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BACKGROUND & AIMS In patients with compensated advanced chronic liver disease (cACLD), the severity of portal hypertension (PH) determines the risk of decompensation. Invasive measurement of the hepatic venous pressure gradient (HVPG) is the diagnostic gold standard for PH. We evaluated the utility of machine learning models (MLMs) based on standard laboratory parameters to predict the severity of PH in cACLD patients. METHODS A detailed laboratory workup of cACLD patients recruited from the VIENNA cohort (NCT03267615) was utilised to predict clinically significant portal hypertension (CSPH, i.e., HVPG≥10mmHg) and severe PH (i.e. HVPG≥16mmHg). The MLMs were then evaluated in individual external datasets and optimised in the merged cohort. RESULTS Among 1232 cACLD patients, the CSPH and severe PH prevalence in VIENNA (n = 163, 67.4%/35.0%) and the validation cohort (n = 1069, 70.3%/34.7%) were similar. The MLMs were based on 3 (3P; platelets, bilirubin, INR) or 5 (5P; +cholinesterase, +gamma-glutamyl transferase, +aPTT replacing INR) laboratory parameters. The MLMs performed robustly in VIENNA with best AUROCs for CSPH by 5P-MLM: 0.813 and for severe PH by 5P-MLM: 0.887 and compared favourably to liver stiffness measurement (AUROC: 0.808). Their performance in external validation datasets was heterogeneous (AUROCs 0.589-0.887). Training on the merged cohort optimized the MLM performance for CSPH (AUROCs: 3P: 0.775, 5P: 0.789) and for severe PH (AUROCs 3P: 0.737, 5P: 0.828). CONCLUSIONS Internally-trained MLMs reliably predicted PH severity in the VIENNA cACLD cohort but exhibited heterogeneous results on external validation. The proposed 3P/5P online tool can reliably identify patients with CSPH or severe PH, thus, at risk for hepatic decompensation. LAY SUMMARY The gold standard for diagnosing portal hypertension is the invasive measurement of the hepatic venous pressure gradient. In this work, we selected the most suitable, widely available laboratory parameters for machine learning models to predict the likelihood and severity of portal hypertension in patients with compensated cirrhosis. This will aid in the identification of patients who are at the highest risk for subsequent hepatic decompensation.

A one-dimensional space curve in $\mathbb{R}^{3}$ is a useful nonlinear medium for modeling vortex filaments and biological soft-matter capable of supporting a variety of wave motions. The Hasimoto transformation defines a mapping between the kinematic evolution of a space curve and nonlinear scalar equations evolving its intrinsic curve geometry. This mapping is quite robust and able to transform general vector fields expressed in the Frenet frame, resulting in a fully nonlinear integro-differential evolution equation, whose coefficient structure is defined by the coordinates of the flow in the Frenet frame. In this paper, we generalize the Hasimoto map to arbitrary flows defined on space curves, which we test against several existing kinematic flows. After this, we consider the time dynamics of length and bending energy to see that binormal flows are generally length preserving, and bending energy is fragile and unlikely to be conserved in the general case., 12 pages

The adapted Numerov approach was extended to periodic problems and applied to the torsional tunneling splitting of six increasingly complex target systems carrying a hydroxy-group. The deviations from experiment remained on the order of 1 cm−1, except for phenol in which the exceptionally small ground-state tunneling-splitting of 0.0017 cm−1 was found in very good agreement with the experimental value of 0.0019 cm−1. Overall, the accuracy of the periodic Numerov approach for the treatment of torsional tunneling is on the same order as alternative approaches, but at a substantially reduced computational demand due to the restriction of the problem to the respective degree of freedom.

Interfacial adsorption and dissociation of water molecules at the α-Al2O3(0001) surface were studied using a novel hybrid 2D-periodic Self-Consistent Charge Density Functional Tight-Binding/Molecular Mechanics Molecular Dynamics (SCC-DFTB/MM MD) simulation strategy. The (0001) surface of α-Al2O3 (C-plane) was considered to assess the structural and dynamical behavior of adsorbed water at the interface region. In-plane distribution profiles of oxygen and hydrogen with respect to the non-periodic z-coordinate provide detailed information on the ordering of monolayer adsorbed water molecules at the interface. Dissociation of water molecules occured on the picosecond time scale, indicated by the formation of an additional plane-H peak located at 0.056 nm. Along simulation 4.2 OH groups per nm2 were formed at the α-Al2O3(0001) surface.

An adapted formulation of the grid-based Numerov approach to solve Schrodinger’s equation has been extended to four-dimensional systems and applied to problems in vibrational spectroscopy. The advantage of this novel implementation is that no approximations or assumptions with respect to the wavefunctions are required and the achieved accuracy at a given stencil size is only limited by the selected grid-spacing. To validate this approach the vibrational eigenstates and the corresponding wavenumbers of the linear molecules CO 2 , BeH 2 and HCN were investigated. Based on a potential energy grid at CCSD(T)/cc-pVnZ (n = T, Q) level all fundamental wavenumbers could be reproduced with deviations of less than 1% of the experimental values. Furthermore, the hierarchical application of a one- to four-dimensional Numerov treatment provides detailed information about the increasing influence of inter-mode coupling in addition to the inherent account for anharmonic contributions. The associated vibrational states are eigenfunctions of the Numerov matrix eigenvalue problem. Since no vibrational basis functions have to be applied in this approach, the respective eigenstates are characterized using isosurfaces of the wavefunctions in the hyperplane x 4 = 0 . This enables the direct examination of the individual wavefunctions via suitable visualization tools and the assignment of the respective vibrational quantum numbers.

Structural and dynamical properties of Cu+ in 18.6% aqueous ammonia solution at 298.15 K have been investigated via quantum mechanical charge field molecular dynamics (QMCF MD). The QM region was set to a radius of 6.7 A to include the first and second solvation shell. The Hartree-Fock (HF) level was applied to calculate the ion-ligand and ligand-ligand interactions in the QM region using the LANL2DZ-ECP basis set for the ion and DZP-Dunning for the ligands. The Cu+ N and Cu+ O radial distribution functions showed maximum first shell probabilities at distances of 2.23 and 2.30 A, respectively. Predominantly, four NH3 molecules were found to form a tetrahedral [Cu(NH3)4]+ complex, although the formation of a short-lived intermediate [Cu(NH3)3H2O]+ complex was also observed. The mean residence times of NH3 and H2O ligands in the first solvation shell were estimated as 14.6 ps and 1.3 ps, respectively, reflecting the strong interaction between Cu+ and ammonia as well as the occurrence of rapid water exchange. The vibrational power spectrum of the Cu+ N vibration in the first solvation shell revealed a wave number of 252 cm−1 with a corresponding force constant of 43.0 Nm−1. In addition, an NBO analysis was carried out, confirming the strong electrostatic character of the Cu+ NH3 and Cu+ H2O interaction, and highlighting that the presence of H2O ligands may destabilize the first solvation shell.

Structure and dynamics of solvated Ca2+ in liquid ammonia have been investigated using the quantum mechanical charge field molecular dynamics simulation approach, including the ion and its entire first plus second solvation shells in the QM zone. The Ca2+-ammonia interactions were calculated using ab initio HF calculations with Def2-SVP and DZP for Ca2+ and ammonia, respectively. A labile first shell structure at 2.63 A was observed with the dominant coordination numbers being 7 and 8. A number of exchange processes of ammonia ligands occurred throughout the simulation with a first shell mean ligand residence time of12.9 ps.

Purpose The purpose of this study is to examine the ways in which police officers connect their own direct and secondary trauma exposure to negative collateral effects on police-public interactions. Methods Data are drawn from in-depth, semi-structured interviews with 48 police officers from across the U.S., representing a range of professional and personal backgrounds. Data were examined using a blended inductive/deductive coding strategy. Results Officers' narratives show that trauma exposure and related deteriorations in mental health are seen as an inevitable part of police work. Officers linked trauma exposure to negative cognitions about the perception of danger, the controllability of events, and the overarching nature of humanity. Finally, officers connected these negative cognitions directly to the frequency and quality of their contact with the public. Specifically, officers described (1) avoidant behaviors including physical and emotional avoidance of situations that could result in further psychological or bodily harm, and (2) approach behaviors including more defensive, hostile and enforcement-based approaches to the public. Conclusions Findings provide support for a cognitive-behavioral framework to explain the reported effects of police trauma exposure on interactions with the public. Implications for research and practice are discussed.

The axial-ligand properties of [Pd(NH3)4]2+ and [Pt(NH3)4]2+ in aqueous solution have been assessed via quantum mechanical charge field molecular dynamics. Due to the similar distance between the axial ligands and the second solvation shell, an angular-radial distribution analysis has been performed. The result highlight how the character of the solvent influences the interaction between the axial ligands and ion and the respective influence on the experimentally observed ligand exchange rate constant of the first solvation shell. Even though both ions are often considered identical, the current results display key differences, which originate from the individual characteristics of the solvated complex structures.

In this work, the structural and dynamical properties of Zn2+ in pure liquid ammonia have been investigated via a quantum mechanical charge field molecular dynamics (QMCF MD) simulation approach. The average equilibrium Zn–N distance in the first solvation shell resulting from the radial distribution analysis is 2.15 A. Even though the complex displays a high rate of ligand exchange compared to Zn2+ in aqueous solution, the result imply that NH3 is the preferred ligand compared to H2O. This result of this simulation studies provide a fundamental understanding of the characteristic of this metal ion in pure liquid ammonia, which is inter alia essential in the development of applications for CO2 capture based on Zn2+-containing NH3 solutions.

The extensive re-parametrisation of the flexible SPC-mTR water potential resulted in more suitable ensemble averages for the intramolecular geometry of ambient water along with improved vibrational properties and an adequate relative static permittivity. The optimisation strategy followed the example of the successful three-point water models OPC3 and H2O-DC in which overpolarised partial charges and modified intramolecular geometries were employed. The improved structural, vibrational and dielectric properties of the new SPC-mTR2 parametrisation are expected to provide a superior performance in QM/MM-type simulations aimed at the determination of single-ion solvation free energies.

Introduction Association of Acute Disseminated Encephalomyelitis (ADEM) with both recent vaccination and viral infections is well described in current literature. However, the coincidence of ADEM and bacterial infections has been rarely documented. In this report, we present a case of ADEM which occurred after bacterial meningoencephalitis and prior vaccination against tetanus, diphtheria, and pertussis (Tdap). Case presentation A 62-year old woman was hospitalized with an upper respiratory tract infection three weeks after Tdap triple vaccination. A few days after admission, she became somnolent and developed meningism. Cerebrospinal fluid (CSF) analysis revealed pleocytosis and increased protein/lactate levels compatible with bacterial meningoencephalitis. The patient was treated with intravenous antibacterial triple therapy in combination with dexamethasone leading to a significant improvement of clinical symptoms and improvement of CSF parameters. Five days later, the patient's condition worsened again, and she developed aphasia and right-sided hemiparesis. A magnetic resonance imaging (MRI) scan revealed distinct fluid-attenuated inversion recovery sequence (FLAIR)-hyperintense lesions in both hemispheres. Following brain biopsy, the diagnosis of ADEM was made and methylprednisolone pulse therapy was initiated for five days leading to a nearly complete remission of symptoms. Conclusion ADEM is a neurological syndrome which may be associated with bacterial infection of the central nervous system (CNS). We hypothesize that the preceding Tdap triple vaccination may have contributed to the development of ADEM.

The solvation properties of Co3+ and Ir3+ in pure liquid ammonia have been investigated via ab initio quantum mechanical charge field molecular dynamics (QMCF MD) simulations. During the simulation time of 20 ps, octahedral [Co(NH3)6]3+ and [Ir(NH3)6]3+ complexes were formed in the first solvation shell without the occurance of ligand exchange. The respective average first shell ion distance of Co3+ and Ir3+ were found to be 2.07 and 2.18 A, respectively. The solvation properties in the first shells of each system are found in excellent agreement with experimental data. A number of ligands were exchanged between the second solvation shell and the bulk phase in both systems along the simulation. The associated mean residence times of NH3 ligands in the second shell are 3.06 and 2.47 ps for Co3+ and Ir3+, respectively.

In this work, the first investigation of the structural, dynamical and thermodynamical properties of solvated CO2 in liquid ammonia using a recently developed Quantum Mechanical/Molecular Mechanical Molecular Dynamics Thermodynamic Integration (QM/MM MD TI) approach has been carried out. The correlated resolution-of-identity Moller-Plesset Perturbation Theory (RI-MP2) ab initio level of theory has been applied to treat CO2 and its entire first solvation shell. In contrast to aqueous CO2, a negative value for the absolute solvation free energy of −25.9 ± 1.5 kJ/mol was found. This latter value reflects that the solute-solvent interaction is more favorable in liquid ammonia solution. In order to obtain a detailed structural characterisation of solvated CO2, the evaluation of radial distribution functions was performed in conically restricted regions with respect to the main axis of the CO2 molecule. The presented data provides detailed information on the solvation properties of CO2 in pure liquid ammonia. Since knowledge about the latter is a key prerequisite to understand CO2-capture in ammonia solutions, the simulation results can be expected to act as a valuable reference. In addition, the detailed analysis of the individual QM/MM energy contributions showed that the overall potential energy is not affected by artificial contributions, which might influence the determination of solvation free energy.

Background The outcome for patients with unresectable or metastatic soft tissue sarcoma (STS) is poor. Following failure from first-line doxorubicin based chemotherapy no standard therapy has been established. Combination treatment with docetaxel/gemcitabine (gem) has emerged as an effective regimen but administration is limited to fit patients only due to the toxicity profile. Nanoparticle albumin bound paclitaxel (nab-PC) was invented for avoidance of the toxicities related to polyethylated castor oil. In this context, we want to evaluate toxicity and antitumor effect of biweekly nab-PC 150mg/m2 / gem 1000mg/m2 administration in STS patients. Methods We conducted this proof-of-concept phase I trial to assess the safety of biweekly nab-PC/gem administration in the 2nd and 3rd line setting of STS. Results As of 1 April 2019, 6 pts were treated within the phase I. Three pts were male (50%); median age was 67 yrs (range 44 – 72). The current total number of biweekly doses received is 29 (median biweekly doses per patient is 5, range 2 – 7). One dose reduction due to skin toxicity occurred. 3 pts remain on study, 3 stopped treatment due to treatment unrelated reasons (refusal, death unrelated to progression or toxicity and investigator’s decision). The most common treatment-emergent AEs Gr1-2 were fatigue (3 pts), alopecia (3 pts), and neutropenia (2 pts). There were no dose-limiting toxicities or discontinuations due to AEs. We were able to confirm the tolerability of the regimen and are currently accruing patients to a prospective single arm phase II trial. Treatment will be given biweekly until progression, unacceptable toxicity or patient withdrawal. The primary endpoint of the trial is progression-free rate (PFR) at 12 weeks. Secondary endpoints are PFS, overall survival and symptom-specific quality of life. A total of 8 Swiss sites will participate for a total of 37 patients, as required by Simon’s two-stage design. Conclusions These preliminary results indicate that biweekly administration of nab-PC/gem was well tolerated. The phase I established dose and schedule were selected for further evaluation in phase II trial. Clinical trial identification NCT03524898. Editorial acknowledgement Celgene Corporation. Legal entity responsible for the study Swiss Group for Clinical Cancer Research (SAKK). Funding Swiss League Against Cancer, Celgene. Disclosure A. Digklia: Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen, PharmaMar, Servier, BMS; Research grant / Funding (self), Research grant / Funding (institution): Research Funding Recipient Institution. C. Britschgi: Advisory / Consultancy: Roche, Pfizer,takeda,AstraZeneca. Y. Metaxas: Advisory / Consultancy: Roche, MSD, Pierre Fabre, Merck-Serono, BMS. F. Krasniqi: Advisory / Consultancy: Roche Pharma (Schweiz) AG, Mundipharma Medical Company (Schweiz), Celgene GmbH. A. Stathis: Travel / Accommodation / Expenses: Abvie, PharmaMar; Research grant / Funding (institution): Amgen, Bayer, Novartis, Roche, MEI-Pharma. T. Rordorf: Advisory / Consultancy: Bristol-Myers Squibb and Merck KGaA. N. Mach: Honoraria (institution), Advisory / Consultancy: Amgen, AstraZeneca, Bristol-Myers Squibb, F. Hoffmann-La Roche, Merck Sharp and Dohme, Merck Serono, Novartis, Pharma Mar, as well as honorarium for talks in a company’s organised public event from Bristol-Myers Squibb and Pharma Mar. C.A. Rothermundt: Advisory / Consultancy: BMS, Astellas Pharma Schweiz, GSK, Novartis, Roche, Pfizer, PharmaMar; Research grant / Funding (institution): Research Funding Recipient Institution. All other authors have declared no conflicts of interest.

The amino acid [1-(aminomethyl)cyclohexyl]acetic acid was reacted with 2-hydroxynaphthaldehyde to produce the Schiff base ligand [1-({[(Z)-(2-hydroxynaphthalen-1-yl)methylidene]amino}methyl)cyclohexyl]acetic acid (H-HMAC) which was fully characterized spectroscopically and by single crystal diffraction. It was reacted with metal ions to produce compounds with composition [M(HMAC)2] [M = Co(II), Ni(II), Cu(II) and Zn(II)], which were characterized spectroscopically, with distorted tetragonal geometries assigned based on spectroscopic and B3LYP theoretical studies. All synthesized compounds were studied for their thermal stabilities under static air. The coordination compounds were also screened for their free radical scavenging properties using DPPH free radicals and xanthine oxidase inhibitory activities. Only the zinc complex was found to be an inhibitor of the enzymatic activity with IC50 = 0.7 ± 0.01 μM ± SEM better than the standard reference drug used. The inhibitory activity was structurally rationalized by carrying out molecular modeling studies using the auto dock program.

In this article the extension of the grid-based Numerov approach to probe two coupled, localised vibrational modes is assessed. The theoretically obtained wave numbers are compared to experimental results for five increasingly complex organic molecules carrying two OH groups measured in gas-phase as well as carbon tetrachloride. By using an appropriate spacing of the associated potential energy grid a deviation of the predicted wave numbers with experiment of ≤1% is achieved for both the fundamental and the first overtone bands. In particular the calculated wave numbers of aliphatic species in vacuum underline the versatility of this approach. In addition, it is demonstrated that bicubic interpolation is a viable strategy to greatly reduce the required data points and thus, the computational effort. Comparison of predicted wave numbers obtained for different conformers with experimental data enables the identification of the most relevant conformer present in solution. Since especially the accurate calculation of overtone vibrations is known to be challenging in case of strongly anharmonic potentials such as OH bonds, the presented approach provides a particularly efficient route to study the properties of the associated overtone contribution under the influence of inter-mode coupling. This is due to the fact that the Numerov approach requires no assumption about form and composition of the vibrational wave functions. In addition, the presented method also provides one of the simplest routes to access combined excitations of the considered vibrational modes.

In this work, the mid-infrared spectrum of aqueous glycine is predicted by a number of computational approaches. Velocity autocorrelation functions are applied to ab initio QMCF-MD and QM/MM-MD simulations in order to obtain IR power spectra. Furthermore, continuum solvation model augmented geometry optimizations are studied by anharmonic calculations relying on the PT2-VSCF and the VPT2 formalism. In this context, the potential based EFP hydration technique is discussed and the importance of a Monte Carlo search in conjunction with PT2-VSCF calculations is critically assessed. All results are directly compared to newly recorded experimental FT-IR spectroscopic data, elucidating the qualities of the respective methodology. Moreover, the computational approaches are discussed regarding their usefulness for the interpretation of experimental spectra.

An ab initio quantum mechanical charge field molecular dynamics (QMCF-MD) study of the selenate ion in water was performed at the Hartree Fock/6-31G (d,p) level of theory. The intramolecular geometry, structure and dynamics of the hydration shell and the vibrational frequency modes calculated via velocity autocorrelation functions are presented. The resulting bond distances as well as angles and vibrational frequencies are in good agreement with experimental data. The structure and dynamics reveal the hydrogen bonding network between the ion and neighboring water molecules and exchange processes in the hydration sphere characterize the ion as a structure-forming anion.

The previously investigated La3+-hydrate has been re-evaluated by means of the quantum mechanical charge field (QMCF) molecular dynamics (MD) approach. Improved description of the hydration characteristics has been realised by including the full second hydration shell into the quantum mechanically treated region and by introducing the influence of the surrounding bulk via an electrostatic embedding technique. Analytical tools such as the ligand angular radial distribution analysis have been employed to gain deeper insight into the structural features of the hydrate. La3+ simultaneously forms nona- and decahydrates with capped trigonal and quadratic prismatic structure, besides small amounts of an octahydrate.

An ab initio quantum mechanical charge field molecular dynamics (QMCF MD) simulation has been carried out in order to obtain detailed insight into the hydration properties of Mg2+. The ion, being a ‘kosmotrope’, considerably influences the water hydrogen bond network in its vicinity. Certain types of hydrogen bonds are strengthened at the cost of weakening others. The cationic influence on the water hydrogen bonding network have been investigated primarily employing time correlation functions of H-bond dynamics. The frequencies of the MgO6 skeletal normal modes calculated using the normal coordinate analysis shows a close resemblance to the experimental data, thus validating the accuracy of ab initio quantum chemical simulations.

An ab initio quantum mechanical charge field molecular dynamics (QMCF MD) simulation was performed on a single molecule of hydrogen peroxide immersed in water to investigate its stability in aqueous solution, since pure hydrogen peroxide is very unstable. The structural parameters such as radial distribution functions (RDFs), coordination number distributions (CNDs) and angular distribution functions (ADFs) indicate the existence of ∼4 hydrogen bonds between hydrogen peroxide and water molecules, with both molecules acting as hydrogen bond donors and hydrogen bond acceptors. The overall hydration shell consists of ∼6 water molecules surrounding the hydrogen peroxide molecule. The analysis of the hydrogen bond dynamics verified the presence of strong hydrogen bonds compared to pure water, thus confirming the stabilization of hydrogen peroxide in aqueous solution.

The ab initio quantum mechanical charge field molecular dynamics simulation technique was applied for the first time to an electronically excited system, namely hydrated Li(I). This approach does not only provide data for the influence of electronic excitation on structure and composition of the hydrate, but also leads to a spectrum for the excitation band including rotational, translational and vibrational energy transfers. The first excitation band for Li(I) in water peaks at 13.1 eV. The excitation leads to reduced coordination numbers of first and second hydration shell and stabilises the first and labilises the second shell.

Graphical abstract Highlights ►Concise treatment of highly charged ions with very different properties. ► Performed by ab initio simulations with the recent QMCF-MD methodology. ► Treating hydrates with extreme stability, labile hydrates and instable systems with (sub-)picosecond proton transfer reactions., Based on a series of ab initio quantum mechanical charge field molecular dynamics (QMCF MD) simulations, the broad spectrum of structural and dynamical properties of hydrates of trivalent and tetravalent ions is presented, ranging from extreme inertness to immediate hydrolysis. Main group and transition metal ions representative for different parts of the periodic system are treated, as are 2 threefold negatively charged anions. The results show that simple predictions of the properties of the hydrates appear impossible and that an accurate quantum mechanical simulation in cooperation with sophisticated experimental investigations seems the only way to obtain conclusive results.

The ab initio quantum mechanical charge field (QMCF) molecular dynamics (MD) formalism was used to evaluate structure and dynamics of the monomeric hydrated tetravalent hafnium. The ion forms three hydration shells and no hydrolysis reaction occurred during the simulation time of 7 ps. Eight water molecules coordinate in a more or less well-defined square antiprismatic geometry at the hafnium ion, as visible from the O–Hf–O angular distribution function, with a Hf (IV)–O bond length of 2.26 A and a bond force constant of 212 N/m, which classifies this bond as the strongest ion–water bond known so far.

Background: The reduction of treatment-related toxic effects is the main goal in the current trials of the German Hodgkin Study Group (GHSG). In this regard, the protection of the ovarian reserve in young women is very important. Therefore, the GHSG investigated the use of gonadotropin-releasing hormone-analogues (GnRH-a) and oral contraceptives (OC) in young women with advanced-stage Hodgkin lymphoma (HL). Patients and methods: Women (18–40 years) were randomly assigned either to receive daily OC or monthly GnRH-a during escalated combination therapy with bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPesc). Hormonal levels were determined at baseline, during therapy, and at follow-up. Results: The study was closed prematurely after an interim analysis of 12 patients in arm A (OC) and 11 in arm B (GnRH-a), 9 and 10 are assessable for the primary end point. Women’s median age was 25 years in both arms. The anti-Mullerian hormone level after at least 12 months was reduced in all patients. For the entire study cohort, the respective ovarian follicle preservation rate was 0% (95% confidence interval 0% to 12%). Conclusion: We observed no protection of the ovarian reserve with hormonal co-treatment during BEACOPPesc. This result supports efforts of ongoing trials to reduce chemotherapy intensity and toxicity. Alternative strategies for the protection of fertility must be offered to young female HL patients before the start of BEACOPPesc therapy.

Quantum mechanical charge field (QMCF) molecular dynamics (MD) simulations including first and second hydration shell in the QM region have been performed to describe structural and dynamical properties of Ge(II) in water. The first and second hydration shells were treated by ab initio quantum mechanics at restricted Hartree-Fock (RHF) level. The radial distribution function (RDF) showed the maximum probability of the Ge–O bond length at 2.04 A, accompanied by an extended first shell located at ∼2.8 A. A uniquely distorted hydration structure with two tri-pyramidal substructures provides a new basis for the interpretation of the kinetic properties of germanium(II) complexes.

Over the last decade several groups, including ourself, have published a series of findings on a molecule expressed in leukocytes. The molecule was termed Cybr, CYTIP or CASP for its functions and PSCDBP for its binding properties. In this review we attempt to chronicle and combine the findings on the molecule to gain an overview of its features.

The complex and labile hydration structure of the dimeric mercury ion Hg 2 2 + has been studied by means of the novel quantum mechanical charge field molecular dynamics approach (QMCF MD). This system has been chosen as a challenging target to assess and evaluate the applicability of the QMCF approach, as standard MM and QM/MM protocols face obstacles in the formulation of accurate ion–solvent interaction potentials, while the application of the QMCF approach allows to renounce these potentials as the respective contributions are all included in the quantum mechanical framework. The results of the simulation show that the Hg(I) dimer forms a very labile hydration structure. In average 3.7 ligands are bound to each of the Hg atoms, and the water molecules are exchanged on the picosecond timescale.

QMCF-MD simulations of phosphate, sulphate and perchlorate ions in aqueous solution were performed to study the anions’ librational and vibrational motions. The obtained normal modes of the tetrahedral anions are in good agreement with experimental data. The simulations also give a detailed insight into the dynamics of the these three anions in aqueous solution, in particular into ligand exchange processes and spatial distribution of water hydrogen atoms binding to the anions’ oxygens.

The pharmacologically and industrially important palladium(II) ion is usually characterised as square-planar structure in aqueous solution, similar to the platinum(II) ion. Our investigations by means of the most modern experimental and theoretical methods give clear indications, however, that the hydrated palladium(II) ion is hexa-coordinated, with four ligands arranged in a plane at 2.0 A plus two additional ligands in axial positions showing an elongated bond distance of 2.7–2.8 A. The second shell consists in average of 8.0 ligands at a mean distance of 4.4 A. This structure provides a new basis for the interpretation of the kinetic properties of palladium(II) complexes.

For more than a decade Kayser-Threde, a medium-sized enterprise of the German space industry, has been involved in astrobiology research in partnership with a variety of scientific institutes from all over Europe. Previous projects include exobiology research platforms in low Earth orbit on retrievable carriers and onboard the Space Station. More recently, exobiology payloads for in situ experimentation on Mars have been studied by Kayser-Threde under ESA contracts, specifically the ExoMars Pasteur Payload. These studies included work on a sample preparation and distribution systems for Martian rock/regolith samples, instrument concepts such as Raman spectroscopy and a Life Marker Chip, advanced microscope systems as well as robotic tools for astrobiology missions. The status of the funded technical studies and major results are presented. The reported industrial work was funded by ESA and the German Aerospace Center (DLR). (c) 2007 Published by Elsevier Ltd.

Dynamic properties of hydrated aluminium(III) ion have been investigated by ab initio quantum mechanical/molecular mechanical (QM/MM) molecular dynamics (MD) simulations at Hartree–Fock level including only the first or first plus second hydration shell into the QM region. The octahedral Al–O frequencies and ligand exchange processes between second shell and bulk have been evaluated. The results show that quantum effects play a non-negligible role also in the interaction of first and second shell and that inclusion of the latter into the QM region improves the values of sensitive dynamical data.

Dynamic properties of the hydrated Pb(II) ion have been investigated by ab initio quantum mechanical/molecular mechanical (QM/MM) molecular dynamics (MD) simulations at Hartree Fock quantum mechanical level. Librational as well as vibrational motions of first and second shell and the bulk as well as the frequencies of rotations have been evaluated by means of velocity auto correlation functions (VACF). The time evolution of the Pb–O distances and selected O–Pb–O angles in the first shell was evaluated. A lower limit of the mean ligand residence time of water molecules in the first shell was estimated as 0.23 ns, in the second shell a mean residence time of 5.6 ps was observed.

Recent developments in computer speed and capacity have opened the access to highly accurate molecular dynamics simulations based on quantum mechanically calculated forces for the chemically relevant region around ions in solution (QM/MM formalism). This accuracy, although still extremely consuming (30–300 days of CP time per simulation), is needed for reliable structural details and ligand exchange rates. A large number of main group and transition metal ions have been investigated by this approach, giving very detailed insight into the properties of these ions in solution and allowing to classify the ions by various characteristics. Most first-row transition metal ions have a very stable first hexa-coordinated solvation shell, whose vibrational distortions, however, strongly influence the dynamics of the second shell. The dynamical Jahn–Teller effect – shown to be a femto- and picosecond phenomenon – can strongly influence ligand coordination and exchange dynamics. A large number of ions with very labile solvation shell such as most main group ions, but also transition metal ions, e.g. Ag(I) and Hg(II), can change their coordination within the picosecond scale, leading to an almost simultaneous presence of several species hardly accessible by present experimental techniques. Among these ions, the structure breakers are of particular interest, and it could be shown that there are two types of them, one with a large and very labile first coordination shell such as Cs(I), the other characterised by a small first but an unusually large second solvation shell such as Au(I). Investigations of metal ions coordinated to ammonia ligands have shown that coordination to hetero-atoms can accelerate the ligand exchange reaction rates by several orders of magnitude, e.g. for Cu(II) and Ni(II). Simulations of ions in aqueous ammonia gave a very detailed picture of the complexity of species almost simultaneously present and illustrate the enormous difficulties encountered when trying to fit X-ray or neutron diffraction data for such systems. In general, ligand exchange rates situated in the picosecond range are far below the NMR scale, and as femtosecond laser pulse spectroscopy could not be applied so far to ionic solutions, accurate simulations have become a very important tool to access structure and dynamics of solvated ions. A number of VIDEO clips supplied on the Web as supporting material illustrates the processes occurring in solutions of the metal ions.

Activins are members of the transforming growth factor-beta (TGF-beta) family and are important for skin morphogenesis and wound healing. TGF-beta1 is necessary for the population of the epidermis with Langerhans cells (LC). However, a role for activin in LC biology is not known. To address this question, we analyzed skin from transgenic mice overexpressing the activin antagonist follistatin in the epidermis. Using immunofluorescence, we observed a striking decrease in the number of LC in the epidermis of transgenic mice in comparison to wild-type mice. Nevertheless, these LC expressed normal levels of major histocompatibility complex (MHC)-class II and Langerin/ CD207 in situ. In explant cultures of whole ear skin the number of dendritic cells (DC), which migrated into the culture medium, was reduced. This reduction was even more pronounced in cultures of epidermal sheets. Virtually all emigrated cutaneous DC displayed typical morphology with cytoplasmic "veils", showed translocation of MHC-class II to the surface membrane, and expressed the maturation marker 2A1. Thus, cutaneous DC from transgenic mice seemed to mature normally. These results demonstrate that overexpression of follistatin in the epidermis affects LC trafficking but not maturation and suggest a novel role of the follistatin-binding partner activin in LC biology.

Structural properties of the hydrated Ba(II) ion have been investigated by ab initio quantum mechanical/molecular mechanical (QM/MM) molecular dynamics (MD) simulations at double zeta HF quantum mechanical level. The first shell coordination number was found to be 9.3, and several other structural parameters such as angular distribution functions, radial distribution functions and tilt- and θ-angle distributions allowed the full characterization of the hydration structure of the Ba(II) ion in dilute aqueous solution. Velocity autocorrelation functions were used to calculate librational and vibrational motions, ion–ligand motions as well as reorientation times. Different dynamical parameters such as water reorientation, mean ligand residence time, the number of ligand exchange processes and rate constants were also analyzed and the ligand exchange rate constant for the first shell was determined as k = 5.3 × 1010 s−1.