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International audience; Polystannoles with thienyl co-monomers are in many ways similar to polythiophenes, but they display much reduced band gaps. However, their polymerization processes are not well researched. Thiophene can be oxidatively electropolymerized, but as stannoles are organometallic, the fundamental question arises whether their inclusion in a conjugated backbone can protect them sufficiently to be able to perform an oxidative electropolymerization. As well-defined oligothiophenes can be used as models to understand the optical and electronic properties of polythiophenes, we transposed this concept on stannole containing polymers; therefore we synthesized a monomeric 1 and dimeric thiophene-flanked stannole 2 and investigated their optoelectronic properties comparatively including polystannoles and the corresponding oligothiophenes in our analysis. With respect to monomer 1, a significantly redshifted absorption (max = 510 nm  = 93 nm) and a small optical band gap (Eg,opt(2) = 2.13 eV), close to the band gap of polymeric stannoles, was observed. In comparison to oligothiophenes, these thienyl-flanked stannoles exhibited a redshift in absorption and emission as well as a lower oxidation potential. Despite these differences, they showed an oligothiophene-like electrochemical behavior. Stannole 1 and the dimer 2 were subjected to an electropolymerization process. This process was investigated in detail by spectroelectrochemical methods which showed that radical cation species were formed in situ but readily decomposed. Nevertheless, under the milder multiscan cyclovoltammetric conditions, electropolymerization occurred as shown by cyclovoltammetry.

The synthesis of four well-defined conjugated polymers TStTT1–4 containing unusual heterocycle units in the main chain, namely stannole units as building blocks, is reported. The stannole–thiophenyl copolymers were generated by tin-selective Stille coupling reactions in nearly quantitative yields of 94% to 98%. NMR data show that the tin atoms in the rings remain unaffected. Weight-average molecular weights (Mw) were high (4900–10 900 Da and 9600–21 900 Da); and molecular weight distributions (Mw/Mn) were between 1.9 and 2.3. The new materials are strongly absorbing and appear blue-black to purple-black. All iodothiophenyl–stannole monomers St1–4 and the resulting bisthiophenyl–stannole copolymers TStTT1–4 were investigated with respect to their optoelectronic properties. The absorption maxima of the polymers are strongly bathochromically shifted compared to their monomers by about 76 nm to 126 nm in chloroform. Density functional theory calculations support our experimental results of the single stannoles St1–4 showing small HOMO–LUMO energy gaps of 3.17–3.24 eV. The optical band gaps of the polymers are much more decreased and were determined to be only 1.61–1.79 eV. Furthermore, both the molecular structures of stannoles St2 and St3 from single crystal X-ray analyses and the results of the geometry optimisation by DFT confirm the high planarity of the molecules backbone leading to efficient conjugation within the molecule., The synthesis of four well-defined conjugated polymers TStTT1–4 containing unusual heterocycle units in the main chain, namely stannole units as building blocks, is reported.

The aim of this research was to synthesize and chemically characterize a cancer-specific 177Lu-Au-nanoradiopharmaceutical based on gold nanoparticles (NPs), the nuclear localization sequence (NLS)-Arg-Gly-Asp peptide and an aptamer (HS-pentyl-pegaptanib) to target both the α(v)β(3) integrin and the vascular endothelial growth factor (VEGF) overexpressed in the tumor neovasculature, as well as to evaluate by the tube formation assay, the nanosystem capability to inhibit angiogenesis. 177Lu-NP-RGD-NLS-Aptamer was obtained with a radiochemical purity of 99 ± 1%. Complete inhibition of tube formation (angiogenesis) was demonstrated when endothelial cells (EA.hy926), cultured in a 3D-extracellular matrix support, were treated with the developed nanosystem.

Zirconacyclopentadienes are versatile precursors for a large number of heteroles, which are accessible by Zr‐element exchange reactions. The vast majority of reports describe their preparation by the use of Negishi′s reagent, which is a species that is formed in situ. The zirconacyclopentadiene is then formed by the addition of one equivalent of a diyne or two equivalents of a monoyne moiety to this Negishi species. Another route involves Rosenthal′s reagent (Cp2Zr(py)Me3SiC≡CSiMe3), which then reacts with a diyne or monoyne moiety. In this work, the efficiency of both routes was compared in terms of reaction time, stability of the product in the reaction mixture, and yield. The synthetic implications of using both routes are evaluated. Novel zirconacyclopentadienes were synthesized, characterized directly from the reaction mixture, and crystal structures could be obtained in most cases., Negishi vs. Rosenthal: Two “Cp2Zr” sources, the Negishi and the Rosenthal reagents, were compared with respect to yield, reaction, time, and product stability. In total, twelve compounds with different substituents were used for the reductive coupling by these zirconium sources.

Stannoles are organometallic rings in which the heteroatom is involved in a form of conjugation that is called σ*−π* conjugation. Only very little is known about how the substituents on the Sn atom or substituents on the stannole ring determine the optoelectronic properties of these heterocycles. In this work, this question has been studied experimentally and theoretically. Calculations of optimized equilibrium geometries, energy gaps between the highest occupied molecular orbitals (HOMOs) and lowest unoccupied molecular orbitals (LUMOs), and of the absorption spectra of a wide range of compounds were performed. The computational data showed that the substituents on the Sn atom influence the optoelectronic properties to a lower extent than the substituents in the 2 and 5 positions of the ring. These substituents in the 2 and 5 positions of the stannole ring can also have a strong influence on the overall planarity of the structure, in which mesomeric effects can play a substantial role only if the structure is planar. Thus, only structures with a planar backbone are of interest in the context of tuning the optoelectronic properties. These were selected for the experimental studies. On the basis of this information, a series of six novel stannoles was synthesized by the formation of a zirconium intermediate and subsequent transmetalation to obtain the tin compound. The calculated electronic HOMO–LUMO energy gaps varied between 2.94 and 2.68 eV. The measured absorption maxima were located between 415 and 448 nm compared to theoretically calculated values ranging from 447 nm (2.77 eV) to 482 nm (2.57 eV). In addition to these optical measurements, cyclic voltammetry data could be obtained, which show two reversible oxidation processes for three of the six stannoles. With this study, it could be demonstrated how the judicious choice of the substituents can lead to large and predictable bathochromic shifts in the absorption spectra.

An ultrahigh performance liquid chromatography-tandem mass spectrometry method for the identification and quantification of neurotransmitters, metabolites and precursors at different stages in zebrafish life was developed. Betaine, glutamine, glutamic acid, γ-aminobutyric acid, phosphocholine, glycerophosphocholine, cytidine 5'-diphosphocholine, choline, acetylcholine, dopamine, norepinephrine, serotonin, tyrosine, epinephrine, tryptophan, 5-hydroxyindolacetic acid and agmatine were selected as analytes. The method consisted of a simple deproteinization of samples using methanol and formic acid, subsequent injection onto the chromatographic equipment and quantification with a triple quadrupole mass spectrometer detector using an electrospray ionization interface in positive mode. Limits of detection ranged from 0.02 to 11ngmL(-1) and limits of quantification from 0.1 to 38ngmL(-1), depending on the analyte. The method was validated according to US Food and Drugs Administration (FDA) guideline for bioanalytical assays. Precision, expressed as relative standard deviation (%RSD), was lower than 15% in all cases, and the determination coefficient (R(2)) was equal or higher than 99.0% with a residual deviation for each calibration point lower than ±25%. Mean recoveries were between 85% and 115%. The method was applied to determine of these compounds in zebrafish from early stages of development to adulthood and showed the time-course of neurotransmitters and others neurocompounds through the life cycle. The possibility of measuring up to 17 compounds related with the main neurotransmitter systems in a simple analytical method will complement and reinforce the use of zebrafish in multiple applications in the field of neurosciences. The proposed method will facilitate future studies related with brain development.

The main objective of this work was to develop a method to measure Leucine (Leu) and β-hydroxymethylbutyrate (HMB) at basal levels in serum, urine, milk and brain microdialysates in rats. Ultrahigh performance liquid chromatography–electrospray-tandem mass spectrometry (UHPLC-ESI-MS/MS) was used as analytical technique. The sample treatment was simple and consisted of dilution with methanol and centrifugation for serum and urine, dilution with water and filtration with an Amicon filter for milk, and treatment with formic acid with no further dilution for microdialyzates. The procedures for sampling and the UHPLC-MS/MS parameters were accurately optimized to achieve the highest recoveries and to enhance the analytical characteristics of the method. For chromatographic separation, an Acquity UPLC BEH Amide column using acetonitrile-water gradient with formic acid as additive was used. The total run time was 4 min. The analytical characteristics (accuracy, selectivity and sensitivity) of the proposed method were evaluated. The limits of detection (LODs) obtained ranged from 0.4 to 7 ng mL −1 and the limits of quantification (LOQs) from 1 to 22 ng mL −1 . Precision, expressed as relative standard deviation (% RSD), was lower than 15% in all cases, and the determination coefficient ( R 2 ) was equal or higher than 99.0% with a residual deviation for each calibration point lower than ±25%. Mean recoveries were between 85 and 115%. The method was successfully applied to these matrices being able to detect significant differences between physiological situations, strains and stages of life.

Heterocycles that contain tin atoms can be aromatic in a similar sense to well-known aromatic compounds such as benzene or thiophene, but such examples are rare. However, due to the low-lying σ*-orbitals of the tin-substituent bond in stannoles, they are capable of σ*-π* conjugation in a way that is exclusive to heavier element containing heterocycles. This makes stannoles very interesting alternatives for purely organic heterocycles in material applications, in which optoelectronic properties are of interest. This Concept article will highlight the synthesis, reactivity and physical properties of stannoles and related fluorenostannoles. At first, a brief introduction to different types of tin-containing heterocycles is presented, followed by a discussion on different approaches to prepare stannoles, their reactivity and their physical properties. In addition, the first stannole-containing polymer will be reviewed.

We investigated the effects of silver nanoparticle (AgNP) exposure in three ovarian cancer cell lines (A2780, SKOV3, and OVCAR3). We found that AgNPs were highly cytotoxic toward A2780 and SKOV3 cells but OVCAR3 cells were less sensitive to AgNPs. In agreement with the cytotoxicity data, AgNPs caused DNA damage in A2780 and SKOV3 cells, but not in OVCAR3 cells. A2780 and SKOV3 showed higher levels of basal reactive oxygen species (ROS) relative to OVCAR3 cells. AgNP exposure increased ROS levels in both A2780 and SKOV3 cells, but not in OVCAR3 cells. We found that the heterogeneous cytotoxicity was specific to the uptake of intact particles and was not due to differences in sensitivity to silver ions. Furthermore, the combination of AgNPs and standard-of-care platinum therapy, cisplatin (cis-diamminedichloroplatinum(II), CDDP), was synergistic for treatment of A2780 and OVCAR3 cells and the combination of AgNPs and CDDP showed a favorable dose reduction in all cell lines tested. These results provide insight into potential applications of AgNPs for treatment of ovarian cancer.

Background: Gestational diabetes mellitus (GDM) and metabolic syndrome have been related to periodontitis. This study’s objective is to establish the relationship between them in pregnant women affected by gestational glucose metabolism disorder. Methods: In 188 pregnant women with positive O’Sullivan test (POT) results, an oral glucose tolerance test (OGTT) was performed to diagnose GDM. The mother’s periodontal parameters, age, prepregnancy weight and height and body mass index (BMI), blood pressure, gestational age, and birth weight were recorded at 24 to 28 weeks of pregnancy, as well as levels of glucose, C-reactive protein, triglycerides, glycated hemoglobin (HbA1c), and total, low-density lipoprotein, high-density lipoprotein (HDL), and very-low-density lipoprotein (VLDL) cholesterol levels. Results: Prepregnancy weight, prepregnancy BMI, systolic and diastolic blood pressure, VLDL cholesterol, and glucose parameters were higher in GDM compared with POT (P

The main objective of the present work was to develop and validate a multicompound method to measure soluble milk glycans (SMGs) in biological fluids such as serum. An ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method for the identification and quantification of the following SMGs and their precursors 2'-fucosyllactose, 3'-sialyllactose, 6'-sialyllactose, lacto-N-neotetraose, N-acetylneuraminic acid, fucose, lactose and glucose in rat serum samples was set up. These analytes were separated in an Acquity UPLC BEH Amide column using acetonitrile-water gradient with ammonia as additive, in a 10 min run, and were detected and quantified using a triple quadrupole (QqQ) mass spectrometer. The mass spectrometric conditions in negative electrospray ionization mode (ESI-) were individually optimized for each analyte to obtain maximum sensitivity in the Selected Reaction Monitoring (SRM) mode. Selection of two specific fragmentation reactions for each compound allowed simultaneous quantification and identification in one run, ensuring a high specificity of the method. The limits of detection (LODs) ranged from 5 to 70 ng mL(-1) and the limits of quantification (LOQs) from 20 to 200 ng mL(-1). The inter- and intra-day variability was lower than 15% and the recoveries ranged from 85% to 115%. A biological application of the method was also described, specifically the time-course of SMGs in rat serum after an oral challenge.

The photoluminescence properties of the new [Eu2(16-ANE-N4)(NO3)3 (CHO2)3]7 (1) and [Tb2 (16-ANE-N4)(NO3)3(CHO2)3CH 2O2]7 (2) compounds at 300 and 20 K show the characteristic fluorescence spectra of the Eu(III) and Tb(III) ions and an intrinsic emission when the samples are excited at 395 and 370 nm, respectively using a xenon lamp. The observed intrinsic emission of these complexes indicates a similar environment around the metals and evidence of the nature of these polymers. The luminescence lifetimes were found to be 1.74 and 2.94 μs for the 5D0 → 7F2 (Eu(III)) and 5D4 → 7F5 (Tb(III)) transitions, respectively at 300K. To our knowledge, these are the shortest lifetimes measured for Eu(III) and Tb(III) complexes so far. Both the fluorescence spectra and the luminescence lifetimes of these complexes suggest an isostructural nature of these homodinuclear polymeric compounds.

The main objective of the present work was to develop a method to determine β-hydroxymethylbutyrate (HMB) and leucine (Leu) in culture media and brain microdialysates. An accurate, selective, and cost-effective method, based on the use of ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS), was developed for the identification and quantification of both compounds. The method consisted of sample dilution, direct injection onto the chromatographic equipment, and quantification with a triple quadrupole mass spectrometer using an electrospray ionization interface in positive mode. The procedure and the UHPLC-MS/MS parameters were accurately optimized to achieve the highest recoveries and to enhance the analytical characteristics of the method. For chromatographic separation, an Acquity UPLC BEH Hilic column using acetonitrile-water gradient with formic acid as additive was employed. The total run time was 4 min. The limits of detection (LODs) obtained ranged from 0.01 to 0.04 μg mL(-1), and the limits of quantification (LOQs) ranged from 0.04 to 0.12 μg mL(-1). Precision (expressed as relative standard deviation) was lower than 15 %, and the determination coefficient (R (2)) was higher than 99.0 % with a residual deviation for each calibration point lower than ±25 %. Mean recoveries were between 85 and 115 %. The method was successfully applied to the analysis of both compounds, HMB and Leu, in samples obtained from an experiment of blood-brain barrier (BBB) passage in vitro and to an experiment of brain microdialysis in rats in vivo after an oral challenge with HMB to detect its appearance in the brain.

This 12-week, double-masked, double-dummy, randomized, parallel-group study compared the efficacy and safety of an estradiol matrix transdermal delivery system (Alora™) in two strengths (50-μg/d estradiol and 100-μg/d estradiol) with placebo in postmenopausal women who were experiencing at least 60 moderate-to-severe hot flushes per week. In 273 postmenopausal women, the reduction in the frequency of moderate-to-severe hot flushes was significantly better than placebo within 2 weeks of initiating therapy in the 100-μg/d group and within 3 weeks of initiating therapy in the 50-μg/d group. The reduction in hot flushes for both active treatment groups remained significantly different from placebo throughout the 12-week trial. Improvement in vaginal cytology profile (maturation index) was observed in both active treatment groups. Serum estradiol concentrations were elevated to early-to-mid-follicular levels, in proportion to dose, and the estradiol/estrone ratio remained within the expected premenopausal range. The incidence of estrogen-related side effects was modest but greater in the active treatment groups than in the placebo group: Breast pain was reported in 4.5% of the patients in the 50-μg/d group, 5.3% of patients in the 100-μg/d group, and none of the patients in the placebo group. Breakthrough bleeding occurred in 3.4% of women in the 50-μg/d group, 20.2% of women in the 100-μg/d group, and 4.4% of women in the placebo group. Only 3 (1.1%) patients terminated treatment because of skin reactions. This study demonstrates that this estradiol matrix transdermal delivery system is effective in the treatment of menopausal symptoms, while providing the skin tolerability desired by patients.

The main objective of the present work is to study the time-course of rat brain neurotransmitters in vivo after an oral challenge with a nutritional ingredient or an external stimulus, such as a chemical agent. An ultrahigh performance liquid chromatography-tandem mass spectrometry method for the identification and quantification of neurotransmitters, metabolites and derivates in microdialysates from rat brain was previously developed. Betaine, glutamine, glutamic acid, gamma-aminobutyric acid, phosphocholine, glycerophosphocholine, cytidine 5'-diphosphocholine, choline, acetylcholine, dopamine, norepinephrine, serotonin, tyrosine, epinephrine, tryptophan and 5-hydroxyindoleacetic acid were selected as analytes. The method involves direct injection of samples of microdialysates from rat brain onto the chromatographic equipment and quantification with a triple quadrupole mass spectrometer detector using an electrospray ionization interface in positive mode. The limits of detection ranged from 0.1 to 50 ng mL(-1) and the limits of quantification from 0.3 to 200 ng mL(-1). The inter- and intra-day variability were lower than 15%. Recovery rates ranged from 85% to 115%.

Lutein and zeaxanthin are carotenoids that accumulate in the macula. The macula is a yellow spot near the center of the retina that is responsible of high resolution vision. Macular pigment acts as a natural blue light filter and protects the eye from damage. Macular pigment optical density (MPOD) increases with lutein administration and is related to visual function and to the prevention of age-related macular degeneration. MOPD can be measured non-invasively and has been related to better cognitive performance. Moreover, compositional analyses of centenarian brains have shown that lutein is the main carotenoid in the brain although not in plasma, indicating a preferential accumulation in neural tissues, and that carotenoids status is correlated with some functional outcomes. Carotenoids are present in human milk with higher concentration in colostrum than in transitional and mature milk. Formula fed-infants have less plasma lutein concentration than breast fed infants. Analyses of brain from infants who died during the first year of life showed that lutein is also the predominant carotenoid of brain. Studies in non-human primates revealed that carotenoids are determinant in the formation of the retinal epithelia. In vitro studies showed that lutein stimulates the differentiation of human stem cells to neural progenitor cells. All this findings together, mostly the presence of lutein in breast milk, plasma concentration in breast-fed infants vs . formula fed infants, preferential accumulation in the brain and evidences of influence on the retina and the functionality of the brain signal the importance of the role of lutein and zeaxanthin on visual maturation and brain development.

Dear Sir,Recently, Spichtig et al. [1] published in this journal aTechnical Note regarding the analysis of sialic acids frominfant formulas using 1,2-diamino-4,5-methylenedioxyben-zene derivatives, a method previously proposed by us in2007 [2]. In this Technical Note, Spichtig et al. stated thatlactose does not interfere with the analysis, conversely towhat we hypothesized in our article. Although in the workreported in their Technical Note they did not include infantformulas or milk, in workpublished in 2010 [3]they appliedthe proposed method to several dairy products, includinginfant formulas. In the most recent work, they used com-mercial lactose and quantified fetuin sialic acids when thisprotein was in lactose solution (no concentration reported)and in aqueous solution. They reported an increase of30 μg/100 mg in the former solution when comparedwith the latter, which they attributed to a certain amountof sialyllactose present in the commercial lactose be-cause of its dairy origin. This residual sialic acid in lactosewas quantified (6.5-24.7 μg/100 mg), and the concentrationdiffered withthe supplierand was consideredverylow bytheauthors.Regarding this controversial topic, and in response to theaforementioned article, we would like to clarify our previousreport.First,weobservedaproblemintheaccuratequantitationof sialic acids from infant formulas and proposed a way toeffectively resolve this via an additional purification step. Wesuggested that lactose could be a possible reason for the ob-served phenomenon. In fact, in a series of recent tests in ourlaboratory, when commercial lactose (from Sigma) was spikedwith different amounts of N-acetylneuraminic acid (Neu5Ac)and quantified using the method reported the recovery in-creased as the amount of Neu5Ac added increased: 5.15 μgwas recovered when 5 μg was added, but 19.55 μg wasrecoveredwhen15μg was added. This represents a matrixeffect caused by lactose that produces a systematic error pro-portional to the concentration of Neu5Ac. So, we do not agreewith the statement in the abstract of the technical note thatlactose does not interfere with the analysis and we stronglyrecommend the purification step if accurate quantitation ofsialic acids in infant formulas is required.References