Spin-crossover in metallomesogens of iron(II)

Covalent grafting mesogenic groups to the coordination cores of the parent mononuclear low-spin and spin-crossover compounds afforded metallomesogenic complexes of iron(II). In comparison with the parent complexes the spin-crossover properties of the alkylated derivatives are substantially modified. The type of the modification was found to be dependent on the properties of the parent system and the nature of the used anion, however, the general tendency is the destabilization of the low-spin state at the favor of spin-crossover or high-spin behavior below 400 K. The structural insight revealed the micro-segregated layered organization. The effect of the alkylation of the parent compounds consists first of all in the change of the lattice to a two-dimensional lamellar one retaining significant intermolecular contacts only within the ionic bilayers. The comprehensive analysis of the structural and thermodynamic data in the homologous series pointed at the mechanism of the interplay between the structural modification on melting and the induced anomalous change of the magnetic properties. A family of one-dimensional spin-crossover polymers was synthesized and characterized using a series of spectroscopic methods, X-ray powder diffraction, magnetic susceptibility measurements and differential scanning calorimetry. The copper analogue of was also synthesized and its crystal structure solved. In comparison with the mononuclear systems, the polymeric mesogens of iron(II) are less sensitive to the glass transition, which was attributed to the moderate concomitant variation of the structure. Nevertheless, the observed increase of the magnetic hysteresis with lengthening of the alkyl substituents was ascribed to the interplay of the structural reorganization of the coordination core due to spin-crossover with the structural delay in the spatial reorganization of the mesogenic substituents. The classification of mononuclear and polymeric metallomesogens according to the interactions between the structural- and the spin-transition and analysis of the data on the reported spin-crossover metallomesogens led to the separation of three types, namely: Type i: systems with coupling between the electronic structure of the iron(II) ions and the mesomorphic behavior of the substance; Type ii: systems where both transitions coexist in the same temperature region but are not coupled due to competition with the dehydration or due to negligible structural transformation; Type iii: systems where both transitions occur in different temperature regions and therefore are uncoupled. Fine-tuning, in particular regarding the temperature at which the spin-transition occurs with hysteresis properties responsible for the memory effect, are still a major challenge towards practical implementation of spin-crossover materials. A possible answer to the problem could be materials in which the spin-crossover transition is coupled with another transition easily controllable by external stimuli. In the present thesis we have shown the viability of the approach realized in the mesogenic systems with coupled phase- and spin-transitions.

Einfluss der Phosphorylierung durch die Casein Kinase II auf den HSP90-Chaperone-Zyklus in humanen Zellen

In der vorliegenden Arbeit wurde eine Analysenmethode auf Basis der Massenbestimmung über Elektrospray-Ionisation qualifiziert, mit der es möglich ist, den Gehalt beider in humanen Zellen vorliegenden isoformen Chaperone HSP90-alpha und HSP90-beta sowie deren Phosphorylierungsstatus in der sog. „charged linker“-Region (CLR) getrennt voneinander zu bestimmen. Die Quantifizierung dieser posttranslationalen Modifikation von HSP90 in der noch wenig untersuchten Region des Chaperons stellte eine besondere Herausforderung an das analytische Messsystem dar, da diese sich fast ausschließlich aus geladenen Aminosäuren zusammensetzt und eine hohe Sequenzhomologie der beiden Isoformen in humanen Zellen vorliegt. Mit dieser Methode ist es gelungen, sowohl die stärkere Expression beider Isoformen in Tumor-Zelllinien im Vergleich zu Nicht-Tumor-Zelllinien als auch signifikant höhere Level beider phosphorylierten Varianten in den Tumor-Zelllinien nachzuweisen. Des Weiteren konnte durch gezielte Arretierung der Tumor-Zelllinie HCT116 in der G0/G1-Phase des Zellzyklus der Nachweis erbracht werden, dass nur HSP90-alpha in diesem Ruhestadium der Zellteilung in der phosphorylierten Form vorliegt. rnDa die Phosphorylierung der CLR von HSP90 als ein Marker für die Substrataktivierung herangezogen werden kann, besteht jetzt die Möglichkeit, Auswirkungen von z. B. HSP90-Inhibitoren auf beide HSP90-Isoformen hinsichtlich ihrer Expression und Phosphorylierung durch die Casein Kinase II (CK II) im zellulären Umfeld zu testen.rnIn-vitro konnte die Phosphorylierung der CLR von HSP90-alpha und -beta mit der CK II an den rekombinant hergestellten Proteinen nachgestellt werden. Dieses typische Phosphorylierungs-Motiv (S-X-X-E/D) findet man bei sehr vielen Co-Chaperonen wie auch bei der Prostaglandin E Synthase p23, das ebenfalls durch eine in-vitro Kinase-Reaktion mit der CK II an drei Positionen phosphoryliert wurde. Durch ein Binde-Assay zeigte sich, dass p23 nur in dieser modifizierten Form an HSP90-alpha bindet. Das Bindeverhalten von p23 an die beta-Isoform wird durch diese Phosphorylierung jedoch nicht beeinflusst. Diese Erkenntnisse erweitern das Verständnis des bis dato beschriebenen Chaperon-Zyklus von HSP90 und zeigen deutliche Unterschiede in den Aktivierungszyklen beider Isoformen auf. Da die Casein Kinase II hier entscheidend in den durch HSP90 vermittelten Aktivierungsprozess eingreift, eröffnet sich ein weites Feld an Möglichkeiten, diese Prozesse an weiteren Co-Chaperonen und Substratproteinen zu studieren.rn

Efficacy and safety of certolizumab pegol in an unselected crohn's disease population: 26-week data of the FACTS II survey

Certolizumab pegol (Cimzia, CZP) was approved for the treatment of Crohn's disease (CD) patients in 2007 in Switzerland as the first country worldwide. This prospective phase IV study aimed to evaluate the efficacy and safety of CZP over 26 weeks in a multicenter cohort of practice-based patients.

Supported Cu(II) polymer catalysts for aqueous phenol oxidation

Supported Cu(II) polymer catalysts were used for the catalytic oxidation of phenol at 30 degrees C and atmospheric pressure using air and H(2)O(2) as oxidants. Heterogenisation of homogeneous Cu(II) catalysts was achieved by adsorption of Cu(II) salts onto polymeric matrices (poly(4-vinylpyridine), Chitosan). The catalytic active sites were represented by Cu(II) ions and showed to conserve their oxidative activity in heterogeneous catalysis as well as in homogeneous systems. The catalytic deactivation was evaluated by quantifying released Cu(II) ions in solution during oxidation, from where Cu-PVP(25) showed the best leaching levels no more than 5 mg L(-1). Results also indicated that Cu-PVP(25) had a catalytic activity (56% of phenol conversion when initial Cu(II) catalytic content was 200 mg L(Reaction)(-1)) comparable to that of commercial catalysts (59% of phenol conversion). Finally, the balance between activity and copper leaching was better represented by Cu-PVP(25) due to the heterogeneous catalytic activity had 86% performance in the heterogeneous phase, and the rest on the homogeneous phase, while Cu-PVP(2) had 59% and CuO/gamma-Al(2)O(3) 68%.

Ovarian stimulation to cryopreserve fertilized oocytes in cancer patients can be started in the luteal phase

OBJECTIVE: To analyze if oocytes can be obtained in all patients before cancer treatment within 2 weeks by initiating ovarian stimulation during the follicular or luteal phase. DESIGN: Prospective controlled multicenter trial. SETTING: Four university-based centers. PATIENT(S): Forty cancer patients before chemotherapy. INTERVENTION(S): Twenty-eight patients were stimulated with gonadotropins in the follicular phase (group I). In 12 patients (group II), ovarian stimulation was initiated in the luteal phase, and these received GnRH antagonists and recombinant FSH. In 14 patients, 143 oocytes were further processed for fertilization by intracytoplasmic sperm injection (ICSI). MAIN OUTCOME MEASURE(S): Number of oocytes aspirated after ovarian stimulation, cumulative FSH/hMG dosage, viability and maturity of oocytes, and fertilization rate by ICSI. RESULT(S): Patients in group I (age 27.6 +/- 4.9 yrs) were stimulated on average for 10.6 days, and patients in group II (age 31.2 +/- 5.7 yrs) for 11.4 days. Total amount of FSH was on average 2,255 IU (I) and 2,720 IU (II) per patient. Average and median numbers of aspirated oocytes were, respectively, 13.1 and 11.5 (I) versus 10.0 and 8.5 (II); 83.7% (I) and 80.4% (II) of the oocytes were mature and viable and could be treated by ICSI. Fertilization rate was 61.0% (I) versus 75.6% (II). CONCLUSION(S): This pilot study suggests that oocytes can be obtained before cancer treatment efficiently irrespective of the phase of the menstrual cycle.

Functionalized Adamantane Tectons Used in the Design of Mixed-Ligand Copper(II) 1,2,4-Triazolyl/Carboxylate Metal–Organic Frameworks

Bistriazoles, 1,3-bis(1,2,4-triazol-4-yl)propane (tr2pr) and 1,3-bis(1,2,4-triazol-4-yl)adamantane (tr2ad), were examined in combination with the rigid tetratopic 1,3,5,7-adamantanetetracarboxylic acid (H4-adtc) platform for the construction of neutral heteroleptic copper(II) metal−organic frameworks. Two coordination polymers, [{Cu4(OH)2(H2O)2}{Cu4(OH)2}(tr2pr)2(H-adtc)4]·2H2O (1) and [Cu4(OH)2(tr2ad)2(H-adtc)2(H2O)2]·3H2O (2), were synthesized and structurally characterized. In complexes 1 and 2, the N1,N2-1,2,4-triazolyl (tr) and μ3-OH− groups serve as complementary bridges between adjacent metal centers supporting the tetranuclear dihydroxo clusters. The structure of 1 represents a unique association of two different kinds of centrosymmetrical {Cu4(OH)2} units in a tight 3D framework, while in compound 2, another configuration type of acentric tetranuclear metal clusters is organized in a layered 3,6-hexagonal motif. In both cases, the {Cu4(OH)2} secondary building block and trideprotonated carboxylate H-adtc3− can be viewed as covalently bound six- and three-connected nodes that define the net topology. The tr ligands, showing μ3- or μ4-binding patterns, introduce additional integrating links between the neighboring {Cu4(OH)2} fragments. A variable-temperature magnetic susceptibility study of 2 demonstrates strong antiferromagnetic intracluster coupling (J1 = −109 cm−1 and J2 = −21 cm−1), which combines for the bulk phase with a weak antiferromagnetic intercluster interaction (zj = −2.5 cm−1).

Micrometer-sized ice particles for planetary-science experiments – II. Bidirectional reflectance

We have measured the bidirectional reflectance of spherical micrometer-sized water-ice particles in the visible spectral range over a wide range of incidence and emission angles. The small ice spheres were produced by spraying fine water droplets directly into liquid nitrogen. The resulting mean particle radii are 1.47 + 0.96 - 0.58 μm. Such a material shares many properties with ice in comets and at the surface of icy satellites. Measurements show that the fresh sample material is highly backscattering, contrasting with natural terrestrial snow and frost. The formation of agglomerates of particles during the sample production results in a noticeable variability of the photometric properties of the samples in their initial state. We have also observed significant temporal evolutions of the scattering behavior of the samples, shifting towards more forward scattering within some tens of hours, resulting most likely from sintering processes. All reflectance data are fitted by the Hapke photometric model (1993 and 2002 formulation) with a one/two/three-parameter Henyey-Greenstein phase function and the resulting Hapke parameters are provided. These parameters can be used to compare laboratory results with the observed photometric behaviors of astronomical objects. We show, in particular, that the optical properties of the fresh micrometer-sized ice samples can be used to reproduce the predominant backscattering in the phase curves of Enceladus and Europa.

Observations of the northern seasonal polar cap on Mars II: HiRISE photometric analysis of evolution of northern polar dunes in spring

We present an overview of our analyses of HiRISE observations of spring evolution of selected dune areas of the north polar erg. The north polar erg is covered annually by seasonal volatile ice layer, a mixture of CO2 and H2O with mineral dust contamination. In spring, this layer sublimes creating visually enigmatic phenomena, e.g. dark and bright fan-shaped deposits, dark–bright–dark bandings, dark down-slope streaks, and seasonal polygonal cracks. Similar phenomena in southern polar areas are believed to be related to the specific process of solid-state greenhouse effect. In the north, it is currently unclear if the solid-state greenhouse effect is able to explain all the observed phenomena especially because the increased influence of H2O on the time scales of this process has not yet been quantified. HiRISE observations of our selected locations show that the ground exhibits a temporal behaviour similar to the one observed in the southern polar areas: a brightening phase starting close to the spring equinox with a subsequent darkening towards summer solstice. The resolution of HiRISE enabled us to study dunes and substrate individually and even distinguish between different developments on windward and slip face sides of single dunes. Differences in the seasonal evolution between steep slip faces and flatter substrate and windward sides of dunes have been identified and compared to CRISM data of CO2 and H2O distributions on dunes. We also observe small scale dark blotches that appear in early observations and tend to sustain a low reflectivity throughout the spring. These blotches can be regarded as the analogue of dark fan deposits in southern polar areas, leading us to the conclusion that both martian polar areas follow similar spring evolutions.

An Innovative Phase I Trial Design Allowing for the Identification of Multiple Potential Maximum Tolerated Doses with Combination Therapy of Targeted Agents

Treatment for cancer often involves combination therapies used both in medical practice and clinical trials. Korn and Simon listed three reasons for the utility of combinations: 1) biochemical synergism, 2) differential susceptibility of tumor cells to different agents, and 3) higher achievable dose intensity by exploiting non-overlapping toxicities to the host. Even if the toxicity profile of each agent of a given combination is known, the toxicity profile of the agents used in combination must be established. Thus, caution is required when designing and evaluating trials with combination therapies. Traditional clinical design is based on the consideration of a single drug. However, a trial of drugs in combination requires a dose-selection procedure that is vastly different than that needed for a single-drug trial. When two drugs are combined in a phase I trial, an important trial objective is to determine the maximum tolerated dose (MTD). The MTD is defined as the dose level below the dose at which two of six patients experience drug-related dose-limiting toxicity (DLT). In phase I trials that combine two agents, more than one MTD generally exists, although all are rarely determined. For example, there may be an MTD that includes high doses of drug A with lower doses of drug B, another one for high doses of drug B with lower doses of drug A, and yet another for intermediate doses of both drugs administered together. With classic phase I trial designs, only one MTD is identified. Our new trial design allows identification of more than one MTD efficiently, within the context of a single protocol. The two drugs combined in our phase I trial are temsirolimus and bevacizumab. Bevacizumab is a monoclonal antibody targeting the vascular endothelial growth factor (VEGF) pathway which is fundamental for tumor growth and metastasis. One mechanism of tumor resistance to antiangiogenic therapy is upregulation of hypoxia inducible factor 1α (HIF-1α) which mediates responses to hypoxic conditions. Temsirolimus has resulted in reduced levels of HIF-1α making this an ideal combination therapy. Dr. Donald Berry developed a trial design schema for evaluating low, intermediate and high dose levels of two drugs given in combination as illustrated in a recently published paper in Biometrics entitled “A Parallel Phase I/II Clinical Trial Design for Combination Therapies.” His trial design utilized cytotoxic chemotherapy. We adapted this design schema by incorporating greater numbers of dose levels for each drug. Additional dose levels are being examined because it has been the experience of phase I trials that targeted agents, when given in combination, are often effective at dosing levels lower than the FDA-approved dose of said drugs. A total of thirteen dose levels including representative high, intermediate and low dose levels of temsirolimus with representative high, intermediate, and low dose levels of bevacizumab will be evaluated. We hypothesize that our new trial design will facilitate identification of more than one MTD, if they exist, efficiently and within the context of a single protocol. Doses gleaned from this approach could potentially allow for a more personalized approach in dose selection from among the MTDs obtained that can be based upon a patient’s specific co-morbid conditions or anticipated toxicities.

Velocity of early BCR-ABL transcript elimination as an optimized predictor of outcome in chronic myeloid leukemia (CML) patients in chronic phase on treatment with imatinib

UNLABELLED Early assessment of response at 3 months of tyrosine kinase inhibitor treatment has become an important tool to predict favorable outcome. We sought to investigate the impact of relative changes of BCR-ABL transcript levels within the initial 3 months of therapy. In order to achieve accurate data for high BCR-ABL levels at diagnosis, beta glucuronidase (GUS) was used as a reference gene. Within the German CML-Study IV, samples of 408 imatinib-treated patients were available in a single laboratory for both times, diagnosis and 3 months on treatment. In total, 301 of these were treatment-naïve at sample collection. RESULTS (i) with regard to absolute transcript levels at diagnosis, no predictive cutoff could be identified; (ii) at 3 months, an individual reduction of BCR-ABL transcripts to the 0.35-fold of baseline level (0.46-log reduction, that is, roughly half-log) separated best (high risk: 16% of patients, 5-year overall survival (OS) 83% vs 98%, hazard ratio (HR) 6.3, P=0.001); (iii) at 3 months, a 6% BCR-ABL(IS) cutoff derived from BCR-ABL/GUS yielded a good and sensitive discrimination (high risk: 22% of patients, 5-year OS 85% vs 98%, HR 6.1, P=0.002). Patients at risk of disease progression can be identified precisely by the lack of a half-log reduction of BCR-ABL transcripts at 3 months.

Dissecting abdominal aortic aneurysm in Ang II-infused mice: suprarenal branch ruptures and apparent luminal dilatation.

AIMS In this work, we provide novel insight into the morphology of dissecting abdominal aortic aneurysms in angiotensin II-infused mice. We demonstrate why they exhibit a large variation in shape and, unlike their human counterparts, are located suprarenally rather than infrarenally. METHODS AND RESULTS We combined synchrotron-based, ultra-high resolution ex vivo imaging (phase contrast X-Ray tomographic microscopy) with in vivo imaging (high-frequency ultrasound and contrast-enhanced micro-CT) and image-guided histology. In all mice, we observed a tear in the tunica media of the abdominal aorta near the ostium of the celiac artery. Independently we found that, unlike the gradual luminal expansion typical for human aneurysms, the outer diameter increase of angiotensin II-induced dissecting aneurysms in mice was related to one or several intramural haematomas. These were caused by ruptures of the tunica media near the ostium of small suprarenal side branches, which had never been detected by the established small animal imaging techniques. The tear near the celiac artery led to apparent luminal dilatation, while the intramural haematoma led to a dissection of the tunica adventitia on the left suprarenal side of the aorta. The number of ruptured branches was higher in those aneurysms that extended into the thoracic aorta, which explained the observed variability in aneurysm shape. CONCLUSION Our results are the first to describe apparent luminal dilatation, suprarenal branch ruptures, and intramural haematoma formation in dissecting abdominal aortic aneurysms in mice. Moreover, we validate and demonstrate the vast potential of phase contrast X-ray tomographic microscopy in cardiovascular small animal applications.

High-Spin Molecules: Synthesis, X-ray Characterization, and Magnetic Behavior of Two New Cyano-Bridged Ni II 9 Mo V 6 and Ni II 9 W V 6 Clusters with a S = 12 Ground State

The preparations, X-ray structures, and magnetic characterizations are presented for two new pentadecanuclear cluster compounds:  [NiII{NiII(MeOH)3}8(μ-CN)30{MV(CN)3}6]·xMeOH·yH2O (MV = MoV (1) with x = 17, y = 1; MV = WV (2) with x = 15, y = 0). Both compounds crystallize in the monoclinic space group C2/c, with cell dimensions of a = 28.4957(18) Å, b = 19.2583(10) Å, c = 32.4279(17) Å, β = 113.155(6)°, and Z = 4 for 1 and a = 28.5278(16) Å, b = 19.2008(18) Å, c = 32.4072(17) Å, β = 113.727(6)°, and Z = 4 for 2. The structures of 1 and 2 consist of neutral cluster complexes comprising 15 metal ions, 9 NiII and 6 MV, all linked by μ-cyano ligands. Magnetic susceptibilities and magnetization measurements of compounds 1 and 2 in the crystalline and dissolved state indicate that these clusters have a S = 12 ground state, originating from intracluster ferromagnetic exchange interactions between the μ-cyano-bridged metal ions of the type NiII−NC−MV. Indeed, these data show clearly that the cluster molecules stay intact in solution. Ac magnetic susceptibility measurements reveal that the cluster compounds exhibit magnetic susceptibility relaxation phenomena at low temperatures since, with nonzero dc fields, χ‘ ‘M has a nonzero value that is frequency dependent. However, there appears no out-of-phase (χ‘ ‘M) signal in zero dc field down to 1.8 K, which excludes the expected signature for a single molecule magnet. This finding is confirmed with the small uniaxial magnetic anisotropy value for D of 0.015 cm-1, deduced from the high-field, high-frequency EPR measurement, which distinctly reveals a positive sign in D. Obviously, the overall magnetic anisotropy of the compounds is too low, and this may be a consequence of a small single ion magnetic anisotropy combined with the highly symmetric arrangement of the metal ions in the cluster molecule.

Genetic Resistance Determinants, In Vitro Time-Kill Curve Analysis and Pharmacodynamic Functions for the Novel Topoisomerase II Inhibitor ETX0914 (AZD0914) in Neisseria gonorrhoeae.

Resistance in Neisseria gonorrhoeae to all available therapeutic antimicrobials has emerged and new efficacious drugs for treatment of gonorrhea are essential. The topoisomerase II inhibitor ETX0914 (also known as AZD0914) is a new spiropyrimidinetrione antimicrobial that has different mechanisms of action from all previous and current gonorrhea treatment options. In this study, the N. gonorrhoeae resistance determinants for ETX0914 were further described and the effects of ETX0914 on the growth of N. gonorrhoeae (ETX0914 wild type, single step selected resistant mutants, and efflux pump mutants) were examined in a novel in vitro time-kill curve analysis to estimate pharmacodynamic parameters of the new antimicrobial. For comparison, ciprofloxacin, azithromycin, ceftriaxone, and tetracycline were also examined (separately and in combination with ETX0914). ETX0914 was rapidly bactericidal for all wild type strains and had similar pharmacodynamic properties to ciprofloxacin. All selected resistant mutants contained mutations in amino acid codons D429 or K450 of GyrB and inactivation of the MtrCDE efflux pump fully restored the susceptibility to ETX0914. ETX0914 alone and in combination with azithromycin and ceftriaxone was highly effective against N. gonorrhoeae and synergistic interaction with ciprofloxacin, particularly for ETX0914-resistant mutants, was found. ETX0914, monotherapy or in combination with azithromycin (to cover additional sexually transmitted infections), should be considered for phase III clinical trials and future gonorrhea treatment.

Dissecting abdominal aortic aneurysm in Angiotensin II-infused mice: the importance of imaging

INTRODUCTION Since the initial publication in 2000, Angiotensin II-infused mice have become one of the most popular models to study abdominal aortic aneurysm in a pre-clinical setting. We recently used phase contrast X-ray based computed tomography to demonstrate that these animals develop an apparent luminal dilatation and an intramural hematoma, both related to mural ruptures in the tunica media in the vicinity of suprarenal side branches. AIMS The aim of this narrative review was to provide an extensive overview of small animal applicable techniques that have provided relevant insight into the pathogenesis and morphology of dissecting AAA in mice, and to relate findings from these techniques to each other and to our recent PCXTM-based results. Combining insights from recent and consolidated publications we aimed to enhance our understanding of dissecting AAA morphology and anatomy. RESULTS AND CONCLUSION We analyzed in vivo and ex vivo images of aortas obtained from macroscopic anatomy, histology, high-frequency ultrasound, contrast-enhanced micro-CT, micro-MRI and PCXTM. We demonstrate how in almost all publications the aorta has been subdivided into a part in which an intact lumen lies adjacent to a remodeled wall/hematoma, and a part in which elastic lamellae are ruptured and the lumen appears to be dilated. We show how the novel paradigm fits within the existing one, and how 3D images can explain and connect previously published 2D structures. We conclude that PCXTM-based findings are in line with previous results, and all evidence points towards the fact that dissecting AAAs in Angiotensin II-infused mice are actually caused by ruptures of the tunica media in the immediate vicinity of small side branches.

Theoretical models of planetary system formation II. Post-formation evolution

Aims. We extend the results of planetary formation synthesis by computing the long-term evolution of synthetic systems from the clearing of the gas disk into the dynamical evolution phase. Methods. We use the symplectic integrator SyMBA to numerically integrate the orbits of planets for 100 Myr, using populations from previous studies as initial conditions. Results. We show that within the populations studied, mass and semimajor axis distributions experience only minor changes from post-formation evolution. We also show that, depending upon their initial distribution, planetary eccentricities can statistically increase or decrease as a result of gravitational interactions. We find that planetary masses and orbital spacings provided by planet formation models do not result in eccentricity distributions comparable to observed exoplanet eccentricities, requiring other phenomena, such as stellar fly-bys, to account for observed eccentricities.