Thermodynamics of the Heusler alloy Co_2-xMn_1+xSi: a combined density functional theory and cluster expansion study

Previous studies indicated that intrinsic point defects play a crucial role for the density of states of ferromagnetic half-metals in the band gap region: At large concentrations, defect-derived bands might close the gap at the Fermi energy in the minority spin channel. In this work, structural disorder in the Co- and Mn-sublattices of the full Heusler alloy Co_2-xMn_1+xSi (-1 < x < 2) is investigated with a cluster expansion approach, parametrized using all-electron density functional theory calculations. By establishing two separate cluster expansions, one for the formation energy and one for the total spin moment, we are in position to determine the stability of different configurations, to predict new (also half-metallic) ground states and to extend the known Slater-Pauling rule for ideally stoichiometric Heusler alloys to non-stoichiometric, Mn-rich compositions. This enables us to identify potentially half-metallic structures in the Mn-rich region. With the help of Monte Carlo simulations based on the cluster expansion, we establish theoretically that Co_2-xMn_1+xSi close to the stoichiometric composition ought to show a high degree of structural order in thermodynamic equilibrium. Hence, samples prepared with the correct stoichiometry should indeed be half-metallic after thermal annealing. Moreover, we predict that adding a small amount of Mn to stoichiometric Co_2MnSi allows to suppress the thermally activated formation of detrimental Co antisites. At Mn-rich compositions (x>1), the ordered ground state structures predicted for zero temperature are found to be thermally unstable and to decompose into Co2MnSi and Mn3Si above room temperature.Comment: 10 pages, 10 figures, typos fixe

To what extent are psychiatrists aware of the comorbid somatic illnesses of their patients with serious mental illnesses? – a cross-sectional secondary data analysis

Background Somatic comorbidities are a serious problem in patients with severe mental illnesses. These comorbidities often remain undiagnosed for a long time. In Germany, physicians are not allowed to access patients’ health insurance data and do not have routine access to documentation from other providers of health care. Against this background, the objective of this article was to investigate psychiatrists’ knowledge of relevant somatic comorbidities in their patients with severe mental illnesses. Methods Cross- sectional secondary data analysis was performed using primary data from a prospective study evaluating a model of integrated care of patients with serious mental illnesses. The primary data were linked with claims data from health insurers. Patients’ diagnoses were derived on the basis of the ICD-10 and the Anatomical Therapeutic Chemical (ATC) classification system. Diabetes, hypertension, coronary artery disease (CAD), hyperlipidaemia, glaucoma, osteoporosis, polyarthritis and chronic obstructive pulmonary disease (COPD) were selected for evaluation. We compared the number of diagnoses reported in the psychiatrists’ clinical report forms with those in the health insurance data. Results The study evaluated records from 1,195 patients with severe mental illnesses. The frequency of documentation of hypertension ranged from 21% in claims data to 4% in psychiatrists’ documentation, for COPD from 12 to 0%, respectively, and for diabetes from 7 to 2%, respectively. The percentage of diagnoses deduced from claims data but not documented by psychiatrists ranged from 68% for diabetes and 83% for hypertension, to 90% for CAD to 98% for COPD. Conclusions The majority of psychiatrists participating in the integrated care programme were insufficiently aware of the somatic comorbidities of their patients. We support allowing physicians to access patients’ entire medical records to increase their knowledge of patients’ medical histories and, consequently, to increase the safety and quality of care

Synthesis of Novel Aza‐aromatic Curcuminoids with Improved Biological Activities towards Various Cancer Cell Lines

Curcumin, a natural compound extracted from the rhizomes of Curcuma longa, displays pronounced anticancer properties but lacks good bioavailability and stability. In a previous study, we initiated structure modification of the curcumin scaffold by imination of the labile -diketone moiety to produce novel -enaminone derivatives. These compounds showed promising properties for elaborate follow-up studies. In this work, we focused on another class of nitrogen-containing curcuminoids with a similar objective: to address the bioavailability and stability issues and to improve the biological activity of curcumin. This paper thus reports on the synthesis of new pyridine-, indole-, and pyrrole-based curcumin analogues (aza-aromatic curcuminoids) and discusses their water solubility, antioxidant activity, and antiproliferative properties. In addition, multivariate statistics, including hierarchical clustering analysis and principal component analysis, were performed on a broad set of nitrogen-containing curcuminoids. Compared to their respective mother structures, that is, curcumin and bisdemethoxycurcumin, all compounds, and especially the pyridin-3-yl -enaminone analogues, showed better water solubility profiles. Interestingly, the pyridine-, indole-, and pyrrole-based curcumin derivatives demonstrated improved biological effects in terms of mitochondrial activity impairment and protein content, in addition to comparable or decreased antioxidant properties. Overall, the biologically active N-alkyl -enaminone aza-aromatic curcuminoids were shown to offer a desirable balance between good solubility and significant bioactivity

Defect Formation Energies without the Band-Gap Problem: Combining DFT and GW for the Silicon Self-Interstitial

We present an improved method to calculate defect formation energies that overcomes the band-gap problem of Kohn-Sham density-functional theory (DFT) and reduces the self-interaction error of the local-density approximation (LDA) to DFT. We demonstrate for the silicon self-interstitial that combining LDA with quasiparticle energy calculations in the G0W0 approach increases the defect formation energy of the neutral charge state by ~1.1 eV, which is in good agreement with diffusion Monte Carlo calculations (E. R. Batista et al. Phys. Rev. B 74, 121102(R) (2006), W.-K. Leung et al. Phys. Rev. Lett. 83, 2351 (1999)). Moreover, the G0W0-corrected charge transition levels agree well with recent measurements.Comment: 4 pages including 3 figures; related publications can be found at http://www.fhi-berlin.mpg.de/th/th.htm

Synthesis of non‐symmetrical nitrogen‐containing curcuminoids in the pursuit of new anticancer candidates

Curcumin is known to display pronounced anticancer effects and a variety of other biological activities. However, the low bioavailability and fast metabolism of this molecule present an issue of concern with respect to its medicinal applications. To address this issue, structural modifications of the curcumin scaffold can be envisioned as a strategy to improve both the solubility and stability of this chemical entity, without compromising its biological activities. Previous work in our group targeted the synthesis of symmetrical azaheteroaromatic curcuminoids, which showed better solubility and cytotoxicity profiles compared to curcumin. In continuation of that work, we now focused on the synthesis of non-symmetrical nitrogen-containing curcuminoids bearing both a phenolic and an azaheteroaromatic moiety. In that way, we aimed to combine good solubility, antioxidant potential and cytotoxic properties into one molecule. Some derivatives were selected for further chemical modification of their rather labile beta-diketone scaffold to the corresponding pyrazole moiety. In this way, thirteen new non-symmetrical aza-aromatic curcuminoids and four pyrazolebased analogues were successfully synthesized in a yield of 11-69%. All newly synthesized analogues were evaluated for their antioxidant properties, reactive oxygen species (ROS) production, water solubility and anticancer activities. Several novel derivatives displayed good cytotoxicity profiles compared to curcumin, in combination with an improved water solubility and stability, and were thus identified as potential hit scaffolds for further optimization studies

Synthesis and biological evaluation of novel quinoline-piperidine scaffolds as antiplasmodium agents

The parasitic disease malaria places almost half of the world's population at risk of infection and is responsible for more than 400,000 deaths each year. The first-line treatment, artemisinin combination therapies (ACT) regimen, is under threat due to emerging resistance of Plasmodium falciparum strains in e.g. the Mekong delta. Therefore, the development of new antimalarial agents is crucial in order to circumvent the growing resistance. Chloroquine, the long-established antimalarial drug, still serves as model compound for the design of new quinoline analogues, resulting in numerous new active derivatives against chloroquine-resistant P. falciparum strains over the past twenty years. In this work, a set of functionalized quinoline analogues, decorated with a modified piperidine-containing side chain, was synthesized. Both amino- and (aminomethyl)quinolines were prepared, resulting in a total of 18 novel quinoline-piperidine conjugates representing four different chemical series. Evaluation of their in vitro antiplasmodium activity against a CQ-sensitive (NF54) and a CQ-resistant (K1) strain of P. falciparum unveiled highly potent activities in the nanomolar range against both strains for five 4-aminoquinoline derivatives. Moreover, no cytotoxicity was observed for all active compounds at the maximum concentration tested. These five new aminoquinoline hit structures are therefore of considerable value for antimalarial research and have the potency to be transformed into novel antimalarial agents upon further hit-to-lead optimization studies

Precision of bone mechanoregulation assessment in humans using longitudinal high-resolution peripheral quantitative computed tomography in vivo.

Local mechanical stimuli in the bone microenvironment are essential for the homeostasis and adaptation of the skeleton, with evidence suggesting that disruption of the mechanically-driven bone remodelling process may lead to bone loss. Longitudinal clinical studies have shown the combined use of high-resolution peripheral quantitative computed tomography (HR-pQCT) and micro-finite element analysis can be used to measure load-driven bone remodelling in vivo; however, quantitative markers of bone mechanoregulation and the precision of these analyses methods have not been validated in human subjects. Therefore, this study utilised participants from two cohorts. A same-day cohort (n = 33) was used to develop a filtering strategy to minimise false detections of bone remodelling sites caused by noise and motion artefacts present in HR-pQCT scans. A longitudinal cohort (n = 19) was used to develop bone imaging markers of trabecular bone mechanoregulation and characterise the precision for detecting longitudinal changes in subjects. Specifically, we described local load-driven formation and resorption sites independently using patient-specific odds ratios (OR) and 99 % confidence intervals. Conditional probability curves were computed to link the mechanical environment to the remodelling events detected on the bone surface. To quantify overall mechanoregulation, we calculated a correct classification rate measuring the fraction of remodelling events correctly identified by the mechanical signal. Precision was calculated as root-mean-squared averages of the coefficient of variation (RMS-SD) of repeated measurements using scan-rescan pairs at baseline combined with a one-year follow-up scan. We found no significant mean difference (p < 0.01) between scan-rescan conditional probabilities. RMS-SD was 10.5 % for resorption odds, 6.3 % for formation odds, and 1.3 % for correct classification rates. Bone was most likely to be formed in high-strain and resorbed in low-strain regions for all participants, indicating a consistent, regulated response to mechanical stimuli. For each percent increase in strain, the likelihood of bone resorption decreased by 2.0 ± 0.2 %, and the likelihood of bone formation increased by 1.9 ± 0.2 %, totalling 38.3 ± 1.1 % of strain-driven remodelling events across the entire trabecular compartment. This work provides novel robust bone mechanoregulation markers and their precision for designing future clinical studies

Comparison of in vitro and in vivo models for the elucidation of metabolic patterns of 7-azaindole-derived synthetic cannabinoids exemplified using cumyl-5F-P7AICA

Due to the dynamic market involving synthetic cannabinoids (SCs), the determination of analytical targets is challenging in clinical and forensic toxicology. SCs usually undergo extensive metabolism, and therefore their main metabolites must be identified for the detection in biological matrices, particularly in urine. Controlled human studies are usually not possible for ethical reasons; thus, alternative models must be used. The aim of this work was to predict the in vitro and in vivo metabolic patterns of 7‐azaindole‐derived SCs using 1‐(5‐fluoropentyl)‐N‐(2‐phenylpropan‐2‐yl)‐1H‐pyrollo[2,3‐b]pyridin‐3‐carboxamide (cumyl‐5F‐P7AICA) as an example. Different in vitro (pooled human liver S9 fraction, pooled human liver microsomes, and pig liver microsomes) and in vivo (rat and pig) systems were compared. Monooxygenase isoenzymes responsible for the most abundant phase I steps, namely oxidative defluorination (OF) followed by carboxylation, monohydroxylation, and ketone formation, were identified. In both in vivo models, OF/carboxylation and N‐dealkylation/monohydroxylation/sulfation could be detected. Regarding pHS9 and pig urine, monohydroxylation/sulfation or glucuronidation was also abundant. Furthermore, the parent compound could still be detected in all models. Initial monooxygenase activity screening revealed the involvement of CYP2C19, CYP3A4, and CYP3A5. Therefore, in addition to the parent compound, the OF/carboxylated and monohydroxylated (and sulfated or glucuronidated) metabolites can be recommended as urinary targets. In comparison to literature, the pig model predicts best the human metabolic pattern of cumyl‐5F‐P7AICA. Furthermore, the pig model should be suitable to mirror the time‐dependent excretion pattern of parent compounds and metabolites

Toxicokinetics of U-47700, tramadol, and their main metabolites in pigs following intravenous administration: is a multiple species allometric scaling approach useful for the extrapolation of toxicokinetic parameters to humans?

New synthetic opioids (NSOs) pose a public health concern since their emergence on the illicit drug market and are gaining increasing importance in forensic toxicology. Like many other new psychoactive substances, NSOs are consumed without any preclinical safety data or any knowledge on toxicokinetic (TK) data. Due to ethical reasons, controlled human TK studies cannot be performed for the assessment of these relevant data. As an alternative animal experimental approach, six pigs per drug received a single intravenous dose of 100 µg/kg body weight (BW) of U-47700 or 1000 µg/kg BW of tramadol to evaluate whether this species is suitable to assess the TK of NSOs. The drugs were determined in serum and whole blood using a fully validated method based on solid-phase extraction and LC–MS/MS. The concentration–time profiles and a population (pop) TK analysis revealed that a three-compartment model best described the TK data of both opioids. Central volumes of distribution were 0.94 L/kg for U-47700 and 1.25 L/kg for tramadol and central (metabolic) clearances were estimated at 1.57 L/h/kg and 1.85 L/h/kg for U-47700 and tramadol, respectively. The final popTK model parameters for pigs were upscaled via allometric scaling techniques. In comparison to published human data, concentration–time profiles for tramadol could successfully be predicted with single species allometric scaling. Furthermore, possible profiles for U-47700 in humans were simulated. The findings of this study indicate that unlike a multiple species scaling approach, pigs in conjunction with TK modeling are a suitable tool for the assessment of TK data of NSOs and the prediction of human TK data