A novel series of 3-amino-1H-thieno[3,2-c]pyrazole derivatives demonstrating high potency in inhibiting Aurora kinases was developed. Here we describe the synthesis and a preliminary structure–activity relationship, which led to the discovery of a representative compound (38), which showed low nanomolar inhibitory activity in the anti-proliferation assay and was able to block the cell cycle in HCT-116 cell line. This compound demonstrated favorable pharmacokinetic properties and good efficacy in the HL-60 xenograft tumor model. 相似文献
The preparation and biological evaluation of a novel series of dimeric camptothecin derivatives are described. All the new compounds showed a significant ability to inhibit human tumor cell growth with IC(50) values ranging from 0.03 to 12.2 μM. The interference with the activity of the nuclear enzymes topoisomerases has been demonstrated, highlighting the poison effect of one of the obtained byproducts toward topoisomerase I. A moderate antiangiogenic activity has been demonstrated for one of the obtained compounds. Moreover, the effects of four new compounds on caspases activity and ROS generation have been studied on transgenic mouse cell. 相似文献
The sarcoglycan complex (SGC) is a multimember transmembrane complex interacting with other members of the dystrophin-glycoprotein complex (DGC) to provide a mechanosignaling connection from the cytoskeleton to the extracellular matrix. The SGC consists of four proteins (alpha, beta, gamma, and delta). A fifth sarcoglycan subunit, epsilon-sarcoglycan, shows a wider tissue distribution. Recently, a novel sarcoglycan, the zeta-sarcoglycan, has been identified. All reports about the structure of SGC showed a common assumption of a tetrameric arrangement of sarcoglycans. Addressing this issue, our immunofluorescence and molecular results showed, for the first time, that all sarcoglycans are always detectable in all observed samples. Therefore, one intriguing possibility is the existence of a pentameric or hexameric complex considering zeta-sarcoglycan of SGC, which could present a higher or lower expression of a single sarcoglycan in conformity with muscle type--skeletal, cardiac, or smooth--or also in conformity with the origin of smooth muscle. 相似文献
Large uncertainties in estimates of methane (CH4) emissions from tropical inland waters reflect the paucity of information at appropriate temporal and spatial scales. CH4 concentrations, diffusive and ebullitive fluxes, and environmental parameters in contrasting aquatic habitats of Lake Janauacá, an Amazon floodplain lake, measured for two years revealed patterns in temporal and spatial variability related to different aquatic habitats and environmental conditions. CH4 concentrations ranged from below detection to 96 µM, CH4 diffusive fluxes from below detection to 2342 µmol m−2 h−1, and CH4 ebullitive fluxes from 0 to 190 mmol m−2 d−1. Vegetated aquatic habitats had higher surface CH4 concentrations than open water habitats, and no significant differences in diffusive CH4 fluxes, likely due to higher k values measured in open water habitats. CH4 emissions were enhanced after a prolonged low water period, when the exposed sediments were colonized by herbaceous plants that decomposed after water levels rose, possibly fueling CH4 production. Statistical models indicated the importance of variables related to CH4 production (temperature, dissolved organic carbon) and consumption (dissolved nitrogen, oxygenated water column), as well as maximum depth, in controlling surface water CH4 concentrations.
Mapping the distribution of invasive species under current and future climate conditions is crucial to implement sustainable and effective conservation strategies. Several studies showed how invasive species may benefit from climate change fostering their invasion rate and, consequently, affecting the native species community. In the Canary Islands and on Tenerife in particular, previous research mostly focused on climate change impacts on the native communities, whereas less attention has been paid on alien species distribution under climate change scenarios. In this study, we modelled the habitat distribution of Pennisetum setaceum, one of the most invasive alien species on Tenerife. In addition, we described the species’ potential distribution shift in the light of two climate change scenarios (RCP2.6, RCP8.5), highlighting the areas that should be prioritized during management and eradication programs. P. setaceum’s suitable areas are located in the coastal area, with higher habitat suitability near cities and below 800 m asl. In both future climate change scenarios, the geographic distribution of P. setaceum suitable areas is characterized by an elevational shift, which is more pronounced in the RCP8.5 scenario. Despite being drought resistant, water supply is crucial for the species’ seed germination, thus supporting future species’ shift to higher elevation and in the north–north–west part of the island, where it could benefit from the combined effect of orographic precipitations and humidity carried by trade winds.
Leigh Van Valen famously stated that under constant conditions extinction probability is independent of species age. To test this 'law of constant extinction', we developed a new method using deep learning to infer age‐dependent extinction and analysed 450 myr of marine life across 21 invertebrate clades. We show that extinction rate significantly decreases with age in > 90% of the cases, indicating that most species died out soon after their appearance while those which survived experienced ever decreasing extinction risk. This age‐dependent extinction pattern is stronger towards the Equator and holds true when the potential effects of mass extinctions and taxonomic inflation are accounted for. These results suggest that the effect of biological interactions on age‐dependent extinction rate is more intense towards the tropics. We propose that the latitudinal diversity gradient and selection at the species level account for this exceptional, yet little recognised, macroevolutionary and macroecological pattern. 相似文献
The ability of styrene–maleic acid (SMAc) co-polymers to spontaneously insert into biological membranes can be exploited to extract G protein-coupled receptors (GPCRs) embedded in styrene–maleic acid lipid particles (SMALPs), preserving the native environment around the protein and thus enhancing the feasibility of functional studies. So far, the SMALP technology has been primarily employed on non-mammalian cells and protocols are not optimized for adherent human cell lines, which cannot be harvested in large amounts. In this work, a fine investigation of key parameters affecting the formation of SMALPs was undertaken with the purpose of maximizing the yield of extraction of a recombinant form of human β2-adrenergic receptor (rhβ2AR) from HEK293T cells. The study highlighted an important influence of ionic strength on the membrane solubilization efficiency and GPCR purification yield of SMAc co-polymers: by lowering the salt concentration of all buffers used in previously published SMALP protocols, the water solubility and extraction efficiency of the selected SMAc co-polymer (commercially supplied as a potassium salt) were enhanced. In-line combination of size-exclusion chromatography (SEC) with immobilized metal affinity chromatography (IMAC) allowed further improvement of the final rhβ2AR yield by reducing the loss of SMALP-embedded GPCRs during the fractionation and purification of SMALPs. The overall findings of this study show that the available SMALP protocols can be significantly optimized in several aspects in order to increase the efficiency of GPCR solubilization and isolation from low-yielding expression systems. 相似文献