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Amyloid‐β (Aβ)‐peptide, the major constituent of the plaques that develop during Alzheimer's disease, is generated via the cleavage of Aβ precursor protein (APP) by β‐site APP‐cleaving enzyme (BACE). Using live‐cell imaging of APP and BACE labeled with pH‐sensitive proteins, we could detect the release events of APP and BACE and their distinct kinetics. We provide kinetic evidence for the cleavage of APP by α‐secretase on the cellular surface after exocytosis. Furthermore, simultaneous dual‐color evanescent field illumination revealed that the two proteins are trafficked to the surface in separate compartments. Perturbing the membrane lipid composition resulted in a reduced frequency of exocytosis and affected BACE more strongly than APP. We propose that surface fusion frequency is a key factor regulating the aggregation of APP and BACE in the same membrane compartment and that this process can be modulated via pharmacological intervention.   相似文献   
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Thylakoid energy metabolism is crucial for plant growth, development and acclimation. Non‐appressed thylakoids harbor several high molecular mass pigment–protein megacomplexes that have flexible compositions depending upon the environmental cues. This composition is important for dynamic energy balancing in photosystems (PS) I and II. We analysed the megacomplexes of Arabidopsis wild type (WT) plants and of several thylakoid regulatory mutants. The stn7 mutant, which is defective in phosphorylation of the light‐harvesting complex (LHC) II, possessed a megacomplex composition that was strikingly different from that of the WT. Of the nine megacomplexes in total for the non‐appressed thylakoids, the largest megacomplex in particular was less abundant in the stn7 mutant under standard growth conditions. This megacomplex contains both PSI and PSII and was recently shown to allow energy spillover between PSII and PSI (Nat. Commun., 6, 2015, 6675). The dynamics of the megacomplex composition was addressed by exposing plants to different light conditions prior to thylakoid isolation. The megacomplex pattern in the WT was highly dynamic. Under darkness or far red light it showed low levels of LHCII phosphorylation and resembled the stn7 pattern; under low light, which triggers LHCII phosphorylation, it resembled that of the tap38/pph1 phosphatase mutant. In contrast, solubilization of the entire thylakoid network with dodecyl maltoside, which efficiently solubilizes pigment–protein complexes from all thylakoid compartments, revealed that the pigment–protein composition remained stable despite the changing light conditions or mutations that affected LHCII (de)phosphorylation. We conclude that the composition of pigment–protein megacomplexes specifically in non‐appressed thylakoids undergoes redox‐dependent changes, thus facilitating maintenance of the excitation balance between the two photosystems upon changes in light conditions.  相似文献   
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We have developed a series of orally efficacious IRAK4 inhibitors, based on a scaffold hopping strategy and using rational structure based design. Efforts to tackle low permeability and high efflux in our previously reported pyrrolopyrimidine series (Scott et al., 2017) led to the identification of pyrrolotriazines which contained one less formal hydrogen bond donor and were intrinsically more lipophilic. Further optimisation of substituents on this pyrrolotriazine core culminated with the discovery of 30 as a promising in vivo probe to assess the potential of IRAK4 inhibition for the treatment of MyD88 mutant DLBCL in combination with a BTK inhibitor. When tested in an ABC-DLBCL model with a dual MyD88/CD79 mutation (OCI-LY10), 30 demonstrated tumour regressions in combination with ibrutinib.  相似文献   
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Our understanding of arthropod responses to environmental pressures is limited, especially for the poorly studied Mediterranean region. In the light of likely further environmental change and the need for protocols for rapid biodiversity assessment, we measured how the abundance and species richness of two taxa, ground spiders and Orthoptera, belonging to different functional groups, fluctuates intra- seasonally (early-mid-late summer) and across habitat types (grasslands, maquis, forests). We also tested their surrogate value. Spiders were found to have higher species richness and abundance almost throughout the investigation. Orthoptera had lower species richness and abundance in forests compared to grasslands and maquis, while no significant difference between habitats was revealed for spiders. Early-summer was the richest period for spiders while mid-summer was the richest for Orthoptera. Canopy cover was found to significantly influence community composition of both groups, while herb height and cover of stones was a determinant factor for Orthoptera only. There was a significant congruence between the two groups and Orthoptera provided the best complementary network. Our results show that diversity patterns of both spiders and Orthoptera are sensitive to environmental changes even over short time-scales (e.g. within the summer period) and space (e.g. across different habitat types), suggesting that small inexpensive experimental designs may still reveal community dynamics. For conservation purposes, we advise a focus on variables regulating habitat heterogeneity and microhabitat characteristics. We provide a list of the most influential species and propose the most effective network for obtaining information on the local fauna.  相似文献   
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Recent research suggests that attributions of aliveness and mental capacities to faces are influenced by social group membership. In this article, we investigated group related biases in mind perception in participants from a Western and Eastern culture, employing faces of varying ethnic groups. In Experiment 1, Caucasian faces that ranged on a continuum from real to artificial were evaluated by participants in the UK (in-group) and in India (out-group) on animacy, abilities to plan and to feel pain, and having a mind. Human features were found to be assigned to a greater extent to faces when these belonged to in-group members, whereas out-group faces had to appear more realistic in order to be perceived as human. When participants in India evaluated South Asian (in-group) and Caucasian (out-group) faces in Experiment 2, the results closely mirrored those of the first experiment. For both studies, ratings of out-group faces were significantly predicted by participants’ levels of ethnocultural empathy. The findings highlight the role of intergroup processes (i.e., in-group favoritism, out-group dehumanization) in the perception of human and mental qualities and point to ethnocultural empathy as an important factor in responses to out-groups.  相似文献   
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