Artemisinins target the SERCA of Plasmodium falciparum

Artemisinins are extracted from sweet wormwood (Artemisia annua) and are the most potent antimalarials available, rapidly killing all asexual stages of Plasmodium falciparum. Artemisinins are sesquiterpene lactones widely used to treat multidrug-resistant malaria, a disease that annually claims 1 million lives. Despite extensive clinical and laboratory experience their molecular target is not yet identified. Activated artemisinins form adducts with a variety of biological macromolecules, including haem, translationally controlled tumour protein (TCTP) and other higher-molecular-weight proteins. Here we show that artemisinins, but not quinine or chloroquine, inhibit the SERCA orthologue (PfATP6) of Plasmodium falciparum in Xenopus oocytes with similar potency to thapsigargin (another sesquiterpene lactone and highly specific SERCA inhibitor). As predicted, thapsigargin also antagonizes the parasiticidal activity of artemisinin. Desoxyartemisinin lacks an endoperoxide bridge and is ineffective both as an inhibitor of PfATP6 and as an antimalarial. Chelation of iron by desferrioxamine abrogates the antiparasitic activity of artemisinins and correspondingly attenuates inhibition of PfATP6. Imaging of parasites with BODIPY-thapsigargin labels the cytosolic compartment and is competed by artemisinin. Fluorescent artemisinin labels parasites similarly and irreversibly in an Fe2+-dependent manner. These data provide compelling evidence that artemisinins act by inhibiting PfATP6 outside the food vacuole after activation by iron.     

等离子喷涂铁基非晶/晶体复合涂层的工艺–结构–性能关系

本研究试图通过优化等离子喷涂参数来开发一种Fe基非晶/晶体涂层,该涂层主要成分来自一种贫乏的铁基合金（Fe_92.6C_3.5P_1.4Si₂Mn_0.5）。这种合金是钢铁厂高炉产出的生铁剩余废料。为了经济有效地重新利用这种残留物,这种合金在合成时对成分进行了最少的修改。同时,本研究还探讨了涂层的结构、机械、腐蚀和磨损性能对喷涂参数（等离子功率、主气体流速、送粉速度和间隔距离）的依赖性。X射线衍射表明,在最优的喷涂参数下沉积的涂层存在无定形/晶体相。在较低等离子功率和最高气体流速下沉积的涂层表现出更好的密度、硬度和耐磨性。所有涂层都表现出良好的耐腐蚀性（腐蚀环境:3.5wt% NaCl 溶液）。机械、磨损和摩擦学研究表明,单一的工艺参数优化无法提供良好的涂层性能;相反,所有工艺参数在优化涂层性能都具有独一无二的作用,它们主要通过控制飞行中的颗粒温度和速度分布,以及熔滴撞击基材之前的冷却模式来控制涂层性能。     

TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function

Progressive kidney failure is a genetically and clinically heterogeneous group of disorders. Podocyte foot processes and the interposed glomerular slit diaphragm are essential components of the permeability barrier in the kidney. Mutations in genes encoding structural proteins of the podocyte lead to the development of proteinuria, resulting in progressive kidney failure and focal segmental glomerulosclerosis. Here, we show that the canonical transient receptor potential 6 (TRPC6) ion channel is expressed in podocytes and is a component of the glomerular slit diaphragm. We identified five families with autosomal dominant focal segmental glomerulosclerosis in which disease segregated with mutations in the gene TRPC6 on chromosome 11q. Two of the TRPC6 mutants had increased current amplitudes. These data show that TRPC6 channel activity at the slit diaphragm is essential for proper regulation of podocyte structure and function.     

Dehydrogenases in diethylstilbestrol-induced kidney tumors of the syrian hamster

Zusammenfassung Vier oxidative Enzyme wurden in Schnitten von Diäthylstilbestrol-induzierten Nierentumoren in Syrischen Hamstern nachgewiesen. Die Aktivitäten der Bernsteinsäure- und -Hydroxybutter-Säure-Dehydrogenasen waren schwächer im Tumor als in der normalen Niere, diejenigen der Glucose-6-Phosphat- und Isocitronensäure-Dehydrogenasen dagegen stärker.

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This investigation was supported by grants No. CA-06142 and No. C-6516 from The National Cancer Institute, US Public Health Service, and grant No. FR-05219 from the USPHS Division of Research Facilities and Resources.     

High-energy ion treatments of amorphous As40Se60 thin films for optical applic ations

The treatment of 100 MeV Ag swift-heavy ion(SHI) irradiation with five different fluences(3 1010, 1 1011, 3 1011, 1 1012, and3 1012ions/cm2) was used to design optical and structural properties of amorphous(a-) As40Se60 chalcogenide thin films. Swanepoel method was applied on transmission measurements to determine the changes in optical bandgap, Tauc parameter and linear optical parameters, i.e., linear optical absorption, extinction coefficient and linear refractive index. Dispersion of the material was determined by Wemple–DiDomenico relation.Changes in nonlinear optical parameters of third-order optical susceptibility and nonlinear refractive index were determined using semi-empirical relations. Changes in surface morphology of the films were investigated using SEM observation, which indicated that fluence 3 1012ions/cm2was upper threshold limit for these films for ion treatment. It is observed that optical bandgap reduces from 1.76 eV to 1.64 eV, and nonlinear refractive index increases from 1.31 10 10[esu] to 1.74 10 10[esu]. Linear refractive index initially increases from 2.80 to 3.52(for fluence3 1010ions/cm2) and then keeps decreasing. The observed changes in optical properties upon irradiation were explained in terms of structural rearrangements by Raman measurement. The study was compiled with the previous literature to propose SHI as an effective optical engineering technique to achieve desired changes according to the need of optical/photonic applications.     

A daily rhythm in hCG binding to ovarian follicles of the cyclic hamster

Summary On each day of the estrous cycle hCG binding to follicle increased from 09.00 to 21.00 h; then hCG binding was static until 09.00 h of the next day. FSH binding did not exhibit rhythmicity. This pattern of hCG binding may be related to the pulsing of LH on each cycle day.Acknowledgments. This work was supported by grants from NICHD (15 526, KO478) to P.F.T. and Center grant to the Kansas Center of Mental Retardation and Human Development (HD 02528). A. K. was supported in part by the Council for International Exchange of Scholars (Fulbright Foundation).     

Convergent evolution of similar function in two structurally divergent enzymes

An example of two related enzymes that catalyse similar reactions but possess different active sites is provided by comparing the structure of Escherichia coli thioredoxin reductase with glutathione reductase. Both are dimeric enzymes that catalyse the reduction of disulphides by pyridine nucleotides through an enzyme disulphide and a flavin. Human glutathione reductase contains four structural domains within each molecule: the flavin-adenine dinucleotide (FAD)- and nicotinamide-adenine dinucleotide phosphate (NADPH)-binding domains, the 'central' domain and the C-terminal domain that provides the dimer interface and part of the active site. Although both enzymes share the same catalytic mechanism and similar tertiary structures, their active sites do not resemble each other. We have determined the crystal structure of E. coli thioredoxin reductase at 2 A resolution, and show that thioredoxin reductase lacks the domain that provides the dimer interface in glutathione reductase, and forms a completely different dimeric structure. The catalytically active disulphides are located in different domains on opposite sides of the flavin ring system. This suggests that these enzymes diverged from an ancestral nucleotide-binding protein and acquired their disulphide reductase activities independently.