Discovery of new diketopiperazines inhibiting Burkholderia cenocepacia quorum sensing in vitro and in vivo

Burkholderia cenocepacia, an opportunistic respiratory pathogen particularly relevant for cystic fibrosis patients, is difficult to eradicate due to its high level of resistance to most clinically relevant antimicrobials. Consequently, the discovery of new antimicrobials as well as molecules capable of inhibiting its virulence is mandatory. In this regard quorum sensing (QS) represents a good target for anti-virulence therapies, as it has been linked to biofilm formation and is important for the production of several virulence factors, including proteases and siderophores. Here, we report the discovery of new diketopiperazine inhibitors of the B. cenocepacia acyl homoserine lactone synthase CepI, and report their anti-virulence properties. Out of ten different compounds assayed against recombinant CepI, four were effective inhibitors, with IC50 values in the micromolar range. The best compounds interfered with protease and siderophore production, as well as with biofilm formation, and showed good in vivo activity in a Caenorhabditis elegans infection model. These molecules were also tested in human cells and showed very low toxicity. Therefore, they could be considered for in vivo combined treatments with established or novel antimicrobials, to improve the current therapeutic strategies against B. cenocepacia

Beyond genomic selection: the animal model strikes back (one generation)!

Genome inheritance is by segments of DNA rather than by independent loci. We introduce the ancestral regression (AR) as a recursive system of simultaneous equations, with grandparental path coefficients as novel parameters. The information given by the pedigree in the AR is complementary with that provided by a dense set of genomic markers, such that the resulting linear function of grandparental BV is uncorrelated to the average of parental BV in the absence of inbreeding. AR is then connected to segmental inheritance by a causal multivariate Gaussian density for BV. The resulting covariance structure (Σ) is Markovian, meaning that conditional on the BV of parents and grandparents, the BV of the animal is independent of everything else. Thus, an algorithm is presented to invert the resulting covariance structure, with a computing effort that is linear in the number of animals as in the case of the inverse additive relationship matrix.Instituto de Genética Veterinari

Nanodiamonds-induced effects on neuronal firing of mouse hippocampal microcircuits

Fluorescent nanodiamonds (FND) are carbon-based nanomaterials that can efficiently incorporate optically active photoluminescent centers such as the nitrogen-vacancy complex, thus making them promising candidates as optical biolabels and drug-delivery agents. FNDs exhibit bright fluorescence without photobleaching combined with high uptake rate and low cytotoxicity. Focusing on FNDs interference with neuronal function, here we examined their effect on cultured hippocampal neurons, monitoring the whole network development as well as the electrophysiological properties of single neurons. We observed that FNDs drastically decreased the frequency of inhibitory (from 1.81 Hz to 0.86 Hz) and excitatory (from 1.61 Hz to 0.68 Hz) miniature postsynaptic currents, and consistently reduced action potential (AP) firing frequency (by 36%), as measured by microelectrode arrays. On the contrary, bursts synchronization was preserved, as well as the amplitude of spontaneous inhibitory and excitatory events. Current-clamp recordings revealed that the ratio of neurons responding with AP trains of high-frequency (fast-spiking) versus neurons responding with trains of low-frequency (slow-spiking) was unaltered, suggesting that FNDs exerted a comparable action on neuronal subpopulations. At the single cell level, rapid onset of the somatic AP ("kink") was drastically reduced in FND-treated neurons, suggesting a reduced contribution of axonal and dendritic components while preserving neuronal excitability.Comment: 34 pages, 9 figure

Photo-physical properties of He-related color centers in diamond

Diamond is a promising platform for the development of technological applications in quantum optics and photonics. The quest for color centers with optimal photo-physical properties has led in recent years to the search for novel impurity-related defects in this material. Here, we report on a systematic investigation of the photo-physical properties of two He-related (HR) emission lines at 535 nm and 560 nm created in three different diamond substrates upon implantation with 1.3 MeV He+ ions and subsequent annealing. The spectral features of the HR centers were studied in an "optical grade" diamond substrate as a function of several physical parameters, namely the measurement temperature, the excitation wavelength and the intensity of external electric fields. The emission lifetimes of the 535 nm and 560 nm lines were also measured by means of time-gated photoluminescence measurements, yielding characteristic decay times of (29 +- 5) ns and (106 +- 10) ns, respectively. The Stark shifting of the HR centers under the application of an external electrical field was observed in a CVD diamond film equipped with buried graphitic electrodes, suggesting a lack of inversion symmetry in the defects' structure. Furthermore, the photoluminescence mapping under 405 nm excitation of a "detector grade" diamond sample implanted at a 1x1010 cm-2 He+ ion fluence enabled to identify the spectral features of both the HR emission lines from the same localized optical spots. The reported results provide a first insight towards the understanding of the structure of He-related defects in diamond and their possible utilization in practical applicationsComment: 9 pages, 3 figure

Measurement and modelling of anomalous polarity pulses in a multi-electrode diamond detector

In multi-electrode detectors, the motion of excess carriers generated by ionizing radiation induces charge pulses at the electrodes, whose intensities and polarities depend on the geometrical, electrostatic and carriers transport properties of the device. The resulting charge sharing effects may lead to bipolar currents, pulse height defects and anomalous polarity signals affecting the response of the device to ionizing radiation. This latter effect has recently attracted attention in commonly used detector materials, but different interpretations have been suggested, depending on the material, the geometry of the device and the nature of the ionizing radiation. In this letter, we report on the investigation in the formation of anomalous polarity pulses in a multi-electrode diamond detector with buried graphitic electrodes. In particular, we propose a purely electrostatic model based on the Shockley-Ramo-Gunn theory, providing a satisfactory description of anomalous pulses observed in charge collection efficiency maps measured by means of Ion Beam Induced Charge (IBIC) microscopy, and suitable for a general application in multi-electrode devices and detectors.Comment: 8 pages, 4 figure

Çok acı bir kayıp:Osman Cemal Kaygılı hayata gözlerini yumdu

Taha Toros Arşivi, Dosya No: 114-Osman Cemal KaygılıUnutma İstanbul projesi İstanbul Kalkınma Ajansı'nın 2016 yılı "Yenilikçi ve Yaratıcı İstanbul Mali Destek Programı" kapsamında desteklenmiştir. Proje No: TR10/16/YNY/010

CDH1 mutation distribution and type suggests genetic differences between the etiology of orofacial clefting and gastric cancer

Pathogenic variants in CDH1, encoding epithelial cadherin (E-cadherin), have been implicated in hereditary diffuse gastric cancer (HDGC), lobular breast cancer, and both syndromic and non-syndromic cleft lip/palate (CL/P). Despite the large number of CDH1 mutations described, the nature of the phenotypic consequence of such mutations is currently not able to be predicted, creating significant challenges for genetic counselling. This study collates the phenotype and molecular data for available CDH1 variants that have been classified, using the American College of Medical Genetics and Genomics criteria, as at least ‘likely pathogenic’, and correlates their molecular and structural characteristics to phenotype. We demonstrate that CDH1 variant type and location differ between HDGC and CL/P, and that there is clustering of CL/P variants within linker regions between the extracellular domains of the cadherin protein. While these differences do not provide for exact prediction of the phenotype for a given mutation, they may contribute to more accurate assessments of risk for HDGC or CL/P for individuals with specific CDH1 variants

A 3-dimensional interdigitated electrode geometry for the enhancement of charge collection efficiency in diamond detectors

In this work, a single crystal CVD diamond film with a novel three-dimensional (3D) interdigitated electrode geometry has been fabricated with the reactive ion etching (RIE) technique in order to increase the charge collection efficiency (CCE) with respect to that obtained by standard superficial electrodes. The geometrical arrangement of the electric field lines due to the 3D patterning of the electrodes results in a shorter travel path for the excess charge carriers, thus contributing to a more efficient charge collection mechanism. The CCE of the device was mapped by means of the ion beam induced charge (IBIC) technique. A 1MeV proton microbeam was raster-scanned over the active area of the diamond detector under different bias voltage conditions, enabling to probe the charge transport properties of the detector up to a depth of 8 ìm below the sample surface. The experimental results, supported by the numerical simulations, show a significant improvement in the 3D detector performance (i.e. CCE, energy resolution, extension of the active area) if compared with the results obtained by standard surface metallic electrodes