, no significant IGF‐1 expression could be detected. Gene therapy caused significantly faster wound closure (83%) than both controls (native‐cell therapy = 57%; control wounds = 32%). Conclusions The present study demonstrates that optimized nonviral gene transfer increased IGF‐1 expression in diabetic wounds by up to 900‐fold. This high IGF‐1 concentration in combination with cell therapy improved diabetic wound healing significantly. Copyright © 2008 John Wiley & Sons, Ltd.
    Type of Medium: Online Resource
    ISSN: 1099-498X , 1521-2254
    URL: Issue
    URL: Article
    DOI: 10.1002/jgm.v10:11
    DOI: 10.1002/jgm.1251
    Language: English
    Publisher: Wiley
    Publication Date: 2008
    detail.hit.zdb_id: 2002203-7
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  • 3
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    Targeted mutagenesis of the ring‐exported protein‐1 of Plasmodium falciparum disrupts the architecture of Maurer's cleft organelles
    Wiley ; 2008
    In:  Molecular Microbiology Vol. 69, No. 4 ( 2008-08), p. 938-953
    Details
    In: Molecular Microbiology, Wiley, Vol. 69, No. 4 ( 2008-08), p. 938-953
    Abstract: Mature red blood cells have no internal trafficking machinery, so the intraerythrocytic malaria parasite, Plasmodium falciparum , establishes its own transport system to export virulence factors to the red blood cell surface. Maurer's clefts are parasite‐derived membranous structures that form an important component of this exported secretory system. A protein with sequence similarity to a Golgi tethering protein, referred to as ring‐exported protein‐1 (REX1), is associated with Maurer's clefts. A REX1–GFP chimera is trafficked to the Maurer's clefts and preferentially associates with the edges of these structures, as well as with vesicle‐like structures and with stalk‐like extensions that are involved in tethering the Maurer's clefts to other membranes. We have generated transfected P. falciparum expressing REX1 truncations or deletion. Electron microscopy reveals that the Maurer's clefts of REX1 truncation mutants have stacked cisternae, while the 3D7 parent line has unstacked Maurer's clefts. D10 parasites, which have lost the right end of chromosome 9, including the rex1 gene, also display Maurer's clefts with stacked cisternae. Expression of full‐length REX1–GFP in D10 parasites restores the 3D7‐type unstacked Maurer's cleft phenotype. These studies reveal the importance of the REX1 protein in determining the ultrastructure of the Maurer's cleft system.
    Type of Medium: Online Resource
    ISSN: 0950-382X , 1365-2958
    URL: Issue
    URL: Article
    DOI: 10.1111/mmi.2008.69.issue-4
    DOI: 10.1111/j.1365-2958.2008.06329.x
    Language: English
    Publisher: Wiley
    Publication Date: 2008
    detail.hit.zdb_id: 1501537-3
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  • 4
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    Spatial dissection of the cis ‐ and trans ‐Golgi compartments in the malaria parasite Plasmodium falciparum
    Wiley ; 2008
    In:  Molecular Microbiology Vol. 67, No. 6 ( 2008-03), p. 1320-1330
    Details
    In: Molecular Microbiology, Wiley, Vol. 67, No. 6 ( 2008-03), p. 1320-1330
    Abstract: The Golgi apparatus forms the heart of the secretory pathway in eukaryotic cells where proteins are modified, processed and sorted. The transport of proteins from the endoplasmic reticulum (ER) to the cis‐ side of the Golgi complex takes place at specialized ER sub‐domains known as transitional ER (tER). We used the Plasmodium falciparum orthologue of Sec13p to analyse tER organization. We show that the distribution of Pf Sec13p is restricted to defined areas of the ER membrane. These foci are juxtaposed to the Golgi apparatus and might represent tER sites. To further analyse cis ‐ to trans ‐Golgi architecture, we generated a double transfectant parasite line that expresses the Golgi marker Golgi reassembly stacking protein (GRASP) as a green fluorescent protein fusion and the trans‐ Golgi marker Rab6 as a DsRed fusion protein. Our data demonstrate that Golgi multiplication is closely linked to tER multiplication, and that parasite maturation is accompanied by the spatial separation of the cis‐ and trans‐ face of this organelle.
    Type of Medium: Online Resource
    ISSN: 0950-382X , 1365-2958
    URL: Issue
    URL: Article
    DOI: 10.1111/mmi.2008.67.issue-6
    DOI: 10.1111/j.1365-2958.2008.06125.x
    Language: English
    Publisher: Wiley
    Publication Date: 2008
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  • 5
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    Sequence requirements for the export of the Plasmodium falciparum Maurer's clefts protein REX2
    Wiley ; 2009
    In:  Molecular Microbiology Vol. 71, No. 4 ( 2009-02), p. 1003-1017
    Details
    In: Molecular Microbiology, Wiley, Vol. 71, No. 4 ( 2009-02), p. 1003-1017
    Abstract: A short motif termed Plasmodium export element (PEXEL) or vacuolar targeting signal (VTS) characterizes Plasmodium proteins exported into the host cell. These proteins mediate host cell modifications essential for parasite survival and virulence. However, several PEXEL‐negative exported proteins indicate that the currently predicted malaria exportome is not complete and it is unknown whether and how these proteins relate to PEXEL‐positive export. Here we show that the N‐terminal 10 amino acids of the PEXEL‐negative exported protein REX2 (ring‐exported protein 2) are necessary for its targeting and that a single‐point mutation in this region abolishes export. Furthermore we show that the REX2 transmembrane domain is also essential for export and that together with the N‐terminal region it is sufficient to promote export of another protein. An N‐terminal region and the transmembrane domain of the unrelated PEXEL‐negative exported protein SBP1 (skeleton‐binding protein 1) can functionally replace the corresponding regions in REX2, suggesting that these sequence features are also present in other PEXEL‐negative exported proteins. Similar to PEXEL proteins we find that REX2 is processed, but in contrast, detect no evidence for N‐terminal acetylation.
    Type of Medium: Online Resource
    ISSN: 0950-382X , 1365-2958
    URL: Issue
    URL: Article
    DOI: 10.1111/mmi.2009.71.issue-4
    DOI: 10.1111/j.1365-2958.2008.06582.x
    Language: English
    Publisher: Wiley
    Publication Date: 2009
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  • 6
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    Proximity‐dependent biotinylation approaches to study apicomplexan biology
    Wiley ; 2022
    In:  Molecular Microbiology Vol. 117, No. 3 ( 2022-03), p. 553-568
    Details
    In: Molecular Microbiology, Wiley, Vol. 117, No. 3 ( 2022-03), p. 553-568
    Abstract: In the last 10 years, proximity‐dependent biotinylation (PDB) techniques greatly expanded the ability to study protein environments in the living cell that range from specific protein complexes to entire compartments. This is achieved by using enzymes such as BirA* and APEX that are fused to proteins of interest and biotinylate proteins in their proximity. PDB techniques are now also increasingly used in apicomplexan parasites. In this review, we first give an overview of the main PDB approaches and how they compare with other techniques that address similar questions. PDB is particularly valuable to detect weak or transient protein associations under physiological conditions and to study cellular structures that are difficult to purify or have a poorly understood protein composition. We also highlight new developments such as novel smaller or faster‐acting enzyme variants and conditional PDB approaches, providing improvements in both temporal and spatial resolution which may offer broader application possibilities useful in apicomplexan research. In the second part, we review work using PDB techniques in apicomplexan parasites and how this expanded our knowledge about these medically important parasites.
    Type of Medium: Online Resource
    ISSN: 0950-382X , 1365-2958
    URL: Issue
    URL: Article
    DOI: 10.1111/mmi.v117.3
    DOI: 10.1111/mmi.14815
    Language: English
    Publisher: Wiley
    Publication Date: 2022
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  • 7
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    Targeting of the Ring Exported Protein 1 to the Maurer’s Clefts is Mediated by a Two‐Phase Process
    Wiley ; 2008
    In:  Traffic Vol. 9, No. 8 ( 2008-08), p. 1316-1326
    Details
    In: Traffic, Wiley, Vol. 9, No. 8 ( 2008-08), p. 1316-1326
    Abstract: Early development of Plasmodium falciparum within the erythrocyte is characterized by the large‐scale export of proteins to the host cell. In many cases, export is mediated by a short sequence called the Plasmodium export element (PEXEL) or vacuolar transport signal; however, a number of previously characterized exported proteins do not contain such an element. In this study, we investigated the mechanisms of export of the PEXEL‐negative ring exported protein 1 (REX1). This protein localizes to the Maurer’s clefts, parasite‐induced structures in the host‐cell cytosol. Transgenic parasites expressing green fluorescent protein–REX1 chimeras revealed that the single hydrophobic stretch plus an additional 10 amino acids mediate the export of REX1. Biochemical characterization of these chimeras indicated that REX1 was exported as a soluble protein. Inclusion of a sequence containing a predicted coiled‐coil motif led to the correct localization of REX1 at the Maurer’s clefts, suggesting that association with the clefts occurs at the final stage of protein export only. These results indicate that PEXEL‐negative exported proteins can be exported in a soluble state and that sequences without any apparent resemblance to a PEXEL motif can mediate export across the parasitophorous vacuole membrane.
    Type of Medium: Online Resource
    ISSN: 1398-9219 , 1600-0854
    URL: Issue
    URL: Article
    DOI: 10.1111/tra.2008.9.issue-8
    DOI: 10.1111/j.1600-0854.2008.00768.x
    Language: English
    Publisher: Wiley
    Publication Date: 2008
    detail.hit.zdb_id: 2020962-9
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  • 8
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    Dissection of Minimal Sequence Requirements for Rhoptry Membrane Targeting in the Malaria Parasite
    Wiley ; 2012
    In:  Traffic Vol. 13, No. 10 ( 2012-10), p. 1335-1350
    Details
    In: Traffic, Wiley, Vol. 13, No. 10 ( 2012-10), p. 1335-1350
    Abstract: Rhoptries are specialized secretory organelles characteristic of single cell organisms belonging to the clade Apicomplexa. These organelles play a key role in the invasion process of host cells by accumulating and subsequently secreting an unknown number of proteins mediating host cell entry. Despite their essential role, little is known about their biogenesis, components and targeting determinants. Here, we report on a conserved apicomplexan protein termed Armadillo Repeats‐Only ( ARO ) protein that we localized to the cytosolic face of Plasmodium falciparum and Toxoplasma gondii rhoptries. We show that the first 20 N‐terminal amino acids are sufficient for rhoptry membrane targeting. This protein relies on both – myristoylation and palmitoylation motifs – for membrane attachment. Although these lipid modifications are essential, they are not sufficient to direct ARO to the rhoptry membranes. Mutational analysis revealed additional residues within the first 20 amino acids of ARO that play an important role for rhoptry membrane attachment: the positively charged residues R9 and K14 . Interestingly, the exchange of R9 with a negative charge entirely abolishes membrane attachment, whereas the exchange of K14 (and to a lesser extent K16 ) alters only its membrane specificity. Additionally, 17 proteins predicted to be myristoylated and palmitoylated in the first 20 N‐terminal amino acids were identified in the genome of the malaria parasite. While most of the corresponding GFP fusion proteins were trafficked to the parasite plasma membrane, two were sorted to the apical organelles. Interestingly, these proteins have a similar motif identified for ARO .
    Type of Medium: Online Resource
    ISSN: 1398-9219 , 1600-0854
    URL: Issue
    URL: Article
    DOI: 10.1111/tra.2012.13.issue-10
    DOI: 10.1111/j.1600-0854.2012.01394.x
    Language: English
    Publisher: Wiley
    Publication Date: 2012
    detail.hit.zdb_id: 2020962-9
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  • 9
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    Human beta‐defensin‐3 promotes wound healing in infected diabetic wounds
    Wiley ; 2009
    In:  The Journal of Gene Medicine Vol. 11, No. 3 ( 2009-03), p. 220-228
    Details
    In: The Journal of Gene Medicine, Wiley, Vol. 11, No. 3 ( 2009-03), p. 220-228
    Abstract: Infected wounds present a major complication in patients with diabetes. Staphylococcus aureus is the most common single isolate in diabetic wounds. Human beta‐defensin (hBD)‐3 is antimicrobial active and appears to play a key role in the immune response. The present study aimed to analyse the effect of hBD‐3 expression in a model of infected diabetic wounds. Methods Excisional wounds were created on the backs of Yorkshire pigs and Ad5‐CMV‐hBD‐3 vectors were microseeded. Wounds were inoculated with S. aureus , covered with a polyurethane chamber and analysed for transgene expression, bacterial infection, re‐epithelialization, wound contraction, wound fluid production and blood vessel formation. Results hBD‐3‐treated wounds showed a total bacterial load of 2.1 × 10 8 colony‐forming units (CFU)/g tissue, versus 1.3 × 10 9 CFU/g tissue for controls ( p 〈 0.001) at day 4. At day 12, no statistical difference could be detected. Re‐epithelialization showed 75 ± 15% wound closure for hBD‐3 expressing wounds and 50 ± 16% for controls ( p 〈 0.01). hBD‐3 expression was in the range 15–20 ng/ml of wound fluid during day 1–4. The lower dose of 2 × 10 9 Ad5‐CMV‐hBD‐3 showed no effect, suggesting a dose dependency for hBD‐3. Conclusions In the present study, we show that hBD‐3 expression significantly promotes wound closure in S. aureus infected diabetic wounds in a preclinical large‐animal model. Furthermore, a ten‐fold reduction of bacterial growth on day 4 was detected. These findings indicate that beta‐defensin‐3 may play a major role in diabetic wound healing and wound infections. Copyright © 2008 John Wiley & Sons, Ltd.
    Type of Medium: Online Resource
    ISSN: 1099-498X , 1521-2254
    URL: Issue
    URL: Article
    DOI: 10.1002/jgm.v11:3
    DOI: 10.1002/jgm.1287
    Language: English
    Publisher: Wiley
    Publication Date: 2009
    detail.hit.zdb_id: 2002203-7
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  • 10
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    The P lasmodium falciparum exportome contains non‐canonical PEXEL / HT proteins
    Wiley ; 2015
    In:  Molecular Microbiology Vol. 97, No. 2 ( 2015-07), p. 301-314
    Details
    In: Molecular Microbiology, Wiley, Vol. 97, No. 2 ( 2015-07), p. 301-314
    Abstract: The pathogenicity of P lasmodium falciparum is partly due to parasite‐induced host cell modifications. These modifications are facilitated by exported P . falciparum proteins, collectively referred to as the exportome. Export of several hundred proteins is mediated by the PEXEL / HT , a protease cleavage site. The PEXEL / HT is usually comprised of five amino acids, of which R at position 1, L at position 3 and E , D or Q at position 5 are conserved and important for export. Non‐canonical PEXEL / HT s with K or H at position 1 and/or I at position 3 are presently considered non‐functional. Here, we show that non‐canonical PEXEL / HT proteins are overrepresented in P . falciparum and other P lasmodium species. Furthermore, we show that non‐canonical PEXEL / HT s can be cleaved and can promote export in both a REX 3 and a GBP reporter, but not in a KAHRP reporter, indicating that non‐canonical PEXEL / HT s are functional in concert with a supportive sequence environment. We then selected P . falciparum proteins with a non‐canonical PEXEL / HT and show that some of these proteins are exported and that their export depends on non‐canonical PEXEL / HT s. We conclude that PEXEL / HT plasticity is higher than appreciated and that non‐canonical PEXEL / HT proteins cannot categorically be excluded from P lasmodium exportome predictions.
    Type of Medium: Online Resource
    ISSN: 0950-382X , 1365-2958
    URL: Issue
    URL: Article
    DOI: 10.1111/mmi.2015.97.issue-2
    DOI: 10.1111/mmi.13024
    Language: English
    Publisher: Wiley
    Publication Date: 2015
    detail.hit.zdb_id: 1501537-3
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