Input: Specific features of LiGen are the use of a pharmacophore-based docking procedure which allows Flexible docking without conformer enumeration and accurate and flexible reactant mapping coupled with reactant tagging through substructure searching.


Input: The full description of LiGen functionalities is herein presented.


Input: Structures, Dynamics, and Stabilities of Fully Modified Locked Nucleic Acid (beta-d-LNA and alpha-l-LNA) Duplexes in Comparison to Pure DNA and RNA Duplexes.


Input: Locked nucleic acid (LNA) is a chemical modification which introduces a-O-CH2-linkage in the furanose sugar of nucleic acids and blocks its conformation in a particular state.

furanose sugar


Input: Two types of modifications, namely, 2'-O, 4'-C-methylene-beta-d-ribofuranose (beta-d-LNA) and 2'-O, 4'-C-methylene-alpha-l-ribofuranose (alpha-l-LNA), have been shown to yield RNA and DNA duplex-like structures, respectively.

2'-O, 4'-C-methylene-beta-d-ribofuranose

2'-O, 4'-C-methylene-alpha-l-ribofuranose


Input: LNA modifications lead to increased melting temperatures of DNA and RNA duplexes, and have been suggested as potential therapeutic agents in antisense therapy.


Input: In this study, molecular dynamics (MD) simulations were performed on fully modified LNA duplexes and pure DNA and RNA duplexes sharing a similar sequence to investigate their structure, stabilities, and solvation properties.


Input: Both LNA duplexes undergo unwinding of the helical structure compared to the pure DNA and RNA duplexes.


Input: Though the alpha-LNA substituent has been proposed to mimic deoxyribose sugar in its conformational properties, the fully modified duplex was found to exhibit unique structural and dynamic properties with respect to the other three nucleic acid structures.

deoxyribose sugar


Input: Free energy calculations accurately capture the enhanced stabilization of the LNA duplex structures compared to DNA and RNA molecules as observed in experiments.


Input: pi-stacking interaction between bases from complementary strands is shown to be one of the contributors to enhanced stabilization upon LNA substitution.


Input: A combination of two factors, namely, nature of the-O-CH2-linkage in the LNAs vs their absence in the pure duplexes and similar conformations of the sugar rings in DNA and alpha-LNA vs the other two, is suggested to contribute to the stark differences among the four duplexes studied here in terms of their structural, dynamic, and energetic properties.


Input: Interview with m frederick hawthorne.


Input: M Frederick Hawthorne is a world-renowned scientist in the field of molecular medicine and a pioneer in boron chemistry.

boron


Input: He currently serves as the founding Director of the University of Missouri International Institute of Nano and Molecular Medicine (MO, USA).


Input: Prof.


Input: Hawthorne is a University of Missouri Curators' Distinguished Professor and University Professor of Chemistry Emeritus of the University of California, Los Angeles (CA, USA).


Input: He is a member of the US National Academy of Sciences and the recipient of many national and international honors, including the 2003 King Faisal Prize in Science, the American Chemical Society' s 2009 Priestley Medal and the 2011 National Medal of Science.


Input: Prof.


Input: Hawthorne has authored or co-authored more than 540 research articles, 30 patents, ten book chapters and two books.


Input: Prof.


Input: Hawthorne spoke to Future Medicinal Chemistry on how he became involved in the field, the future of boron neutron capture therapy, and provides his advice for the next generation of boron scientists.

boron

boron


Input: Interview conducted by Isaac Bruce, Managing Commissioning Editor.


Input: Boron chemicals in diagnosis and therapeutics.

Boron


Input: Advances in the field of boron chemistry have expanded the application of boron from material use to medicine.

boron

boron


Input: Boron-based drugs represent a new class of molecules that possess several biomedical applications including use as imaging agents for both optical and nuclear imaging as well as therapeutic agents with anticancer, antiviral, antibacterial, antifungal and other disease-specific activities.

Boron


Input: For example, bortezomib (Velcade ((R))), the only drug in clinical use with boron as an active element, was approved in 2003 as a proteasome inhibitor for the treatment of multiple myeloma and non-Hodgkin' s lymphoma.

bortezomib

Velcade

boron


Input: Several other boron-based compounds are in various phases of clinical trials, which illustrates the promise of this approach for medicinal chemists working in the area of boron chemistry.

boron

boron


Input: It is expected that in the near future, several boron-containing drugs should become available in the market with better efficacy and potency than existing drugs.

boron


Input: This article discusses the current status of the development of boron-based compounds as diagnostic and therapeutic agents in humans.

boron


Input: Boronated carbohydrate derivatives as potential boron neutron capture therapy reagents.

Boronated carbohydrate

boron


Input: The treatment of cancer remains one of the most challenging problems for humanity.


Input: Boron neutron capture therapy is a binary approach for cancer treatment that is particularly attractive in treating high-grade gliomas and metastatic brain tumors.

Boron


Input: Among the types of boron-containing molecules used as boron neutron capture therapy agents, boronated carbohydrate derivatives have received significant attention because of their preferential uptake by growing tumor cells.

boron

boron

boronated carbohydrate


Input: This review provides a summary of the recent developments in the chemistry of carborane-containing carbohydrates.

carborane

carbohydrates


Input: Dissecting Colloidal Stabilization Factors in Crowded Polymer Solutions by Forming Self-Assembled Monolayers on Gold Nanoparticles.


Input: An ideal colloidal system should be highly stable in a diverse range of buffer conditions while still retaining its surface accessibility.


Input: We recently reported that dispersing citrate-capped gold nanoparticles (AuNPs) in polymers such as polyethylene glycol (PEG) can achieve such a goal due to contributions from depletion stabilization.

citrate

AuNPs

polyethylene glycol

PEG


Input: Since AuNPs can weakly adsorb PEG to exert steric stabilization and the remaining citrate can impart charge stabilization, the extent of the contribution of depletion stabilization is unclear.

PEG

citrate


Input: In this work, we aim to dissect the contribution of each stabilizing factor.


Input: This is achieved by coating AuNPs with a layer of thiolated compound, which inhibits the adsorption of PEG and also allows the control of surface charge.

AuNPs

PEG


Input: We found that depletion stabilization alone was insufficient to stabilize AuNPs at room temperature.

AuNPs


Input: However, when working together with other stabilization mechanisms, ultrahigh stability can be achieved.


Input: The size of both AuNPs and PEG was systematically varied and the trend was compared with theoretical calculations.

AuNPs

PEG


Input: Finally, we report the importance of the surface chemistry of commercial AuNPs.


Input: Structural Characterization of a Model Gram-negative Bacterial Surface Using Lipopolysaccharides from Rough Strains of Escherichia coli.


Input: Lipopolysaccharides (LPS) make up approximately 75% of the Gram-negative bacterial outer membrane (OM) surface, however, due to the complexity of the molecule, there are very few model OMs that include LPS.


Input: The LPS molecule consists of lipid A, which anchors the LPS within the OM, a core polysaccharide region and a variable O-antigen polysaccharide chain.

lipid A


Input: In this work we used RcLPS (consisting of lipid A plus the first seven sugars of the core polysaccharide) from a rough strain of E. coli to form stable monolayers of LPS at the air-liquid interface.

lipid A

sugars


Input: The vertical structure RcLPS monolayers were characterized using neutron and X-ray reflectometry whilst the lateral structure was investigated using grazing incidence X-ray diffraction and Brewster Angle Microscopy.


Input: It was found that RcLPS monolayers at surface pressures of 20 mN m (-1) and above are resolved as hydrocarbon tails, an inner headgroup and an outer headgroup of polysaccharide with increasing solvation from tails to outer headgroups.

hydrocarbon


Input: The lateral organization of the hydrocarbon lipid chains displays an oblique hexagonal unit cell at all surface pressures, with only the chain tilt angle changing with surface pressure.

hydrocarbon


Input: This is in contrast to lipid A which displays hexagonal or, above 20 mN m (-1), distorted hexagonal packing.

lipid A


Input: This work provides the first complete structural analysis of a realistic E. coli OM surface model.


Input: Probing the Role of the Vancomycin E-Ring Aryl Chloride: Selective Divergent Synthesis and Evaluation of Alternatively Substituted E-Ring Analogues.

Vancomycin

Aryl Chloride


Input: The selective functionalization of a vancomycin aglycon derivative through direct conversion of the E-ring aryl chloride to a reactive boronic acid, and its use in the synthesis of a systematic series of vancomycin E-ring analogues are described.

vancomycin

aryl chloride

boronic acid

vancomycin


Input: The series of analogues was used to examine the impact of the E-ring chloride in binding D-Ala-D-Ala and on antimicrobial activity.

D-Ala-D-Ala


Input: In contrast to the reduced activity of the unsubstituted E-ring derivatives, hydrophobic and relatively non-polar substituents approach or match the chloro substituted vancomycin and was insensitive to the electronic character of the substituent (e. g. Cl vs CN or OMe), whereas highly polar substituents fail to provide the enhancements.

chloro substituted vancomycin

Cl

CN

OMe


Input: Moreover, the active permethylated vancomycin aglycon derivatives examined exhibit VanB VRE antimicrobial activity at levels that approach (typically within 2-fold) their activity against sensitive bacteria.

vancomycin

VanB


Input: The robust borylation reaction also enabled the selective functionalization of a minimally protected vancomycin aglycon (N-Boc vancomycin aglycon), and provides a direct method for the preparation of previously inaccessible analogues.

vancomycin

N-Boc vancomycin


Input: Characterization of the nucleation process of lysozyme at physiological pH: Primary but not sole process.


Input: We report on a kinetic study of the heat-induced aggregation process of lysozyme at physiological pH.


Input: The time evolution of the aggregation extent and the conformational changes of the protein were followed by dynamic light scattering (DLS) and FTIR spectroscopy, respectively, whereas the morphology of the aggregates was observed by Atomic Force Microscopy (AFM).


Input: The conformational changes of the secondary and tertiary structures were simultaneous and distinct in time with respect to the formation of aggregates.


Input: Oligomer formation occurred through at least two different aggregation processes: a nucleation process and a homogeneous non-nucleative diffusion-controlled process.


Input: FTIR measurements showed that supramolecular aggregation proceeded without the formation of beta-aggregated structures and AFM images revealed the presence of oligomers and amorphous aggregates; no fibrillar structures were observed.


Input: Expression of WWOX and FHIT is downregulated by exposure to arsenite in human uroepithelial cells.

arsenite


Input: Ecological studies in Taiwan, Chile, Argentina, Bangladesh, and Mexico have confirmed significant dose-dependent associations between ingestion of arsenic-contaminated drinking water and the risk of various human malignancies.

arsenic


Input: The FHIT and WWOX genes are active in common fragile sites FRA3B and FRA16D, respectively.


Input: Reduced expression of FHIT or WWOX is known to be an early indicator of carcinogen-induced cancers.


Input: However, the effect of arsenite on the expressions and molecular mechanisms of these markers is still unclear.

arsenite


Input: The aims of this study were (i) to observe the expression of ATR, WWOX and FHIT proteins in urothelial carcinoma (UC) between endemic and non-endemic areas of blackfoot disease (BFD) by immunohistochemical analyses; (ii) to compare expression of these genes between arsenite-treated SV-HUC-1 human epithelial cells and rat uroepithelial cells; and (iii) to determine the role of DNMT and MEK inhibitors on expressions of WWOX and FHIT in response to arsenite in SV-HUC-1.

arsenite

arsenite


Input: The experiments revealed that expressions of ATR, WWOX and FHIT in UC significantly differed between BFD areas and non-BFD areas (p = 0. 003, 0. 009 and 0. 021, respectively).


Input: In fact, the results for the arsenite-treated groups showed that ATR, WWOX and FHIT are downregulated by arsenite in SV-HUC-1.

arsenite

arsenite


Input: However, the inhibitors suppressed the effects of arsenite on WWOX and FHIT proteins and mRNA expression.

arsenite


Input: In conclusion, arsenite decreased expressions of ATR, WWOX and FHIT via ERK1/2 activation in SV-HUC-1 cells.


Input: These findings confirm that dysregulations of these markers may contribute to arsenite-induced carcinogenesis.

arsenite


Input: Smad3 mediates cigarette smoke extract (CSE) induction of VEGF release by human fetal lung fibroblasts.


Input: Cigarette smoke is the major cause of chronic obstructive pulmonary disease (COPD), yet pathogenic mechanisms are not fully understood.


Input: Vascular endothelial growth factor (VEGF) is one of the major regulators of endothelial cell survival and is believed to play a role in the pathogenesis of COPD.


Input: Fibroblasts are a significant source of VEGF in the lungs; however the effect of cigarette smoke exposure on VEGF release by fibroblasts is not fully understood.


Input: We hypothesized that cigarette smoke-induced disturbed VEGF release by human lung fibroblasts is a potential pathogenic mechanism that could contribute to COPD.


Input: Cigarette smoke extract (CSE) was prepared by modification of the methods of Carp and Janoff (American Review of Respiratory Disease, 1978).


Input: Human fetal lung fibroblasts (HFL-1) were exposed to different concentrations of CSE and for different durations.


Input: VEGF release into the media was measured using ELISA.


Input: TGF-beta 1 receptor (T beta R1)/Smad3 as a potential pathway for CSE modulated VEGF release was also investigated using biochemical analyses and siRNA inhibition of Smad3 and siRNA and pharmacologic inhibition of T beta R1.


Input: CSE induced VEGF release by HFL-1 in concentration and time dependent manner.


Input: This was confirmed in two additional types of primary human fetal lung fibroblasts.


Input: CSE induced Smad3 phosphorylation and nuclear translocation in HFL-1 cells.


Input: Silencing of Smad3 by siRNA not only eliminated the stimulatory effect of CSE on VEGF release but also inhibited baseline VEGF production.


Input: Suppression of T beta R1 by the pharmacological inhibitor (SB431542) markedly reduced VEGF release by HFL-1 in response to CSE and this effect was confirmed by T beta R1 siRNA.


Input: In contrast, nicotine inhibited VEGF release by HFL-1 in a dose and time dependent manner.


Input: Our findings indicate that CSE stimulates Smad3-mediated VEGF release by lung fibroblasts.


Input: Nicotine does not account for the CSE stimulation of VEGF in HFL-1.

Nicotine


Input: The ability of lung fibroblasts to produce VEGF may play a role in pathogenesis of cigarette smoke induced lung disease.


Input: 2, 3, 7, 8-TCDD induces neurotoxicity and neuronal apoptosis in the rat brain cortex and PC12 cell line through the down-regulation of the Wnt/beta-catenin signaling pathway.

2, 3, 7, 8-TCDD


Input: TCDD exposure has various toxic effects on in the human nervous system resulting in various developmental and behavioral deficits.

TCDD


Input: However the underlying molecular mechanism of TCDD-induced adverse effects on the CNS and associated signaling pathways remains largely unknown.

TCDD


Input: Herein we analyzed acute TCDD exposure in the rat brain cortex to investigate whether misregulation of the Wnt/beta-catenin signaling pathway plays a role in neurotoxicity.

TCDD


Input: Western blot and immunohistochemical experiments revealed a significant down-regulation of beta-catenin and phospho-glycogen synthase kinase-3 beta (pSer9-GSK-3 beta) after TCDD exposure.

TCDD


Input: TUNEL assay results showed apoptosis occurs mainly at day 7 after TCDD treatment.

TCDD


Input: Immunofluorescent labeling indicated that beta-catenin was localized mainly in the neurons; co-localization of beta-catenin and active caspase-3 was found following TCDD exposure.

TCDD


Input: Further, TCDD exposure decreased the level of pSer9-GSK-3 beta and beta-catenin, and increased apoptosis in the PC12 neuronal cell line in a dose-dependent manner.

TCDD


Input: Interestingly the application of lithium chloride, a GSK-3 beta inhibitor, reversed the suppressive effect of TCDD on beta-catenin in PC12 cells and primary cortical neurons restoring cell viability and protecting cells from apoptosis as compared to untreated controls.

lithium chloride

TCDD


Input: Taken together, these results indicate that the canonical Wnt/beta-catenin signaling pathway may play an important role in TCDD-induced neurotoxicity and neuronal apoptosis.

TCDD


Input: Relationships between pharmacokinetics and efficacy of Xie-xin decoction in rats with experimental ulcerative colitis.


Input: ETHNOPHARMACOLOGICAL RELEVANCE: Xie-xin decoction (XXD) has been used as a classic formula in China for the treatment of gastrointestinal dysfunction such as ulcerative colitis (UC).


Input: However, no potential action mechanisms and active compounds had been systematically investigated.


Input: AIM OF THE STUDY: To explore the effectiveness and the material basis of XXD in trinitrobenzene sulfonic acid (TNBS)-induced UC rats.

trinitrobenzene sulfonic acid

TNBS


Input: MATERIALS AND METHODS: XXD was administered orally for 8 days at a dosage of 2 or 4g/kg/day.


Input: Plasma pharmacokinetic properties and colon tissue concentrations of multiple compounds from XXD were detected.


Input: Tissue damage scores, production of interleukin (IL)-10 and myeloperoxidase (MPO), expression of tumor necrosis factor-alpha (TNF-alpha) and nuclear factor-kappa Bp65 (NF-kappa Bp65) in colon tissues were examined.


Input: Canonical correlation analysis was performed to evaluate the relationships between pharmacokinetics and efficacy to elucidate significantly active compounds of XXD.


Input: RESULTS: XXD promoted the recovery of colitis and inhibited the colonic inflammation damage in UC rats by reducing the level of MPO and the expression of TNF-alpha and NF-kappa Bp65, and increasing the production of IL-10 in colon tissues.


Input: Efficacy of XXD was positively related with AUC of five plasma compounds (baicalin, berberine, wogonoside, wogonin, and rhein) and concentrations of six colon tissue compounds (coptisine, jatrorrhizine, palmatine, berberine, baicalein and emodin), respectively.

baicalin

berberine

wogonoside

wogonin

rhein

coptisine

jatrorrhizine

palmatine

berberine

baicalein

emodin


Input: CONCLUSIONS: The multiple compounds in plasma and colon tissues from XXD might be the main material basis for therapeutic potentials in UC rats.


Input: The anti-cancer activity of Antrodia camphorata against human ovarian carcinoma (SKOV-3) cells via modulation of HER-2/neu signaling pathway.


Input: ETHNOPHARMACOLOGICAL RELEVANCE: Antrodia camphorata (AC) is well known in Taiwan as a traditional Chinese medicinal fungus.


Input: However, the anticancer activity of AC against human HER-2/neu-overexpressing ovarian cancers is poorly understood.


Input: MATERIALS AND METHODS: The aim of this study is to investigate whether a submerged fermentation culture of AC can inhibit human ovarian carcinoma cell (SKOV-3) proliferation by suppressing the HER-2/neu signaling pathway.


Input: Cell viability, colony formation, DCFH-DA fluorescence microscopy, western blotting, HER-2/neu immunofluorescence imaging, flow cytometry, and TUNEL assays were carried out to determine the anti-cancer effects of AC.


Input: RESULTS: MTT and colony formation assays showed that AC induced a dose-dependent reduction in SKOV-3 cell growth.

MTT


Input: Immunoblot analysis demonstrated that HER-2/neu activity and tyrosine phosphorylation were significantly inhibited by AC.

tyrosine


Input: Furthermore, AC treatment significantly inhibited the activation of PI3K/Akt and their downstream effector beta-catenin.


Input: We also observed that AC caused G2/M arrest mediated by down-regulation of cyclin D1, cyclin A, cyclin B1, and Cdk1 and increased p27 expression.


Input: Notably, AC induced apoptosis, which was associated with DNA fragmentation, cytochrome c release, caspase-9/-3 activation, PARP degradation, and Bcl-2/Bax dysregulation.


Input: An increase in intracellular reactive oxygen species (ROS) was observed in AC-treated cells, whereas the antioxidant N-acetylcysteine (NAC) prevented AC-induced cell death, HER-2/neu depletion, PI3K/Akt inactivation, and Bcl-2/Bax dysregulation, indicating that AC-induced cell death was mediated by ROS generation.

oxygen

N-acetylcysteine

NAC


Input: CONCLUSIONS: These results suggest that AC may exert anti-tumor activity against human ovarian carcinoma by suppressing HER-2/neu signaling pathways.


Input: Comparative effectiveness of dabigatran, rivaroxaban, apixaban and warfarin in the management of patients with non-valvular atrial fibrillation.

dabigatran

rivaroxaban

apixaban

warfarin


Input: Alternative anticoagulants to warfarin (dabigatran, rivaroxaban and apixaban) are becoming available for the prevention of thromboembolic stroke in atrial fibrillation, but there is a lack of information on their comparative effectiveness.

warfarin

dabigatran

rivaroxaban

apixaban


Input: We evaluated this using a discrete event simulation with a lifetime horizon of analysis, based on an indirect comparison of the RE-LY, ROCKET-AF and ARISTOTLE trial results for patients with the characteristics of the US atrial fibrillation population.


Input: Over a lifetime, apixaban, dabigatran and rivaroxaban accrued 0. 130 (95% central range [CR]-0. 030 to 0. 264), 0. 106 (95% CR-0. 048 to 0. 248) and 0. 095 (95% CR-0. 052 to 0. 242) more quality-adjusted life-years than warfarin, respectively, with apixaban having a 55% probability of accruing the highest total lifetime QALYs.

apixaban

dabigatran

rivaroxaban

warfarin

apixaban


Input: In the absence of a definitive trial, and acknowledging the limitations of an indirect comparison, the available evidence suggests apixaban to be the more effective anticoagulant. Clinical Pharmacology & Therapeutics (2013); accepted article preview online 25 April 2013; doi: 10. 1038/clpt. 2013. 83.

apixaban


Input: Tandutinib (MLN518/CT53518) targeted to stem-like cells by inhibiting the function of ATP-binding cassette subfamily G member 2.

Tandutinib

ATP


Input: Tandutinib is a novel inhibitor of tyrosine kinases FLT3, PDGFR and KIT.

Tandutinib

tyrosine


Input: Our study was to explore the capability of tandutinib to reverse ABC transporter-mediated multidrug resistance.

tandutinib


Input: Tandutinib reversed ABCG2-mediated drug resistance in ABCG2-482-R2, ABCG2-482-G2, ABCG2-482-T7 and S1-M1-80 cells and increased the accumulation of doxorubicin, rhodamine 123 and [H (3)] mitoxantrone in ABCG2-overexpressing cells.

Tandutinib

doxorubicin

rhodamine 123

[H (3)] mitoxantrone


Input: Importantly, tandutinib selectively sensitized side population cells to mitoxantrone.

tandutinib

mitoxantrone


Input: Taken together, our results advocate the potency of tandutinib as an ABCG2 modulator and stem-like cells targeted agent to increase efficiency of anticancer drugs.

tandutinib


Input: How do polymeric micelles cross epithelial barriers?


Input: Non-parenteral delivery of drugs using nanotechnology-based delivery systems is a promising non-invasive way to achieve effective local or systemic drug delivery.


Input: The efficacy of drugs administered non-parenterally is limited by their ability to cross biological barriers, and epithelial tissues particularly present challenges.


Input: Polymeric micelles can achieve transepithelial drug delivery because of their ability to be internalized into cells and/or cross epithelial barriers, thereby delivering drugs either locally or systematically following non-parenteral administration.


Input: This review discusses the particular characteristics of various epithelial barriers and assesses their potential as non-parenteral routes of delivery.


Input: The material characteristics of polymeric micelles (e. g., size, surface charge, and surface decoration) and of unimers dissociated from polymeric micelles determine their interactions (non-specific and/or specific) with mucus and epithelial cells as well as their intracellular fate.


Input: This paper outlines the mechanisms governing the major modes of internalization of polymeric micelles into epithelial cells, with an emphasis on specific recent examples of the transport of drug-loaded polymeric micelles across epithelial barriers.


Input: Rapamycin allosterically inhibits the proteasome.

Rapamycin


Input: Rapamycin is a canonical allosteric inhibitor of the mTOR kinase with immunosuppressive and pro-apoptotic activities.

Rapamycin


Input: We found that in vitro rapamycin also regulates the proteasome, an essential intracellular protease of the ubiquitin-proteasome pathway.

rapamycin


Input: Rapamycin inhibits proteinase and selected peptidase activities of the catalytic core proteasome at low micromolar concentrations.

Rapamycin


Input: Moreover, the drug interferes with binding of the 19S cap essential for processing of polyubiquitinylated substrates, and the PA200 activator to the 20S catalytic core proteasome.


Input: These protein complexes are known to bind to specific grooves on the alpha face region of the 20S core.


Input: A treatment with rapamycin affects conformational dynamics of the proteasomal gate, a centrally positioned within the alpha face and allosterically regulated element responsible for the intake of substrates.

rapamycin


Input: Interestingly, we showed that rapamycin shares all the proteasome targeting properties not only with other two-domain, closed-ring analogs (rapalogs), but also with its single domain mimics, and with seco-rapamycin.

rapamycin

seco-rapamycin


Input: The latter is the first in vivo open-ring metabolite of rapamycin that does not affect mTOR.

rapamycin


Input: We hypothesize that the rapamycin and related compounds bind to the alpha face and allosterically impact the proteasome function.

rapamycin


Input: The implications of our finding for mechanism of in vivo actions of rapamycin and for design of novel allosteric drugs targeting the proteasome are discussed.

rapamycin


Input: Insulin-like growth factor 1 (IGF-1) expression is up-regulated in lymphoblastoid cell lines of lithium responsive bipolar disorder patients.

lithium


Input: Bipolar disorder (BD) is a debilitating psychiatric disease characterized by alternating episodes of mania and depression.


Input: Among mood stabilizers, lithium is the mainstay for the treatment of BD, with approximately one-third of patients showing remission from episode recurrence.

lithium


Input: While there is evidence suggesting genetic load for lithium response in BD, its molecular underpinnings are still not completely understood.

lithium


Input: To identify genes potentially involved in (or correlated with) lithium response, we carried out a genome-wide expression analysis on lymphoblastoid cell lines (LCLs) from 10 BD patients responders (R) and 10 non-responders (NR) to lithium.

lithium

lithium


Input: We compared expression levels of the two groups and tested whether in vitro lithium treatment had different effects in LCLs of R compared to NR.

lithium


Input: At basal, 2060 genes were differentially expressed between R and NR while no genes were differentially regulated by lithium in the two groups.

lithium


Input: After pathway analysis based on the 2060 genes, 9 genes were selected for validation with qRT-PCR.


Input: Eight genes were validated in the same sample of LCLs while only insulin-like growth factor 1 (IGF-1) was significantly over-expressed in R compared to NR in the same sample as well as in an independent sample comprised of 6 R and 6 NR (sample 1, fold change = 1. 94; p = 0. 005; sample 2, fold change = 2. 21; p = 0. 005).


Input: IGF-1 was also significantly over-expressed in R but not in NR when compared to a sample of non-psychiatric controls.


Input: Our findings suggest that IGF-1 may be involved in lithium response, supporting further investigation on its potential as a biomarker.

lithium


Input: Polymorphism in porphyrin monolayers: the relation between adsorption configuration and molecular conformation.

porphyrin


Input: Self-assembled monolayers of meso-5, 10, 15, 20-tetrakis (undecyl) porphyrin copper (ii) on a graphite/1-octanoic acid interface have been studied by Scanning Tunnelling Microscopy.

meso-5, 10, 15, 20-tetrakis (undecyl) porphyrin copper (ii)

graphite

1-octanoic acid


Input: Four distinct polymorphs were observed, varying in their unit cell size.


Input: Arrays of unit cells of the various polymorphs seamlessly connect to each other via shared unit cell vectors.


Input: The monolayers are not commensurate, but coincident with the underlying graphite substrate.

graphite


Input: The seamless transition between the polymorphs is proposed to be the result of an adaptation of the molecular conformations in the polymorphs and at the boundaries, which is enabled by the conformational freedom of the alkyl tails of these molecules.

alkyl


Input: Random Regret-Based Discrete-Choice Modelling: An Application to Healthcare.


Input: BACKGROUND: A new modelling approach for analysing data from discrete-choice experiments (DCEs) has been recently developed in transport economics based on the notion of regret minimization-driven choice behaviour.


Input: This so-called Random Regret Minimization (RRM) approach forms an alternative to the dominant Random Utility Maximization (RUM) approach.


Input: The RRM approach is able to model semi-compensatory choice behaviour and compromise effects, while being as parsimonious and formally tractable as the RUM approach.


Input: OBJECTIVES: Our objectives were to introduce the RRM modelling approach to healthcare-related decisions, and to investigate its usefulness in this domain.


Input: METHODS: Using data from DCEs aimed at determining valuations of attributes of osteoporosis drug treatments and human papillomavirus (HPV) vaccinations, we empirically compared RRM models, RUM models and Hybrid RUM-RRM models in terms of goodness of fit, parameter ratios and predicted choice probabilities.


Input: RESULTS: In terms of model fit, the RRM model did not outperform the RUM model significantly in the case of the osteoporosis DCE data (p = 0. 21), whereas in the case of the HPV DCE data, the Hybrid RUM-RRM model outperformed the RUM model (p < 0. 05).


Input: Differences in predicted choice probabilities between RUM models and (Hybrid RUM-) RRM models were small.


Input: Derived parameter ratios did not differ significantly between model types, but trade-offs between attributes implied by the two models can vary substantially.


Input: CONCLUSION: Differences in model fit between RUM, RRM and Hybrid RUM-RRM were found to be small.


Input: Although our study did not show significant differences in parameter ratios, the RRM and Hybrid RUM-RRM models did feature considerable differences in terms of the trade-offs implied by these ratios.


Input: In combination, our results suggest that RRM and Hybrid RUM-RRM modelling approach hold the potential of offering new and policy-relevant insights for health researchers and policy makers.


Input: Genetic Variants in 2q31 and 5p15 Are Associated With Aggressive Benign Prostatic Hyperplasia in a Chinese Population.


Input: BACKGROUND: Benign prostatic hyperplasia (BPH) is a common disease prevalent in elderly men.


Input: However, the genetic determinants of BPH remain unclear.


Input: Because BPH and prostate cancer (PCa) share some common pathological characteristics, we investigated whether susceptibility loci for PCa contributed to BPH risk and BPH aggressiveness in Chinese men.


Input: METHODS: Fourteen SNPs associated with PCa risk in a Chinese population were genotyped in 426 BPH cases (184 aggressive and 242 non-aggressive BPH cases) and 1, 008 controls.


Input: The association between the SNPs and BPH risk/aggressiveness was estimated using logistic regression analysis.


Input: In addition, effects of the 14 SNPs on BPH related clinical traits, including International Prostate Symptom Score (IPSS), prostate volume, total PSA, and free PSA were evaluated using linear regression analysis.


Input: RESULTS: Two SNPs, rs12621278 in ITGA6 at 2q31 (OR = 0. 82, P = 0. 05) and rs339331 in RFX6 at 6q22 (OR = 1. 22, P = 0. 04) were significantly associated with BPH.


Input: In addition, rs12621278 (OR = 0. 73, P = 0. 05) and rs12653946, 13 kb upstream of IRX4 at 5p15 (OR = 1. 40, 0. 03), were significantly associated with aggressive BPH.


Input: Moreover, the risk allele of rs12621278 (G) and rs12653946 (T) for aggressive BPH were significantly associated with elevated IPSS after treatment (P = 0. 01).


Input: CONCLUSIONS: This is the first systematic investigation on the contributions of PCa susceptibility loci to risk and aggressiveness of BPH.


Input: Our findings advance our understanding of the genetic basis of BPH, especially aggressive BPH.


Input: In addition, our results provide new insights into the genetic determinants shared between BPH and PCa.


Input: Prostate 9999: XX-XX.


Input: (c) 2013 Wiley Periodicals, Inc.


Input: Chip-scale Mid-Infrared chemical sensors using air-clad pedestal silicon waveguides.

silicon


Input: Towards a future lab-on-a-chip spectrometer, we demonstrate a compact chip-scale air-clad silicon pedestal waveguide as a Mid-Infrared (Mid-IR) sensor capable of in situ monitoring of organic solvents.


Input: The sensor is a planar crystalline silicon waveguide, which is highly transparent, between lambda = 1. 3 and 6. 5 mu m, so that its operational spectral range covers most characteristic chemical absorption bands due to bonds such as C-H, N-H, O-H, C-C, N-O, C [double bond, length as m-dash] O, and C [triple bond, length as m-dash] N, as opposed to conventional UV, Vis, Near-IR sensors, which use weaker overtones of these fundamental bands.

silicon

C-H

N-H

O-H

C-C

N-O

C

O

C

N


Input: To extend light transmission beyond lambda = 3. 7 mu m, a spectral region where a typical silicon dioxide under-clad is absorbing, we fabricate a unique air-clad silicon pedestal waveguide.

silicon dioxide

silicon


Input: The sensing mechanism of our Mid-IR waveguide sensor is based on evanescent wave absorption by functional groups of the surrounding chemical molecules, which selectively absorb specific wavelengths in the mid-IR, depending on the nature of their chemical bonds.


Input: From a measurement of the waveguide mode intensities, we demonstrate in situ identification of chemical compositions and concentrations of organic solvents.


Input: For instance, we show that when testing at lambda = 3. 55 mu m, the Mid-IR sensor can distinguish hexane from the rest of the tested analytes (methanol, toluene, carbon tetrachloride, ethanol and acetone), since hexane has a strong absorption from the aliphatic C-H stretch at lambda = 3. 55 mu m.

hexane

methanol

toluene

carbon tetrachloride

ethanol

acetone

hexane

C-H


Input: Analogously, applying the same technique at lambda = 3. 3 mu m, the Mid-IR sensor is able to determine the concentration of toluene dissolved in carbon tetrachloride, because toluene has a strong absorption at lambda = 3. 3 mu m from the aromatic C-H stretch.

toluene

carbon tetrachloride

toluene

C-H


Input: With our demonstration of an air-clad silicon pedestal waveguide sensor, we move closer towards the ultimate goal of an ultra-compact portable spectrometer-on-a-chip.

silicon


Input: A New Proposed Rodent Model of Chemically Induced Prostate Carcinogenesis: Distinct Time-Course Prostate Cancer Progression in the Dorsolateral and Ventral Lobes.


Input: BACKGROUND: Characterization of novel rodent models for prostate cancer studies requires evaluation of either spontaneous and carcinogen-induced tumors as well as tumor incidence in different prostatic lobes.


Input: We propose a new short-term rodent model of chemically induced prostate carcinogenesis in which prostate cancer progression occurs differentially in the dorsolateral and ventral lobes.


Input: METHODS: Adult gerbils were treated with MNU alone or associated with testosterone for 3 or 6 months of treatment.

MNU

testosterone


Input: Tumor incidence, latency, localization, and immunohistochemistry (AR, PCNA, smooth muscle alpha-actin, p63, MGMT, and E-cadherin) were studied in both lobes.


Input: RESULTS: Comparisons between both lobes revealed that lesions developed first in the DL while the VL presented longer tumor latency.


Input: However, after 6 months, there was a dramatic increase in tumor multiplicity in the VL, mainly in MNU-treated groups.

MNU


Input: Lesions clearly progressed from a premalignant to a malignant phenotype over time and tumor latency was decreased by MNU + testosterone administration.

MNU

testosterone


Input: Three-dimensional reconstruction of the prostatic complex showed that the DL developed tumors exclusively in the periurethral area and showed intense AR, PCNA, and MGMT immunostaining.


Input: Moreover, VL lesions emerged throughout the entire lobe.


Input: MNU-induced lesions presented markers indicative of an aggressive phenotype: lack of basal cells, rupture of the smooth muscle cell layer, loss of E-cadherin, and high MGMT staining.

MNU


Input: CONCLUSIONS: There are distinct pathways involved in tumor progression in gerbil prostate lobes.


Input: This animal provides a good model for prostate cancer since it allows the investigation of advanced steps of carcinogenesis with shorter latency periods in both lobes.


Input: Prostate (c) 2013 Wiley Periodicals, Inc.


Input: The Effect of BCRP, MDR1 and OATP1B3 on the Antitumor Efficacy of the Lipophilic Camptothecin AR-67 In Vitro.

Camptothecin AR-67


Input: AR-67 is a lipophilic camptothecin analogue, currently under early stage clinical trials.

camptothecin


Input: Transporters are known to have an impact on the disposition of camptothecins and on the response to chemotherapeutics in general due to their expression in tumor tissues.

camptothecins


Input: Therefore, the interplay between the BCRP, MDR1 and OATP1B1/OATP1B3 transporters and AR-67 and their impact on the toxicity profile of AR-67 was investigated.


Input: Using cell lines expressing the aforementioned transporters, we showed that the lipophilic AR-67 lactone form is a substrate for efflux transporters BCRP and MDR1.

AR-67 lactone


Input: Additionally, OATP1B1 and OATP1B3 facilitated the uptake of AR-67 carboxylate in SLCO1B1 and SLCO1B3-transfected cell systems compared to the mock-transfected ones.

AR-67 carboxylate


Input: Notably, both BCRPand MDR1, conferred resistance to AR-67 lactone.

AR-67 lactone


Input: Prompted by recent studies showing increased OATP1B3 expression in certain cancer types, we investigated the effect of OATP1B3 expression on cell viability after exposure to AR-67 carboxylate.

AR-67 carboxylate


Input: OATP1B3 expressing cells had increased carboxylate uptake as compared to mock transfected cells, but were not sensitized because the intracellular amount of lactone was fifty-fold higher than that of carboxylate and comparable between OATP1B3 expressing and non-expressing cells.

carboxylate

lactone

carboxylate


Input: In conclusion, BCRP-and MDR1-mediated efflux of AR-67 lactone confers resistance to AR-67, but OATP1B3-mediated uptake of the AR-67 carboxylate does not sensitize OATP1B3 expressing tumor cells.

AR-67 lactone

AR-67 carboxylate


Input: High salt diets during pregnancy affected fetal and offspring renal renin-angiotensin system.


Input: Intrauterine environments are linked to fetal renal development and postnatal health.


Input: Influence of salt diets during pregnancy on renal functions and renin-angiotensin system (RAS) were determined in the ovine fetus and offspring.


Input: Pregnant ewes were fed high-salt diet (HSD) or normal-salt diet (NSD) for two months during middle-later gestation.


Input: Fetal renal functions, plasma hormones, mRNA and protein expressions of the key elements of renal RAS were measured in the fetus and offspring.


Input: Fetal renal excretion of sodium was increased while urine volume decreased in HSD group.

sodium


Input: Fetal blood urea nitrogen was increased, while kidney/body weight ratio decreased in HSD group.

urea nitrogen


Input: The altered ratio also was observed in the offspring at 15-day-old and 90-day-old.


Input: Maternal and fetal plasma antidiuretic hormone was elevated without change in plasma renin activity and Ang I levels, while plasma Ang II was decreased.


Input: The key elements of local renal RAS, including angiotensinogen, ACE, ACE2, AT1 and AT2 receptor expression in both mRNA and protein, except renin, were altered following maternal high salt intake.


Input: The results suggest that High intake of salt during pregnancy affected fetal renal development associated with an altered expression of the renal key elements of RAS, some alterations of fetal origins remained after birth as possible risks in developing renal or cardiovascular diseases.


Input: Metallothionein gene transfection reverses the phenotype of activated human hepatic stellate cells.


Input: Metallothionein (MT) gene therapy leads to resolution of liver fibrosis in mouse model.


Input: The present study was undertaken to test the hypothesis that reversal of the phenotype of activated hepatic stellate cells (HSC) contributes to the fibrinolysis effect of MT.


Input: Human HSC LX-2 cells were activated after cultured for 24 hrs, as indicated by expression of alpha-smooth muscle actin (alpha-SMA) and collagen-I, and depressed expression of collagenases.


Input: Transfection with a plasmid containing human MT-II gene in the activated HSCs effectively increased the protein level of MT.


Input: The expression of MT was accompanied by the reduction of protein levels of alpha-SMA and collagen-I, and the decrease in their mRNA levels.


Input: Importantly, MT gene transfection resulted in upregulation of MMP-1,-8 and-13, which are importantly involved in the resolution of liver fibrosis.


Input: This study demonstrates that reversal of the phenotype of activated HSCs, particularly the upregulation of collagenases, is likely involved in the resolution of liver fibrosis observed in MT gene therapy.


Input: Magnetic Porous Sugar-Functionalized PEG Microgels for Efficient Isolation and Removal of Bacteria from Solution.

Sugar

PEG


Input: Here we present a new microparticle system for the selective detection and magnetic removal of bacteria from contaminated solutions.


Input: The novelty of this system lies in the combination of a biocompatible scaffold reducing unspecific interactions with high capacity for bacteria binding.


Input: We apply highly porous poly (ethylene glycol) (PEG) microparticles and functionalize them introducing both sugar ligands for specific bacteria targeting and cationic moieties for electrostatic loading of superparamagnetic iron oxide nanoparticles.

poly (ethylene glycol)

PEG

sugar

iron oxide


Input: The resulting magnetic, porous, sugar-functionalized (MaPoS) PEG microgels are able to selectively bind and discriminate between different strains of bacteria Escherichia coli.

PEG


Input: Furthermore, they allow for a highly efficient removal of bacteria from solution as their increased surface area can bind three times more bacteria than non-porous particles.


Input: All in all, MaPoS particles represent a novel generation of magnetic beads introducing for the first time a porous, biocompatible and easy to functionalize scaffold and show great potential for various biotechnological applications.


Input: Gliptins (dipeptidyl peptidase-4 inhibitors) and risk of acute pancreatitis.


Input: Introduction: Dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins) play an increasing role in the management of type 2 diabetes.


Input: Such incretin-based therapies offer some advantages over other glucose-lowering agents, but might be associated with an increased risk of acute pancreatitis.

glucose


Input: Areas covered: An extensive literature search was performed to analyze clinical cases of acute pancreatitis reported in the literature or to the Food and Drug Administration (FDA), in randomized clinical trials, and in observational studies with five DPP-4 inhibitors: sitagliptin, vildagliptin, saxagliptin, alogliptin, and linagliptin.

sitagliptin

vildagliptin

saxagliptin

alogliptin

linagliptin


Input: Expert opinion: An increased risk of pancreatitis has been reported in diabetic versus nondiabetic patients.


Input: Several anecdotal clinical cases of pancreatitis have been reported with sitagliptin and vildagliptin and an increased relative risk reported to the FDA with sitagliptin versus other comparators, but reporting bias cannot be excluded.

sitagliptin

vildagliptin

sitagliptin


Input: In rather short-term clinical trials with well-selected diabetic patients, no increased risk of acute pancreatitis has been observed with any of the five commercialized DPP-4 inhibitors: sitagliptin, vildagliptin, saxagliptin, alogliptin, and linagliptin.

sitagliptin

vildagliptin

saxagliptin

alogliptin

linagliptin


Input: Similarly, real-life cohort studies showed no increased incidence of pancreatitis with gliptins compared with other glucose-lowering agents, a finding recently challenged by a case-control study.

glucose


Input: These results must be confirmed in postmarketing surveillance programs and in ongoing large prospective trials with cardiovascular outcomes.


Input: Microbial degradation of microcystins.

microcystins


Input: Hepatotoxic microcystins that are produced by freshwater cyanobacteria pose a risk to public health.

microcystins


Input: These compounds may be eliminated by enzymatic degradation.


Input: Here, we review the enzymatic pathways for the degradation of these hepatotoxins, some of which are newly discovered processes.


Input: The efficiencies of microcystin biodegradation pathways are documented in several papers and are compared here.

microcystin


Input: Additionally, a comprehensive description of the microcystin enzymatic degradation scheme has been supplemented with a proposal for a new biodegradation pathway.

microcystin


Input: Critical comments on less documented hypotheses are also included in this review.


Input: The genetic aspects of biodegradation activity are discussed in detail.


Input: We also describe some methods that are useful for studying the biological decomposition of microcystins, including screening for microcystin degraders and detecting microcystin degradation products, with an emphasis on mass spectrometric methodology.

microcystins

microcystin

microcystin


Input: Insertion of CO2 and COS into Bi-C Bonds: Reactivity of a Bismuth NCN Pincer Complex of an Oxyaryl Dianionic Ligand, [2, 6-(Me2NCH2) 2C6H3] Bi (C6H2tBu2O).

COS

Bi-C

Bismuth NCN

Oxyaryl

[2, 6-(Me2NCH2) 2C6H3] Bi (C6H2tBu2O)


Input: The reactivity of the unusual oxyaryl dianionic ligand, (C6H2tBu2-3, 5-O-4) 2-, in the Bi3 + NCN pincer complex Ar' Bi (C6H2tBu2-3, 5-O-4), 1, [Ar' = 2, 6-(Me2NCH2) 2C6H3] has been explored with small molecule substrates and electrophiles.

oxyaryl

(C6H2tBu2-3, 5-O-4) 2

Bi3 + NCN

Ar' Bi (C6H2tBu2-3, 5-O-4)

2, 6-(Me2NCH2) 2C6H3


Input: The first insertion reactions of CO2 and COS into Bi-C bonds are observed with this oxyaryl dianionic ligand complex.

COS

Bi-C

oxyaryl


Input: These reactions generate new dianions that have quinoidal character similar to the oxyaryl dianionic ligand in 1.

oxyaryl


Input: The oxyarylcarboxy and oxyarylthiocarboxy dianionic ligands were identified by X-ray crystallography in Ar' Bi [O2C (C6H2tBu2-3-5-O-4)-kappa 2O, O'], 2 and Ar' Bi [OSC (C6H2tBu2-3-5-O-4)-kappa 2O, S], 3, respectively.

oxyarylcarboxy

oxyarylthiocarboxy

Ar' Bi [O2C (C6H2tBu2-3-5-O-4)-kappa 2O, O']

Ar' Bi [OSC (C6H2tBu2-3-5-O-4)-kappa 2O, S]


Input: Silyl halides and pseudohalides, R3SiX (X = Cl, CN, N3; R = Me, Ph), react with 1 by attaching X to bismuth and R3Si to the oxyaryl oxygen to form Ar' Bi (X) (C6H2tBu2-3, 5-OSiR3-4) complexes, a formal addition across five bonds.

Silyl halides

pseudohalides

Cl

CN

Me

Ph

bismuth

oxyaryl oxygen

Ar' Bi (X) (C6H2tBu2-3, 5-OSiR3-4)


Input: These react with additional R3SiX to generate Ar' BiX2 complexes and R3SiOC6H3tBu2-2, 6.

Ar' BiX2

R3SiOC6H3tBu2-2, 6


Input: The reaction of 1 with I2 forms Ar' BiI2 and the coupled quinone, 3, 3', 5, 5'-tetra-tert-butyl-4, 4'-diphenoquinone, by oxidative coupling.

Ar' BiI2

quinone

3, 3', 5, 5'-tetra-tert-butyl-4, 4'-diphenoquinone


Input: High-Accuracy Estimates for the Vinylidene-Acetylene Isomerization Energy and the Ground State Rotational Constants of: C = CH2.

Vinylidene

Acetylene

: C = CH2


Input: Highly accurate calculations are reported for properties of vinylidene (H2C = C:), specically the position of its zero-point vibrational level relative to that of acetylene and its equilibrium structure and ground state rotational constants.

vinylidene

H2C = C:

acetylene


Input: The isomerization energy of vinylidene calculated at the HEAT-456QP level of theory is 45. 530. 15 kcal mol1, in agreement with the previous best estimate, but associated with a much smaller uncertainty.

vinylidene


Input: In addition, the thermochemical calculations presented here also allow a determination of the: C = CH2 bond energy of the vinyl radical at the HEAT-345 (Q) level of theory, which is 77. 70. 3 kcal mol1.

: C = CH2

vinyl


Input: The equilibrium structure of vinylidene, estimated with an additivity scheme that includes treatment of correlation eects beyond CCSD (T) as well as relativistic and adiabatic (diagonal Born-Oppenheimer correction) contributions is rCC = 1. 29820. 0003 A; rCH = 1. 08440. 0003 A; and CCH = 120. 050. 05o, with zero-point rotational constants (including vibrational contributions and electronic contributions to the moment of inertia) estimated to be A0 = 9. 49250. 0150 cm1; B0 = 1. 32170. 0017 cm1 and C0 = 1. 16020. 0016 cm1.

vinylidene

CCH


Input: INTRODUCTION.


Input: Atomic-Scale Interfacial Band Mapping across Vertically Phased-Separated Polymer/Fullerene Hybrid Solar Cells.

Fullerene


Input: Using cross-sectional scanning tunneling microscope (XSTM) with samples cleaved in situ in an ultrahigh vacuum (UHV) chamber, this study demonstrates the direct visualization of high-resolution interfacial band mapping images across the film thickness in an optimized bulk heterojunction polymer solar cell consisting of nanoscale phase segregated blends of poly (3-hexylthiophene) (P3HT) and [6, 6]-phenyl C61 butyric acid methyl ester (PCBM).

poly (3-hexylthiophene)

[6, 6]-phenyl C61 butyric acid methyl ester

PCBM


Input: We were able to achieve the direct observation of the interfacial band alignments at the donor (P3HT)-acceptor (PCBM) interfaces and at the interfaces between the photoactive P3HT: PCBM blends and the poly (3, 4-ethylenedioxythiophene) poly (styrenesulfonate) (PEDOT: PSS) anode modification layer with an atomic-scale spatial resolution.

PCBM

PCBM

poly (3, 4-ethylenedioxythiophene) poly (styrenesulfonate)

PEDOT

PSS


Input: The unique advantage of using XSTM to characterize polymer: fullerene bulk heterojunction solar cells allows us to explore simultaneously the quantitative link between the vertical morphologies and their corresponding local electronic properties.

fullerene


Input: This provides an atomic insight of interfacial band alignments between the two opposite electrodes, which will be crucial for improving the efficiencies of the charge generation, transport, and collection and the corresponding device performance of polymer solar cells.


Input: Hydrazides/Hydrazones as antimicrobial and anticancer agents in the new millennium.

Hydrazides

Hydrazones


Input: Hydrazide/hydrazone derivatives are of quite interest for medicinal chemists because of their vast spectrum of biological activity.

Hydrazide

hydrazone


Input: Literature reports reveal that the hydrazide derivatives have been extensively studied for their biological profile during the past decade.

hydrazide


Input: The aim of the present work is to collect literature reports focusing the antimicrobial and anticancer study of different hydrazide/hydrazone derivatives carried out during the past decade which will serve as a valuable source of information for the researchers working in the field of antimicrobial and anticancer research.

hydrazide

hydrazone


Input: Evaluation of Chlorpheniramine Maleate microparticles in orally disintegrating film and orally disintegrating tablet for pediatrics.

Chlorpheniramine Maleate


Input: Abstract Objective: To mask the bitterness of Chlorpheniramine Maleate via encapsulating drug into Eudragit EPO microparticles, and then incorporate these microparticles into orally disintegrating films (ODF) and orally disintegrating tablets (ODT) for pediatric uses.

Chlorpheniramine Maleate

Eudragit EPO


Input: Methods: Spray drying of water-in-oil emulsion was utilized to encapsulate Chlorpheniramine Maleate into Eudragit EPO microparticles.

Chlorpheniramine Maleate

Eudragit EPO


Input: Based on an orthogonal experimental design L9 (3 (3)), polynomial regression models were developed to evaluate correlation between microparticle properties (encapsulation efficiency and drug release) and variables (X1: weight ratio of polymer to drug, X2: volume ratio of oil to water and X3: Q-flow of spray dryer).


Input: ODF and ODT formulations were evaluated including weight variation, content uniformity, tensile strength, disintegration time, friability and dissolution profiles.


Input: The bitterness taste test was evaluated in 10 adult volunteers.


Input: Results and discussion: From polynomial regression analysis, the best values of variables leading to the optimized microparticles were X1 = 10, X2 = 3 and X3 = 45.


Input: The optimized microparticles were incorporated into ODF and ODT with satisfactory weight and drug content uniformity, and acceptable physical strength.


Input: Both dosage forms disintegrated immediately (less than 40 s) in simulated saliva solutions.


Input: The outcome of taste-masking test indicated that microparticles alleviated drug bitterness significantly; bitterness was not discernible with microparticles incorporated in ODT, whereas only slight bitterness was detected from microparticles incorporated into ODF.


Input: Conclusion: Both ODF and ODT are shown to be suitable vehicles for taste masked Chlorpheniramine Maleate microparticles with potential for pediatric uses.

Chlorpheniramine Maleate


Input: Amniotic membrane extract-loaded double-layered wound dressing: evaluation of gel properties and wound healing.


Input: Abstract The conservative single-layered wound dressing system is decomposed when mixed in polyvinyl alcohol (PVA) solution, which means it cannot be used with a temperature-sensitive drug.

polyvinyl alcohol

PVA


Input: The goal of this investigation was to make an amniotic membrane extract (AME)-loaded double-layered wound dressing with an improved healing result compared to the conservative single-layered wound dressing systems.


Input: The double-layered wound dressing was developed with PVA/sodium alginate using a freeze-melting technique; one layer was PVA layer and the other was the drug-loaded sodium alginate layer.

PVA

sodium alginate

PVA

sodium alginate


Input: Its gel properties were assessed compared to single-layered wound dressings.


Input: Moreover, in vivo wound-healing effects and histopathology were calculated compared to commercial products.


Input: The double-layered wound dressing gave a similar gel fraction and Young' s module as single-layered wound bandages developed with only PVA, and a similar inflammation ability and WVTR as single-layered wound dressings developed with PVA and sodium alginate.

PVA

PVA

sodium alginate


Input: Our data indicate that these double-layered wound bandages were just as swellable, but more elastic and stronger than single-layered wound dressings comprised of the same polymers and quantities, possibly giving an acceptable level of moisture and accumulation of exudates in the wound zone.


Input: Compared to the commercial product, the double-layered wound dressing comprising 6. 7% PVA, 0. 5% sodium alginate and 0. 01% AME significantly enhanced the wound-healing effect in the wound-healing test.

PVA

sodium alginate


Input: Histological investigations showed that superior full-thickness wound-healing effects compared to the commercial product.


Input: Therefore, the double-layered wound dressing would be an outstanding wound-dressing system with improved wound healing and good gel property.


Input: Triterpenes from the Aerial Parts of Cimicifuga yunnanensis and Their Antiproliferative Effects on p53 (N236S) Mouse Embryonic Fibroblasts.

Triterpenes


Input: Nine new triterpene derivatives, yunnanterpenes A-F (1-6), 15, 16-seco-cimiterpenes A and B (7, 8), and cimilactone C (9), and 15 known analogues (10-24) were isolated from the aerial parts of Cimicifuga yunnanensis.

triterpene

yunnanterpenes A-F

15, 16-seco-cimiterpenes A and B

cimilactone C


Input: The new structures were established using a combination of MS, NMR, and single-crystal X-ray diffraction techniques.


Input: WT MEFs (wild-type mouse embryonic fibroblasts) and tumorigenic cell lines p53 (-/-) + H-RasV12 and p53 (-/-) + p53 (N236S) + H-RasV12 were used for evaluating active structures, targeting p53 (N236S) (corresponding to p53 (N239S) in humans) mutation.


Input: Compound 5 showed nonselective activities against these cell lines, with IC50 values of 5. 8, 8. 6, and 6. 0 mu M, respectively.


Input: Compound 4 exhibited greater selectivity against the p53 (-/-) + p53 (N236S) + H-RasV12 cells (IC50 5. 5 mu M) than against the WT MEFs cells (IC50 14. 3 mu M).


Input: Cytotoxic Bisbenzylisoquinoline Alkaloids from Stephania epigaea.

Bisbenzylisoquinoline Alkaloids


Input: Six new bisbenzylisoquinoline alkaloids (1-6) and seven known compounds (8-14) were isolated from the tubers of Stephania epigaea, in addition to the major alkaloid, cepharanthine (7).

bisbenzylisoquinoline alkaloids

cepharanthine


Input: The structures of 1-6 were elucidated by combined spectroscopic data analysis and chemical methods, with their configurations determined from their optical rotation values and confirmed using circular dichroism.


Input: Compounds 1-6 belong to the oxyacanthine type of bisbenzylisoquinoline alkaloids and have a rare methylenedioxy substituent.

oxyacanthine

bisbenzylisoquinoline alkaloids

methylenedioxy


Input: Compound 1, a dimer composed of benzylisoquinoline and seco-aristolactam units, represents a new type of bisbenzylisoquinoline alkaloid, while compounds 3-6 are bisbenzylisoquinoline N-oxides.

benzylisoquinoline

seco-aristolactam

bisbenzylisoquinoline alkaloid

bisbenzylisoquinoline N-oxides


Input: These compounds were evaluated for their in vitro cytotoxicities against six human cancer cell lines (A-549, ECA109, HL-60, MCF-7, SMMC-7721, and SW480).


Input: Cepharanthine (7), the major component of S. epigaea, exhibited cytotoxicity against all of these cancer cell lines except ECA109, while its known analogue, 10, displayed cytotoxicity against all six cancer cell lines.

Cepharanthine


Input: An archaeal RadA paralog influences presynaptic filament formation.


Input: Recombinases of the RecA family play vital roles in homologous recombination, a high-fidelity mechanism to repair DNA double-stranded breaks.


Input: These proteins catalyze strand invasion and exchange after forming dynamic nucleoprotein filaments on ssDNA.


Input: Increasing evidence suggests that stabilization of these dynamic filaments is a highly conserved function across diverse species.


Input: Here, we analyze the presynaptic filament formation and DNA binding characteristics of the Sulfolobus solfataricus recombinase SsoRadA in conjunction with the SsoRadA paralog SsoRal1.


Input: In addition to constraining SsoRadA ssDNA-dependent ATPase activity, the paralog also enhances SsoRadA ssDNA binding, effectively influencing activities necessary for presynaptic filament formation.


Input: These activities result in enhanced SsoRadA-mediated strand invasion in the presence of SsoRal1 and suggest a filament stabilization function for the SsoRal1 protein.


Input: Melanogenesis inhibitory daphnane diterpenoids from the flower buds of Daphne genkwa.

daphnane diterpenoids


Input: Two new daphnane-type diterpene esters, daphneresiniferins A (1) and B (2), along with seven known diterpenes, yuanhuacine (3), yuanhuadine (4), yuanhuahine (5), genkwadaphnin (6), genkwanine A (7), genkwanine F (8), and genkwanine H (9), were isolated from the methanol extract of the flower buds of Daphne genkwa.

daphneresiniferins A (1) and B

diterpenes

yuanhuacine

yuanhuadine

yuanhuahine

genkwadaphnin

genkwanine A

genkwanine F

genkwanine H

methanol


Input: Their structures were elucidated on the basis of spectroscopic methods, especially 2D NMR spectra such as HMQC, HMBC, and NOESY.


Input: All the isolates were evaluated for their inhibitory effects of the melanogenesis against alpha-melanocyte stimulating hormone (alpha-MSH)-activated B16 melanoma cells.


Input: Synthesis of pyrazolo [1, 5-a] pyrimidine linked aminobenzothiazole conjugates as potential anticancer agents.

pyrazolo [1, 5-a] pyrimidine

aminobenzothiazole


Input: A series of pyrazolo [1, 5-a] pyrimidine linked 2-aminobenzothizole conjugates (6a-t) were synthesized and evaluated for their anticancer activity against five human cancer cell lines.

pyrazolo [1, 5-a] pyrimidine


Input: Among them two compounds 6p and 6m showed significant anticancer activity with IC50 values ranging from 2. 01 to 7. 07 and 1. 94-3. 46 mu M, respectively.


Input: Moreover, cell cycle arrest in G2/M and reduction in Cdk1 expression level were observed upon treatment of these compounds and they also induced caspase-3 dependent apoptosis.


Input: This was further confirmed by staining as well as DNA fragmentation analysis.


Input: Germ Cell Specification Requires Zygotic Mechanisms Rather Than Germ Plasm in a Basally Branching Insect.


Input: BACKGROUND: Primordial germ cell (PGC) specification is a universal process across animals, but the molecular mechanisms specifying PGCs are remarkably diverse.


Input: In Drosophila, PGCs are specified by maternally provided, asymmetrically localized cytoplasmic factors (germ plasm).


Input: In contrast, historical literature on most other arthropods reports that PGCs arise from mesoderm during midembryogenesis, suggesting that an arthropod last common ancestor may have specified PGCs via zygotic mechanisms.


Input: However, there has been no direct experimental evidence to date for germ plasm-independent arthropod PGC specification.


Input: RESULTS: Here we show that in a basally branching insect, the cricket Gryllus bimaculatus, conserved germ plasm molecules are ubiquitously, rather than asymmetrically, localized during oogenesis and early embryogenesis.


Input: Molecular and cytological analyses suggest that Gryllus PGCs arise from abdominal mesoderm during segmentation, and twist RNAi embryos that lack mesoderm fail to form PGCs.


Input: Using RNA interference we show that vasa and piwi are not required maternally or zygotically for PGC formation but rather are required for primary spermatogonial divisions in adult males.


Input: CONCLUSIONS: These observations suggest that Gryllus lacks a maternally inherited germ plasm, in contrast with many holometabolous insects, including Drosophila.


Input: The mesodermal origin of Gryllus PGCs and absence of instructive roles for vasa and piwi in PGC formation are reminiscent of mouse PGC specification and suggest that zygotic cell signaling may direct PGC specification in Gryllus and other Hemimetabola.


Input: Molecular and functional characterization of flavin-containing monooxygenases in cynomolgus macaque.

flavin


Input: Flavin-containing monooxygenases (FMOs), drug-metabolizing enzymes essential for the metabolism of endogenous biochemicals and foreign compounds, have been characterized in human (including FMO1-5 and FMO6P), but remain to be investigated in cynomolgus macaque.

Flavin


Input: In this study, cDNAs of cynomolgus FMO1-5 and FMO6 were isolated and characterized.


Input: Amino acid sequences of cynomolgus FMO1-5, respectively, shared high sequence identities (94-98%) and were closely clustered in a phylogenetic tree, with human FMO1-5.

Amino acid


Input: Eight different transcripts, due to alternative splicing, were isolated for cynomolgus FMO6, which is highly identical (~ 96%) to human FMO6P.


Input: Among the 10 tissue types analyzed, cynomolgus FMO1, FMO2, FMO4, and FMO6 were most abundantly expressed in kidney, while cynomolgus FMO3 and FMO5 were most abundantly expressed in liver.


Input: In kidney and liver, the most abundantly expressed cynomolgus FMO genes were FMO1 and FMO3 respectively.


Input: Cynomolgus FMO1, FMO2, FMO3, and FMO5 metabolized benzydamine, and FMO1/FMO3 and FMO3 also metabolized methimazole and trimethylamine, respectively.

benzydamine

methimazole

trimethylamine


Input: Rates of benzydamine N-oxygenation (catalyzed by FMO3) varied (approximately 20-fold) among the 28 cynomolgus livers and were significantly correlated with FMO3 protein expression, indicating that the inter-animal variations in benzydamine N-oxygenation might be partly accounted for by the variable FMO3 expression.

benzydamine N

benzydamine N


Input: Cynomolgus FMO6 metabolized benzydamine only slightly, but minimal expression of FMO6 in all tissue precludes the importance of FMO6 in drug metabolism, unlike cynomolgus FMO1, FMO2, FMO3, and FMO5 which were all functional.

benzydamine


Input: Abundant expression of FMO1 and FMO3 in kidney and liver, respectively, suggest their importance in drug metabolism in cynomolgus macaque, similar to human.


Input: Intestinal Organoids as Tissue Surrogates for Toxicological and Pharmacological Studies.


Input: Recently developed cell culture protocols have allowed for the derivation of multi-cellular structures dubbed intestinal " organoids " from embryonic stem cells (ESCs), induced pluripotent stem cells (IPSCs), and adult intestinal stem cells (ISCs).


Input: These structures resemble in vivo intestinal crypts, both in structure and developmental processes, and can be grown quickly and in relatively large quantities.


Input: Although much research has focused on developing intestinal organoids for tissue repair, more immediate applications include high-throughput screening for agents that target intestinal epithelium.


Input: Here we describe current methods for deriving mouse and human intestinal organoids and discuss some applications aimed at developing novel therapies or preventive agents for diseases of the lower GI tract such as inflammatory bowel diseases and colorectal cancer.


Input: GABAA receptor modulation by piperine and a non-TRPV1 activating derivative.

piperine


Input: The action of piperine (the pungent component of pepper) and its derivative SCT-66 ((2E, 4E)-5-(1, 3-benzodioxol-5-yl))-N, N-diisobutyl-2, 4-pentadienamide) on different gamma-aminobutyric acid (GABA) type A (GABAA) receptors, transient-receptor-potential-vanilloid-1 (TRPV1) receptors and behavioral effects were investigated.

piperine

SCT-66 ((2E, 4E)-5-(1, 3-benzodioxol-5-yl))-N, N-diisobutyl-2, 4-pentadienamide)

gamma-aminobutyric acid

GABA


Input: GABAA receptor subtypes and TRPV1 receptors were expressed in Xenopus laevis oocytes.


Input: Modulation of GABA-induced chloride currents (IGABA) by piperine and SCT-66 and activation of TRPV1 was studied using the two-microelectrode-voltage-clamp technique and fast perfusion.

GABA

chloride

piperine


Input: Their effects on explorative behavior, thermoregulation and seizure threshold were analyzed in mice.


Input: Piperine acted with similar potency on all GABAA receptor subtypes (EC50 range: 42. 8 +/- 7. 6 mu M (alpha 2 beta 2)-59. 6 +/- 12. 3 mu M (alpha 3 beta 2)).

Piperine


Input: IGABA modulation by piperine did not require the presence of a gamma 2S-subunit, suggesting a binding site involving only alpha and beta subunits.

piperine


Input: IGABA activation was slightly more efficacious on receptors formed from beta 2/3 subunits (maximal IGABA stimulation through alpha 1 beta 3 receptors: 332 +/- 64% and alpha 1 beta 2: 271 +/- 36% vs. alpha 1 beta 1: 171 +/- 22%, p < 0. 05) and alpha 3-subunits (alpha 3 beta 2: 375 +/- 51% vs. alpha 5 beta 2: 136 +/- 22%, p < 0. 05).


Input: Replacing the piperidine ring by a N-di-isobutyl residue (SCT-66) prevents interactions with TRPV1 and simultaneously increases the potency and efficiency of GABAA receptor modulation.

piperidine

N-di-isobutyl


Input: SCT-66 displayed greater efficacy on GABAA receptors than piperine, with different subunit-dependence.

piperine


Input: Both compounds induced anxiolytic, anticonvulsant effects and reduced locomotor activity; however, SCT-66 induced stronger anxiolysis without decreasing body temperature and without the proconvulsive effects of TRPV1 activation and thus may serve as a scaffold for the development of novel GABAA receptor modulators.


Input: The accurate measurement of second virial coefficients using self-interaction chromatography: Experimental considerations.


Input: Measurement of B22, the second virial coefficient, is an important technique for describing the solution behaviour of proteins, especially as it relates to precipitation, aggregation and crystallisation phenomena.


Input: This paper describes the best practise for calculating B22 values from self-interaction chromatograms (SIC) for aqueous protein solutions.


Input: Detailed analysis of SIC peak shapes for lysozyme shows that non-Gaussian peaks are commonly encountered for SIC, with typical peak asymmetries of 10%.


Input: This asymmetry reflects a non-linear chromatographic retention process, in this case heterogeneity of the protein-protein interactions.


Input: Therefore, it is important to use the centre of mass calculations for determining accurate retention volumes and thus B22 values.


Input: Empirical peak maximum chromatogram analysis, often reported in the literature, can result in errors of up to 50% in B22 values.


Input: A methodology is reported here for determining both the mean and the variance in B22 from SIC experiments, includes a correction for normal longitudinal peak broadening.


Input: The variance in B22 due to chemical effects is quantified statistically and is a measure of the heterogeneity of protein-protein interactions in solution.


Input: In the case of lysozyme, a wide range of B22 values are measured which can vary significantly from the average B22 values.


Input: Recent advances in quantitative neuroproteomics.


Input: The field of proteomics is undergoing rapid development in a number of different areas including improvements in mass spectrometric platforms, peptide identification algorithms and bioinformatics.


Input: In particular, new and/or improved approaches have established robust methods that not only allow for in-depth and accurate peptide and protein identification and modification, but also allow for sensitive measurement of relative or absolute quantitation.


Input: These methods are beginning to be applied to the area of neuroproteomics, but the central nervous system poses many specific challenges in terms of quantitative proteomics, given the large number of different neuronal cell types that are intermixed and that exhibit distinct patterns of gene and protein expression.


Input: This review highlights the recent advances that have been made in quantitative neuroproteomics, with a focus on work published over the last five years that applies emerging methods to normal brain function as well as to various neuropsychiatric disorders including schizophrenia and drug addiction as well as of neurodegenerative diseases including Parkinson' s disease and Alzheimer' s disease.


Input: While older methods such as two-dimensional polyacrylamide electrophoresis continued to be used, a variety of more in-depth MS-based approaches including both label (ICAT, iTRAQ, TMT, SILAC, SILAM), label-free (label-free, MRM, SWATH) and absolute quantification methods, are rapidly being applied to neurobiological investigations of normal and diseased brain tissue as well as of cerebrospinal fluid (CSF).

polyacrylamide


Input: While the biological implications of many of these studies remain to be clearly established, that there is a clear need for standardization of experimental design and data analysis, and that the analysis of protein changes in specific neuronal cell types in the central nervous system remains a serious challenge, it appears that the quality and depth of the more recent quantitative proteomics studies is beginning to shed light on a number of aspects of neuroscience that relates to normal brain function as well as of the changes in protein expression and regulation that occurs in neuropsychiatric and neurodegenerative disorders.


Input: Maternal nicotine exposure during lactation alters hypothalamic neuropeptides expression in the adult rat progeny.

nicotine


Input: Maternal exposure to nicotine during lactation causes hyperleptinemia in the pups and, at adulthood, these animals are overweight and hyperleptinemic, while, in their hypothalamus, the leptin signaling pathway is reduced, evidencing a central leptin resistance.


Input: Then, we evaluated the expression of pro-opiomelanocortin (POMC), alpha-melanocyte stimulating hormone (alpha-MSH), cocaine and amphetamine-regulated transcript (CART), neuropeptide Y (NPY), agouti-related peptide (AgRP) and others in different hypothalamic nuclei in order to better understand the mechanisms underlying the obese phenotype observed in these animals at adulthood.

cocaine

amphetamine


Input: On the 2nd postnatal day (P2), dams were subcutaneously implanted with osmotic minipumps releasing nicotine (NIC-6mg/kg/day) or saline for 14days.

nicotine

NIC


Input: Offspring were killed in P180 and immunohistochemistry and Western blot analysis were carried out.


Input: Significance data had p < 0. 05.


Input: Adult NIC offspring showed more intense NPY staining in the paraventricular nucleus (PVN) (+ 21%) and increased number of POMC-positive cells in the: arcuate nucleus (+ 33%), as an increase in fiber density of alpha-MSH in PVN (+ 85%).

NIC


Input: However, the number of CART-positive cells was reduced in the PVN (-25%).


Input: CRH staining was more intense in NIC offspring (+ 136%).

NIC


Input: Orexins and AgRP were not altered.


Input: Thus, maternal nicotine exposure changes hypothalamic neuropeptides in the adult progeny that is partially compatible with leptin resistance.

nicotine


Input: Modulation of the peroxiredoxin system by cytokines in insulin-producing RINm5F cells: Down-regulation of PRDX6 increases susceptibility of beta cells to oxidative stress.


Input: Peroxiredoxins are a family of six antioxidant enzymes (PRDX1-6), and may be an alternative system for the pancreatic beta cells to cope with oxidative stress.


Input: This study investigated whether the main diabetogenic pro-inflammatory cytokines or the anti-inflammatory cytokine IL-4 modulate PRDXs levels and putative intracellular pathways important for this process in the insulin-producing RINm5F cells.


Input: RINm5F cells expressed significant amounts of PRDX1, PRDX3 and PRDX6 enzymes.


Input: Only PRDX6 was modulated by cytokines, showing both mRNA and protein down-regulation following incubation of RINm5F cells with TNF-alpha and IFN-gamma but not with IL-1beta.


Input: Separately IFN-gamma or TNF-alpha decreased PRDX6 protein but not mRNA levels.


Input: The blockage of the JNK signalling and of the calpains and proteasome proteolysis systems restored PRDX6 protein levels.


Input: IL-4 alone did not modulate PRDXs levels.


Input: However, pre/co-incubation with IL-4 substantially prevented the decrease in PRDX6 induced by pro-inflammatory cytokines.


Input: Knockdown of PRDX6 increased susceptibility of RINm5F cells to the deleterious effects of pro-inflammatory cytokines and to oxidative stress.


Input: These results show that, from the PRDXs significantly expressed in RINm5F cells, only PRDX6 is modulated by the diabetogenic cytokines IFN-gamma and TNF-alpha.


Input: This PRDX6 down-regulation depends on the calpain and proteasome systems and JNK signalling.


Input: PRDX6 is an important enzyme for protection against oxidative stress and the interaction between pro-and anti-inflammatory cytokines might be important to determine the antioxidant capacity of the cells.


Input: Developmental immunotoxicity in male rats after juvenile exposure to ethanol.

ethanol


Input: The aim of the present study was to determine the sensitivity of the developing immune system to ethanol (EtOH) after exposure from postnatal day (PND) 10 onward.

ethanol

EtOH


Input: Adult Wistar dams and litters were exposed to EtOH via drinking water (0, 0. 25, 1. 5, 2. 75, 4, 5. 25, or 6. 5% (w/v) EtOH ad libitum) and drinking water exposure of the F1 was continued from weaning until sacrifice.

EtOH

EtOH


Input: Immune assessments were performed at postnatal days (PNDs) 21, 42, and 70.


Input: Furthermore, Keyhole Limpet Hemocyanin (KLH) specific immune responses were evaluated following subcutaneous immunizations on PNDs 21 and 35.


Input: EtOH exposure affected innate immune responses, such as LPS-induced NO-production by adherent splenocytes, as well as adaptive immune responses as represented by KLH-specific parameters.

EtOH

NO


Input: The most sensitive developmental parameters included effects on maternal and pup bodyweight with calculated BMDs of 4. 0% and 4. 3% EtOH, respectively.

EtOH


Input: The most sensitive immune parameters were affected at dose levels lower than those affecting developmental parameters and included KLH-specific immune responses, LPS-induced NO production by adherent splenocytes, and IL-10 production by ConA stimulated splenocytes.

NO


Input: Calculated BMDs for these parameters were between 0. 01% and 0. 1% EtOH.

EtOH


Input: A comparison of the results of this juvenile study with an extended one-generation reproductive toxicity study revealed that the juvenile study design may result in a higher sensitivity related to differences in the exposure design.


Input: These findings demonstrate the relative sensitivity of the developing immune system for EtOH exposure, the additional value of assessing functional immune parameters, and the importance of the juvenile window in developmental immunotoxicity testing.

EtOH


Input: Relationship between protein digestibility and allergenicity: Comparisons of pepsin and cathepsin.


Input: An association between protein allergenicity and resistance to pepsin digestion in the gastrointestinal tract has been proposed.


Input: However, although widely accepted, such an association is inconsistent with known labile allergens and resistant non-allergens.


Input: Given the central role of antigen presenting cells, and in particular dendritic cells (DCs), in the development of allergic responses, the stability of allergens to intracellular processing may be more relevant than resistance to extracellular pepsin digestion.


Input: We have characterised the expression by DC of cathepsins (proteolytic enzymes), and compared the proteolytic activity of the most highly expressed cathepsin with pepsin for a range of 9 allergens and 4 putative nonallergens.


Input: Cathepsin expression in bone marrow-derived DC (BM-DC) derived from BALB/c strain mice was characterised by flow cytometry; cathepsins D, E and S were identified, with cathepsin D being the most highly expressed.


Input: Digestion studies revealed that the majority of allergens (5/9) were pepsin resistant, whereas non-allergens (3/4) were labile.


Input: If the generation of pepsin-resistant fragments was considered as a feature of allergenicity, this increased to 7/9 allergens and 4/4 nonallergens.


Input: In contrast, most of the proteins examined were resistant to cathepsin digestion, with significant digestion recorded for only 2/9 allergens and 2/4 non-allergens.


Input: Chemical reduction (to mimic intracellular reducing conditions) increased the susceptibility of proteins to digestion by cathepsins, but did not improve discrimination between allergens and nonallergens on this basis.


Input: These data confirm that there is a general relationship between resistance to digestion with pepsin and allergenicity.


Input: The relationship is not absolute, but the information gained from this characteristic does provide useful information in a weight of evidence approach for allergenicity assessment.


Input: The most abundant cathepsin detected in antigen processing BM-DC, cathepsin D, is not an appropriate substitute for pepsin.


Input: The hypothesis that pepsin stability may be a surrogate for stability to digestion within DC may still hold true, but consideration of a single enzyme in this context is possibly an oversimplification.


Input: Structural requirements within protoporphyrin IX in the inhibition of heat shock protein 90.

protoporphyrin IX


Input: Porphyrins are used for photodynamic therapy for their light-absorbing properties, and some of them were approved for the treatment of certain types of cancers.

Porphyrins


Input: Porphyrins prevent activation of hypoxia inducible factor-1 alpha (HIF-1 alpha) by inhibiting heat shock protein 90 (HSP90).

Porphyrins


Input: This study investigated the structural requirements within protoporphyrin IX (PPIX) for the inhibition of HSP90 activity.

protoporphyrin IX

PPIX


Input: In HCT116, HT29 and DLD-1 cells, PPIX treatment directly hindered the binding between HSP90 and HIF-1 alpha; PPIX treatment inhibited the chaperone activity of HSP90, accelerating protein degradation of HIF-1 alpha.

PPIX

PPIX


Input: In addition, PPIX treatment suppressed cancer cell migration, endothelial cell tube formation, and aortic ring sprouting, being consistent with its anti-tumor and anti-angiogenic activities.

PPIX


Input: In silico analysis, molecular docking model indicated that a tetrapyrrole macrocycle and two propionate chains within PPIX are necessary for the binding to the adenosine triphosphate (ATP)-binding pocket of HSP90.

tetrapyrrole macrocycle

propionate

PPIX

adenosine triphosphate

ATP


Input: The predicted structural requirement was verified by the differential inhibitory effects of PPIX analogs, or the precursor of PPIX, on HIF-1 alpha; compounds lacking either the tetrapyrrole macrocycle or the propionate chains were inactive.

PPIX

PPIX

tetrapyrrole macrocycle

propionate


Input: Our results show that a tetrapyrrole macrocycle and two attached propionate chains in PPIX coordinately interact with the ATP-binding pocket of HSP90, offering structural information on the inhibitory effect of porphyrins on angiogenesis.

tetrapyrrole macrocycle

propionate

PPIX

ATP


Input: Viscosity of high concentration protein formulations of monoclonal antibodies of the IgG1 and IgG4 subclass-Prediction of viscosity through protein-protein interaction measurements.


Input: The purpose of this work was to explore the relation between protein-protein interactions (PPIs) and solution viscosity at high protein concentration using three monoclonal antibodies (mAbs), two of the IgG4 subclass and one of the IgG1 subclass.


Input: A range of methods was used to quantify the PPI either at low concentration (interaction parameter (kD) obtained from dynamic light scattering, DLS) or at high concentration (solution storage modulus (G') from ultrasonic shear rheology).


Input: We also developed a novel method for the determination of PPI using the apparent radius of the protein at either low or high protein concentration determined using DLS.


Input: The PPI measurements were correlated with solution viscosity (measured by DLS using polystyrene nanospheres and ultrasonic shear rheology) as a function of pH (4-9) and ionic strength (10, 50 and 150mM).

polystyrene


Input: Our measurements showed that the highest solution viscosity was observed under conditions with the most negative kD, the highest apparent radius and the lowest net charge.


Input: An increase in ionic strength resulted in a change in the nature of the PPI at low pH from repulsive to attractive.


Input: In the neutral to alkaline pH region the mAbs behaved differently with respect to increase in ionic strength.


Input: Two mAbs (A and B) showed little or no effect of increasing ionic strength, whereas mAb-C showed a remarkable decrease in attractive PPI and viscosity.


Input: Previous studies have mainly investigated mAbs of the IgG1 and IgG2 subclass.


Input: We show here, for the first time, that mAbs of the IgG4 subclass behave similar as the other subclasses.


Input: By comparison of the three tested mAbs with mAbs investigated in other studies a clear linear trend emerges between the pH of strongest attractive PPI and highest solution viscosity.


Input: The determination of PPI using either kD or apparent radius is thus a useful prediction tool in the determination of solution conditions that favors low solution viscosity at high protein concentration of therapeutically used mAb molecules.


Input: The novel methodology using apparent radius is a simple and rapid alternative to determine relative PPI directly under formulation conditions.


Input: The method can potentially serve as a high-throughput screening tool in formulation development.


Input: Pullulan-based nanoparticles as carriers for transmucosal protein delivery.


Input: Polymeric nanoparticles have revealed very effective in transmucosal delivery of proteins.


Input: Polysaccharides are among the most used materials for the production of these carriers, owing to their structural flexibility and propensity to evidence biocompatibility and biodegradability.


Input: In parallel, there is a preference for the use of mild methods for their production, in order to prevent protein degradation, ensure lower costs and easier procedures that enable scaling up.


Input: In this work we propose the production of pullulan-based nanoparticles by a mild method of polyelectrolyte complexation.


Input: As pullulan is a neutral polysaccharide, sulfated and aminated derivatives of the polymer were synthesized to provide pullulan with a charge.


Input: These derivatives were then complexed with chitosan and carrageenan, respectively, to produce the nanocarriers.


Input: Positively charged nanoparticles of 180-270nm were obtained, evidencing ability to associate bovine serum albumin, which was selected as model protein.


Input: In PBS pH 7. 4, pullulan-based nanoparticles were found to have a burst release of 30% of the protein, which maintained up to 24h.


Input: Nanoparticle size and zeta potential were preserved upon freeze-drying in the presence of appropriate cryoprotectants.


Input: A factorial design was approached to assess the cytotoxicity of raw materials and nanoparticles by the metabolic test MTT.

MTT


Input: Nanoparticles demonstrated to not cause overt toxicity in a respiratory cell model (Calu-3).


Input: Pullulan has, thus, demonstrated to hold potential for the production of nanoparticles with an application in protein delivery.


Input: Liberation of drugs from multi-wall carbon nanotube carriers.

carbon


Input: MWCNTs in the' nanotube-drug' hybrids can play a role of carriers or additives (enhancers) in the more complex formulations.


Input: This work reviews qualitative and quantitative analyses of Drug Delivery Systems (DDSs) based on multi-wall carbon nanotubes (MWCNTs) and their chemically modified analogues (mainly oxidised MWCNTs).

carbon


Input: A special emphasis was placed on the chemical interactions between drug molecules and the nanotube carrier critical both in the stage of preparation/synthesis of the hybrids and liberation of the drug.


Input: Oxidative damage induced by chlorpyrifos in the hepatic and renal tissue of Kunming mice and the antioxidant role of vitamin E.

chlorpyrifos

vitamin E


Input: Chlorpyrifos is a broad-spectrum, chlorinated organophosphate pesticide employed for pest control in various agricultural and animal husbandries.

Chlorpyrifos

chlorinated organophosphate


Input: Acute and chronic exposure to CPF can elicit several adverse effects, including oxidative stress.

CPF


Input: We investigated neurotoxicity of CPF-treated mice, and evaluated the antioxidant effect of vitamin E against oxidative stress and histological changes in the livers and kidneys of CPF-treated mice.

CPF

vitamin E

CPF


Input: Kunming mice were divided randomly into five exposure groups of six: (A) peanut oil; (B) 3mg/kg CPF; (C) 6mg/kg CPF; (D) 12mg/kg CPF; (E) vitamin E (100mg/kg), 3h after administration of CPF (12mg/kg) and used as a post-treatment group.

CPF

CPF

CPF

vitamin E

CPF


Input: Oral administration of high-dose groups (12mg/kg) CPF led to a significant increase in levels of reactive oxygen species, DNA-protein crosslinks, 8-hydroxy-2-deoxyguanosine and malondialdehyde, decreases in acetylcholinesterase activity and glutathione level, as well as causing hepatic and renal histopathological change.

CPF

oxygen

malondialdehyde

glutathione


Input: Except for AChE activity levels, administration of vitamin E to CPF-treated mice restored these biochemical parameters to within normal levels, and resulted in overall improvement in damage to livers and kidneys.

vitamin E

CPF


Input: These data suggest that oxidative stress is involved in CPF-induced toxicity and that vitamin E can protect against the tissue damage induced by CPF.

CPF

vitamin E

CPF


Input: Regulation of bone morphogenetic protein signalling and cranial osteogenesis by Gpc1 and Gpc3.


Input: From birth, the vault of the skull grows at a prodigious rate, driven by the activity of osteoblastic cells at the fibrous joints (sutures) that separate the bony calvarial plates.


Input: One in 2500 children is born with a medical condition known as craniosynostosis because of premature bony fusion of the calvarial plates and a cessation of bone growth at the sutures.


Input: Bone morphogenetic proteins (BMPs) are potent growth factors that promote bone formation.


Input: Previously, we found that Glypican-1 (GPC1) and Glypican-3 (GPC3) are expressed in cranial sutures and are decreased during premature suture fusion in children.


Input: Although glypicans are known to regulate BMP signalling, a mechanistic link between GPC1, GPC3 and BMPs and osteogenesis has not yet been investigated.


Input: We now report that human primary suture mesenchymal cells coexpress GPC1 and GPC3 on the cell surface and release them into the media.


Input: We show that they inhibit BMP2, BMP4 and BMP7 activities, which both physically interact with BMP2 and that immunoblockade of endogenous GPC1 and GPC3 potentiates BMP2 activity.


Input: In contrast, increased levels of GPC1 and GPC3 as a result of overexpression or the addition of recombinant protein, inhibit BMP2 signalling and BMP2-mediated osteogenesis.


Input: We demonstrate that BMP signalling in suture mesenchymal cells is mediated by both SMAD-dependent and SMAD-independent pathways and that GPC1 and GPC3 inhibit both pathways.


Input: GPC3 inhibition of BMP2 activity is independent of attachment of the glypican on the cell surface and post-translational glycanation, and thus appears to be mediated by the core glypican protein.


Input: The discovery that GPC1 and GPC3 regulate BMP2-mediated osteogenesis, and that inhibition of endogenous GPC1 and GPC3 potentiates BMP2 responsiveness of human suture mesenchymal cells, indicates how downregulation of glypican expression could lead to the bony suture fusion that characterizes craniosynostosis.


Input: Method for fabrication and verification of conjugated nanoparticle-antibody tuning elements for multiplexed electrochemical biosensors.


Input: There is a critical need for more accurate, highly sensitive and specific assay for disease diagnosis and management.


Input: A novel, multiplexed, single sensor using rapid and label free electrochemical impedance spectroscopy tuning method has been developed.


Input: The key challenges while monitoring multiple targets is frequency overlap.


Input: Here we describe the methods to circumvent the overlap, tune by use of nanoparticle (NP) and discuss the various fabrication and characterization methods to develop this technique.


Input: First sensors were fabricated using printed circuit board (PCB) technology and nickel and gold layers were electrodeposited onto the PCB sensors.

nickel


Input: An off-chip conjugation of gold NP' s to molecular recognition elements (with verification technique) is described as well.


Input: A standard covalent immobilization of the molecular recognition elements is also discussed with quality control techniques.


Input: Finally use and verification of sensitivity and specificity is also presented.


Input: By use of gold NP' s of various sizes, we have demonstrated the possibility and shown little loss of sensitivity and specificity in the molecular recognition of inflammatory markers as " model " targets for our tuning system.


Input: By selection of other sized NP' s or NP' s of various materials, the tuning effect can be further exploited.


Input: The novel platform technology developed could be utilized in critical care, clinical management and at home health and disease management.


Input: Growth and potential damage of human bone-derived cells on fresh and aged fullerene c60 films.

fullerene c60


Input: Fullerenes are nanoparticles composed of carbon atoms arranged in a spherical hollow cage-like structure.

Fullerenes

carbon


Input: Numerous studies have evaluated the therapeutic potential of fullerene derivates against oxidative stress-associated conditions, including the prevention or treatment of arthritis.

fullerene


Input: On the other hand, fullerenes are not only able to quench, but also to generate harmful reactive oxygen species.

fullerenes

oxygen


Input: The reactivity of fullerenes may change in time due to the oxidation and polymerization of fullerenes in an air atmosphere.

fullerenes

fullerenes


Input: In this study, we therefore tested the dependence between the age of fullerene films (from one week to one year) and the proliferation, viability and metabolic activity of human osteosarcoma cells (lines MG-63 and U-2 OS).

fullerene


Input: We also monitored potential membrane and DNA damage and morphological changes of the cells.


Input: After seven days of cultivation, we did not observe any cytotoxic morphological changes, such as enlarged cells or cytosolic vacuole formation.


Input: Furthermore, there was no increased level of DNA damage.


Input: The increasing age of the fullerene films did not cause enhancement of cytotoxicity.

fullerene


Input: On the contrary, it resulted in an improvement in the properties of these materials, which are more suitable for cell cultivation.


Input: Therefore, fullerene films could be considered as a promising material with potential use as a bioactive coating of cell carriers for bone tissue engineering.

fullerene


Input: Excitation and Adaptation in Bacteria-a Model Signal Transduction System that Controls Taxis and Spatial Pattern Formation.


Input: The machinery for transduction of chemotactic stimuli in the bacterium E. coli is one of the most completely characterized signal transduction systems, and because of its relative simplicity, quantitative analysis of this system is possible.


Input: Here we discuss models which reproduce many of the important behaviors of the system.


Input: The important characteristics of the signal transduction system are excitation and adaptation, and the latter implies that the transduction system can function as a " derivative sensor " with respect to the ligand concentration in that the DC component of a signal is ultimately ignored if it is not too large.


Input: This temporal sensing mechanism provides the bacterium with a memory of its passage through spatially-or temporally-varying signal fields, and adaptation is essential for successful chemotaxis.


Input: We also discuss some of the spatial patterns observed in populations and indicate how cell-level behavior can be embedded in population-level descriptions.


Input: High-affinity nicotinic acetylcholine receptor expression and trafficking abnormalities in psychiatric illness.

acetylcholine


Input: RATIONALE: Nicotinic acetylcholine receptors (nAChRs) are a critical component of the cholinergic system of neurotransmission in the brain that modulates important physiological processes such as reward, cognition, and mood.

acetylcholine


Input: Abnormalities in this system are accordingly implicated in multiple psychiatric illnesses, including addiction, schizophrenia, and mood disorders.


Input: There is significantly increased tobacco use, and therefore nicotine intake, in patient populations, and pharmacological agents that act on various nicotinic receptor subtypes ameliorate clinical features of these disorders.

nicotine


Input: Better understanding of the molecular mechanisms underlying cholinergic dysfunction in psychiatric disease will permit more targeted design of novel therapeutic agents.


Input: RESULTS: The objective of this review is to describe the multiple cellular pathways through which chronic nicotine exposure regulates nAChR expression, and to juxtapose these mechanisms with evidence for altered expression of high-affinity nAChRs in human psychiatric illness.

nicotine