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Jiang, Pan-Pan

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Jiang

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Pan-Pan

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Jiang, Pan-Pan
Author's Publications: search.filters.isAuthorOfPublication.52181bec-1c8f-4f41-9a05-998fdd04c75e

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    Accessible Mutational Trajectories for the Evolution of Pyrimethamine Resistance in the Malaria Parasite Plasmodium Vivax
    (Springer Science + Business Media, 2013) Jiang, Pan-Pan; Corbett-Detig, Russell B.; Hartl, Daniel; Lozovsky, Elena
    Antifolate antimalarials, such as pyrimethamine, have experienced a dramatic reduction in therapeutic efficacy as resistance has evolved in multiple malaria species. We present evidence from one such species, Plasmodium vivax, which has experienced sustained selection for pyrimethamine resistance at the dihydrofolate reductase (DHFR) locus since the 1970s. Using a transgenic Saccharomyces cerevisiae model expressing the P. vivax DHFR enzyme, we assayed growth rate and resistance of all 16 combinations of four DHFR amino acid substitutions. These substitutions were selected based on their known association with drug resistance, both in natural isolates and in laboratory settings, in the related malaria species P. falciparum. We observed a strong correlation between the resistance phenotypes for these 16 P. vivax alleles and previously observed resistance data for P. falciparum, which was surprising since nucleotide diversity levels and common polymorphic variants of DHFR differ between the two species. Similar results were observed when we expressed the P. vivax alleles in a transgenic bacterial system. This suggests common constraints on enzyme evolution in the orthologous DHFR proteins. The interplay of negative trade-offs between the evolution of novel resistance and compromised endogenous function varies at different drug dosages, and so too do the major trajectories for DHFR evolution. In simulations, it is only at very high drug dosages that the most resistant quadruple mutant DHFR allele is favored by selection. This is in agreement with common polymorphic DHFR data in P. vivax, from which this quadruple mutant is missing. We propose that clinical dosages of pyrimethamine may have historically been too low to select for the most resistant allele, or that the fitness cost of the most resistant allele was untenable without a compensatory mutation elsewhere in the genome.
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    Genome-Wide Gene Expression Effects of Sex Chromosome Imprinting in Drosophila
    (Genetics Society of America, 2014) Lemos, Bernardo; Branco, Alan; Jiang, Pan-Pan; Hartl, Daniel; Meiklejohn, Colin D.
    Imprinting is well-documented in both plant and animal species. In Drosophila, the Y chromosome is differently modified when transmitted through the male and female germlines. Here, we report genome-wide gene expression effects resulting from reversed parent-of-origin of the X and Y chromosomes. We found that hundreds of genes are differentially expressed between adult male Drosophila melanogaster that differ in the maternal and paternal origin of the sex chromosomes. Many of the differentially regulated genes are expressed specifically in testis and midgut cells, suggesting that sex chromosome imprinting might globally impact gene expression in these tissues. In contrast, we observed much fewer Y-linked parent-of-origin effects on genome-wide gene expression in females carrying a Y chromosome, indicating that gene expression in females is less sensitive to sex chromosome parent-of-origin. Genes whose expression differs between females inheriting a maternal or paternal Y chromosome also show sex chromosome parent-of-origin effects in males, but the direction of the effects on gene expression (overexpression or underexpression) differ between the sexes. We suggest that passage of sex chromosome chromatin through male meiosis may be required for wild-type function in F1 progeny, whereas disruption of Y-chromosome function through passage in the female germline likely arises because the chromosome is not adapted to the female germline environment.
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    Clinical Illness and Outcomes in Patients with Ebola in Sierra Leone
    (New England Journal of Medicine (NEJM/MMS), 2014) Schieffelin, John S.; Shaffer, Jeffrey G.; Goba, Augustine; Gbakie, Michael; Gire, Stephen K; Colubri, Andres; Sealfon, Rachel; Kanneh, Lansana; Moigboi, Alex; Momoh, Mambu; Fullah, Mohammed; Moses, Lina M.; Brown, Bethany L.; Andersen, Kristian G; Winnicki, Sarah; Schaffner, Stephen; Park, Daniel John; Yozwiak, Nathan; Jiang, Pan-Pan; Kargbo, David; Jalloh, Simbirie; Fonnie, Mbalu; Sinnah, Vandi; French, Issa; Kovoma, Alice; Kamara, Fatima K.; Tucker, Veronica; Konuwa, Edwin; Sellu, Josephine; Mustapha, Ibrahim; Foday, Momoh; Yillah, Mohamed; Kanneh, Franklyn; Saffa, Sidiki; Massally, James L.B.; Boisen, Matt L.; Branco, Luis M.; Vandi, Mohamed A.; Grant, Donald S.; Happi, Christian; Gevao, Sahr M.; Fletcher, Thomas E.; Fowler, Robert A.; Bausch, Daniel G.; Sabeti, Pardis; Khan, S. Humarr; Garry, Robert F.
    Background;Limited clinical and laboratory data are available on patients with Ebola virus disease (EVD). The Kenema Government Hospital in Sierra Leone, which had an existing infrastructure for research regarding viral hemorrhagic fever, has received and cared for patients with EVD since the beginning of the outbreak in Sierra Leone in May 2014. Methods;We reviewed available epidemiologic, clinical, and laboratory records of patients in whom EVD was diagnosed between May 25 and June 18, 2014. We used quantitative reverse-transcriptase–polymerase-chain-reaction assays to assess the load of Ebola virus (EBOV, Zaire species) in a subgroup of patients. Results;Of 106 patients in whom EVD was diagnosed, 87 had a known outcome, and 44 had detailed clinical information available. The incubation period was estimated to be 6 to 12 days, and the case fatality rate was 74%. Common findings at presentation included fever (in 89% of the patients), headache (in 80%), weakness (in 66%), dizziness(in 60%), diarrhea (in 51%), abdominal pain (in 40%), and vomiting (in 34%). Clinical and laboratory factors at presentation that were associated with a fatal outcome included fever, weakness, dizziness, diarrhea, and elevated levels of blood urea nitrogen, aspartate aminotransferase, and creatinine. Exploratory analyses indicated that patients under the age of 21 years had a lower case fatality rate than those over the age of 45 years (57% vs. 94%, P=0.03), and patients presenting with fewer than 100,000 EBOV copies per milliliter had a lower case fatality rate than those with 10 million EBOV copies per milliliter or more (33% vs. 94%, P=0.003). Bleeding occurred in only 1 patient.Conclusions; The incubation period and case fatality rate among patients with EVD in Sierra Leone are similar to those observed elsewhere in the 2014 outbreak and in previous outbreaks. Although bleeding was an infrequent finding, diarrhea and other gastrointestinal manifestations were common. (Funded by the National Institutes of Health and others.)
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    Y Not a Dead End: Epistatic Interactions Between Y-Linked Regulatory Polymorphisms and Genetic Background Affect Global Gene Expression in Drosophila melanogaster
    (Genetics Society of America, 2010) Jiang, Pan-Pan; Hartl, Daniel; Lemos, Bernardo
    The Y chromosome, inherited without meiotic recombination from father to son, carries relatively few genes in most species. This is consistent with predictions from evolutionary theory that nonrecombining chromosomes lack variation and degenerate rapidly. However, recent work has suggested a dynamic role for the Y chromosome in gene regulation, a finding with important implications for spermatogenesis and male fitness. We studied Y chromosomes from two populations of Drosophila melanogaster that had previously been shown to have major effects on the thermal tolerance of spermatogenesis. We show that these Y chromosomes differentially modify the expression of hundreds of autosomal and X-linked genes. Genes showing Y-linked regulatory variation (YRV) also show an association with immune response and pheromone detection. Indeed, genes located proximal to the euchromatin–heterochromatin boundary of the X chromosome appear particularly responsive to Y-linked variation, including a substantial number of odorant-binding genes. Furthermore, the data show significant regulatory interactions between the Y chromosome and the genetic background of autosomes and X chromosome. Altogether, our findings support the view that interpopulation, Y-linked regulatory polymorphisms can differentially modulate the expression of many genes important to male fitness, and they also point to complex interactions between the Y chromosome and genetic background affecting global gene expression.