Upregulation of miR-24 is associated with a decreased DNA damage response upon etoposide treatment in highly differentiated CD8(+) T cells sensitizing them to apoptotic cell death

The life-long homeostasis of memory CD8(+) T cells as well as persistent viral infections have been shown to facilitate the accumulation of highly differentiated CD8(+) CD28(-) T cells, a phenomenon that has been associated with an impaired immune function in humans. However, the molecular mechanisms regulating homeostasis of CD8(+) CD28(-) T cells have not yet been elucidated. In this study, we demonstrate that the miR-23～24～27 cluster is up-regulated during post-thymic CD8(+) T-cell differentiation in humans. The increased expression of miR-24 in CD8(+) CD28(-) T cells is associated with decreased expression of the histone variant H2AX, a protein that plays a key role in the DNA damage response (DDR). Following treatment with the classic chemotherapeutic agent etoposide, a topoisomerase II inhibitor, apoptosis was increased in CD8(+) CD28(-) when compared to CD8(+) CD28(+) T cells and correlated with an impaired DDR in this cell type. The reduced capacity of CD8(+) CD28(-) T cell to repair DNA was characterized by the automated fluorimetric analysis of DNA unwinding (FADU) assay as well as by decreased phosphorylation of H2AX at Ser139, of ATM at Ser1981, and of p53 at Ser15. Interleukin (IL)-15 could prevent etoposide-mediated apoptosis of CD8(+) CD28(-) T cells, suggesting a role for IL-15 in the survival and the age-dependent accumulation of CD8(+) CD28(-) T cells in humans.     

The Ovicidal,Larvacidal and Adulticidal Properties of 5,5′-Dimethyl-2,2′-Bipyridyl against Drosophila melanogaster

Insecticide resistance has limited the number of available chemical options for insect pest control. Hence there is a need for new chemistries with novel modes of action. Here we investigate the mode of action for an insecticide that has not yet been released for commercial use. The ovicidal, larvacidal and adulticidal effects of 5,5′-dimethyl -2, 2′-dipyridyl (termed Ha44), which is being developed as a treatment for head lice, were evaluated in the Drosophila melanogaster model system. Ha44 demonstrated significant activity against embryos and was capable of arresting development at a number of stages of embryogenesis. The effects of Ha44 on embryos was shown to be reversible following the addition of the metal ions Fe(II) and Fe(III), Cu and Zn. When larvae were exposed to Ha44, lethality was recorded at similar concentrations to those observed for embryos. Using an eYFP reporter system it was shown that Ha44 was able to reduce the levels of both copper and zinc in the digestive tract, confirming the binding of Ha44 to these metals in vivo. Ha44 has further been shown to inhibit a zinc containing metalloproteinase in vitro. Exposure of adult flies to Ha44 resulted in lethality, but at higher concentrations than those observed for embryos and larvae. The median lethal dose in adult flies was shown to be associated with the type of exposure, with an LD-50 of 1.57 mM being recorded following the direct contact of flies with Ha44, while an LD-50 of 12.29 mM was recorded following the ingestion of the compound. The capacity of Ha44 to act on all stages of the life-cycle and potentially via a range of targets suggests that target site resistance is unlikely to evolve.     

蛇根木细胞悬浮培养进行紫杉醇的生物转化

通过理化及光谱学方法,从蛇根木(Rautwolfia serpentina(L.)Benth.et Kurz.)悬浮细胞内分离到3个紫杉醇同系物,高分辨1H-NMR和MS结构分析表明,它们分别为10-脱乙酰紫杉醇、baccatinⅢ和10-deacetylbaccatinⅢ.本实验未检测出紫杉醇的苷化或羟基化衍生物.     

Psoriasis patients are enriched for genetic variants that protect against HIV-1 disease

An important paradigm in evolutionary genetics is that of a delicate balance between genetic variants that favorably boost host control of infection but which may unfavorably increase susceptibility to autoimmune disease. Here, we investigated whether patients with psoriasis, a common immune-mediated disease of the skin, are enriched for genetic variants that limit the ability of HIV-1 virus to replicate after infection. We analyzed the HLA class I and class II alleles of 1,727 Caucasian psoriasis cases and 3,581 controls and found that psoriasis patients are significantly more likely than controls to have gene variants that are protective against HIV-1 disease. This includes several HLA class I alleles associated with HIV-1 control; amino acid residues at HLA-B positions 67, 70, and 97 that mediate HIV-1 peptide binding; and the deletion polymorphism rs67384697 associated with high surface expression of HLA-C. We also found that the compound genotype KIR3DS1 plus HLA-B Bw4-80I, which respectively encode a natural killer cell activating receptor and its putative ligand, significantly increased psoriasis susceptibility. This compound genotype has also been associated with delay of progression to AIDS. Together, our results suggest that genetic variants that contribute to anti-viral immunity may predispose to the development of psoriasis.     

People favour imperfect catching by assuming a stable world

The visual angle that is projected by an object (e.g. a ball) on the retina depends on the object's size and distance. Without further information, however, the visual angle is ambiguous with respect to size and distance, because equal visual angles can be obtained from a big ball at a longer distance and a smaller one at a correspondingly shorter distance. Failure to recover the true 3D structure of the object (e.g. a ball's physical size) causing the ambiguous retinal image can lead to a timing error when catching the ball. Two opposing views are currently prevailing on how people resolve this ambiguity when estimating time to contact. One explanation challenges any inference about what causes the retinal image (i.e. the necessity to recover this 3D structure), and instead favors a direct analysis of optic flow. In contrast, the second view suggests that action timing could be rather based on obtaining an estimate of the 3D structure of the scene. With the latter, systematic errors will be predicted if our inference of the 3D structure fails to reveal the underlying cause of the retinal image. Here we show that hand closure in catching virtual balls is triggered by visual angle, using an assumption of a constant ball size. As a consequence of this assumption, hand closure starts when the ball is at similar distance across trials. From that distance on, the remaining arrival time, therefore, depends on ball's speed. In order to time the catch successfully, closing time was coupled with ball's speed during the motor phase. This strategy led to an increased precision in catching but at the cost of committing systematic errors.     

Prediction of microbial growth rate versus biomass yield by a metabolic network with kinetic parameters

Identifying the factors that determine microbial growth rate under various environmental and genetic conditions is a major challenge of systems biology. While current genome-scale metabolic modeling approaches enable us to successfully predict a variety of metabolic phenotypes, including maximal biomass yield, the prediction of actual growth rate is a long standing goal. This gap stems from strictly relying on data regarding reaction stoichiometry and directionality, without accounting for enzyme kinetic considerations. Here we present a novel metabolic network-based approach, MetabOlic Modeling with ENzyme kineTics (MOMENT), which predicts metabolic flux rate and growth rate by utilizing prior data on enzyme turnover rates and enzyme molecular weights, without requiring measurements of nutrient uptake rates. The method is based on an identified design principle of metabolism in which enzymes catalyzing high flux reactions across different media tend to be more efficient in terms of having higher turnover numbers. Extending upon previous attempts to utilize kinetic data in genome-scale metabolic modeling, our approach takes into account the requirement for specific enzyme concentrations for catalyzing predicted metabolic flux rates, considering isozymes, protein complexes, and multi-functional enzymes. MOMENT is shown to significantly improve the prediction accuracy of various metabolic phenotypes in E. coli, including intracellular flux rates and changes in gene expression levels under different growth rates. Most importantly, MOMENT is shown to predict growth rates of E. coli under a diverse set of media that are correlated with experimental measurements, markedly improving upon existing state-of-the art stoichiometric modeling approaches. These results support the view that a physiological bound on cellular enzyme concentrations is a key factor that determines microbial growth rate.     

Colmation and Depth Filtration within Streambeds: Retention of Particles in Hyporheic Interstices

Colmation refers to the retention processes that can lead to the clogging of the top layer of channel sediments and decolmation refers to the resuspension of deposited fine particles. Internal colmation, clogging of the interstices directly below the armor layer, may form a thin seal that disconnects surface water from hyporheic water by inhibiting exchange processes. The settling of particles under low flow conditions can cause external colmation. Colmated channel sediments are characterized by reduced porosity and hydraulic conductivity as well as by a consolidated texture. The term ‘depth filtration’ refers to the transport and storage of fine matrix sediments in interstitial layers. Depth filtration is of significance for the transport of colloidal and fine particulate inorganic as well as organic matter within the hyporheic interstices and into the alluvial aquifer. The role of depth filtration is assessed for the content (given in mg per liter) of matrix fine particles retained in the coarse framework sediment of a gravel-bed river in Switzerland. Sediment samples were taken by freeze-coring with liquid nitrogen down to 70 cm depth and by piezometers down to 150 cm depth. Seventy-two percent of the mobile matrix fine particles were smaller than 0.1 mm and 50% were smaller than 0.03 mm. The content of fines tended to increase with depth, although higher accumulations were found at intermediate depths in sediments influenced by exfiltrating ground water. Interstitial detrital particles >90 μm showed vertical distribution patterns opposing those of total particles. These relationships revealed a differential significance of import, storage, and transport within three types of hydrological exchange zones (infiltration, horizontal advection, exfiltration) in the cross-section of the stream.