The spin–orbit charge-transfer-induced intersystem crossing (SOCT-ISC) in Bodipy-phenoxazine (BDP-PXZ) compact electron-donor/-acceptor dyads was studied. PXZ is the electron donor, and BDP is the electron acceptor. The molecular geometry is varied by applying different steric hindrance on the rotation about the linker between the two subunits. Charge-transfer (CT) absorption bands were observed for the dyads with more coplanar geometry (electronic coupling matrix elements is up to 2580 cm–1). Ultrafast charge separation (0.4 ps) and slow charge recombination (3.8 ns, i.e., SOCT-ISC process) were observed. Efficient ISC (ΦT = 54%) and long triplet-state lifetime (τT = 539 μs) were observed for the dyads. Notably, the triplet-state lifetime is 2-fold of that accessed with heavy-atom effect, indicating the advantage of using a heavy-atom-free photosensitizer. The low-lying CT state in the dyads in polar solvents was confirmed with intermolecular triplet photosensitizing method. Time-resolved electron paramagnetic resonance spectroscopy show that the electron spin polarization of the triplet state formed by the SOCT-ISC is the same as that of spin–orbit-ISC (SO-ISC). 3CT and localized excited triplet states (3LE) were simultaneously observed for one of the dyads, which is rare. Normally, the CT state was observed as spin-correlated radical pair. The dyads were used as triplet photosensitizers for triplet–triplet annihilation upconversion, the quantum yield is up to 12.3%. A large anti-Stokes shift (5905 cm–1) was achieved by excitation into the CT absorption band, not the conventional LE absorption band.
SummaryHistone lysine acetylation, normally associated with euchromatin and active genes, is regulated by different families of histone acetyltransferases (HATs). A single Plasmodium falciparum MYST (PfMYST) HAT was expressed as a long and a short version in intraerythrocytic stages. Whereas the recombinant PfMYST expressed in prokaryotes and insect cells did not show HAT activity, recombinant PfMYST purified from the parasites exhibited a predilection to acetylate histone H4 in vitro at K5, K8, K12 and K16. Tagging PfMYST with the green fluorescent protein at the C-terminus showed that PfMYST protein was localized in both the nucleus and cytoplasm. Consistent with the importance of H4 acetylation in var gene expression, PfMYST was recruited to the active var promoter. Attempts to disrupt PfMYST were not successful, suggesting that PfMYST is essential for asexual intraerythrocytic growth. However, overexpression of the long, active or a truncated, non-active version of PfMYST by stable integration of the expression cassette in the parasite genome resulted in changes of H4 acetylation and cell cycle progression. Furthermore, parasites with PfMYST overexpression showed changes in sensitivity to DNA-damaging agents. Collectively, this study showed that PfMYST plays important roles in cellular processes such as gene activation, cell cycle control and DNA repair.
SummaryTranslation regulation plays an important role during gametocytogenesis in the malaria parasite, a process that is obligatory for the transmission of the parasite through mosquito vectors. In this study we determined the function of PfPuf2, a member of the Puf family of translational repressors, in gametocytogenesis of Plasmodium falciparum. Tagging of the endogenous PfPuf2 protein with green fluorescent protein showed that PfPuf2 was expressed in both male and female gametocytes, and the protein was localized in the cytoplasm of the parasite. Targeted disruption of the PfPuf2 gene did not affect asexual growth of the parasite, but promoted the formation of gametocytes and differentiation of male gametocytes. Complementation studies were performed to confirm that the resultant phenotypic changes were due to disruption of the PfPuf2 gene. Episomal expression of PfPuf2 under its cognate promoter almost restored the gametocytogenesis rate in a PfPuf2 disruptant to the level of the wild-type parasite. It also partially restored the effect of PfPuf2 disruption on male-female sex ratio. In addition, episomal overexpression of PfPuf2 under its cognate promoter but with a higher concentration of the selection drug or under the constitutive hsp86 promoter in both the PfPuf2-disruptant and wild-type 3D7 lines, further dramatically reduced gametocytogenesis rates and sex ratios. These findings suggest that in this early branch of eukaryotes the function of PfPuf2 is consistent with the ancestral function of suppressing differentiation proposed for Puf-family proteins. one Pumilio protein, it plays multiple roles in embryonic morphogenesis (Murata and Wharton, 1995), germline development and maintenance (Asaoka-Taguchi et al., 1999;Forbes and Lehmann, 1998;Parisi and Lin, 1999), and dendrite morphogenesis, neuronal excitability and learning (Mee et al., 2004;Menon et al., 2004;Muraro et al., 2008;Schweers et al., 2002;Ye et al., 2004). Based on related functions of Pufs in controlling germline switch in C. elegans, regulating aging and mitochondrial function in yeast, and promoting vegetative growth in the slime mold Dictyostelium (Souza et al., 1999), it has been suggested that the ancestral function of Puf proteins is to promote proliferation and to suppress differentiation .Translational regulation of gene expression in protozoan parasites is not well understood. In malaria parasites of the genus Plasmodium, the life cycle takes place in two hosts. In the blood of a vertebrate host, in response to poorly defined cues, a small proportion of the parasites differentiates into gametocytes, a process termed gametocytogenesis. Transmission to the mosquito vector is accomplished by the sexually dimorphic male and female gametocytes. Molecular investigations into the sexual biology of malaria parasites have led to the identification of a number of gametocyte-and sex-specific molecules and elucidation of their functions during sexual development (reviewed by Alano, 2007;Dixon et al., 2008;Kooij and Matuschewski, 2007;Talm...
cArtemisinin resistance in Plasmodium falciparum parasites in Southeast Asia is a major concern for malaria control. Its emergence at the China-Myanmar border, where there have been more than 3 decades of artemisinin use, has yet to be investigated. Here, we comprehensively evaluated the potential emergence of artemisinin resistance and antimalarial drug resistance status in P. falciparum using data and parasites from three previous efficacy studies in this region. These efficacy studies of dihydroartemisinin-piperaquine combination and artesunate monotherapy of uncomplicated falciparum malaria in 248 P. falciparum patients showed an overall 28-day adequate clinical and parasitological response of >95% and day 3 parasite-positive rates of 6.3 to 23.1%. Comparison of the 57 K13 sequences (24 and 33 from day 3 parasite-positive and -negative cases, respectively) identified nine point mutations in 38 (66.7%) samples, of which F446I (49.1%) and an N-terminal NN insertion (86.0%) were predominant. K13 propeller mutations collectively, the F446I mutation alone, and the NN insertion all were significantly associated with day 3 parasite positivity. Increased ring-stage survival determined using the ring-stage survival assay (RSA) was highly associated with the K13 mutant genotype. Day 3 parasite-positive isolates had ϳ10 times higher ring survival rates than day 3 parasitenegative isolates. Divergent K13 mutations suggested independent evolution of artemisinin resistance. Taken together, this study confirmed multidrug resistance and emergence of artemisinin resistance in P. falciparum at the China-Myanmar border. RSA and K13 mutations are useful phenotypic and molecular markers for monitoring artemisinin resistance.
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