Molecular Tweezers with Varying Anions: A Comparative Study

Selective binding of the phosphate-substituted molecular tweezer 1a to protein lysine residues was suggested to explain the inhibition of certain enzymes and the aberrant aggregation of amyloid petide Aβ42 or α-synuclein, which are assumed to be responsible for Alzheimer’s and Parkinson’s disease, respectively. In this work we systematically investigated the binding of four water-soluble tweezers 1a−d (substituted by phosphate, methanephosphonate, sulfate, or O-methylenecarboxylate groups) to amino acids and peptides containing lysine or arginine residues by using fluorescence spectroscopy, NMR spectroscopy, and isothermal titration calorimetry (ITC). The comparison of the experimental results with theoretical data obtained by a combination of QM/MM and ab initio 1H NMR shift calculations provides clear evidence that the tweezers 1a−c bind the amino acid or peptide guest molecules by threading the lysine or arginine side chain through the tweezers’ cavity, whereas in the case of 1d the guest molecule is preferentially positioned outside the tweezer’s cavity. Attractive ionic, CH-π, and hydrophobic interactions are here the major binding forces. The combination of experiment and theory provides deep insight into the host−guest binding modes, a prerequisite to understanding the exciting influence of these tweezers on the aggregation of proteins and the activity of enzymes

Hygienization and control of Diplodia seriata fungus in vine pruning waste composting and its seasonal variability in open and closed systems

After the ban on sodium arsenite, waste management alternatives to the prevalent burning method, such as the hygienization and biodegradation in solid phase by composting, are required for the pruned material from grapevines affected by various fungi. In this work the dynamics of a fungus associated with vine decay (Diplodia seriata) during the composting process of a mixture of laying hen manure and vine pruning waste (2:1 w/w) have been investigated in an open pile and a discontinuous closed biodigester. Through the optimization of the various physical–chemical parameters, hygienization of the infected waste materials was attained, yielding class-A organo-mineral fertilizers. Nevertheless, important differences in the efficiency of each system were observed: whereas in the open pile it took 10 days to control D. seriata and 35 additional composting days to achieve full inactivation, in the discontinuous biodigester the fungus was entirely inactivated within the first 3–7 days. Finally, the impact of seasonal variability was assessed and summer temperatures shown to have greater significance in the open pile

Sub-barrier fusion of 6He with 206Pb

Cross-sections for the production of 210Po nuclei in 6He + 206Pb collisions over the incident energy range 14–18MeV were measured by means of the activation technique and a radiochemical analysis. The elastic scattering at 18.0MeV was also measured providing a precise value for the 210Po production cross-section at this energy. The results are at variance with the earlier experimental data and rather in accord with the predictions of a density-dependent barrier penetration model for the fusion process. A proper treatment of beam energy distribution for the evaluation of the activation data is discussed

Breakup and neutron-transfer effects on 6He+206Pb elastic scattering below the Coulomb barrier

The elastic scattering and inclusive α-particle yield for the 6He + 206Pb system at an incident energy of 18 MeV, just below the nominal Coulomb barrier, have been measured. The α-particle yield at forward angles is also reported. The data are analyzed by means of continuum-discretized coupled-channels, distorted wave Born approximation, and coupled reaction channels calculations. Couplings to the one-neutron- and two-neutron-transfer reactions are found to be able to account for most of the absorption in the entrance channel.This work was supported in part by Grant No. FPA2010-22131-C02-01 from the Spanish Ministry of Science.Departamento de Física AplicadaDepartamento de Ingeniería Eléctrica y Térmic

“Proteotranscriptomic analysis of advanced colorectal cancer patient derived organoids for drug sensitivity prediction”

BACKGROUND: Patient-derived organoids (PDOs) from advanced colorectal cancer (CRC) patients could be a key platform to predict drug response and discover new biomarkers. We aimed to integrate PDO drug response with multi-omics characterization beyond genomics. METHODS: We generated 29 PDO lines from 22 advanced CRC patients and provided a morphologic, genomic, and transcriptomic characterization. We performed drug sensitivity assays with a panel of both standard and non-standard agents in five long-term cultures, and integrated drug response with a baseline proteomic and transcriptomic characterization by SWATH-MS and RNA-seq analysis, respectively. RESULTS: PDOs were successfully generated from heavily pre-treated patients, including a paired model of advanced MSI high CRC deriving from pre- and post-chemotherapy liver metastasis. Our PDOs faithfully reproduced genomic and phenotypic features of original tissue. Drug panel testing identified differential response among PDOs, particularly to oxaliplatin and palbociclib. Proteotranscriptomic analyses revealed that oxaliplatin non-responder PDOs present enrichment of the t-RNA aminoacylation process and showed a shift towards oxidative phosphorylation pathway dependence, while an exceptional response to palbociclib was detected in a PDO with activation of MYC and enrichment of chaperonin T-complex protein Ring Complex (TRiC), involved in proteome integrity. Proteotranscriptomic data fusion confirmed these results within a highly integrated network of functional processes involved in differential response to drugs. CONCLUSIONS: Our strategy of integrating PDOs drug sensitivity with SWATH-mass spectrometry and RNA-seq allowed us to identify different baseline proteins and gene expression profiles with the potential to predict treatment response/resistance and to help in the development of effective and personalized cancer therapeutics

Functional upgrading in China’s export processing sector

Functional upgrading occurs when a firm acquires more sophisticated functions within an existing value chain. In this paper, we analyze if there is evidence of this type of upgrading in China’s export processing regime by investigating dynamics in the relative prevalence of Import & Assembly (IA) versus Pure Assembly (PA) processing trade over the period 2000-2013. Firms in both regimes provide similar manufacturing services to foreign companies, but IA firms also conduct the sophisticated tasks of quality control, searching, financing and storing imported materials. Consistent with a trend of functional upgrading, we show that the share of IA trade in total processing trade has increased rapidly during the period 2000-2006, both overall and within product categories. Furthermore, we find that this trend has gone hand in hand with improvements in a sector’s labor productivity and unit values. Against expectations, we find that this process has slowed down notably during the period 2006-2013.status: publishe

Measurement of the Depth of Maximum of Extensive Air Showers above 10^18 eV

We describe the measurement of the depth of maximum, Xmax, of the longitudinal development of air showers induced by cosmic rays. Almost four thousand events above 10^18 eV observed by the fluorescence detector of the Pierre Auger Observatory in coincidence with at least one surface detector station are selected for the analysis. The average shower maximum was found to evolve with energy at a rate of (106 +35/-21) g/cm^2/decade below 10^(18.24 +/- 0.05) eV and (24 +/- 3) g/cm^2/decade above this energy. The measured shower-to-shower fluctuations decrease from about 55 to 26 g/cm^2. The interpretation of these results in terms of the cosmic ray mass composition is briefly discussed.Comment: Accepted for publication by PR