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Hassing Rafferty posted an update 6 months, 2 weeks ago
2 L/h/m2 (67%); half-life was 14.6 h (73%). In multivariate analysis, the effect of increasing age for a given BSA was an increase in neuropathy while the effect of increasing BSA for a given age was a decrease in neuropathy. Conclusion Pharmacokinetics of both drugs were highly variable. For actinomycin-D, there was no correlation between demographic or pharmacokinetic parameters and target toxicities. For vincristine, the correlations of age and BSA and neuropathy are confounded by the correlation between age and BSA in children and the ability to ascertain neuropathy in infants. Variability may be attributed to dose reductions and capped doses for both drugs. Investigation of BSA-based dosing in young children is warranted to decrease variability of exposure.Positively charged amino acid side-chains play important roles in anion binding and permeation through the CFTR chloride channel. One pore-lining lysine residue in particular (K95) has been shown to be indispensable for anion binding, conductance, and selectivity. Here, we use functional investigation of CFTR to show that a nearby arginine (R134) plays a functionally analogous role. Removal of this positive charge (in the R134Q mutant) drastically reduces single-channel conductance, weakens binding of both permeant and blocking anions, and abolishes the normal anion conductance selectivity pattern. Each of these functional effects was reversed by a second-site mutation (S1141K) that introduces an ectopic positive charge to a nearby pore-lining residue. Substituted cysteine accessibility experiments confirm that R134-but not nearby residues in the same transmembrane helix-is accessible within the pore lumen. These results suggest that K95 and R134, which are very close together within the inner vestibule of the pore, play analogous, important roles, and that both are required for the normal anion binding and anion conductance properties of the pore. Nevertheless, that fact that both positive charges can be “transplanted” to other sites in the inner vestibule with little effect on channel permeation properties indicates that it is the overall number of charges-rather than their exact locations-that controls pore function.For a long time, PLS3 (plastin 3, also known as T-plastin or fimbrin) has been considered a rather inconspicuous protein, involved in F-actin-binding and -bundling. However, in recent years, a plethora of discoveries have turned PLS3 into a highly interesting protein involved in many cellular processes, signaling pathways, and diseases. PLS3 is localized on the X-chromosome, but shows sex-specific, inter-individual and tissue-specific expression variability pointing towards skewed X-inactivation. PLS3 is expressed in all solid tissues but usually not in hematopoietic cells. When escaping X-inactivation, PLS3 triggers a plethora of different types of cancers. Elevated PLS3 levels are considered a prognostic biomarker for cancer and refractory response to therapies. When it is knocked out or mutated in humans and mice, it causes osteoporosis with bone fractures; it is the only protein involved in actin dynamics responsible for osteoporosis. Instead, when PLS3 is upregulated, it acts as a highly protective SMN-independent modifier in spinal muscular atrophy (SMA). Here, it seems to counteract reduced F-actin levels by restoring impaired endocytosis and disturbed calcium homeostasis caused by reduced SMN levels. In contrast, an upregulation of PLS3 on wild-type level might cause osteoarthritis. #link# This emphasizes that the amount of PLS3 in our cells must be precisely balanced; both too much and too little can be detrimental. Actin-dynamics, regulated by PLS3 among others, are crucial in a lot of cellular processes including endocytosis, cell migration, axonal growth, neurotransmission, translation, and others. Also, PLS3 levels influence the infection with different bacteria, mycosis, and other pathogens.The soil bacterium and plant pathogen Agrobacterium fabrum C58 has two phytochrome photoreceptors, Agp1 and Agp2. We found that plant infection and tumor induction by A. fabrum is down-regulated by light and that phytochrome knockout mutants of A. fabrum have diminished infection rates. The regulation pattern of infection matches with that of bacterial conjugation reported earlier, suggesting similar regulatory mechanisms. In the regulation of conjugation and plant infection, phytochromes are active in darkness. This is a major difference to plant phytochromes, which are typically active after irradiation. We also found that propagation and motility were affected in agp1- and agp2- knockout mutants, although propagation was not always affected by light. The regulatory patterns can partially but not completely be explained by modulated histidine kinase activities of Agp1 and Agp2. In a mass spectrometry-based proteomic study, 24 proteins were different between light and dark grown A. fabrum, whereas 382 proteins differed between wild type and phytochrome knockout mutants, pointing again to light independent roles of Agp1 and Agp2.
Apart from confinement of Ne1 to a 4.45 Mb genomic segment, markers closely linked to Ne2 were identified and incomplete dominance of both genes in conditioning necrosis severity was shown. Hybrid necrosis in plants is characterized by premature death of leaves or plants in F
hybrids. Interaction of two complementary dominant genes Ne1 and Ne2 in wheat (Triticum aestivum L.) is known to cause hybrid necrosis. However, the mechanism underlying this necrosis is still elusive. To obtain markers closely-linked to these two genes, Ne1-carrying cultivar Zheng891 was crossed with Ne2-carrying cultivar Pan555. Using BC
F
plants derived from crosses of the F
plants with the two parental lines, Ne1 and Ne2 were mapped to a 2.2cM interval and a 2.3cM interval with newly developed markers, respectively. Ne1 was further delimited to a 0.19cM interval using 2015 Ne2-carrying F
plants. Xwgrc3146, Xwgrc3147 and Xwgrc3150, three of the four markers co-segregating with Ne1, were all Zheng891-dominant, suggesting tha was crossed with Ne2-carrying cultivar Pan555. Using BC1F1 plants derived from crosses of the F1 plants with the two parental lines, Ne1 and Ne2 were mapped to a 2.2 cM interval and a 2.3 cM interval with newly developed markers, respectively. Ne1 was further delimited to a 0.19 cM interval using 2015 Ne2-carrying F2 plants. Xwgrc3146, Xwgrc3147 and Xwgrc3150, three of the four markers co-segregating with Ne1, were all Zheng891-dominant, suggesting that, compared with Pan555, Ne1 is located in a region with substantial sequence diversity. The Ne1 interval is syntenic to chromosomes 5H, 4, 9 and 2 of barley, Brachypodium distachyon, rice and sorghum, respectively, and corresponds to a 4.45 Mb Chinese Spring sequence. G418 in necrosis severity of the F2 plants differing in Ne1 and Ne2 genotypes implied that these two genes are incompletely dominant in determining the timing and severity of necrosis.
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