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The coupling between superconductors and oscillation cycles of light pulses, i.e., lightwave engineering, is an emerging control concept for superconducting quantum electronics. Although progress has been made towards terahertz-driven superconductivity and supercurrents, the interactions able to drive non-equilibrium pairing are still poorly understood, partially due to the lack of measurements of high-order correlation functions. In particular, the sensing of exotic collective modes that would uniquely characterize light-driven superconducting coherence, in a way analogous to the Meissner effect, is very challenging but much needed. Here we report the discovery of parametrically driven superconductivity by light-induced order-parameter collective oscillations in iron-based superconductors. The time-periodic relative phase dynamics between the coupled electron and hole bands drives the transition to a distinct parametric superconducting state out-of-equalibrium. This light-induced emergent coherence is characterized by a unique phase–amplitude collective mode with Floquet-like sidebands at twice the Higgs frequency. We measure non-perturbative, high-order correlations of this parametrically driven superconductivity by separating the terahertz-frequency multidimensional coherent spectra into pump–probe, Higgs mode and bi-Higgs frequency sideband peaks. We find that the higher-order bi-Higgs sidebands dominate above the critical field, which indicates the breakdown of susceptibility perturbative expansion in this parametric quantum matter.

Light-induced supercurrents chart a path forward for the electromagnetic design of emergent materials phases and collective modes for quantum engineering applications. However, controlled spatial–temporal modulation of the complex order parameter characterizing such non-equilibrium macroscopic quantum states remains elusive. Such ultrafast phase-amplitude modulation can manifest via high harmonic modes beyond those allowed by equilibrium symmetries. Here, we drive moving condensate states via subcycle dynamical symmetry breaking achieved with nonlinear oscillating terahertz photocurrents. These non-equilibrium macroscopic quantum states with broken inversion symmetry are controlled via Cooper pair acceleration by asymmetric and multi-cycle terahertz photoexcitations. The observed supercurrent-carrying states evolve during a lightwave cycle and exhibit three distinguishing features: Anderson pseudo-spin precessions forbidden by equilibrium symmetry, strong high harmonic coherent oscillations assisted by pairing and long-lived gapless superfluidity with minimal condensate quench. Lightwave tuning of persistent photocurrents can be extended for quantum control of unconventional superconductors and topological matter, with implications on quantum gate and sensing functionalities.

The local structure of the nonplanar phthalocyanine, vanadyl phthalocyanine (VOPc), adsorbed on Cu(111) at a coverage of approximately one-half of a saturated molecular layer, has been investigated by a combination of normal-incidence X-ray standing waves (NIXSW), scanned-energy mode photoelectron diffraction (PhD), and density-functional theory (DFT), complemented by scanning tunnelling microscopy (STM). Qualitative assessment of the NIXSW data clearly shows that both “up” and “down” orientations of the molecule (with V═O pointing out of, and into, the surface) must coexist on the surface. O 1s PhD proves to be inconclusive regarding the molecular orientation. DFT calculations, using two different dispersion correction schemes, show good quantitative agreement with the NIXSW structural results for equal co-occupation of the two different molecular orientations and clearly favor the many body dispersion (MBD) method to deal with long-range dispersion forces. The calculated relative adsorption energies of the differently oriented molecules at the lowest coverage show a strong preference for the “up” orientation, but at higher local coverages, this energetic difference decreases, and mixed orientation phases are almost energetically equivalent to pure “up”-oriented phases. DFT-based Tersoff–Hamann simulations of STM topographs for the two orientations cast some light on the extent to which such images provide a reliable guide to molecular orientation.

PurposeThe purpose of the study was to investigate nailfold microvascular morphology in exfoliation syndrome with or without glaucoma (XFS/XFG) compared with primary open-angle glaucoma (POAG) and control subjects using nailfold capillary videomicroscopy.Patients and methodsWe used a JH-1004 capillaroscope to perform nailfold capillary videomicroscopy on the fourth and fifth digit of the non-dominant hand. We enrolled 56 XFS/XFG patients, 87 POAG patients, and 75 control subjects. Masked observers graded the videos for hemorrhages, avascular zones ≥200 microns (μm), and degree of microvascular tortuosity on a four-point subjective scale. Multivariable odds ratios, 95% confidence intervals and P-for trends for assessing the relation between morphological changes and POAG or XFS/XFG were obtained from logistic regression analyses. We also assessed this relation with XFS/XFG compared with POAG in multivariable models.ResultsAfter adjusting for multiple covariates, nailfold hemorrhages, avascular zones ≥200 μm, and higher degree of vascular tortuosity were more common in XFS/XFG vs controls (P-for trend ≤0.0001) and in POAG vs controls (P-for trend ≤0.01). For each 100 capillaries, the number of hemorrhages was similar (P-for trend=0.91) between XFS/XFG and POAG patients; however, there were more avascular zones per 100 capillaries with borderline significance (P-for trend=0.04) in the XFS/XFG group. XFS/XFG patients had more tortuosity than POAG patients; specifically, having a tortuosity score ≥1.5 was associated with a 4.4-fold increased odds of XFS/XFG (95% confidence interval: 1.5–13.3) relative to a tortuosity score <1.0 (P-for trend=0.005).ConclusionA high degree of nailfold capillary tortuosity is a distinct non-ocular feature associated with XFS/XFG compared with either POAG or controls.

Multiferroic materials attract considerable interest because of the wide range of potential applications such as spintronic devices, data storage devices and sensors. As a strong candidate for the applications among the limited list of single-phase multiferroic materials, BiFeO3(BFO) is a quite attractive material due to its multiferroic properties at room temperature (RT). However, BFO is widely known to have large leakage current and small spontaneous polarization due to the existence of crystalline defects such as oxygen vacancies. Furthermore, the magnetic moment of pure BFO is very weak owing to its antiferromagnetic nature. In this paper, the effects of Ni2+substitution on the magnetic properties of bulk BFO were investigated. BFO, and BiFe0.99Ni0.01O3, BiFe0.98Ni0.02O3and BiFe0.97Ni0.03O3(BFNO: Ni-doped BFO) ceramics were prepared by solid-state reaction and rapid sintering, and analyzed by structural and magnetic-property measurements. The leakage current density was measured at RT by using a standard ferroelectric tester. All the Ni-doped BFO samples exhibited the similar rhombohedral perovskite structure (R3c) to that of BFO. The magnetic properties of Ni-doped BFO were much enhanced with respect to BFO prepared at the same conditions, because the enhanced ferromagnetic interaction is caused by the Fe/Ni coupling.

Knowledge of maternal malnutrition of ruminants and effects on development of the immune system of their offspring is lacking. A study was conducted to investigate the effects of maternal protein or energy restriction during late gestation on immune status of their offspring at different ages. Sixty-three pregnant goats (local breed, Liuyang black goat, 22.2 ± 1.5 kg at d 90 of gestation) were fed control (CON, ME = 9.34 MJ/kg and CP = 12.5%, DM basis), 40% protein restricted (PR), or 40% energy restricted (ER) diets from d 91 of gestation to parturition, after which all animals received an adequate diet for nutritional recovery. Plasma concentrations of complement components (C3, C4), C-reactive protein (CRP) and immunoglobulins (IgG and IgM), jejunum cytokines (IL-2, IL-6, and IL-10) expression levels and morphology in the offspring were measured. Additionally, plasma concentration of complement and IL-6, and cytokines expression levels in gastrointestinal tract obtained at 6 wk from young goats were assessed under saline or lipopolysaccharide (LPS) challenging conditions. Maternal PR or ER decreased (P< 0.05) plasma C3, C4, IgG, and IgM concentrations, and IL-2and IL-6mRNA expression in the jejunum from neonatal kids, but did not alter (P> 0.05) plasma CRP concentration. The IL-10mRNA expression of jejunum from PR kids was also less (P< 0.01) than that from CON kids. Moreover, jejunum villous height (P< 0.10 in PR, P< 0.05 in ER) and crypt depth (P< 0.05 both in PR and ER) were reduced in neonatal kids from malnourished mothers. At 6 wk of age, there were no differences (P> 0.05) in any plasma or tissue immune parameters among the 3 treatments. However, when given a LPS challenge, ER and PR kids had greater (P= 0.02) IL-6 concentration compared with CON kids. Our results suggest that both PR and ER during late gestation induced short-term as well as long-lasting alterations on immune responses in their offspring, which may make the animals more susceptible to a bacterial pathogen challenge. The present findings expand the existing knowledge in immunological mechanisms responsible for the development of disease in later life.

Chaga mushroom (Inonotus obliquas)has been used as a folk remedy for several illnesses including gastrointestinal disorders. We recently reported the potent anti-inflammatory effect of chaga extract in experimental colitis. However, its effects on colorectal cancer (CRC) have not been clearly elucidated. We investigated the effects of an aqueous extract of Inonotus obliquus(IOAE) in vitroin HCT116 and DLD1 cell lines and in vivofor adenoma in APCMin/+mice and colitis-associated colon cancer in AOM/DSS-treated mice. Results show that IOAE suppressed the proliferation of both cell lines, and inhibited the growth of intestinal polyps in APCMin/+and colon tumors in AOM/DSS-treated mice. IOAE induced mitochondrial intrinsic pathway of apoptosis, autophagy, and S phase cell cycle arrest. IOAE suppressed the expression levels of iNOS and Cox-2 and mRNA levels of pro-inflammatory cytokines (IL-6, IL-1ß, TNF-a and IFN-?) in the intestine of mice models. IOAE suppressed the nuclear levels of ß-catenin and inhibited its downstream targets (cyclin D1 and c-Myc) along with CRC oncogene CDK8. IOAE inhibited the expression of NF-?B at cytoplasmic and nuclear levels. Our results demonstrate that IOAE possess potent anti-inflammatory and anti-proliferative properties through downregulation of Wnt/ß-catenin and NF-?B pathways. Considering recent anticancer approaches involving natural products with minimal side effects, we advocate that Inonotus obliquuscould be a beneficial supplement in prevention of colorectal cancer.

Maternal malnutrition can have temporary or long-lasting effects on development and physiological function of offspring. Our objective was to investigate whether maternal protein or energy restriction in late gestation affects the antioxidant status of plasma, immune organs (thymus and spleen), and natural barrier organs (jejunum) in neonatal goats and whether the effects could be reversed after nutritional recovery. Forty-five pregnant goats (Liuyang Blacks) of similar age (2.0 ± 0.3 yr) and BW (22.2 ± 1.5 kg at d 90 of gestation) were assigned to 3 dietary treatments during late gestation: control (ME = 9.34 MJ/kg and CP = 12.5%, DM basis), 40% protein restricted (PR), and 40% energy restricted (ER) until parturition, after which offspring received the normal diet for nutritional recovery. Plasma and tissues of kids were sampled to determine antioxidant enzymes [superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), total antioxidant capacity (T-AOC), and catalase (CAT)] and gene expression of antioxidant enzymes (Cu/Zn-SOD [SOD1], CAT, and peroxiredoxin 2 [PRDX2]). Maternal protein or energy restriction decreased (P< 0.05) SOD activities in plasma, liver, thymus, and spleen and SOD1expression in thymus, and maternal energy restriction also decreased (P< 0.05) plasma GSH-Px activity and expressions of SOD1and CATin liver at birth. After nutritional recovery of 6 wk, SOD activities in thymus (both in PR and ER) and spleen (only in PR) were greater (P< 0.05), but CAT activity of thymus (both in PR and ER) and CATexpression (only in ER) were less (P< 0.01) than those in control. After nutritional recovery of 22 wk, SOD1and PRDX2expression in thymus (both in PR and ER) and SOD1expression in liver (only in ER) were greater (P< 0.05) whereas CATexpression in thymus (both in PR and ER) was less (P< 0.001) than in control. The current results indicate that maternal protein or energy restriction can decrease the antioxidant capacity of the neonatal kids and result in an imbalance of SOD and hydrogen peroxide-inactivating systems in thymus, even after 6 or 22 wk of nutritional recovery.

To determine the immediate and long-term therapeutic efficacies of Gufoni and head-shaking maneuvers in apogeotropic type of benign paroxysmal positional vertigo involving the horizontal semicircular canal (HC-BPPV), a randomized, prospective, sham-controlled study was conducted.

For over a century, rolling contact fatigue in bearings has been recognised as a key feature limiting bearing life. The phenomenon is manifested through dark etching regions, 30 and 80° white etching bands as well as white etching areas, the latter often forming intricate defects commonly referred to as butterflies. Their presence depends on testing conditions, such as contact pressure, temperature, number of revolutions and steel cleanliness. Microstructural inspection demonstrates that precipitate shearing, dissolution, cell and nanocrystal formation as well as matrix/inclusion debonding may take place throughout bearing life. Such microstructural features have a negative effect on bearing hardness, strength, ductility and toughness, usually preceding failure. The present review shows how such phenomena are interconnected, highlighting the need for integral characterisation and modelling across the scales. This will aid in the conception of new heat treatments, steel grades and microstructures for enhanced rolling contact fatigue, leading to increased bearing life.

Background:Although studies have indicated that hyperthyroidism is associated with hypercoagulability, most such studies have focused only on examining the incidence of venous thrombosis. As far as we know, no study has attempted to explore the risk of pulmonary embolism (PE) among patients with hyperthyroidism. Objective:Using a nationwide population‐based dataset, this study was aimed at estimating the risk of PE among hyperthyroidism patients during a 5‐year period, as compared with non‐hyperthyroidism patients during the same period. Methods:Data sourced from the Taiwan Longitudinal Health Insurance Database were analyzed. The study included 8903 patients with hyperthyroidism as a study cohort and 44 515 randomly selected patients without hyperthyroidism as a comparison cohort. Stratified Cox proportional hazard regressions were used to compute the 5‐year PE‐free survival rate between these two cohorts. Results:Of the total of 53 418 patients, 41 patients (0.08%) were identified as having PE during the follow‐up period, 14 from the study cohort (0.16% of the hyperthyroidism patients) and 27 comparison patients (0.06% of patients from the comparison cohort). After adjustment for geographic region, monthly income, hypertension, diabetes, hyperlipidemia, peripheral vascular disease, coronary heart disease, cancer, recent surgery, recent fracture, pregnancy and the use of anticoagulants, the risk of having PE during the 5‐year follow‐up period was 2.31 times greater (95% confidence interval 1.20–4.45, P= 0.012) for patients with hyperthyroidism than for patients in the comparison cohort. Conclusion:We found an increased risk of PE in patients with hyperthyroidism. Clinicians should be aware of this increased risk.

This study was to evaluate the frequency of colorectal neoplasia in renal transplant recipients and to investigate the association with Epstein‐Barr virus (EBV) and cytomegalovirus (CMV) infection. We compared the frequency of colorectal neoplasia among renal transplant recipients with that of the healthy subjects. Specimens of colorectal neoplasia were examined for EBV and CMV using in situhybridization and immunohistochemistry, respectively. Of 796 renal transplantation cohorts, 315 were enrolled. The frequency of colorectal neoplasia among the patients was 22.9%. Compared with the healthy subjects, the odds ratio (OR) for advanced adenoma was 3.32 (95% CI, 1.81–6.10). The frequency of cancer among the patients was 1.9% (OR, 12.0; 95% CI, 1.45–99.7). A long interval between transplantation and colonoscopy was a significant factor in the development of advanced colorectal neoplasia. EBV positivity was detected in 30.6% of colorectal neoplasia specimens from renal transplant recipients, which was higher than that for the controls (p = 0.002). CMV was not detected in any lesions of patients or controls. In conclusion, renal transplant recipients have a significantly increased risk of advanced colorectal neoplasia. EBV was more frequently found in specimens of advanced colorectal neoplasm obtained from the renal transplant recipients.

This study was to evaluate the frequency of colorectal neoplasia in renal transplant recipients and to investigate the association with Epstein‐Barr virus (EBV) and cytomegalovirus (CMV) infection. We compared the frequency of colorectal neoplasia among renal transplant recipients with that of the healthy subjects. Specimens of colorectal neoplasia were examined for EBV and CMV using in situhybridization and immunohistochemistry, respectively. Of 796 renal transplantation cohorts, 315 were enrolled. The frequency of colorectal neoplasia among the patients was 22.9%. Compared with the healthy subjects, the odds ratio (OR) for advanced adenoma was 3.32 (95% CI, 1.81–6.10). The frequency of cancer among the patients was 1.9% (OR, 12.0; 95% CI, 1.45–99.7). A long interval between transplantation and colonoscopy was a significant factor in the development of advanced colorectal neoplasia. EBV positivity was detected in 30.6% of colorectal neoplasia specimens from renal transplant recipients, which was higher than that for the controls (p = 0.002). CMV was not detected in any lesions of patients or controls. In conclusion, renal transplant recipients have a significantly increased risk of advanced colorectal neoplasia. EBV was more frequently found in specimens of advanced colorectal neoplasm obtained from the renal transplant recipients.

Glucagon-like peptide-1 (GLP-1) and its analog exendin-4 (EX) have been considered as a growth factor implicated in pancreatic islet mass increase and {szligbeta}-cell proliferation. This study aimed to investigate the effect of EX on cyclin D1 expression, a key regulator of the cell cycle, in the pancreatic {szligbeta}-cell line INS-1. We demonstrated that EX significantly increased cyclin D1 mRNA and subsequently its protein levels. Although EX induced phosphorylation of Raf-1 and extracellular-signal-regulated kinase (ERK), both PD98059 and exogenous ERK1 had no effect on the cyclin D1 induction by EX. Instead, the cAMP-elevating agent forskolin induced cyclin D1 expression remarkably and this response was inhibited by pretreatment with H-89, a protein kinase A (PKA) inhibitor. Promoter analyses revealed that the cAMP-responsive element (CRE) site (at position –48; 5'-TAACGTCA-3') of cyclin D1 gene was required for both basal and EX-induced activation of the cyclin D1 promoter, which was confirmed by site-directed mutagenesis study. For EX to activate the cyclin D1 promoter effectively, CRE-binding protein (CREB) should be phosphorylated and bound to the putative CRE site, according to the results of electrophoretic mobility shift and chromatin immunoprecipitation assays. Lastly, a transfection assay employing constitutively active or dominant-negative CREB expression plasmids clearly demonstrated that CREB was largely involved in both basal and EX-induced cyclin D1 promoter activities. Taken together, EX-induced cyclin D1 expression is largely dependent on the cAMP/PKA signaling pathway, and EX increases the level of phosphorylated CREB and more potently trans-activates cyclin D1 gene through binding of the CREB to the putative CRE site, implicating a potential mechanism underlying {szligbeta}-cell proliferation by EX.

Glucagon-like peptide-1 (GLP-1) and its analog exendin-4 (EX) have been considered as a growth factor implicated in pancreatic islet mass increase and β-cell proliferation. This study aimed to investigate the effect of EX on cyclin D1 expression, a key regulator of the cell cycle, in the pancreatic β-cell line INS-1. We demonstrated that EX significantly increased cyclin D1 mRNA and subsequently its protein levels. Although EX induced phosphorylation of Raf-1 and extracellular-signal-regulated kinase (ERK), both PD98059 and exogenous ERK1 had no effect on the cyclin D1 induction by EX. Instead, the cAMP-elevating agent forskolin induced cyclin D1 expression remarkably and this response was inhibited by pretreatment with H-89, a protein kinase A (PKA) inhibitor. Promoter analyses revealed that the cAMP-responsive element (CRE) site (at position −48; 5′-TAACGTCA-3′) of cyclin D1 gene was required for both basal and EX-induced activation of the cyclin D1 promoter, which was confirmed by site-directed mutagenesis study. For EX to activate the cyclin D1 promoter effectively, CRE-binding protein (CREB) should be phosphorylated and bound to the putative CRE site, according to the results of electrophoretic mobility shift and chromatin immunoprecipitation assays. Lastly, a transfection assay employing constitutively active or dominant-negative CREB expression plasmids clearly demonstrated that CREB was largely involved in both basal and EX-induced cyclin D1 promoter activities. Taken together, EX-induced cyclin D1 expression is largely dependent on the cAMP/PKA signaling pathway, and EX increases the level of phosphorylated CREB and more potently trans-activates cyclin D1 gene through binding of the CREB to the putative CRE site, implicating a potential mechanism underlying β-cell proliferation by EX.

Diacylglycerol (DAG) lactones with altered functionality (C&dbd;O → CH2 or C&dbd;O → C&dbd;S) at the sn-1 and sn-2 carbonyl pharmacophores were synthesized and used as probes to dissect the individual role of each carbonyl in the binding to protein kinase C (PKC). The results suggest that the hydrated sn-1 carbonyl is engaged in very strong hydrogen-bonding interactions with the charged lipid headgroups and organized water molecules at the lipid interface. Conversely, the sn-2 carbonyl has a more modest contribution to the binding process as a result of its involvement with the receptor (C1 domain) via conventional hydrogen bonding to the protein. The parent DAG-lactones, E-6 and Z-7, were designed to bind exclusively in the sn-2 binding mode to ensure the correct orientation and disposition of pharmacophores at the binding site.

The pharmacokinetic interaction between clozapine, an atypical antipsychotic with metabolic complications, including weight gain, and green tea consumption has not been evaluated, although green tea is responsible for beneficial effects, including weight reduction, and is widely consumed in the world. Commercial green tea extract (175 mg kg−1) or saline was administered orally for 4 days before the oral administration of clozapine (20 mg kg−1) to rats. Plasma concentrations of clozapine were measured up to 5 h after clozapine administration, and then hepatic CYP1A2 expression and activity were determined. There was no significant difference in the elimination half‐life of clozapine between the green tea extract and saline groups. However, the time to reach peak concentration (Tmax) was significantly increased by green tea extract. The mean total area under the plasma concentration‐time curve (AUC0‐∞) and maximal peak plasma concentration (Cmax) of clozapine in the green tea extract group were significantly lower than those of controls. Green tea extract induced a ∼2‐fold increase in hepatic CYP1A2 levels, while the activity increased slightly (by 10% of control). Because of this reduction in AUC and Tmaxof clozapine by green tea extract pretreatment, we suggest that both the rate and amount of absorption of clozapine may be reduced by green tea extract, although the hepatic elimination phase may not be significantly altered. Therefore, the clinical implications of the effects of green tea on the bioavailability of clozapine in patients should be further evaluated.

The pharmacokinetic interaction between clozapine, an atypical antipsychotic with metabolic complications, including weight gain, and green tea consumption has not been evaluated, although green tea is responsible for beneficial effects, including weight reduction, and is widely consumed in the world. Commercial green tea extract (175 mg kg−1) or saline was administered orally for 4 days before the oral administration of clozapine (20 mg kg−1) to rats. Plasma concentrations of clozapine were measured up to 5 h after clozapine administration, and then hepatic CYP1A2 expression and activity were determined. There was no significant difference in the elimination half-life of clozapine between the green tea extract and saline groups. However, the time to reach peak concentration (Tmax) was significantly increased by green tea extract. The mean total area under the plasma concentration-time curve (AUC0-∞) and maximal peak plasma concentration (Cmax) of clozapine in the green tea extract group were significantly lower than those of controls. Green tea extract induced a ∼2-fold increase in hepatic CYP1A2 levels, while the activity increased slightly (by 10% of control). Because of this reduction in AUC and Tmaxof clozapine by green tea extract pretreatment, we suggest that both the rate and amount of absorption of clozapine may be reduced by green tea extract, although the hepatic elimination phase may not be significantly altered. Therefore, the clinical implications of the effects of green tea on the bioavailability of clozapine in patients should be further evaluated.

We designed a peptide−polymer conjugate (CPCCtat) as a novel gene carrier that could control gene expression responding to the intracellular caspase-3 signal. This carrier consists of an uncharged main polymer chain and a cationic peptide side chain, which includes the substrate sequence of caspase-3 and the protein transduction domain sequence of HIV-1 Tat. In the present study, CPCCtat formed a tight complex with DNA through an electrostatic interaction, and in this state the gene expression was totally suppressed. In contrast, the complex disintegrated in the presence of caspase-3 due to cleavage of the cationic portion from CPCCtat. This event led to an activation of gene expression. Our results also indicate that the complex can be delivered into living cells due to the cell-permeable peptide side chain of CPCCtat. This intracellular signal-responsive system with CPCCtat will be useful for the cell-specific gene expression system.

Commercially available 2-methylenepropane-1,3-diol was converted to chiral epoxide (R)-2 via Sharpless asymmetric epoxidation in >96% ee. Regiospecific epoxide ring opening and reduction of the intermediate alkyne set the stage for a one-pot lactonization to give (R)-6, a convenient precursor for all functionalized chiral DAG-lactones used as potent PK-C ligands. The synthesis of the most potent DAG-lactones known to date, (Z)-10 and (E)-10, served to confirm PK-C's exclusive preference for the (R)-stereochemistry in this class of compounds.

A series of macrocyclic diacylglycerol (DAG)-bis-lactones were investigated as extreme conformationally constrained analogues of DAG-lactones in order to seek more potent protein kinase C (PKC) ligands with higher binding affinities and less lipophilicity than previous compounds. The additional constraint achieved the desired objective as exemplified by the macrocyclic DAG-bis-lactone 57, which exhibited a 6-fold higher binding affinity for PKCα (Ki = 6.07 nM) than the corresponding nonmacrocyclic 3-alkylidene DAG-lactone 6. A structure−activity relationship (SAR) analysis of the macrocyclic DAG-bis-lactones demonstrated a parabolic relationship between activity and lipophilicity, as well as a predilection for the Z-alkylidene isomers as the preferred ligands. Molecular docking studies revealed that macrocyclic DAG-bis-lactone 57 bound to the C1b domain of PKCα exclusively in the sn-1 binding mode in contrast to DAG-lactone 6, which showed both sn-1 and sn-2 binding modes. It is proposed that the high potency displayed by these macrocyclic DAG-bis-lactones results from a set of more favorable hydrogen bonding and hydrophobic interactions with PKCα as well as from a reduced entropy penalty due to conformational restriction.

Coke formation on KVO3−B2O3/SA5203 catalysts during naphtha pyrolysis in a fixed-bed reactor was studied. As the KVO3 loading increased, the amount of coke deposited on KVO3−B2O3/SA5203 decreased, but CO2 formation increased, indicating that KVO3 plays a key role in retarding coke accumulation but not in enhancing the product yields. The coke layers formed on the support and KVO3−B2O3/SA5203 were different in their properties. The coke layer formed on KVO3−B2O3/ SA5203 was free of soluble coke, which dissolves in the CH2Cl2 solution, and consisted of mainly insoluble coke; in contrast, the coke layer formed on the support consisted of both soluble and insoluble coke. The coke layer on KVO3−B2O3/SA5203 catalyst was porous, whereas that on SA5203 was nonporous. KVO3 on the catalyst apparently plays a key role in catalyzing the gasification of soluble coke to CO2.

Receptor-associated protein (RAP) is a ligand for all members of low-density lipoprotein (LDL) receptor families. RAP is internalized into cells via receptor-mediated endocytic trafficking, making it an attractive mechanism for efficient gene delivery. In this study, we have developed a gene delivery system using RAP as a targeting ligand. A RAP cDNA lacking a C-terminal heparin-binding domain was amplified by polymerase chain reaction (PCR) from a human liver cDNA library and was reamplified by using a primer containing a cysteine codon at its carboxyl end to facilitate its conjugation to polylysine (polyK). RAP was purified using a bacterial expression system and coupled to poly-d-lysine (PDL) or poly-l-lysine (PLL) of average MW 50 kDa via the heterobifunctional cross-linker SPDP. Using fluorescence-labeled RAP ligand, cellular uptake of the transfection complexes into HepG2 cells was shown to be highly efficient and more specific to PDL-conjugated RAP compared with PLL-conjugated one. Plasmid DNA containing a luciferase reporter gene was condensed with either RAP−PDL or RAP−PLL. In vitro transfection into HepG2 cells with RAP−PDL conjugate resulted in significantly higher luciferase expression levels in comparison to either nonconjugated PDL, or RAP−PLL, or LipofecAMINE/DNA complexes in the presence of 10% fetal bovine serum. Luciferase expression was inhibited by the addition of excess RAP. Treatment of the cells with Lovastatin, which inhibits HMG-Co reductase and increases expression of LDL receptor, stimulates luciferase expression, suggesting that the gene delivery is specifically mediated by LDL receptor. Thus, RAP−PDL conjugates have the potential to be used as a new nonviral gene delivery vector.

We treated 35 brachymetatarsal rays of 18 feet in 12 patients by one-stage lengthening with interpositional bone grafts or by gradual lengthening with callotasis combined with shortening of the adjacent metatarsals and phalanges. Definition of the two parabolas which connect the metatarsal heads and the tips of the toes, and recognition of three patterns of metatarsal length, were helpful guides in treatment. In total, 36 excisions of the phalanges and/or the metatarsals were undertaken. The mean shortening was 8 mm.The radiological results were satisfactory. The mean values were as follows: one-stage lengthening, length gain, 1.3 cm; healing index, 1.3 months/cm; percentage increase, 30%; gradual lengthening, length gain, 2.0 cm; healing index, 2.0 months/cm; percentage increase, 50%.Associated shortening of an adjacent bone can avoid the disadvantages of one-stage lengthening which may not achieve target length and can result in neurovascular complications. Reduction of the target length enables the surgeon to carry out one-stage instead of gradual lengthening. It also shortens the length of treatment in the group undergoing callotasis and improves cosmesis.

The structures of N-hydroxylamides 1a and 1b, previously reported by Lee et al. in J. Med. Chem. 2001, 44, 4309−4312 as strong protein kinase C (PK-C) ligands, were incorrect and correspond instead to esters 2a and 2b, respectively. Here, we report the synthesis and complete characterization of 1a and 1b together with the associated biological activity in terms of PK-C binding affinity.

An approach to reduce the log P in a series of diacylglycerol (DAG)-lactones known for their high binding affinity for protein kinase C (PK-C) is presented. Branched alkyl groups with reduced lipophilicity were selected and combined with the replacement of the ester or lactone oxygens by NH or NOH groups. Compound 6a with an isosteric N-hydroxyl amide arm represents the most potent and least lipophilic DAG analogue known to date.

The PHENIX experiment consists of a large detector system located at the newly commissioned relativistic heavy ion collider (RHIC) at the Brookhaven National Laboratory. The primary goal of the PHENIX experiment is to look for signatures of the QCD prediction of a deconfined high-energy-density phase of nuclear matter quark gluon plasma. PHENIX started data taking for Au+Au collisions at √sNN=130 GeV in June 2000. The signals from the beam-beam counter (BBC) and zero degree calorimeter (ZDC) are used to determine the centrality of the collision. A Glauber model reproduces the ZDC spectrum reasonably well to determine the participants in a collision. Charged particle multiplicity distribution from the first PHENIX paper is compared with the other RHIC experiment and the CERN, SPS results. Transverse momentum of photons are measured in the electro-magnetic calorimeter (EMCal) and preliminary results are presented. Particle identification is made by a time of flight (TOF) detector and the results show clear separation of the charged hadrons from each other.

Using C 1s scanned-energy mode photoelectron diffraction (PhD), the local geometry of CO adsorbed onto a Ni(111)(2×2)-O surface has been investigated as a function of the temperature of dosing or subsequent annealing. Around room temperature the CO adopts local atop sites in agreement with the previous interpretation of vibrational spectroscopy, but at low temperature a substantial fraction of the CO molecules adopt the hollow sites occupied in the absence of the preadsorbed O, generally consistent with the results of an earlier PhD study. Heating such a surface leads to a new state in which only atop sites are occupied, but this appears to be a result of desorption of the hollow species rather than any transformation of sites. The results confirm the qualitative site occupations deduced in a recent study of this system which used C 1s and O 1s photoelectron binding energy shifts to fingerprint the local site changes.