Tuning the in vitro cell cytotoxicity of dinuclear arene ruthenium trithiolato complexes: Influence of the arene ligand

A new series of cationic dinuclear arene ruthenium complexes bridged by three thiophenolato ligands, [(η6-arene)2Ru2(μ2-SR)3]+ with arene = indane, R = met: 1 (met = 4-methylphenyl); R = mco: 4 (mco = 4-methylcoumarin-7-yl); arene = biphenyl, R = met: 2; R = mco: 5; arene = 1,2,3,4-tetrahydronaphthalene, R = met: 3; R = mco: 6, have been prepared from the reaction of the neutral precursor [(η6-arene)Ru(μ2-Cl)Cl]2 and the corresponding thiophenol RSH. All cationic complexes have been isolated as chloride salts and fully characterized by spectroscopic and analytical methods. The molecular structure of 1, solved by X-ray structure analysis of a single crystal of the chloride salt, shows the two ruthenium atoms adopting a pseudo-octahedral geometry without metal–metal bond in accordance with the noble gas rule. All complexes are stable in H2O at 37 °C, but only 1 remains soluble in a 100 mM aqueous NaCl solution, while significant percentages (30–60 %) of 2–6 precipitate as chloride salts under these conditions. The 4-methylphenylthiolato complexes (R = met) are highly cytotoxic towards human ovarian cancer cells, the IC50 values being in the sub-micromolar range, while the 4-methylcoumarin-7-yl thiolato complexes (R = mco) are only slightly cytotoxic. Complexes 1 and 3 show the highest in vitro anticancer activity with IC50 values inferior to 0.06 μM for the A2780 cell line. The results demonstrate that the arene ligand is an important parameter that should be more systematically evaluated when designing new half-sandwich organometallic complexes.

Electronic tuning effects via π-linkers in tetrathiafulvalene-based dyes

Four new tetrathiafulvalene (TTF)-based dyes featured with a donor–bridge–acceptor (D–π–A) structure were synthesized and characterized. All of them undergo two reversible oxidations to form stable radical cation and dication species. The electronic interactions between the TTF donor and the cyanoacrylic acid acceptor through the different π-linkers have been demonstrated by the presence of a photo-induced intramolecular charge-transfer (ICT) absorption band in the visible region. A red shift of the ICT state can be finely tuned by the degree of aromaticity and extended conjugation of π-bridges. To some extent, the oxidation potentials of these dyes are affected by the nature of π-bridges. They have been applied in organic dye-sensitized solar cells, showing relatively low power conversion efficiencies of up to 0.87% due to substantial charge recombination losses.

Microbiota-mediated fine-tuning of the threshold of intestinal inflammasome activation in host-microbial mutualism

The inflammasome is a complex of proteins that controls the activity of caspase-1, pro-IL-1b and pro-IL-18. It acts in inflammatory processes and in pyropoptosis. The lower intestine is densely populated by a community of commensal bacteria that, under healthy conditions, are beneficial to the host. Some evidence suggests that the gut microbiota influences regulation of the inflammasome. Components of inflammasomes have been shown to have a protective function against development of experimental colitis, dependent on IL-18 production. However the precise mechanisms and the role of the inflammasome in maintaining a healthy host-microbial mutualism remains unknown. To address this question, we have performed axenic (GF) and gnotobiotic in vivo experiments to investigate how the inflammasome components mainly at the level of intestinal epithelial cells (IECs) are regulated under different hygiene conditions. We have established that gene expression of the inflammasome components NLRC4, NLRP3, NLRP6, NLRP12, caspase-1, ASC and IL-18 do not differ between germ-free and colonised conditions under steady-state. In contrast, induction in IL-18 was observed following infection with the pathobiont Segmented Filamentous Bacteria or the pathogen C. rodentium. Additional preliminar findings suggest that a more diverse intestinal flora, like specific pathogen-free (SPF) flora, is more efficient in inducing basal activation of the inflammasome and especially production of IL-18 by IECs, shortly after colonisation. We are also in the process of testing if basal activation of the inflammasome upon intestinal colonization with commensal bacteria helps to protect the host from potential pathobiont bacteria, like C. rodentium, SFB, Prevotella and TM7.

Photopic and scotopic spatiotemporal tuning of adult zebrafish vision.

Sensitivity to spatial and temporal patterns is a fundamental aspect of vision. Herein, we investigated this sensitivity in adult zebrafish for a wide range of spatial (0.014 to 0.511 cycles/degree [c/d]) and temporal frequencies (0.025 to 6 cycles/s) to better understand their visual system. Measurements were performed at photopic (1.8 log cd m(-2)) and scotopic (-4.5 log cd m(-2)) light levels to assess the optokinetic response (OKR). The resulting spatiotemporal contrast sensitivity (CS) functions revealed that the OKR of zebrafish is tuned to spatial frequency and speed but not to temporal frequencies. Thereby, optimal test parameters for CS measurements were identified. At photopic light levels, a spatial frequency of 0.116 ± 0.01 c/d (mean ± SD) and a grating speed of 8.42 ± 2.15 degrees/second (d/s) was ideal; at scotopic light levels, these values were 0.110 ± 0.02 c/d and 5.45 ± 1.31 d/s, respectively. This study allows to better characterize zebrafish mutants with altered vision and to distinguish between defects of rod and cone photoreceptors as measurements were performed under different light conditions.

Three-State Single-Molecule Naphthalenediimide Switch: Integration of a Pendant Redox Unit for Conductance Tuning

We studied charge transport through core-substituted naphthalenediimide (NDI) single-molecule junctions using the electrochemical STM-based break-junction technique in combination with DFT calculations. Conductance switching among three well-defined states was demonstrated by electrochemically controlling the redox state of the pendent diimide unit of the molecule in an ionic liquid. The electrical conductances of the dianion and neutral states differ by more than one order of magnitude. The potential-dependence of the charge-transport characteristics of the NDI molecules was confirmed by DFT calculations, which account for electrochemical double-layer effects on the conductance of the NDI junctions. This study suggests that integration of a pendant redox unit with strong coupling to a molecular backbone enables the tuning of charge transport through single-molecule devices by controlling their redox states.

The Effect of Increasing Intracranial Pressure on Ocular Vestibular-Evoked Myogenic Potential Frequency Tuning.

OBJECTIVE Ocular vestibular-evoked myogenic potentials (oVEMPs) represent extraocular muscle activity in response to vestibular stimulation. The authors sought to investigate whether posture-induced increase of the intracranial pressure (ICP) modulated oVEMP frequency tuning, that is, the amplitude ratio between 500-Hz and 1000-Hz stimuli. DESIGN Ten healthy subjects were enrolled in this study. The subjects were positioned in the horizontal plane (0 degree) and in a 30-degree head-downwards position to elevate the ICP. In both positions, oVEMPs were recorded using 500-Hz and 1000-Hz air-conducted tone bursts. RESULTS When tilting the subject from the horizontal plane to the 30-degree head-down position, oVEMP amplitudes in response to 500-Hz tone bursts distinctly decreased (3.40 μV versus 2.06 μV; p < 0.001), whereas amplitudes to 1000 Hz were only slightly diminished (2.74 μV versus 2.48 μV; p = 0.251). Correspondingly, the 500/1000-Hz amplitude ratio significantly decreased when tilting the subjects from 0- to 30-degree inclination (1.59 versus 1.05; p = 0.029). Latencies were not modulated by head-down position. CONCLUSIONS Increasing ICP systematically alters oVEMPs in terms of absolute amplitudes and frequency tuning characteristics. oVEMPs are therefore in principle suited for noninvasive ICP monitoring.

A hypoxia complement differentiates the muscle response to endurance exercise

Metabolic stress is believed to constitute an important signal for training-induced adjustments of gene expression and oxidative capacity in skeletal muscle. We hypothesized that the effects of endurance training on expression of muscle-relevant transcripts and ultrastructure would be specifically modified by a hypoxia complement during exercise due to enhanced glycolytic strain. Endurance training of untrained male subjects in conditions of hypoxia increased subsarcolemmal mitochondrial density in the recruited vastus lateralis muscle and power output in hypoxia more than training in normoxia, i.e. 169 versus 91% and 10 versus 6%, respectively, and tended to differentially elevate sarcoplasmic volume density (42 versus 20%, P = 0.07). The hypoxia-specific ultrastructural adjustments with training corresponded to differential regulation of the muscle transcriptome by single and repeated exercise between both oxygenation conditions. Fine-tuning by exercise in hypoxia comprised gene ontologies connected to energy provision by glycolysis and fat metabolism in mitochondria, remodelling of capillaries and the extracellular matrix, and cell cycle regulation, but not fibre structure. In the untrained state, the transcriptome response during the first 24 h of recovery from a single exercise bout correlated positively with changes in arterial oxygen saturation during exercise and negatively with blood lactate. This correspondence was inverted in the trained state. The observations highlight that the expression response of myocellular energy pathways to endurance work is graded with regard to metabolic stress and the training state. The exposed mechanistic relationship implies that the altitude specificity of improvements in aerobic performance with a 'living low-training high' regime has a myocellular basis.

Innate-like control of human iNKT cell autoreactivity via the hypervariable CDR3beta loop

Invariant Natural Killer T cells (iNKT) are a versatile lymphocyte subset with important roles in both host defense and immunological tolerance. They express a highly conserved TCR which mediates recognition of the non-polymorphic, lipid-binding molecule CD1d. The structure of human iNKT TCRs is unique in that only one of the six complementarity determining region (CDR) loops, CDR3beta, is hypervariable. The role of this loop for iNKT biology has been controversial, and it is unresolved whether it contributes to iNKT TCR:CD1d binding or antigen selectivity. On the one hand, the CDR3beta loop is dispensable for iNKT TCR binding to CD1d molecules presenting the xenobiotic alpha-galactosylceramide ligand KRN7000, which elicits a strong functional response from mouse and human iNKT cells. However, a role for CDR3beta in the recognition of CD1d molecules presenting less potent ligands, such as self-lipids, is suggested by the clonal distribution of iNKT autoreactivity. We demonstrate that the human iNKT repertoire comprises subsets of greatly differing TCR affinity to CD1d, and that these differences relate to their autoreactive functions. These functionally different iNKT subsets segregate in their ability to bind CD1d-tetramers loaded with the partial agonist alpha-linked glycolipid antigen OCH and structurally different endogenous beta-glycosylceramides. Using surface plasmon resonance with recombinant iNKT TCRs and different ligand-CD1d complexes, we demonstrate that the CDR3beta sequence strongly impacts on the iNKT TCR affinity to CD1d, independent of the loaded CD1d ligand. Collectively our data reveal a crucial role for CDR3beta for the function of human iNKT cells by tuning the overall affinity of the iNKT TCR to CD1d. This mechanism is relatively independent of the bound CD1d ligand and thus forms the basis of an inherent, CDR3beta dependent functional hierarchy of human iNKT cells.

Uniform approach to linear and nonlinear interrelation patterns in multivariate time series

Currently, a variety of linear and nonlinear measures is in use to investigate spatiotemporal interrelation patterns of multivariate time series. Whereas the former are by definition insensitive to nonlinear effects, the latter detect both nonlinear and linear interrelation. In the present contribution we employ a uniform surrogate-based approach, which is capable of disentangling interrelations that significantly exceed random effects and interrelations that significantly exceed linear correlation. The bivariate version of the proposed framework is explored using a simple model allowing for separate tuning of coupling and nonlinearity of interrelation. To demonstrate applicability of the approach to multivariate real-world time series we investigate resting state functional magnetic resonance imaging (rsfMRI) data of two healthy subjects as well as intracranial electroencephalograms (iEEG) of two epilepsy patients with focal onset seizures. The main findings are that for our rsfMRI data interrelations can be described by linear cross-correlation. Rejection of the null hypothesis of linear iEEG interrelation occurs predominantly for epileptogenic tissue as well as during epileptic seizures.

Femur Specific Polyaffine Model to Regularize the Log-Domain Demons Registration

Osteoarticular allograft transplantation is a popular treatment method in wide surgical resections with large defects. For this reason hospitals are building bone data banks. Performing the optimal allograft selection on bone banks is crucial to the surgical outcome and patient recovery. However, current approaches are very time consuming hindering an efficient selection. We present an automatic method based on registration of femur bones to overcome this limitation. We introduce a new regularization term for the log-domain demons algorithm. This term replaces the standard Gaussian smoothing with a femur specific polyaffine model. The polyaffine femur model is constructed with two affine (femoral head and condyles) and one rigid (shaft) transformation. Our main contribution in this paper is to show that the demons algorithm can be improved in specific cases with an appropriate model. We are not trying to find the most optimal polyaffine model of the femur, but the simplest model with a minimal number of parameters. There is no need to optimize for different number of regions, boundaries and choice of weights, since this fine tuning will be done automatically by a final demons relaxation step with Gaussian smoothing. The newly developed synthesis approach provides a clear anatomically motivated modeling contribution through the specific three component transformation model, and clearly shows a performance improvement (in terms of anatomical meaningful correspondences) on 146 CT images of femurs compared to a standard multiresolution demons. In addition, this simple model improves the robustness of the demons while preserving its accuracy. The ground truth are manual measurements performed by medical experts.