NCS Group Research Articles

Hypothalamic-Pituitary-Adrenal (HPA) Axis Functioning in Overtraining Syndrome: Findings from Endocrine and Metabolic Responses on Overtraining Syndrome (EROS)\u2014EROS-HPA Axis

BackgroundOvertraining syndrome (OTS) results from excessive training load without adequate recovery and leads to decreased performance and fatigue. The pathophysiology of OTS in athletes is not fully understood, which makes accurate diagnosis difficult. Previous studies indicate that alterations in the hypothalamus-pituitary-adrenal (HPA) axis may be responsible for OTS; however, the data is not conclusive. This study aimed to compare, through gold standard and exercise-independent tests, the response of the HPA axis in OTS-affected athletes (OTS group) to healthy physically active subjects (ATL group) and healthy non-active subjects (NCS group).MethodsSelected subjects were evaluated for cortisol response to a 250-μg cosyntropin stimulation test (CST), cortisol and adrenocorticotropic hormone (ACTH) responses during an insulin tolerance test (ITT), and salivary cortisol rhythm (SCR).ResultsA total of 51 subjects were included (OTS, n = 14; ATL, n = 25; and NCS, n = 12). Cortisol response in the CST was similar among the three groups. Conversely, mean cortisol response during an ITT was significantly higher in ATL (21.7 μg/dL; increase = 9.2 μg/dL) compared to OTS (17.9 μg/dL; 6.3 μg/dL) and NCS (16.9 μg/dL; 6.0 μg/dL) (p ≤ 0.001; p = 0.01). Likewise, median ACTH response during an ITT was significantly higher in ATL (91.4 pg/mL; increase = 45.1 pg/mL) compared to OTS (30.3 pg/mL; 9.7 pg/mL) and NCS (51.4 pg/mL; 38.0 pg/mL) (p = 0.006; p = 0.004). For SCR, mean cortisol 30 min after awakening was significantly higher in ATL (500 ng/dL) compared to OTS (323 ng/dL) and NCS (393 ng/dL) (p = 0.004). We identified the following cutoffs that could help exclude or confirm OTS: cortisol level at 30 min after awakening (exclusion = > 530 ng/dL); cortisol response to ITT (exclusion = > 20.5 μg/dL; confirmation = < 17 μg/dL or increase < 9.5 μg/dL); and ACTH response (exclusion = > 106 pg/mL or increase > 70 pg/mL; confirmation = < 35 pg/mL and increase < 14.5 pg/mL).ConclusionThe findings of the present study showed that healthy athletes disclose adaptions to exercises that helped improve sport-specific performance, whereas this sort of hormonal conditioning was at least partially lost in OTS, which may explain the decrease in performance in OTS.

Fast food diet-induced non-alcoholic fatty liver disease exerts early protective effect against acetaminophen intoxication in mice

BackgroundAcetaminophen (APAP) is a readily available and safe painkiller. However, its overdose is the most common cause of acute liver injury (ALI). Many predisposing factors contribute to susceptibility to APAP-induced ALI. Non-alcoholic fatty liver disease (NAFLD), the major cause of chronic liver disease, is considered an important predictor of APAP-induced ALI, although the exact mechanism controversial. In this study, we aimed to elucidate the effects of NAFLD on APAP-induced ALI.MethodsTwo groups of mice, normal chow (NC) diet-fed and fast food (FF) diet-fed mice for 14 weeks, were further divided into two subgroups: intraperitoneally injected with either saline (NC-S and FF-S groups) or APAP (NC-A and FF-A groups). Biochemical tests, histological analysis, quantitative PCR, and western blotting were conducted.ResultsAlanine aminotransferase (ALT) level (199.0 ± 39.0 vs. 63.8 ± 7.4 IU/L, p < 0.05) and NAFLD activity score (0 vs. 4.5 ± 0.22) were significantly higher in mice in FF-S group than those in NC-S group. ALI features such as ALT level (8447.8 ± 1185.3 vs. 836.6 ± 185.1 IU/L, p < 0.001) and centrizonal necrosis were prominent and mRNA levels of Trib3 (RR, 1.81) was high in mice in the NC-A group. Levels of CYP2E1 and anti-inflammatory molecules such as PPAR-γ, p62, and NRF2 were high in mice in the FF-A group.ConclusionsOur results showed that while the FF diet clearly induced non-alcoholic steatohepatitis and metabolic syndrome, NAFLD also attenuates APAP-induced ALI by inducing anti-inflammatory molecules such as PPAR-γ.

Doxorubicin-Wrapped Zinc Oxide Nanoclusters for the Therapy of Colorectal Adenocarcinoma.

Doxorubicin (DOX)-wrapped zinc oxide nanoclusters (ZnO NCs) were developed for the therapy of colorectal cancer. DOX was coated onto the agglomerates of ZnO nanoparticles using a facile coating process. DOX-ZnO NCs with a hydrodynamic size of 170 nm, narrow size distribution, and positive zeta potential were fabricated. The aggregated shape of developed DOX-ZnO NCs was observed by transmission electron microscopy (TEM) imaging. The result of Fourier-transform infrared (FT-IR) analysis suggested the interaction between DOX and ZnO in DOX-ZnO NCs. The existence of DOX in the outer surface of DOX-ZnO NCs was further identified by X-ray powder diffractometer (XRD) and X-ray photoelectron spectroscopy (XPS) analyses. Cellular uptake efficiency and antiproliferation efficacy of developed DOX-ZnO NCs were tested in Caco-2 (human colorectal adenocarcinoma) cells. The cellular accumulated amount of DOX-ZnO NCs was 3.19-fold higher than that of free DOX (p < 0.05). The DOX-ZnO NCs group also exhibited improved antiproliferation potentials, compared with the DOX and ZnO groups, in Caco-2 cells at 0.5 and 1 μg/mL DOX concentrations. All these findings imply that developed DOX-ZnO NCs can be efficient hybrid nanoformulations for the therapy of colorectal cancers.

Synthesis and characterization of two new zinc(II) coordination polymers with bidentate flexible ligands: Formation of a 2D structure with (44.62)-sql topology

Zinc(II) coordination polymers [Zn(bip)2(NCS)2]n (1) and [Zn(μ-bbd)(N3)2]n (2) were synthesized by using the neutral flexible bidentate N-donor ligands 1,4-bis(3,5-dimethylpyrazolyl)butane (bbd) and 1,3-bis(imidazolyl)propane (bip), mono-anionic NCS− or N3−ligand and zinc(II) chloride salts. The results of the X-ray analyses demonstrate that in the structure of 1, the zinc(II) ion is located on an inversion center and exhibits an ZnN6 octahedral arrangement while, in the structure of 2, the zinc(II) ion adopts an ZnN4 tetrahedral geometry. In the polymer 1, the NCS groups are terminally N-bonded to the metal center and the each bip with anti-gauche conformation acts as bridging connecting four zinc(II) ions to form a two-dimensional network with a sql [point symbol (44.62)] topology while, in the polymer 1, the N3 groups are terminally bonded to the metal center and each bbd with anti-anti-anti conformation acts as bridging ligand connecting two zinc(II) ions to form a one-dimensional zig-zag chain. Coordination compounds 1 and 2 have been characterized by infrared spectroscopy, elemental analyses and single-crystal X-ray diffraction. Thermal analyses of polymers were also presented.

Effect of Miscanthus sinensis var. purpurascens Flower Extract on Proliferation and Molecular Regulation in Human Dermal Papilla Cells and Stressed C57BL/6 Mice.

To investigate the hair growth-promoting effect of Miscanthus sinensis var. purpurascens (MSP) flower extracton on in vitro and in vivo models. MSP flower extract was extracted in 99.9% methanol and applied to examine the proliferation of human dermal papilla cells (hDPCs) in vitro at the dose of 3.92-62.50 μg/mL and hair growth of C57BL/6 mice in vivo at the dose of 1000 μg/mL. The expression of transforming growth factor β1 (TGF-β1), hepatocyte growth factor (HGF), β-catenin, substance P was measured by relative quantitative realtime polymerase chain reaction. Histopathological and immunohistochemical analysis were performed. MSP (7.81 μg/mL) down-regulated TGF-β1 and up-regulated HGF and β-catenin in hDPCs (P<0.01). MSP (1000 μg/mL)-treated mice showed the earlier transition of hair follicles from the telogen to the anagen phase. The number of mast cells was lower in the MSP-treated mice than in other groups (P<0.05 vs. NCS group). Substance P and TGF-β1 were expressed in hair follicles and skin of the MSP group lower than that in negative control. Stem cell factor in hair follicles was up-regulated in the MSP-treated mice (P<0.01). The MSP flower extract may have hair growth-promotion activities.

Selective hybridization of organic dyes with CuSCN during its electrochemical growth

Nine different organic dyes have been used for electrochemical self-assembly (ESA) of CuSCN/dye hybrid thin films. One of these dyes was added to the bath for cathodic electrodeposition of CuSCN, containing Cu2+ and SCN− ions in ethanol. While anionic xanthene dyes having a carboxylic acid group were not loaded into the film, resulting in colorless CuSCN thin films with unchanged morphology and crystal orientation with the c-axis of β-CuSCN perpendicular to the substrate, all the other dyes were loaded to yield colorful CuSCN/dye hybrid thin films with specific hybrid nanostructures and preferential orientation to lay down the c-axis in parallel with the substrate. The hard and soft, acid and base (HSAB) principle nicely explains the successful ESA of dyes having a soft Lewis basic –NCS group for stable coordination to soft Lewis acidic Cu(I) sites of CuSCN. This further explains why the xanthene dyes, having hard Lewis basic carboxylate, did not coordinate with the CuSCN during electrodeposition, but did yield ESA with hard Lewis acidic ZnO in our previous studies. On the other hand, partial replacement of Cu+ ions of CuSCN with cationic dyes was found to be another efficient loading mechanism of ESA. These two mechanisms were confirmed by ESA in bath containing excess SCN− and Cu2+ respectively.

Human Cannabinoid Receptor 2 Ligand-Interaction Motif: Transmembrane Helix 2 Cysteine, C2.59(89), as Determinant of Classical Cannabinoid Agonist Activity and Binding Pose.

Cannabinoid receptor 2 (CB2R)-dependent signaling is implicated in neuronal physiology and immune surveillance by brain microglia. Selective CB2R agonists hold therapeutic promise for inflammatory and other neurological disorders. Information on human CB2R (hCB2R) ligand-binding and functional domains is needed to inform the rational design and optimization of candidate druglike hCB2R agonists. Prior demonstration that hCB2R transmembrane helix 2 (TMH2) cysteine C2.59(89) reacts with small-molecule methanethiosulfonates showed that this cysteine residue is accessible to sulfhydryl derivatization reagents. We now report the design and application of two novel, pharmacologically active, high-affinity molecular probes, AM4073 and AM4099, as chemical reporters to interrogate directly the interaction of classical cannabinoid agonists with hCB2R cysteine residues. AM4073 has one electrophilic isothiocyanate (NCS) functionality at the C9 position of its cyclohexenyl C-ring, whereas AM4099 has NCS groups at that position and at the terminus of its aromatic A-ring C3 side chain. Pretreatment of wild-type hCB2R with either probe reduced subsequent [3H]CP55,940 specific binding by ∼60%. Conservative serine substitution of any hCB2R TMH cysteine residue except C2.59(89) did not affect the reduction of [3H]CP55,940 specific binding by either probe, suggesting that AM4073 and AM4099 interact irreversibly with this TMH2 cysteine. In contrast, AM841, an exceptionally potent hCB2R megagonist and direct AM4073/4099 congener bearing a single electrophilic NCS group at the terminus of its C3 side chain, had been demonstrated to bind covalently to TMH6 cysteine C6.47(257) and not C2.59(89). Molecular modeling indicates that the AM4073-hCB2R* interaction at C2.59(89) orients this classical cannabinoid away from TMH6 and toward the TMH2-TMH3 interface in the receptor's hydrophobic binding pocket, whereas the AM841-hCB2R* interaction at C6.47(257) favors agonist orientation toward TMH6/7. These data constitute initial evidence that TMH2 cysteine C2.59(89) is a component of the hCB2R binding pocket for classical cannabinoids. The results further demonstrate how interactions between classical cannabinoids and specific amino acids within the hCB2R* ligand-binding domain act as determinants of agonist pharmacological properties and the architecture of the agonist-hCB2R* conformational ensemble, allowing the receptor to adopt distinct activity states, such that interaction of classical cannabinoids with TMH6 cysteine C6.47(257) favors a binding pose more advantageous for agonist potency than does their interaction with TMH2 cysteine C2.59(89).

Factors associated with 10 years of continuous viral load suppression on HAART.

BackgroundThe principal goal of HAART is sustained viral load (VL) suppression resulting in immune reconstitution and improved HIV outcomes. We studied the factors associated with 10 years of continuous VL suppression on HAART in the US Military HIV Natural History Study.MethodsParticipants with continuous VL suppression (CS, n = 149) were compared to those who did not have continuous viral load suppression (NCS, n = 127) for ≥10 years on HAART. Factors associated with >10 years of VL suppression were evaluated by multivariate logistic regression. Additionally, association between CS and CD4 reconstitution was analyzed with a mixed effects model.ResultsCompared to NCS participants, a lower proportion of CS participants started HAART in the early HAART era (66 vs 90 %, for years 1996–1999; p < 0.001) and had less antiretroviral use prior to HAART (37 vs 83 %; p < 0.001). At initial HAART, the median CD4 cell count was higher and VL was lower for CS compared to NCS participants (375 cells/uL [256, 499] vs 261 cells/uL [146, 400]; p < 0.001 and 4.4 log10 copies/mL [3.5, 4.9] vs 4.5 log10 copies/mL [3.8, 5.0]; p = 0.048, respectively). New AIDS events were lower during HAART (5 vs 13 %; p = 0.032) and post-HAART CD4 trajectories were greater for the CS compared to NCS group. Factors negatively associated with ≥10 years of VL suppression included log10 VL at first HAART (OR 0.61, 95 % CI 0.4, 0.92; p = 0.020) and antiretroviral use prior to HAART (OR 0.16, 95 % CI 0.06, 0.38; p < .001).ConclusionsSustained VL suppression is a key to long-term health in HIV-infected patients, as demonstrated by the lower proportion of AIDS events observed 10 years after HAART initiation. The current use of more potent and well-tolerated regimens may mitigate the negative factors of pre-HAART VL and prior ARV use encountered by treatment initiated in the early HAART era.

Calculated impact of ferromagnetic substrate on the spin crossover in aFe(1,10−phenanthroline)2(NCS)2molecule

Spin crossover in the ${\mathrm{Fe}(1,10\ensuremath{-}\text{phenanthroline})}_{2}{(\mathrm{NCS})}_{2}$ (Fephen) molecule adsorbed on ferromagnetic cobalt (001) and (111) surfaces as well as a gold (001) surface has been studied using the projector augmented wave method in conjunction with the density functional theory within the generalized gradient approximation, including a Hubbard interaction $U$ at the iron site and a van der Waals weak interaction between the molecule and the surface. It is shown that the energy difference between the high-spin (HS) and the low-spin (LS) states and the energy barrier of Fephen/Co(111) are significantly reduced compared to those of the adsorbed molecule on Cu(001) and Au(001). This makes the switching of the molecule from the HS to the LS state much easier than when the molecule is adsorbed on a copper or gold substrate. It is also shown that an indirect exchange mechanism is responsible for the ferromagnetic coupling between the Fe center of Fephen and the cobalt substrate and that, in the LS state, the Fephen/Co interface remains magnetically active due to small induced magnetic moments in the NCS group and iron center. This magnetic coupling between the molecule and the substrate decreases in an oscillatory fashion as a function of the number of copper layers inserted between the molecule and the cobalt substrate, in a manner similar to that of the interlayer magnetic exchange coupling. Finally, scanning tunneling microscopy images at the Fermi level show that the separation between the phen lobes is larger in the HS state than in the LS state and the work functions of cobalt, gold, and copper substrates are strongly reduced upon adsorption of the Fephen molecule.

A water-soluble and retrievable ruthenium-based probe for colorimetric recognition of Hg(II) and Cys

A new ruthenium-based complex 1 [(bis(4,4′-dimethylphosphonic-2,2′-bipyridine) dithiocyanato ruthenium (II))] was developed as a colorimetric probe for the detection of Hg(II) and Cys (Cysteine). The obtained compound 1 can give interconversional color changes upon the alternating addition of Hg(II) and Cys in 100% aqueous solution. The specific coordination between NCS groups with Hg(II) can lead to the formation of 1-Hg2+ complex, which can induce a remarkable spectral changes of probe 1. Afterwards the formed 1-Hg2+ complex can act as effective colorimetric sensor for Cys. Owing to the stronger binding affinity of sulfhydryl group to Hg2+, Cys can extract Hg2+ from 1-Hg2+ complex resulting in the release of 1 and the revival of absorption profile of the probe 1. By introducing the hydrophilic phosphonic acid groups, the proposed probe exhibited excellent water solubility. The limits of detection (LODs) of the assay for Hg2+ and Cys are calculated to be 15nM and 200nM, respectively.

Exchange Coupling of Spin-Crossover Molecules to Ferromagnetic Co Islands.

The properties of Fe(1,10-phenanthroline)2(NCS)2 (Fe-phen) molecules deposited on Co/Cu(111) are studied with scanning tunneling microscopy (STM) operated in ultrahigh vacuum at low temperature (4 K) and ab initio calculations. Both the experimental and theoretical results are used to identify the high-spin (HS) state of Fe-phen. Additionally, the calculations reveal a strong spin-polarization of the density of states (DOS) and is validated experimentally using the spin sensitivity of spin-polarized STM. Finally, it is shown that the magnetic moment of the Fe-ion within HS Fe-phen is strongly magnetically coupled to the underlying magnetic Co through the NCS groups. These findings enable promising spintronic perspectives.

Structural and stereochemical nonrigidity of 7-(heptaphenylcycloheptatrienyl) isothiocyanate

By means of DFT B3LYP/6-31G(d, p) calculations of 7-(heptaphenylcycloheptatrienyl) isothiocyanate, the dissociation–recombination mechanism for intramolecular migrations of the isothiocyanato group has been revealed, and the structure of the transition state preceding the formation of a tight ion pair has been found for the first time. According to calculations, the high activation barrier for displacements of the isothiocyanato group ΔEZPE≠ = 21.3 kcal/mol is related to the stable conformation of the molecule with the equatorial–NCS group and the orthogonally located phenyl substituent in the axial position. The rearrangement of the molecule to the form favorable for migrations of the–NCS group involves the inversion of the seven-membered ring accompanied by rotation of the phenyl group.

11 COMPARISON OF CONTROLLED INTERNAL DRUG-RELEASE INSERT–BASED AND PROGESTERONE-FREE METHODS FOR OVULATION SYNCHRONIZATION AND TIMED ARTIFICIAL INSEMINATION OF GOATS

A CIDR synchronization program is an important tool for facilitating ovulation synchronization and timed AI (OvSynch-TAI). The objective of this study was to test the efficacy of reusing CIDR for OvSynch-TAI compared with that for a progesterone-free OvSynch-TAI protocol (NCS) or a breed by oestrus detection (ED) control. A total of 87 does were randomised into 1 of 5 treatments: (1) ED (control, n = 18), (2) NCS (n = 18), (3) CIDR6-New (n = 17), (4) CIDR6–1X (n = 17), and (5) CIDR6–2X (n = 17). Does in the ED group received two 15-mg doses of PGF2α at a 10-d interval and were bred 12 h after the onset of oestrus following the second PGF2α injection. The NCS group received 15 mg of PGF2α on Day 0, 50 μg of gonadotropin-releasing hormone on Day 8, 15 mg of PGF2α on Day 15, and 50 μg of gonadotropin-releasing hormone on Day 18, concurrently with TAI. The CIDR groups (new, 1X-used, or 2X-used) received a P4 device for a 6-d period, and 15 mg of PGF2α was administered at CIDR removal. Does were bred 48 h after CIDR removal and were given 50 μg of gonadotropin-releasing hormone at TAI. The CIDR in the CIDR6–1X group were previously in place for 10 days before use, whereas CIDR in the CIDR6–2X group were previously in place for 16 days before use. Reused CIDR were rinsed in a diluted Nolvasan solution, followed by a clean water rinse, allowed to air dry, and stored in a refrigerator until time of use. The experiment was conducted in 2 replicates. Within each replicate, all treatments were scheduled so that does were bred during the same 2-day period, and all does were inseminated with a single dose of frozen semen using a nonsurgical (transcervical) technique. Blood samples were taken daily in all treatment groups to monitor concentrations of serum progesterone until the time of breeding. Pregnancy was determined by ultrasonography at 54 and 85 days of gestation. Data were analysed using GLM procedures of SAS (SAS Institute Inc., Cary, NC, USA). Data for pregnancy rates were analysed with a model that included effects of treatment, replicate, and their interactions. Data for serum progesterone concentrations were analysed with a model that included the effects of treatment, replicate, day, and their interactions. Means were separated by Duncan’s test. Mean progesterone differed (P &lt; 0.001) with treatment (5.3 ± 0.8bc, 3.5 ± 0.8c, 7.0 ± 0.8ab, 7.9 ± 0.8a, 6.2 ± 0.8ab ng mL–1 for ED, NCS, CIDR6-New, CIDR6–1X, and CIDR6–2X, respectively; least squares mean ± standard error of the mean). Pregnancy rates for the ED, NCS, CIDR6-New, CIDR6–1X, and CIDR6–2X treatment groups were 39 ± 11%bc, 22 ± 11%c, 64 ± 12%ab, 77 ± 12%a, and 57 ± 12%ab, respectively. In conclusion, reused CIDR were as effective as new CIDR for attaining satisfactory pregnancy rates. Timed AI using a once-used CIDR was more effective for establishing pregnancy than ED and NCS treatments. The lower pregnancy rates in the ED and NCS groups were associated with lower mean progesterone levels during the Ovsynch treatment period before breeding. This research was supported by the North Carolina Agricultural Experiment Station.

Abstract 2440: Evaluation of structural changes in SN79-derived sigma-2 receptor modulators: effect on apoptotic efficacy in SK-N-SH neuroblastoma

Abstract Sigma receptors are a unique class of membrane bound receptors with key roles in mediating cell survival. The sigma-2 subtype has received attention due to its significant upregulation in rapidly proliferating tumor cells as compared to non-cancerous cells. When activated, the sigma-2 receptor induces apoptosis. Previously, we described the use of -NCS derivatives of SN79, a moderately sigma-2 selective antagonist (Ki = 290 and 30 nM at sigma-1 and sigma-2, respectively), to induce apoptosis in breast, brain, and pancreatic cancer cell lines (Nicholson et al., Proc. Amer. Assoc. Cancer Res. 74: #3237, 2014). CM572, a potent selective partial agonist of the sigma-2 receptor (Ki = &amp;gt;10μM and 15nM at sigma-1 and sigma-2, respectively), was found to irreversibly bind and induce apoptosis in several cancer cell lines. Here we present a series of heterocyclic ring structural variants of CM572 and our evaluation of these ligands for use as potential chemotherapeutics. When the methyl ketone group on the heterocyclic ring of SN79 was substituted with -NO2, the resulting ligand showed low or no selectivity (≤2-fold) for the sigma-2 receptor over the sigma-1 receptor, while -NCS substituted ligands showed higher selectivity (≥10-fold) for the sigma-2 receptor. Substitution of the -O- in the heterocyclic ring of SN79 with -S- resulted in excellent sigma-2 receptor affinity but greatly reduced selectivity, suggesting potential interaction at this position in the binding pocket of the sigma-1 receptor. Substituting this position with -N-Me significantly increased selectivity by reducing sigma-1 receptor affinity, suggesting that steric hindrance rendered this position less amenable to sigma-1 receptor binding. -NCS derivatives of SN79 were cytotoxic to SK-N-SH neuroblastoma, while substitution of -NCS for -NO2 reduced efficacy, potency, and eliminated irreversible binding capability. Substitution of the -NCS group with -NH2 eliminated agonist properties, rendering these ligands unable to induce apoptosis up to 50 μM. Interestingly, while high sigma-2 receptor affinity was retained for -NH2-substituted ligands, they were unable to attenuate agonist activity at the sigma-2 receptor, suggesting poor antagonist activity compared to the parent compound. This data implies that the presence of an electron withdrawing group on the heterocyclic ring imparts agonist activity. We conclude that the greatest potential for a potent, highly efficacious, selective sigma-2 receptor -targeted chemotherapeutic agent will result from an SN79 derivative containing an -NCS at the 4 position of the aromatic moiety and an N-Me group in the heterocyclic ring. Future work will focus on the effects of these compounds in tumor xenograft models across a variety of cancer types, as well as using structural variants to predict characteristics of the binding pockets of sigma-1 and sigma-2 receptors. Citation Format: Hilary Elaine Nicholson, Walid Alsharif, Christopher R. McCurdy, Wayne D. Bowen. Evaluation of structural changes in SN79-derived sigma-2 receptor modulators: effect on apoptotic efficacy in SK-N-SH neuroblastoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2440. doi:10.1158/1538-7445.AM2015-2440

Hydrogen bonding induced polymorphism in the scandium(III) complex with ε-caprolactam

Abstract Two polymorphs of [Sc(cpl)6][Cr(NCS)6] (cpl=ε- C6H11NO), trigonal and monoclinic, form purple elongated narrow plates and brownish-purple prisms and are formed concomitantly irrespectively of the crystallization conditions. In the trigonal polymorph both cation and anion possess C 3i site symmetry while in the monoclinic form cation and anion lie on inversion centre and 2-fold axis respectively. The nature of the polymorphism traces back to a redistribution of inter- and intramolecular hydrogen bonds that causes different conformation of the complex cations, different hydrogen bonding and different molecular packings. The [Sc(cpl)6]3+ cations in the structure of the trigonal polymorph form intermolecular N(H)…S, and in the monoclinic form both N(H)…S inter- and N(H)…O intramolecular hydrogen bonds with NCS groups of [Cr(NCS)6]3− and cpl ligands. This aggregation leads to chains, where the cations and the anions alternate, in the trigonal modification and to layers, in which each ion is surrounded by four counterions, in the monoclinic form. Both polymorphs possess thermochromic properties, and a reversible color change from light purple to dark green takes place at 470–475 K.

The same or different: An investigation of cognitive and metalinguistic correlates of Chinese word reading for native and non-native Chinese speaking children

We investigated cognitive and metalinguistic correlates of Chinese word reading in children with L2 Chinese learning experience and compared these to those in L1 Chinese speaking children. In total, 102 third and fourth grade children were recruited for the study. We examined a range of Chinese and English word reading related cognitive and metalinguistic skills. Compared to the native Chinese speaking group (NCSS), the non-native Chinese speaking group (NNCS) only performed better in English vocabulary knowledge and English working memory. On Chinese word reading related skills the NNCS group performed significantly worse than the NCS group. Hierarchical regression analyses revealed that the unique correlates of Chinese word reading for both groups were Chinese vocabulary, working memory, lexical tone awareness, and orthographic skills. For the NNCS group only, visual skills were also unique correlates of word reading skills. The results suggest cognitive similarities and differences in reading among native and non-native Chinese speakers.

Crystal structure of bis-[trans-(1,4,8,11-tetra-aza-cyclo-tetra-decane-κ(4) N)bis-(thio-cyanato-κN)chromium(III)] tetra-chlorido-zincate from synchrotron data.

The structure of the title compound, [Cr(NCS)2(cyclam)]2[ZnCl4] (cyclam = 1,4,8,11-tetra-aza-cyclo-tetra-decane, C10H24N4), has been determined from synchrotron data. The asymmetric unit contains two independent halves of the Cr(III) complex cations and half of a tetra-chlorido-zincate anion. In each complex cation, the Cr(III) atom is coordinated by the four N atoms of the cyclam ligand in the equatorial plane and by two N-bound NCS(-) anions in a trans axial arrangement, displaying a distorted octa-hedral geometry with crystallographic inversion symmetry. The mean Cr-N(cyclam) and Cr-N(NCS) bond lengths are 2.065 (4) and 1.995 (6) Å, respectively. The macrocyclic cyclam moieties adopt centrosymmetric trans-III configurations with six- and five-membered chelate rings in chair and gauche configurations, respectively. The [ZnCl4](2-) anion, which lies about a twofold rotation axis, has a slightly distorted tetra-hedral geometry. The crystal packing is stabilized by hydrogen-bonding inter-actions between the N-H groups of the cyclam ligands, the S atoms of the NCS(-) groups and the Cl(-) ligands of the anion.

Novel (89)Zr cell labeling approach for PET-based cell trafficking studies.

BackgroundWith the recent growth of interest in cell-based therapies and radiolabeled cell products, there is a need to develop more robust cell labeling and imaging methods for in vivo tracking of living cells. This study describes evaluation of a novel cell labeling approach with the positron emission tomography (PET) isotope 89Zr (T1/2 = 78.4 h). 89Zr may allow PET imaging measurements for several weeks and take advantage of the high sensitivity of PET imaging.MethodsA novel cell labeling agent, 89Zr-desferrioxamine-NCS (89Zr-DBN), was synthesized. Mouse-derived melanoma cells (mMCs), dendritic cells (mDCs), and human mesenchymal stem cells (hMSCs) were covalently labeled with 89Zr-DBN via the reaction between the NCS group on 89Zr-DBN and primary amine groups present on cell surface membrane protein. The stability of the label on the cell was tested by cell efflux studies for 7 days. The effect of labeling on cellular viability was tested by proliferation, trypan blue, and cytotoxicity/apoptosis assays. The stability of label was also studied in in vivo mouse models by serial PET scans and ex vivo biodistribution following intravenous and intramyocardial injection of 89Zr-labeled hMSCs. For comparison, imaging experiments were performed after intravenous injections of 89Zr hydrogen phosphate (89Zr(HPO4)2).ResultsThe labeling agent, 89Zr-DBN, was prepared in 55% ± 5% decay-corrected radiochemical yield measured by silica gel iTLC. The cell labeling efficiency was 30% to 50% after 30 min labeling depending on cell type. Radioactivity concentrations of labeled cells of up to 0.5 MBq/106 cells were achieved without a negative effect on cellular viability. Cell efflux studies showed high stability of the radiolabel out to 7 days. Myocardially delivered 89Zr-labeled hMSCs showed retention in the myocardium, as well as redistribution to the lung, liver, and bone. Intravenously administered 89Zr-labeled hMSCs also distributed primarily to the lung, liver, and bone, whereas intravenous 89Zr(HPO4)2 distributed to the liver and bone with no activity in the lung. Thus, the in vivo stability of the radiolabel on the hMSCs was evidenced.ConclusionsWe have developed a robust, general, and biostable 89Zr-DBN-based cell labeling strategy with promise for wide applications of PET-based non-invasive in vivo cell trafficking.

Relaxation frequencies for flip-flop rotation of three- and four-ring compounds and dual frequency addressing mixtures with high birefringence

Relaxation frequencies fr characterising the molecular rotation around the short axes (flip-flop movement) of 45 three- and four-ring polar compounds with high birefringence (mainly cyclohexyl, phenyl and biphenyl tolanes and quaterphenyls terminated with F, OCF3, NCS group) have been measured. These compounds exhibit a large positive dielectric anisotropy Δε = ε║ − ε⊥ in the nematic phase and relatively low fr values (in the range of dozens kHz). The dependence of fr upon molecular structures and physical properties of systems (molecular rigid core length, polarity and viscosity) is discussed. Mixtures for dual frequencies addressing display with the crossover frequency fco of the order of ~1 kHz have been prepared by joining the above compounds with a mixture consisted of two, three and four fluoro-substituted in the lateral position tolanes and phenyltolanes showing negative dielectric anisotropy. It was stated that relaxation frequency is correlated mainly with their length and polarity.

Monitoring the intramolecular charge transfer process in the Z907 solar cell sensitizer: a transient Vis and IR spectroscopy and ab initio investigation.

We have analyzed the excited state dynamics of the heteroleptic [(NCS)2Ru(bpy-(COOH)2)(bpy-(C6H13)2)] Z907 solar cell sensitizer in solution and when adsorbed onto thin TiO2 films, by combining transient visible and infrared (IR) spectroscopies with ab initio Density Functional Theory (DFT) and Time-Dependent DFT (TDDFT) calculations. Upon excitation with ultra-short pulses in ethanol and dimethyl-sulphoxide solutions, the visible spectra show the appearance of a positive signal around 650 nm, within the instrumental time resolution (<100 fs), which in ethanol undergoes a red-shift in about 20 ps. Measurements in the IR indicate that, upon excitation, both the CN and CO marker bands, associated with the NCS and COOH groups, downshift in frequency, in response to intramolecular ligand + metal (Ru-NCS) to ligand' (bpy-COOH2) charge transfer (LML'CT). Vibrational cooling is observed in both solvents; in ethanol it is overtaken by the hydrogen bond dynamics. On the basis of DFT/TDDFT calculations, explicitly modeling the interaction of the NCS and COOH groups with solvent (ethanol) molecules, we rationalize the observed IR and visible spectral evolution as arising from the change in the hydrogen-bond network, which accompanies the transition to the lowest-energy triplet state. This interpretation provides a consistent explanation of what is also observed in the transient visible spectra. Transient IR measurements repeated for molecules adsorbed on TiO2 and ZrO2 films, allow us to identify the structural changes signaling the dye triplet excited state formation and evidence multiexponential electron injection rates into the semiconductor TiO2 film.