Mechanistic investigation of halopentaaquachromium(III) complexes: Comparison of computational and experimental results

The mechanism for the substitution reactions of halopentaaquachromium(III) complexes in the series, [CrX(H2O)5]2+, where X = F−, Cl−, Br−, or I− have been investigated using density functional theory. Several different mechanistic pathways were explored including associative interchange (Ia), dissociative (D) and the associatively activated dissociation mechanisms (Da). The lowest overall activation enthalpy (ΔH‡) obtained for the fluoride system is for the Ia pathway, with immediate proton abstraction leading to the formation of HF and the conjugate base. For the chloride, bromide and iodide systems the Da pathway has the lowest ΔH‡ values. Activation enthalpies determined at the PBE0/cc-pVDZ level, in aqueous solution (PCM), are in excellent agreement with the experimental results (MAD is 1.0 kJ mol−1). Reaction profiles were analyzed in terms of activation volumes to explain the observed trends

Investigation of mono-, bis- and tris-glycinatochromium(III): Comparisons of computational and experimental results

The synthesis and characterization of mono-, bis- and tris-glycinatochromium(III) complexes by elemental analysis, UV–Vis, electron paramagnetic resonance (EPR), ATR-FTIR and Raman spectroscopy has been performed in this work. IR stretching bands obtained from DFT calculations of the mono-, bis- and tris-glycinatochromium(III) complexes are in good agreement with experimental data. Different mechanistic pathways were explored for the water exchange reactions of [Cr(+NH3CH2COO−)(H2O)5]3+ and its conjugate base species including, associative interchange (Ia), and dissociative (D) mechanisms. The lowest activation enthalpies for the mono- and bis-complexes are obtained for the Ia pathways with explicit outer sphere solvation (88 and 76 kJ mol−1), which are in good agreement with the experimental values (87 and 75 kJ mol−1). In comparison, tris-glycinatochromium(III) undergoes aquation via the dissociative (D) mechanism. Investigation of these systems in the pH range ∼3.0 to ∼8.5 by UV–Vis monitoring, helps identify the speciation of these complexes in physiological environments

Engineered binding to erythrocytes induces immunological tolerance to E. coli asparaginase.

Antigen-specific immune responses to protein drugs can hinder efficacy and compromise safety because of drug neutralization and secondary clinical complications. We report a tolerance induction strategy to prevent antigen-specific humoral immune responses to therapeutic proteins. Our modular, biomolecular approach involves engineering tolerizing variants of proteins such that they bind erythrocytes in vivo upon injection, on the basis of the premise that aged erythrocytes and the payloads they carry are cleared tolerogenically, driving the deletion of antigen-specific T cells. We demonstrate that binding the clinical therapeutic enzyme Escherichia coli l-asparaginase to erythrocytes in situ antigen-specifically abrogates development of antibody titers by >1000-fold and extends the pharmacodynamic effect of the drug 10-fold in mice. Additionally, a single pretreatment dose of erythrocyte-binding asparaginase tolerized mice to multiple subsequent doses of the wild-type enzyme. This strategy for reducing antigen-specific humoral responses may enable more effective and safer treatment with therapeutic proteins and drug candidates that are hampered by immunogenicity

Increased yield stability of field-grown winter barley (Hordeum vulgare L.) varietal mixtures through ecological processes

Crop variety mixtures have the potential to increase yield stability in highly variable and unpredictable environments, yet knowledge of the specific mechanisms underlying enhanced yield stability has been limited. Ecological processes in genetically diverse crops were investigated by conducting field trials with winter barley varieties (Hordeum vulgare), grown as monocultures or as three-way mixtures in fungicide treated and untreated plots at three sites. Mixtures achieved yields comparable to the best performing monocultures whilst enhancing yield stability despite being subject to multiple predicted and unpredicted abiotic and biotic stresses including brown rust (Puccinia hordei) and lodging. There was compensation through competitive release because the most competitive variety overyielded in mixtures thereby compensating for less competitive varieties. Facilitation was also identified as an important ecological process within mixtures by reducing lodging. This study indicates that crop varietal mixtures have the capacity to stabilise productivity even when environmental conditions and stresses are not predicted in advance. Varietal mixtures provide a means of increasing crop genetic diversity without the need for extensive breeding efforts. They may confer enhanced resilience to environmental stresses and thus be a desirable component of future cropping systems for sustainable arable farming

Self Consistent Molecular Field Theory for Packing in Classical Liquids

Building on a quasi-chemical formulation of solution theory, this paper proposes a self consistent molecular field theory for packing problems in classical liquids, and tests the theoretical predictions for the excess chemical potential of the hard sphere fluid. Results are given for the self consistent molecular fields obtained, and for the probabilities of occupancy of a molecular observation volume. For this system, the excess chemical potential predicted is as accurate as the most accurate prior theories, particularly the scaled particle (Percus-Yevick compressibility) theory. It is argued that the present approach is particularly simple, and should provide a basis for a molecular-scale description of more complex solutions.Comment: 6 pages and 5 figure

An Immunocompetent Mouse Model of HPV16(+) Head and Neck Squamous Cell Carcinoma

The incidence of human papilloma virus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) is increasing and implicated in more than 60% of all oropharyngeal carcinomas (OPSCCs). Although whole-genome, transcriptome, and proteome analyses have identified altered signaling pathways in HPV-induced HNSCCs, additional tools are needed to investigate the unique pathobiology of OPSCC. Herein, bioinformatics analyses of human HPV(+) HNSCCs revealed that all tumors express full-length E6 and identified molecular subtypes based on relative E6 and E7 expression levels. To recapitulate the levels, stoichiometric ratios, and anatomic location of E6/E7 expression, we generated a genetically engineered mouse model whereby balanced expression of E6/E7 is directed to the oropharyngeal epithelium. The addition of a mutant PIK3CAE545K allele leads to the rapid development of pre-malignant lesions marked by immune cell accumulation, and a subset of these lesions progress to OPSCC. This mouse provides a faithful immunocompetent model for testing treatments and investigating mechanisms of immunosuppression

fMRI-Targeted High-Angular Resolution Diffusion MR Tractography to Identify Functional Language Tracts in Healthy Controls and Glioma Patients

Background MR Tractography enables non-invasive preoperative depiction of language subcortical tracts, which is crucial for the presurgical work-up of brain tumors; however, it cannot evaluate the exact function of the fibers. Purpose A systematic pipeline was developed to combine tractography reconstruction of language fiber bundles, based on anatomical landmarks (Anatomical-T), with language fMRI cortical activations. A fMRI-targeted Tractography (fMRI-T) was thus obtained, depicting the subsets of the anatomical tracts whose endpoints are located inside a fMRI activation. We hypothesized that fMRI-T could provide additional functional information regarding the subcortical structures, better reflecting the eloquent white matter structures identified intraoperatively. Methods Both Anatomical-T and fMRI-T of language fiber tracts were performed on 16 controls and preoperatively on 16 patients with left-hemisphere brain tumors, using a q-ball residual bootstrap algorithm based on High Angular Resolution Diffusion Imaging (HARDI) datasets (b = 3000 s/mm(2); 60 directions); fMRI ROIs were obtained using picture naming, verbal fluency, and auditory verb generation tasks. In healthy controls, normalized MNI atlases of fMRI-T and Anatomical-T were obtained. In patients, the surgical resection of the tumor was pursued by identifying eloquent structures with intraoperative direct electrical stimulation mapping and extending surgery to the functional boundaries. Post-surgical MRI allowed to identify Anatomical-T and fMRI-T non-eloquent portions removed during the procedure. Results MNI Atlases showed that fMRI-T is a subset of Anatomical-T, and that different task-specific fMRI-T involve both shared subsets and task-specific subsets - e.g., verbal fluency fMRI-T strongly involves dorsal frontal tracts, consistently with the phonogical-articulatory features of this task. A quantitative analysis in patients revealed that Anatomical-T removed portions of AF-SLF and IFOF were significantly greater than verbal fluency fMRI-T ones, suggesting that fMRI-T is a more specific approach. In addition, qualitative analyses showed that fMRI-T AF-SLF and IFOF predict the exact functional limits of resection with increased specificity when compared to Anatomical-T counterparts, especially the superior frontal portion of IFOF, in a subcohort of patients. Conclusion These results suggest that performing fMRI-T in addition to the 'classic' Anatomical-T may be useful in a preoperative setting to identify the 'high-risk subsets' that should be spared during the surgical procedure

DT/T beyond linear theory

The major contribution to the anisotropy of the temperature of the Cosmic Microwave Background (CMB) radiation is believed to come from the interaction of linear density perturbations with the radiation previous to the decoupling time. Assuming a standard thermal history for the gas after recombination, only the gravitational field produced by the linear density perturbations present on a $\Omega\neq 1$ universe can generate anisotropies at low z (these anisotropies would manifest on large angular scales). However, secondary anisotropies are inevitably produced during the nonlinear evolution of matter at late times even in a universe with a standard thermal history. Two effects associated to this nonlinear phase can give rise to new anisotropies: the time-varying gravitational potential of nonlinear structures (Rees-Sciama RS effect) and the inverse Compton scattering of the microwave photons with hot electrons in clusters of galaxies (Sunyaev-Zeldovich SZ effect). These two effects can produce distinct imprints on the CMB temperature anisotropy. We discuss the amplitude of the anisotropies expected and the relevant angular scales in different cosmological scenarios. Future sensitive experiments will be able to probe the CMB anisotropies beyong the first order primary contribution.Comment: plain tex, 16 pages, 3 figures. Proceedings of the Laredo Advance School on Astrophysics "The universe at high-z, large-scale structure and the cosmic microwave background". To be publised by Springer-Verla

Pioneer neutrophils release chromatin within in vivo swarms

Neutrophils are rapidly recruited to inflammatory sites where their coordinated migration forms clusters, a process termed neutrophil swarming. The factors that modulate early stages of neutrophil swarming are not fully understood, requiring the development of new in vivo models. Using transgenic zebrafish larvae to study endogenous neutrophil migration in a tissue damage model, we demonstrate that neutrophil swarming is a conserved process in zebrafish immunity, sharing essential features with mammalian systems. We show that neutrophil swarms initially develop around an individual pioneer neutrophil. We observed the violent release of extracellular cytoplasmic and nuclear fragments by the pioneer and early swarming neutrophils. By combining in vitro and in vivo approaches to study essential components of neutrophil extracellular traps (NETs), we provide in-depth characterisation and high-resolution imaging of the composition and morphology of these release events. Using a photoconversion approach to track neutrophils within developing swarms, we identify that the fate of swarm-initiating pioneer neutrophils involves extracellular chromatin release and that the key NET components gasdermin, neutrophil elastase, and myeloperoxidase are required for the swarming process. Together our findings demonstrate that release of cellular components by pioneer neutrophils is an initial step in neutrophil swarming at sites of tissue injury

Measurement of the polarisation of W bosons produced with large transverse momentum in pp collisions at sqrt(s) = 7 TeV with the ATLAS experiment

This paper describes an analysis of the angular distribution of W->enu and W->munu decays, using data from pp collisions at sqrt(s) = 7 TeV recorded with the ATLAS detector at the LHC in 2010, corresponding to an integrated luminosity of about 35 pb^-1. Using the decay lepton transverse momentum and the missing transverse energy, the W decay angular distribution projected onto the transverse plane is obtained and analysed in terms of helicity fractions f0, fL and fR over two ranges of W transverse momentum (ptw): 35 < ptw < 50 GeV and ptw > 50 GeV. Good agreement is found with theoretical predictions. For ptw > 50 GeV, the values of f0 and fL-fR, averaged over charge and lepton flavour, are measured to be : f0 = 0.127 +/- 0.030 +/- 0.108 and fL-fR = 0.252 +/- 0.017 +/- 0.030, where the first uncertainties are statistical, and the second include all systematic effects.Comment: 19 pages plus author list (34 pages total), 9 figures, 11 tables, revised author list, matches European Journal of Physics C versio