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  • 1
    Online-Ressource
    Online-Ressource
    Drosophila Muller F Elements Maintain a Distinct Set of Genomic Properties Over 40 Million Years of Evolution
    Oxford University Press (OUP) ; 2015
    In:  G3 Genes|Genomes|Genetics Vol. 5, No. 5 ( 2015-05-01), p. 719-740
    Details
    In: G3 Genes|Genomes|Genetics, Oxford University Press (OUP), Vol. 5, No. 5 ( 2015-05-01), p. 719-740
    Kurzfassung: The Muller F element (4.2 Mb, ~80 protein-coding genes) is an unusual autosome of Drosophila melanogaster; it is mostly heterochromatic with a low recombination rate. To investigate how these properties impact the evolution of repeats and genes, we manually improved the sequence and annotated the genes on the D. erecta, D. mojavensis, and D. grimshawi F elements and euchromatic domains from the Muller D element. We find that F elements have greater transposon density (25–50%) than euchromatic reference regions (3–11%). Among the F elements, D. grimshawi has the lowest transposon density (particularly DINE-1: 2% vs. 11–27%). F element genes have larger coding spans, more coding exons, larger introns, and lower codon bias. Comparison of the Effective Number of Codons with the Codon Adaptation Index shows that, in contrast to the other species, codon bias in D. grimshawi F element genes can be attributed primarily to selection instead of mutational biases, suggesting that density and types of transposons affect the degree of local heterochromatin formation. F element genes have lower estimated DNA melting temperatures than D element genes, potentially facilitating transcription through heterochromatin. Most F element genes (~90%) have remained on that element, but the F element has smaller syntenic blocks than genome averages (3.4–3.6 vs. 8.4–8.8 genes per block), indicating greater rates of inversion despite lower rates of recombination. Overall, the F element has maintained characteristics that are distinct from other autosomes in the Drosophila lineage, illuminating the constraints imposed by a heterochromatic milieu.
    Materialart: Online-Ressource
    ISSN: 2160-1836
    URL: Article
    DOI: 10.1534/g3.114.015966
    Sprache: Englisch
    Verlag: Oxford University Press (OUP)
    Publikationsdatum: 2015
    ZDB Id: 2629978-1
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 2
    Online-Ressource
    Online-Ressource
    Lack of Artemisinin Resistance in Plasmodium falciparum in Uganda Based on Parasitological and Molecular Assays
    American Society for Microbiology ; 2015
    In:  Antimicrobial Agents and Chemotherapy Vol. 59, No. 8 ( 2015-08), p. 5061-5064
    Details
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 59, No. 8 ( 2015-08), p. 5061-5064
    Kurzfassung: We evaluated markers of artemisinin resistance in Plasmodium falciparum isolated in Kampala in 2014. By standard in vitro assays, all isolates were highly sensitive to dihydroartemisinin (DHA). By the ring-stage survival assay, after a 6-h DHA pulse, parasitemia was undetectable in 40 of 43 cultures at 72 h. Two of 53 isolates had nonsynonymous K13-propeller gene polymorphisms but did not have the mutations associated with resistance in Asia. Thus, we did not see evidence for artemisinin resistance in Uganda.
    Materialart: Online-Ressource
    ISSN: 0066-4804 , 1098-6596
    URL: Article
    DOI: 10.1128/AAC.00921-15
    RVK:
    XA 24552
    Sprache: Englisch
    Verlag: American Society for Microbiology
    Publikationsdatum: 2015
    ZDB Id: 1496156-8
    SSG: 12
    SSG: 15,3
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 3
    Online-Ressource
    Online-Ressource
    Getting trichy: tools and approaches to interrogating Trichomonas vaginalis in a post-genome world
    Elsevier BV ; 2013
    In:  Trends in Parasitology Vol. 29, No. 1 ( 2013-01), p. 17-25
    Details
    In: Trends in Parasitology, Elsevier BV, Vol. 29, No. 1 ( 2013-01), p. 17-25
    Materialart: Online-Ressource
    ISSN: 1471-4922
    URL: Article
    DOI: 10.1016/j.pt.2012.10.004
    Sprache: Englisch
    Verlag: Elsevier BV
    Publikationsdatum: 2013
    ZDB Id: 2019381-6
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 4
    Online-Ressource
    Online-Ressource
    Associations between Malaria-Preventive Regimens and Plasmodium falciparum Drug Resistance-Mediating Polymorphisms in Ugandan Pregnant Women
    American Society for Microbiology ; 2020
    In:  Antimicrobial Agents and Chemotherapy Vol. 64, No. 12 ( 2020-11-17)
    Details
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 64, No. 12 ( 2020-11-17)
    Kurzfassung: Intermittent preventive treatment in pregnancy (IPTp) with monthly sulfadoxine-pyrimethamine (SP) is recommended for malaria-endemic parts of Africa, but efficacy is compromised by resistance, and, in recent trials, dihydroartemisinin-piperaquine (DP) has shown better antimalarial protective efficacy. We utilized blood samples from a recent trial to evaluate selection by IPTp with DP or SP of Plasmodium falciparum genetic polymorphisms that alter susceptibility to these drugs. The prevalence of known genetic polymorphisms associated with altered drug susceptibility was determined in parasitemic samples, including 375 collected before IPTp drugs were administered, 125 randomly selected from those receiving SP, and 80 from those receiving DP. For women receiving DP, the prevalence of mixed/mutant sequences was greater in samples collected during IPTp than that in samples collected prior to the intervention for PfMDR1 N86Y (20.3% versus 3.9%;  P   〈  0.001), PfMDR1 Y184F (73.0% versus 53.0%; P 〈 0.001), and PfCRT K76T (46.4% versus 24.0%; P 〈 0.001). Considering SP, prior to IPTp, the prevalence of all 5 common antifolate mutations was over 92%, and this prevalence increased following exposure to SP, although none of these changes were statistically significant. For two additional mutations associated with high-level SP resistance, the prevalence of PfDHFR 164L (13.7% versus 4.0%; P = 0.004), but not PfDHPS 581G (1.9% versus 3.0%; P = 0.74), was greater in samples collected during IPTp compared to those collected before the intervention. Use of IPTp in Uganda selected for parasites with mutations associated with decreased susceptibility to IPTp regimens. Thus, a potential drawback of IPTp is selection of parasites with decreased drug susceptibility.
    Materialart: Online-Ressource
    ISSN: 0066-4804 , 1098-6596
    URL: Article
    DOI: 10.1128/AAC.01047-20
    RVK:
    XA 24552
    Sprache: Englisch
    Verlag: American Society for Microbiology
    Publikationsdatum: 2020
    ZDB Id: 1496156-8
    SSG: 12
    SSG: 15,3
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 5
    Online-Ressource
    Online-Ressource
    Impact of Antimalarial Treatment and Chemoprevention on the Drug Sensitivity of Malaria Parasites Isolated from Ugandan Children
    American Society for Microbiology ; 2015
    In:  Antimicrobial Agents and Chemotherapy Vol. 59, No. 6 ( 2015-06), p. 3018-3030
    Details
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 59, No. 6 ( 2015-06), p. 3018-3030
    Kurzfassung: Changing treatment practices may be selecting for changes in the drug sensitivity of malaria parasites. We characterized ex vivo drug sensitivity and parasite polymorphisms associated with sensitivity in 459 Plasmodium falciparum samples obtained from subjects enrolled in two clinical trials in Tororo, Uganda, from 2010 to 2013. Sensitivities to chloroquine and monodesethylamodiaquine varied widely; sensitivities to quinine, dihydroartemisinin, lumefantrine, and piperaquine were generally good. Associations between ex vivo drug sensitivity and parasite polymorphisms included decreased chloroquine and monodesethylamodiaquine sensitivity and increased lumefantrine and piperaquine sensitivity with pfcrt 76T, as well as increased lumefantrine sensitivity with pfmdr1 86Y, Y184, and 1246Y. Over time, ex vivo sensitivity decreased for lumefantrine and piperaquine and increased for chloroquine, the prevalences of pfcrt K76 and pfmdr1 N86 and D1246 increased, and the prevalences of pfdhfr and pfdhps polymorphisms associated with antifolate resistance were unchanged. In recurrent infections, recent prior treatment with artemether-lumefantrine was associated with decreased ex vivo lumefantrine sensitivity and increased prevalence of pfcrt K76 and pfmdr1 N86, 184F, and D1246. In children assigned chemoprevention with monthly dihydroartemisinin-piperaquine with documented circulating piperaquine, breakthrough infections had increased the prevalence of pfmdr1 86Y and 1246Y compared to untreated controls. The noted impacts of therapy and chemoprevention on parasite polymorphisms remained significant in multivariate analysis correcting for calendar time. Overall, changes in parasite sensitivity were consistent with altered selective pressures due to changing treatment practices in Uganda. These changes may threaten the antimalarial treatment and preventive efficacies of artemether-lumefantrine and dihydroartemisinin-piperaquine, respectively.
    Materialart: Online-Ressource
    ISSN: 0066-4804 , 1098-6596
    URL: Article
    DOI: 10.1128/AAC.05141-14
    RVK:
    XA 24552
    Sprache: Englisch
    Verlag: American Society for Microbiology
    Publikationsdatum: 2015
    ZDB Id: 1496156-8
    SSG: 12
    SSG: 15,3
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 6
    Online-Ressource
    Online-Ressource
    Artemether-Lumefantrine and Dihydroartemisinin-Piperaquine Exert Inverse Selective Pressure on Plasmodium Falciparum Drug Sensitivity-Associated Haplotypes in Uganda
    Oxford University Press (OUP) ; 2017
    In:  Open Forum Infectious Diseases Vol. 4, No. 1 ( 2017-01-01)
    Details
    In: Open Forum Infectious Diseases, Oxford University Press (OUP), Vol. 4, No. 1 ( 2017-01-01)
    Kurzfassung: Altered sensitivity to multiple antimalarial drugs is mediated by polymorphisms in pfmdr1, which encodes the Plasmodium falciparum multidrug resistance transporter. In Africa the N86Y and D1246Y polymorphisms have been shown to be selected by treatment, with artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP) selecting for wild-type and mutant alleles, respectively. However, there has been little study of pfmdr1 haplotypes, in part because haplotype analyses are complicated by multiclonal infections. Methods We fit a haplotype frequency estimation model, which accounts for multiclonal infections, to the polymorphic pfmdr1 N86Y, Y184F, and D1246Y alleles in samples from a longitudinal trial comparing AL and DP to treat uncomplicated P falciparum malaria in Tororo, Uganda from 2007 to 2012. We regressed estimates onto covariates of trial arm and selective drug pressure. Results Yearly trends showed increasing frequency estimates for haplotypes with wild type pfmdr1 N86 and D1246 alleles and decreasing frequency estimates for haplotypes with the mutant pfmdr1 86Y allele. Considering days since prior therapy, we saw evidence suggestive of selection by AL for haplotypes with N86 combined with 184F, D1246, or both, and against all haplotypes with 86Y, and evidence suggestive of selection by DP for 86Y only when combined with Y184 and 1246Y (haplotype YYY) and against haplotypes NFD and NYY. Conclusions Based on our model, AL selected several haplotypes containing N86, whereas DP selection was haplotype specific, demonstrating the importance of haplotype analyses. Inverse selective pressure of AL and DP on the complementary haplotypes NFD and YYY suggests that rotating artemisinin-based antimalarial combination regimens may be the best treatment option to prevent resistance selection.
    Materialart: Online-Ressource
    ISSN: 2328-8957
    URL: Article
    DOI: 10.1093/ofid/ofw229
    Sprache: Englisch
    Verlag: Oxford University Press (OUP)
    Publikationsdatum: 2017
    ZDB Id: 2757767-3
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 7
    Online-Ressource
    Online-Ressource
    Maternal Cardiovascular Dysregulation During Early Pregnancy After In Vitro Fertilization Cycles in the Absence of a Corpus Luteum
    Ovid Technologies (Wolters Kluwer Health) ; 2019
    In:  Hypertension Vol. 74, No. 3 ( 2019-09), p. 705-715
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 74, No. 3 ( 2019-09), p. 705-715
    Kurzfassung: Commonly used in vitro fertilization protocols produce pregnancies without a corpus luteum (CL), a major source of reproductive hormones. In vitro fertilization pregnancies without a CL showed deficient gestational increases of central (aortic) arterial compliance during the first trimester and were at increased risk for developing preeclampsia. Here, we investigated whether there was generalized impairment of cardiovascular adaptation in in vitro fertilization pregnancies without a CL compared with pregnancies conceived spontaneously or through ovarian stimulation, which lead to 1 and 〉 1 CL, respectively (n=19–26 participants per cohort). Prototypical maternal cardiovascular adaptations of gestation were serially evaluated noninvasively, initially during the follicular phase before conception, 6× in pregnancy, and then, on average, 1.6 years post-partum. The expected increases of cardiac output, left atrial dimension, peak left ventricular filling velocity in early diastole (E wave velocity), peripheral/central arterial pulse pressure ratio, and global AC, as well as decrease in augmentation index were significantly attenuated or absent during the first trimester in women who conceived without a CL, when compared with the 1 and 〉 1 CL cohorts, which were comparable. Thereafter, these cardiovascular measures showed recovery in the 0 CL group except for E wave velocity, which remained depressed. These results provided strong support for a critical role of CL factor(s) in the transformation of the maternal cardiovascular system in early gestation. Regimens that lead to the development of a CL or replacement of missing CL factor(s) may be indicated to improve cardiovascular function and reduce preeclampsia risk in in vitro fertilization pregnancies.
    Materialart: Online-Ressource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/HYPERTENSIONAHA.119.13015
    Sprache: Englisch
    Verlag: Ovid Technologies (Wolters Kluwer Health)
    Publikationsdatum: 2019
    ZDB Id: 2094210-2
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 8
    Online-Ressource
    Online-Ressource
    The Diversity of the Plasmodium falciparum K13 Propeller Domain Did Not Increase after Implementation of Artemisinin-Based Combination Therapy in Uganda
    American Society for Microbiology ; 2019
    In:  Antimicrobial Agents and Chemotherapy Vol. 63, No. 10 ( 2019-10)
    Details
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 63, No. 10 ( 2019-10)
    Kurzfassung: Artemisinin-based combination therapies (ACTs) are the standard of care to treat uncomplicated falciparum malaria. However, resistance to artemisinins, defined as delayed parasite clearance after therapy, has emerged in Southeast Asia, and the spread of resistance to sub-Saharan Africa could have devastating consequences. Artemisinin resistance has been associated in Southeast Asia with multiple nonsynonymous single nucleotide polymorphisms (NS-SNPs) in the propeller domain of the gene encoding the Plasmodium falciparum K13 protein (K13PD). Some K13PD NS-SNPs have been seen in Africa, but the relevance of these mutations is unclear. To assess whether ACT use has selected for specific K13PD mutations, we compared the K13PD genetic diversity in clinical isolates collected before and after the implementation of ACT use from seven sites across Uganda. We detected K13PD NS-SNPs in 16 of 683 (2.3%) clinical isolates collected between 1999 and 2004 and in 26 of 716 (3.6%) isolates collected between 2012 and 2016 ( P = 0.16), representing a total of 29 different polymorphisms at 27 codons. Individual NS-SNPs were usually detected only once, and none were found in more than 0.7% of the isolates. Three SNPs (C469F, P574L, and A675V) associated with delayed clearance in Southeast Asia were seen in samples collected between 2012 and 2016, each in a single isolate. No differences in diversity following implementation of ACT use were found at any of the seven sites, nor was there evidence of selective pressures acting on the locus. Our results suggest that selection by ACTs is not impacting on K13PD diversity in Uganda.
    Materialart: Online-Ressource
    ISSN: 0066-4804 , 1098-6596
    URL: Article
    DOI: 10.1128/AAC.01234-19
    RVK:
    XA 24552
    Sprache: Englisch
    Verlag: American Society for Microbiology
    Publikationsdatum: 2019
    ZDB Id: 1496156-8
    SSG: 12
    SSG: 15,3
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 9
    Online-Ressource
    Online-Ressource
    Susceptibilities of Ugandan Plasmodium falciparum Isolates to Proteasome Inhibitors
    American Society for Microbiology ; 2022
    In:  Antimicrobial Agents and Chemotherapy Vol. 66, No. 10 ( 2022-10-18)
    Details
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 66, No. 10 ( 2022-10-18)
    Kurzfassung: The proteasome is a promising target for antimalarial chemotherapy. We assessed ex vivo susceptibilities of fresh Plasmodium falciparum isolates from eastern Uganda to seven proteasome inhibitors: two asparagine ethylenediamines, two macrocyclic peptides, and three peptide boronates; five had median IC 50 values 〈 100 nM. TDI8304, a macrocylic peptide lead compound with drug-like properties, had a median IC 50 of 16 nM. Sequencing genes encoding the β2 and β5 catalytic proteasome subunits, the predicted targets of the inhibitors, and five additional proteasome subunits, identified two mutations in β2 (I204T, S214F), three mutations in β5 (V2I, A142S, D150E), and three mutations in other subunits. The β2 S214F mutation was associated with decreased susceptibility to two peptide boronates, with IC 50 s of 181 nM and 2635 nM against mutant versus 62 nM and 477 nM against wild type parasites for MMV1579506 and MMV1794229, respectively, although significance could not be formally assessed due to the small number of mutant parasites with available data. The other β2 and β5 mutations and mutations in other subunits were not associated with susceptibility to tested compounds. Against culture-adapted Ugandan isolates, two asparagine ethylenediamines and the peptide proteasome inhibitors WLW-vinyl sulfone and WLL-vinyl sulfone (which were not studied ex vivo ) demonstrated low nM activity, without decreased activity against β2 S214F mutant parasites. Overall, proteasome inhibitors had potent activity against P. falciparum isolates circulating in Uganda, and genetic variation in proteasome targets was uncommon.
    Materialart: Online-Ressource
    ISSN: 0066-4804 , 1098-6596
    URL: Article
    DOI: 10.1128/aac.00817-22
    RVK:
    XA 24552
    Sprache: Englisch
    Verlag: American Society for Microbiology
    Publikationsdatum: 2022
    ZDB Id: 1496156-8
    SSG: 12
    SSG: 15,3
    Standort Signatur Einschränkungen Verfügbarkeit
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    Online-Ressource
  • 10
    Online-Ressource
    Online-Ressource
    Optimization of a Ligase Detection Reaction-Fluorescent Microsphere Assay for Characterization of Resistance-Mediating Polymorphisms in African Samples of Plasmodium falciparum
    American Society for Microbiology ; 2013
    In:  Journal of Clinical Microbiology Vol. 51, No. 8 ( 2013-08), p. 2564-2570
    Details
    In: Journal of Clinical Microbiology, American Society for Microbiology, Vol. 51, No. 8 ( 2013-08), p. 2564-2570
    Kurzfassung: Genetic polymorphisms in the malaria parasite Plasmodium falciparum mediate alterations in sensitivity to important antimalarial drugs. Surveillance for these polymorphisms is helpful in assessing the prevalence of drug resistance and designing strategies for malaria control. Multiple methods are available for the assessment of P. falciparum genetic polymorphisms, but they suffer from low throughput, technical limitations, and high cost. We have optimized and tested a multiplex ligase detection reaction-fluorescent microsphere (LDR-FM) assay for the identification of important P. falciparum genetic polymorphisms. For 84 clinical samples from Kampala, Uganda, a region where both transmission intensity and infection complexity are high, DNA was extracted from dried blood spots, genes of interest were amplified, amplicons were subjected to multiplex ligase detection reactions to add bead-specific oligonucleotides and biotin, fragments were hybridized to magnetic beads, and polymorphism prevalences were assessed fluorometrically in a multiplex format. A total of 19 alleles from the pfcrt , pfmdr1 , pfmrp1 , pfdhfr , and pfdhps genes were analyzed by LDR-FM and restriction fragment length polymorphism (RFLP) analyses. Considering samples with results from the two assays, concordance between the assays was good, with 78 to 100% of results identical at individual alleles, most nonconcordant results differing only between a mixed and pure genotype call, and full disagreement at individual alleles in only 0 to 3% of results. We estimate that the LDR-FM assay offers much higher throughput and lower cost than RFLP. Our results suggest that the LDR-FM system offers an accurate high-throughput means of classifying genetic polymorphisms in field samples of P. falciparum .
    Materialart: Online-Ressource
    ISSN: 0095-1137 , 1098-660X
    URL: Article
    DOI: 10.1128/JCM.00904-13
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: American Society for Microbiology
    Publikationsdatum: 2013
    ZDB Id: 1498353-9
    SSG: 12
    Standort Signatur Einschränkungen Verfügbarkeit
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