Modern software engineering of electronic structure codes has seen a paradigm shift from monolithic workflows towards object-based modularity. Software objectivity allows for greater flexibility in ...the application of electronic structure calculations, with particular benefits when integrated with approaches for data-driven analysis. Here, we discuss different approaches to create "deep" modular interfaces that connect big-data workflows and electronic structure codes, and explore the diversity of use cases that they can enable. We present two such interface approaches for the semi-empirical electronic structure package, DFTB+. In one case, DFTB+ is applied as a library and provides data to an external workflow; and in another, DFTB+ receives data via external bindings and processes the information subsequently within an internal workflow. We provide a general framework to enable data exchange workflows for embedding new machine-learning-based Hamiltonians within DFTB+, or to enabling deep integration of DFTB+ in multiscale embedding workflows. These modular interfaces demonstrate opportunities in emergent software and workflows to accelerate scientific discovery by harnessing existing software capabilities.
The selenised yeast produced by Saccharomyces cerevisiae CNCM I‐3060 is authorized in the EU as a nutritional additive for all species. The current assessment was focused on the zootechnical ...consequences of the use of the additive claimed by the applicant. Concerning selenium deposition in animal tissues and products, the FEEDAP Panel concluded that (i) a certain increase of the selenium content of edible tissues and products is a characteristic consequence of Se supplementation to the diet principally independent from the source of dietary Se, (ii) Sel‐Plex® is more effective than sodium selenite, and (iii) the higher relative potency of Sel‐Plex® increases with higher Sel‐Plex® levels. The better availability of Se in Sel‐Plex® compared to other inorganic Se sources is based on the specific nutritional property of selenomethionine ‐ effects typical of nutritional additives. The FEEDAP Panel concluded further that (i) there was no evidence that dietary supplementation with Sel‐Plex® would further reduce lipid oxidation in meat or improve colour of animal products in comparison with inorganic Se, and (ii) the supplementation of feed with Se, regardless of the Se source, had no effect on the water binding capacity of meat. Consumer exposure was calculated for adults and children (age 1–3 years), based on P95 consumption values of consumers only from the Comprehensive European Food Consumption Database and adding background intake. Exposure of adults was below the UL (300 µg/day) for all Se supplementation levels and both Se sources. For children the likely total exposure after consuming milk, meat and eggs from animals treated with 0.2‐0.26 and 0.3‐0.35 mg Se/kg feed from Sel‐Plex® was 66 and 75 µg/day (UL: 60 µg/day), respectively. The FEEDAP Panel concluded that a maximum supplementation level of 0.2 mg Se/kg feed from Sel‐Plex® is unlikely to result in a health risk for consumers.
Lymphoblastoid cell lines (LCLs) are human B cells latently infected and immortalized by Epstein-Barr virus (EBV). Presenting viral antigens, they efficiently induce EBV-specific T-cell responses in ...vitro. Analogous ways to generate T-cell cultures specific for other antigens of interest are highly desirable. Previously, we constructed a mini-EBV plasmid that consists of less than half the EBV genome, is unable to cause virus production, but still immortalizes B cells in vitro. Mini-EBV–immortalized B-cell lines (mini-LCLs) are efficiently produced by infection of B cells with viruslike particles carrying only mini-EBV DNA. Mini-EBV plasmids can be engineered to express an additional gene in immortalized B cells. Here we present a mini-EBV coding for a potent CD8+ T-cell antigen, the matrix phosphoprotein pp65 of human cytomegalovirus (CMV). By means of this pp65 mini-EBV, pp65-expressing mini-LCLs could be readily established from healthy donors in a one-step procedure. We used these pp65 mini-LCLs to reactivate and expand effector T cells from autologous peripheral blood cells in vitro. When generated from cytomegalovirus (CMV)–seropositive donors, these effector T-cell cultures displayed strong pp65-specific HLA-restricted cytotoxicity. A large fraction of CD8+ T cells with pp65 epitope specificity was present in such cultures, as demonstrated by direct staining with HLA/peptide tetramers. We conclude that the pp65 mini-EBV is an attractive tool for CMV-specific adoptive immunotherapy. Mini-EBVs could also facilitate the generation of T cells specific for various other antigens of interest.
The function of heme proteins is, to a significant extent, influenced by the ligand field probed by the heme iron, which itself can be affected by deformations of the heme macrocycle. The exploration ...of this field is difficult because the heme structure obtained from X-ray crystallography is not resolved enough to unambiguously identify structural changes on the scale of 10-2 Å. However, asymmetric deformations in this order of magnitude affect the depolarization ratio of the resonance Raman lines assignable to normal vibrations of the heme group. We have measured the dispersion of the depolarization ratios of four structure sensitive Raman bands (i.e., ν4, ν11, ν21, and ν28) in yeast iso-1-ferrocytochrome c and its mutants N52V, Y67F, and N52VY67F with B- and Q-band excitation. The DPR dispersion of all bands indicates the presence of asymmetric in-plane and out-of-plane deformations. The replacement of the polar tyrosine residue at position 67 by phenylalanine significantly increases the triclinic B 2 g deformation, which involves a distortion of the pyrrole symmetry. We relate this deformation to changes of the electronic structure of pyrrole A, which modulates the interaction between its propionate substituents and the protein environment. This specific heme deformation is eliminated in the double mutant N52VY67F. The additional substitution of N52 by valine induces a tetragonal B 1 g deformation which involves asymmetric changes of the Fe−N distances and increases the rhombicity of the ligand field probed by the heme iron. This heme deformation might be caused by the elimination of the water−protein hydrogen-bonding network in the heme cavity. The single mutation N52V does not significantly perturb the heme symmetry, but a small B 1 g deformation is consistent with our data and the heme structure obtained from a 1 ns molecular dynamics simulation of the protein.
The irradiation of various tissue-like materials by therapeutic proton beams was simulated using Monte Carlo. The contribution of inelastic reaction products to the depth-dose distribution was ...determined. The use of silicon microdosimeters for verifying Monte Carlo calculations was also investigated. The importance of these studies to Monte Carlo-based treatment planning systems is emphasized.
The adsorption of mixtures of poly(diallyldimethylammonium chloride) (PDADMAC) and sodium N-lauroyl-N-methyltaurate (SLMT) at the water / vapor interface has been studied using drop profile ...tensiometry and neutron reflectometry. This study sheds light on the mechanisms involved in the adsorption of polyelectrolyte-oppositely charged surfactants by the characterization of both equilibrium and dynamics features associated with the layer formation at the fluid interface. The results are discussed in terms of an adsorption-equilibration of the interfacial layers as a two-step process: the initial stages involve the adsorption of polyelectrolyte-surfactant complexes formed in the bulk, and a subsequent stage involves reorganization of the interface. This work contributes to the understanding of the physico-chemical features of systems that undergo complex bulk and interfacial interactions with importance in science and technology.
The function of heme proteins is, to a significant extent, influenced by the ligand field probed by the heme iron, which itself can be affected by deformations of the heme macrocycle. The exploration ...of this field is difficult because the heme structure obtained from X-ray crystallography is not resolved enough to unambiguously identify structural changes on the scale of 10 super(-2) Aa. However, asymmetric deformations in this order of magnitude affect the depolarization ratio of the resonance Raman lines assignable to normal vibrations of the heme group. We have measured the dispersion of the depolarization ratios of four structure sensitive Raman bands (i.e., nu sub(4), nu sub(11), nu sub(21), and nu sub(28)) in yeast iso-1-ferrocytochrome c and its mutants N52V, Y67F, and N52VY67F with B- and Q-band excitation. The DPR dispersion of all bands indicates the presence of asymmetric in-plane and out-of-plane deformations. The replacement of the polar tyrosine residue at position 67 by phenylalanine significantly increases the triclinic B sub(2) sub(g) deformation, which involves a distortion of the pyrrole symmetry. We relate this deformation to changes of the electronic structure of pyrrole A, which modulates the interaction between its propionate substituents and the protein environment. This specific heme deformation is eliminated in the double mutant N52VY67F. The additional substitution of N52 by valine induces a tetragonal B sub(1) sub(g) deformation which involves asymmetric changes of the Fe-N distances and increases the rhombicity of the ligand field probed by the heme iron. This heme deformation might be caused by the elimination of the water-protein hydrogen-bonding network in the heme cavity. The single mutation N52V does not significantly perturb the heme symmetry, but a small B sub(1) sub(g) deformation is consistent with our data and the heme structure obtained from a 1 ns molecular dynamics simulation of the protein.
Eugenol, eugenyl acetate, 1‐methoxy‐4‐(prop‐1(trans)‐enyl)benzene (trans‐anethole) and 4‐allyl‐2, 6‐dimethoxyphenol are flavouring substances belonging to chemical group 18, defined as ...‘allylhydroxybenzenes’. All four additives are currently authorised for use as flavours in food and are naturally found in various herbs and plants. The use of eugenol and eugenyl acetate in fish is contra‐indicated. The range of use levels 5–25 mg/kg feed for eugenol and trans‐anethole proposed by the applicant is safe for all animal species (other than fish), with a low margin of safety (2 to 6). For 4‐allyl‐2, 6‐dimethoxyphenol and eugenyl acetate, the proposed range of use levels 1–5 mg/kg feed is safe for all animal species (other than fish), with a higher margin of safety (10 to 30). The use of eugenol, eugenyl acetate, trans‐anethole and 4‐allyl‐2, 6‐dimethoxyphenol as flavours in mammals up to the highest use levels proposed in feed is safe for the consumer. However, the lack of data on metabolism and residues in poultry precludes an assessment of consumer exposure from this source. No data on the safety for the user was provided. The applicant indicated possible effects of eugenol on the respiratory system. Eugenol and 4‐allyl‐2, 6‐dimethoxyphenol are also described as irritating to eyes and skin, and eugenyl acetate as a skin irritant. Both eugenol and trans‐anethole may cause skin sensitisation. The impact on the environment from the use of eugenol, eugenyl acetate, trans‐anethole and 4‐allyl‐2, 6‐dimethoxyphenol in animal feed is expected to be low. Since eugenol, eugenyl acetate, trans‐anethole and 4‐allyl‐2, 6‐dimethoxyphenol are used in food as flavourings, and their function in feed is essentially the same as that in food, no further demonstration of efficacy is considered necessary.
Purpose: To evaluate the efficacy and tolerability of levetiracetam as add-on therapy in patients with refractory partial-onset seizures in a protocol designed to reflect clinical practice.
Methods: ...All patients in this open-label, single-arm study entered an 8-week baseline period followed by a 4-week titration period and a 12-week maintenance period. Patients initially received levetiracetam 1000
mg/day (administered bid) and could increase to 2000
mg/day after 2 weeks, and to 3000
mg/day after another 2 weeks, to obtain adequate seizure control. During the 12-week maintenance period, the dose of levetiracetam could not be increased but could be decreased once if tolerability warranted. Seizure count and adverse events were recorded by patients in a diary. Quality of life and global evaluation of disease evolution were also evaluated.
Results: Ninety-nine patients were enrolled and 91 completed the study. A steady dose was maintained over the last 8 weeks of treatment or longer in 84 patients, with 89.3% of these patients receiving 3000
mg/day, 9.5% receiving 2000
mg/day, and 1.2% receiving 1000
mg/day. A 35.9% median percent reduction from baseline in weekly frequency of partial-onset seizures was observed over the entire treatment period. The median partial-onset seizure count decreased from 2.3 per week during the baseline period to 1.3 per week over the treatment period. A total of 42.4% of patients were responders (≥50% reduction from baseline in weekly seizure frequency) over the treatment period; two patients were seizure-free from the first day of treatment throughout the treatment period. The most frequent drug-related adverse events were fatigue (27.3% of patients), somnolence (11.1%), headache (8.1%), and dizziness (8.1%).
Conclusion: Levetiracetam as add-on therapy at doses up to 3000
mg/day effectively reduced the frequency of partial-onset seizures in patients with refractory epilepsy and was well-tolerated in this study, bridging conditions of placebo-controlled clinical trials and clinical practice.
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