Plasmodium parasites, the causative agents of malaria, express many variant antigens on cell surfaces. Variant surface antigens (VSAs) are typically organized into large subtelomeric gene families ...that play critical roles in virulence and immune evasion. Many important aspects of VSA function and evolution remain obscure, impeding our understanding of virulence mechanisms and vaccine development. To gain further insights into VSA function and evolution, we comparatively classified and examined known VSA gene families across seven Plasmodium species.
We identified a set of ultra-conserved orthologs within the largest Plasmodium gene family pir, which should be considered as high-priority targets for experimental functional characterization and vaccine development. Furthermore, we predict a lipid-binding domain in erythrocyte surface-expressed PYST-A proteins, suggesting a role of this second largest rodent parasite gene family in host cholesterol salvage. Additionally, it was found that PfMC-2TM proteins carry a novel and putative functional domain named MC-TYR, which is conserved in other P. falciparum gene families and rodent parasites. Finally, we present new conclusive evidence that the major Plasmodium VSAs PfEMP1, SICAvar, and SURFIN are evolutionarily linked through a modular and structurally conserved intracellular domain.
Our comparative analysis of Plasmodium VSA gene families revealed important functional and evolutionary insights, which can now serve as starting points for further experimental studies.
Cis all round: Dichlorobis1‐(dicyclohexylphosphanyl)piperidinepalladium, (P{(NC5H10)(C6H11)2})2Pd(Cl)2, is a highly efficient alkyne hydrothiolation catalyst and the first generally applicable system ...that selectively generates cis‐configured anti‐Markovnikov adducts in excellent yields within only a few minutes at 120 °C in the presence of only 0.05 mol % of the catalyst (see scheme).
Intrahepatic cholangiocarcinoma (ICC) is a fatal primary liver cancer (PLC) that affects 5-10% of all PLCs. Here we sequence tumour and matching control sample pairs of a large cohort of 103 ICC ...patients in China, resulting in the identification of an ICC-specific somatic mutational signature that is associated with liver inflammation, fibrosis and cirrhosis. We further uncover 25 significantly mutated genes including eight potential driver genes (TP53, KRAS, IDH1, PTEN, ARID1A, EPPK1, ECE2 and FYN). We find that TP53-defective ICC patients are more likely to be HBsAg-seropositive, whereas mutations in the oncogene KRAS are nearly exclusively found in HBsAg-seronegative ICC patients. Three pathways (Ras/phosphatidylinositol-4,5-bisphosphate 3-kinase signalling, p53/cell cycle signalling and transforming growth factor-β/Smad signalling), genes important for epigenetic regulation and oxidative phosphorylation are substantially affected in ICC. We reveal mutations in this study that may be valuable for designing further studies, better diagnosis and effective therapies.
Dichlorobis{1‐(dicyclohexylphosphanyl)piperidine}palladium (P{(NC5H10)(C6H11)2})2PdCl2 (1) is a highly active and generally applicable CC cross‐coupling catalyst. Apart from its high catalytic ...activity in Suzuki, Heck, and Negishi reactions, compound 1 also efficiently converted various electronically activated, nonactivated, and deactivated aryl bromides, which may contain fluoride atoms, trifluoromethane groups, nitriles, acetals, ketones, aldehydes, ethers, esters, amides, as well as heterocyclic aryl bromides, such as pyridines and their derivatives, or thiophenes into their respective aromatic nitriles with K4Fe(CN)6 as a cyanating agent within 24 h in NMP at 140 °C in the presence of only 0.05 mol % catalyst. Catalyst‐deactivation processes showed that excess cyanide efficiently affected the molecular mechanisms as well as inhibited the catalysis when nanoparticles were involved, owing to the formation of inactive cyanide complexes, such as Pd(CN)42−, (CN)3Pd(H)2−, and (CN)3Pd(Ar)2−. Thus, the choice of cyanating agent is crucial for the success of the reaction because there is a sharp balance between the rate of cyanide production, efficient product formation, and catalyst poisoning. For example, whereas no product formation was obtained when cyanation reactions were examined with Zn(CN)2 as the cyanating agent, aromatic nitriles were smoothly formed when hexacyanoferrate(II) was used instead. The reason for this striking difference in reactivity was due to the higher stability of hexacyanoferrate(II), which led to a lower rate of cyanide production, and hence, prevented catalyst‐deactivation processes. This pathway was confirmed by the colorimetric detection of cyanides: whereas the conversion of β‐solvato‐α‐cyanocobyrinic acid heptamethyl ester into dicyanocobyrinic acid heptamethyl ester indicated that the cyanide production of Zn(CN)2 proceeded at 25 °C in NMP, reaction temperatures of >100 °C were required for cyanide production with K4Fe(CN)6. Mechanistic investigations demonstrate that palladium nanoparticles were the catalytically active form of compound 1.
A balancing act: Compound 1 (see scheme) is a highly active cyanation catalyst. Furthermore, a sharp balance between the rates of cyanide generation, efficient product formation, and catalyst deactivation owing to excess cyanide was observed in deactivation processes.
Genes underlying important phenotypic differences between Plasmodium species, the causative agents of malaria, are frequently found in only a subset of species and cluster at dynamically evolving ...subtelomeric regions of chromosomes. We hypothesized that chromosome-internal regions of Plasmodium genomes harbour additional species subset-specific genes that underlie differences in human pathogenicity, human-to-human transmissibility, and human virulence. We combined sequence similarity searches with synteny block analyses to identify species subset-specific genes in chromosome-internal regions of six published Plasmodium genomes, including Plasmodium falciparum, Plasmodium vivax, Plasmodium knowlesi, Plasmodium yoelii, Plasmodium berghei, and Plasmodium chabaudi. To improve comparative analysis, we first revised incorrectly annotated gene models using homology-based gene finders and examined putative subset-specific genes within syntenic contexts. Confirmed subset-specific genes were then analyzed for their role in biological pathways and examined for molecular functions using publicly available databases. We identified 16 genes that are well conserved in the three primate parasites but not found in rodent parasites, including three key enzymes of the thiamine (vitamin B1) biosynthesis pathway. Thirteen genes were found to be present in both human parasites but absent in the monkey parasite P. knowlesi, including genes specifically upregulated in sporozoites or gametocytes that could be linked to parasite transmission success between humans. Furthermore, we propose 15 chromosome-internal P. falciparum-specific genes as new candidate genes underlying increased human virulence and detected a currently uncharacterized cluster of P. vivax-specific genes on chromosome 6 likely involved in erythrocyte invasion. In conclusion, Plasmodium species harbour many chromosome-internal differences in the form of protein-coding genes, some of which are potentially linked to human disease and thus promising leads for future laboratory research.
Dichloro‐bis(aminophosphine) complexes are stable depot forms of palladium nanoparticles and have proved to be excellent Suzuki–Miyaura catalysts. Simple modifications of the ligand (and/or the ...addition of water to the reaction mixture) have allowed their formation to be controlled. Dichlorobis1‐(dicyclohexylphosphanyl)piperidinepalladium (3), the most active catalyst of the investigated systems, is a highly convenient, reliable, and extremely active Suzuki catalyst with excellent functional group tolerance that enables the quantitative coupling of a wide variety of activated, nonactivated, and deactivated and/or sterically hindered functionalized and heterocyclic aryl and benzyl bromides with only a slight excess (1.1–1.2 equiv) of arylboronic acid at 80 °C in the presence of 0.2 mol % of the catalyst in technical grade toluene in flasks open to the air. Conversions of >95 % were generally achieved within only a few minutes. The reaction protocol presented herein is universally applicable. Side‐products have only rarely been detected. The catalytic activities of the aminophosphine‐based systems were found to be dramatically improved compared with their phosphine analogue as a result of significantly faster palladium nanoparticle formation. The decomposition products of the catalysts are dicyclohexylphosphinate, cyclohexylphosphonate, and phosphate, which can easily be separated from the coupling products, a great advantage when compared with non‐water‐soluble phosphine‐based systems.
Effective Suzuki catalysts! Dichlorobis(aminophosphine)palladium complexes are extremely active and reliable Suzuki catalysts with excellent functional group tolerance. Aminophosphines promote the formation of palladium nanoparticles (see scheme). Decomposition products are dicyclohexylphosphinate, cyclohexylphosphonate, and phosphate, which can easily be separated from the coupling products.
Feeling the pinch: Aryl bromides can be coupled with phenylboronic acid quantitatively within a few minutes by using pincer‐type catalysts bearing aminophosphine substituents. Pd(Cl)2P(NR2)3 has been ...used as a template for the pincer core directly on the metal center (see scheme, NR2=piperidinyl, X=NH or O), which makes the independent synthesis and purification of the air‐ and moisture‐sensitive ligand systems unnecessary.
BACKGROUND
Peripheral blood stem cells mobilized with granulocyte–colony‐stimulating factor (G‐CSF) with or without chemotherapy are routinely used for autologous hematopoietic cell transplantation. ...Plerixafor, a chemokine‐receptor inhibitor, increases the amount of circulating CD34+ cells and improves harvest results. However, limited information is available regarding the composition of apheresis products with respect to CD34+ and lymphocyte subtypes collected after various mobilization regimens.
STUDY DESIGN AND METHODS
We used a recently established single‐platform multicolor flow‐cytometric analysis including CD45RA and CD133 to define CD34+ subpopulations and lymphocyte subsets in products obtained either after G‐CSF with or without chemotherapy alone (G, n = 40) or with addition of plerixafor (GP, n = 40).
RESULTS
Absolute numbers of white blood cells and lymphocyte subtypes were significantly higher after plerixafor, which was not observed for absolute CD34+ counts. However, distinct differences in terms of CD34+ subtypes were observed. The most primitive multipotent progenitors (CD45RA–CD133+CD34+CD38low) predominated significantly after G (median, 49.2%; range, 15.2%‐63%) compared to GP (median, 34.4%; range, 12%‐62%; p < 0.001), whereas more differentiated subsets clearly prevailed after GP.
CONCLUSION
In contrast to the findings of other authors, our study shows a clear shift toward more committed CD34+ subsets after plerixafor in poor mobilizers and elucidates the importance of informative surface markers like CD45RA and CD133 in addition to CD38 to discriminate earlier from more committed CD34+ cells. Further studies are needed to analyze whether these findings have an impact on clinical outcome.
Five-coordinated rhenium(I) hydride complexes of the type Re(Br)(H)(NO)(PR3)2 (R = Cy 2a, iPr 2b) were prepared from Re(Br)2(NO)(PR3)2(η2-H2) (R = Cy 1a, iPr 1b) via deprotonation of the η2-H2 ...ligands with various bases. Filling the vacant site of 2a or 2b by various less bulky two-electron donors produced the 18-electron complexes Re(Br)(H)(NO)(PR3)2(L) (L = O2 3, CH2CH2 4, acetylene 5, H2 6, CO 7, CH3CN 8). The influence of the trans-coordinated ligand on the Re−H bond was examined. The 1H NMR chemical shift of the hydride depends on L in the order O2 > acetylene > CH2CH2 > H2 > CO > CH3CN. The reactions of 2a or 2b with the IMes or SIMes ligands afforded the five-coordinated complex Re(Br)(H)(NO)(PR3)(NHC) (NHC = IMes 9 (IMes = 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene), SIMes 10 (SIMes = 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)) via replacement of one phosphine. The reaction of 2a or 2b with n-BuLi leads to the formation of the n-butene-coordinated dihydride complexes Re(H)2(NO)(PR3)2(η2-n-CH2CHC2H5) (R = Cy 12a, iPr 12b). Species 1a and 1b reacted also with NaNMe2·BH3, affording the tetrahydride complexes Re(H)4(NO)(PR3)2 (R = Cy 14a, iPr 14b) via the intermediacy of 2a and 2b. The molecular structures of complexes 8b, 10a, and 10b were established by single-crystal X-ray diffraction studies. The five-coordinated rhenium(I) hydride complexes 2a, 2b, 9a, and 9b catalyzed the dehydrocoupling of Me2NH·BH3 and the transfer hydrogenation of olefins using Me2NH·BH3 as a hydrogen donor, which showed high activities. Mechanistic studies were carried out indicating that these rhenium(I) hydride catalyses allowed formation of dihydrogen hydride complexes. A plausible catalytic cycle for both dehydrocoupling and transfer hydrogenation was proposed, which implies the ability of rhenium(I) complexes to activate B−H and N−H bonds by the facile redox interplay of Re(I) and Re(III) species.
Sequential addition of 1,1′,1′′‐phosphinetriyltripiperidine and 1,3‐diaminobenzene or resorcinol to toluene solutions of (cyclooctadiene)palladium dichloride Pd(cod)(Cl)2 under nitrogen in “one pot” ...almost quantitatively yielded the aminophosphine‐based pincer complexes {C6H3‐2,6‐(XP{piperidinyl}2)2Pd(Cl)} (X=NH 1; X=O 2). Complex 1 (and to a minor extent 2) proved to be efficient Sonogashira catalysts, which allow the quantitative coupling of various electronically deactivated and/or sterically hindered and functionalized aryl iodides and aryl bromides with several alkynes as coupling partners within very short reaction times and low catalyst loadings. Importantly, in contrast to most of the Sonogashira catalysts, which either are both air‐ and moisture‐sensitive and/or require the addition of co‐catalysts, such as copper(I) iodide CuI, for example, or a large excess of an amine, the coupling reactions were carried out without the use of amines, co‐catalysts or other aditives and without exclusion of air and moisture. Moreover, the desired products were exclusively formed (no side‐products were detected) without employing an excess of one of the substrates. Ethylene glycol and potassium phosphate (K3PO4) were found to be the ideal solvent and base for this transformation. Experimental observations strongly indicate that palladium nanoparticles are not the catalytically active form of 1 and 2. On the other hand, their transformation into another homogeneous catalytically active species cannot be excluded.
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