Input: We provide evidence that fluorescent pirenzepine derivatives, with the M1 antagonist fused to the Bodipy [558/568] fluorophore via spacers of varying lengths, exhibit orthosteric/allosteric binding properties at muscarinic M1 receptors.

pirenzepine

Bodipy [558/568]


Input: This behaviour was inferred from a combination of functional, radioligand and FRET binding experiments, performed under equilibrium and kinetic conditions on EGFP-fused M1 receptors.


Input: Though displaying a common orthosteric component, the fluorescent compounds inherit bitopic properties from a linker-guided positioning of their Bodipy moiety within the M1 allosteric vestibule.

Bodipy


Input: Depending on linker length, the fluorophore is allowed to reach neighbouring allosteric domains, overlapping or not with the classical gallamine site, but distinct from the allosteric indocarbazolole' WIN' site.

gallamine

indocarbazolole


Input: Site-directed mutagenesis, as well as molecular modeling and ligand docking studies based on recently solved muscarinic receptor structures, further support the definition of two groups of Bodipy-pirenzepine derivatives exhibiting distinct allosteric binding poses.

Bodipy

pirenzepine


Input: Thus, the linker may dictate pharmacological outcomes for bitopic molecules that are hardly predictable from the properties of individual orthosteric and allosteric building blocks.


Input: Our findings also demonstrate that the fusion of a fluorophore to an orthosteric ligand is not neutral as it may confer, unless carefully controlled, unexpected properties to the resultant fluorescent tracer.


Input: Altogether, this study illustrates the importance of a' multifacette' experimental approach to unravel and validate bitopic ligand binding mechanisms.


Input: Developmental exposure to As, Cd and Pb-mixture diminishes skeletal growth and causes osteopenia at maturity via osteoblast and chondrocyte malfunctioning in female rats.

As

Cd

Pb


Input: We studied the effect of metal mixture (MM), comprising of As, Cd and Pb, in developing female rat skeleton from gestation day-5 until postnatal day-60 (P-60).

As

Cd

Pb


Input: MM resulted in synergistic inhibition in viability and differentiation of osteoblasts in vitro, likely induced by reactive oxygen species.

oxygen


Input: MM, administered at their most frequently occurring concentrations present in the ground-water of India, i. e. As: 0. 38ppm, Pb: 0. 22 ppm and Cd: 0. 098 ppm or 10 x of the ratio to developing rats exhibited a synergistic decrease in ex vivo mineralization of bone marrow stromal (osteoprogenitor) cells.

As

Pb

Cd


Input: MM group showed a dose-dependent attenuation in weight and axial lengths, and shortening of tibias at P-60.


Input: Furthermore, the growth plate was shortened, which was associated with shorter proliferative-and hypertrophic zones, decreased parathyroid hormone-related protein and Indian hedgehog expression in the chondrocytes, reduced primary-and secondary spongiosa, and hypomineralized osteoids-a major characteristic of osteomalacia.


Input: In addition, compared to the control, MM treated rats were clearly osteopenic based on BMD, micro-architecture, biomechanical strength, and particularly the biochemical profile, that suggested high turnover bone loss.


Input: Finally, in comparison to the control, the fracture healing ability of MM group was delayed and accompanied by inferior quality of the healed bone.


Input: Together, these data demonstrated that the mixture of As, Cd and Pb induced synergistic toxicity to developing skeleton thereby diminishing modeling-directed bone accrual, inducing osteopenia and dampening fracture healing.

As

Cd

Pb


Input: Simultaneous determination of five flavonoids during the growth of Fructus Sophorae by capillary electrophoresis.

flavonoids


Input: A method of simultaneous determination of five flavonoids during the growth of Fructus Sophorae by beta-cyclodextrin (beta-CD-) modified capillary zone electrophoresis was developed.

flavonoids

beta-cyclodextrin

beta-CD


Input: The effects of various parameters such as buffer concentration, pH, applied voltage, and beta-CD concentrations were investigated.

beta-CD


Input: After a series of optimization processes, the determination of five flavonoids in Fructus Sophorae was successfully achieved in 20 mmol/L borax buffer (pH 9. 5), 25 kV applied voltage, and 8 mmol/L beta-CD.

flavonoids

beta-CD


Input: The linearity, detection limits, repeatability, and recovery were satisfactory.


Input: Thus, the proposed beta-CD-modified capillary zone electrophoresis method was satisfactorily used to analyze Fructus Sophorae samples.

beta-CD


Input: The results can be useful for the quality control and medicinal resource development of Fructus Sophorae.


Input: Arginase II inhibitory activity of flavonoid compounds from Scutellaria indica.

flavonoid


Input: Arginase II has recently reported as a novel therapeutic target for the treatment of cardiovascular diseases such as atherosclerosis.


Input: In the course of screening plants used in natural medicines as arginase II inhibitory activity, a methanol extract of Scutellaria indica showed significant inhibitory effect.

methanol


Input: Further fractionation and repeated column chromatography led to the isolation of a new flavan-type (1), and seven known compounds (2-8).

flavan


Input: The chemical structures of isolated compounds were elucidated based on extensive 1D and 2D NMR spectroscopic data.


Input: The isolates 1-8 were investigated in vitro for their arginase II inhibitory activity using enzyme solution prepared from kidney of anesthetized C57BL/6 mice.


Input: Compounds 3 and 5 significantly inhibited arginase II activity with IC50 values of 25. 1 and 11. 6 mu M, respectively, whereas the other compounds were apparently inactive.


Input: Synthesis, cytotoxicity and QSAR study of N-tosyl-1, 2, 3, 4-tetrahydroisoquinoline derivatives.

N-tosyl-1, 2, 3, 4-tetrahydroisoquinoline


Input: 1-Substituted-N-tosyl-1, 2, 3, 4-tetrahydroisoquinoline analogs (4a-4l) were synthesized using the modified Pictet-Spengler reaction and evaluated for cytotoxicity.

1-Substituted-N-tosyl-1, 2, 3, 4-tetrahydroisoquinoline


Input: All tetrahydroisoquinolines displayed cytotoxicity against MOLT-3 cell lines, except for p-methoxy analog 4d.

tetrahydroisoquinolines

p-methoxy


Input: Interestingly, the o-hydroxy derivative 4k was shown to be the most potent cytotoxic against HuCCA-1, A-549 and MOLT-3 cell lines.

o-hydroxy


Input: The lowest IC50 value of 1. 23 mu M was observed for MOLT-3 cells.


Input: Trimethoxy analog 4f exerted the most potent activity against HepG2 with an IC50 of 22. 70 mu M, which is lower than the reference drug, etoposide.

Trimethoxy


Input: QSAR studies showed that total symmetry index (Gu), 3D-MoRSE (Mor31v and Mor32u) and 3D Petitjean index (PJI3) were the most important descriptors accounting for the observed cytotoxicities.


Input: The most potent cytotoxic compound (4k) against MOLT-3 had the highest Gu value, correspondingly the inactive p-methoxy analog (4d) had the lowest Gu value.

p-methoxy


Input: On the other hand, the highest molecular mass compound (4f) was shown to be the most potent cytotoxic against HepG2 cells.


Input: The studies disclose that tetrahydroisoquinolines 4f and 4k are potentially interesting lead pharmacophores that should be further explored.

tetrahydroisoquinolines


Input: The QSAR models provided insights into the physicochemical properties of the investigated compounds.


Input: Computational identification of functional introns: high positional conservation of introns that harbor RNA genes.


Input: An appreciable fraction of introns is thought to have some function, but there is no obvious way to predict which specific intron is likely to be functional.


Input: We hypothesize that functional introns experience a different selection regime than non-functional ones and will therefore show distinct evolutionary histories.


Input: In particular, we expect functional introns to be more resistant to loss, and that this would be reflected in high conservation of their position with respect to the coding sequence.


Input: To test this hypothesis, we focused on introns whose function comes about from microRNAs and snoRNAs that are embedded within their sequence.


Input: We built a data set of orthologous genes across 28 eukaryotic species, reconstructed the evolutionary histories of their introns and compared functional introns with the rest of the introns.


Input: We found that, indeed, the position of microRNA-and snoRNA-bearing introns is significantly more conserved.


Input: In addition, we found that both families of RNA genes settled within introns early during metazoan evolution.


Input: We identified several easily computable intronic properties that can be used to detect functional introns in general, thereby suggesting a new strategy to pinpoint non-coding cellular functions.


Input: Ischemic stroke functional outcomes are independently associated with C-reactive protein concentrations and cognitive outcomes with triiodothyronine concentrations: a pilot study.

triiodothyronine


Input: Elevated concentrations of C-reactive protein (CRP) and decreased concentrations of triiodothyronine (T3) were shown to predict poor outcomes in patients with stroke.

triiodothyronine


Input: However, the prognostic value of CRP and T3 has not been studied simultaneously in relation to stroke functional and cognitive outcomes despite of close interaction between inflammatory markers and thyroid function.


Input: We evaluated the association of thyroid hormone and CRP concentrations with immediate outcomes after ischemic stroke.


Input: Eighty-eight ischemic stroke patients on admission to the stroke unit were evaluated for clinical stroke severity (Scandinavian stroke scale or SSS) and concentrations of thyroid-stimulating hormone, free thyroxin, free T3, and CRP.

thyroxin


Input: Functional outcome (modified Rankin scale) and cognitive outcome (Mini mental state examination) were evaluated at discharge.


Input: Greater ln CRP concentrations (r =-0. 35, p = 0. 001), but not thyroid hormone concentrations, correlated with score on the SSS.


Input: In univariate analyses lower free T3 concentrations and higher CRP concentrations were associated with poor functional and poor cognitive outcomes.


Input: After adjustment for clinical stroke severity, higher CRP concentrations (beta = 0. 18, p = 0. 04) remained associated with worse functional outcome and lower free T3 concentrations with worse cognitive outcome (beta = 0. 23, p = 0. 03).


Input: In sum, clinical stroke severity is associated with elevated CRP concentration.


Input: Higher CRP concentration is independently associated with worse functional outcomes and lower free T3 concentration with worse cognitive outcomes at discharge.


Input: T3 and CRP can be important biomarkers in patients with acute ischemic stroke.


Input: Hydrothermal Growth of TiO2 Nanorod Arrays and In Situ Conversion to Nanotube Arrays for Highly Efficient Quantum Dot-Sensitized Solar Cells.


Input: TiO2 nanorod (NR) and nanotube (NT) arrays grown on transparent conductive substrates are attractive electrode for solar cells.


Input: In this paper, TiO2 NR arrays are hydrothermally grown on FTO substrate, and are in situ converted into NT arrays by hydrothermally etching.

FTO


Input: The TiO2 NR arrays are reported as single crystalline, but the TiO2 NR arrays are demonstrated to be polycrystalline with a bundle of 2-5 nm single crystalline nanocolumns grown along [001] throughout the whole NR from bottom to top.


Input: TiO2 NRs can be converted to NTs by hydrothermal selective etching of the (001) core and remaining the inert sidewall of (110) face.


Input: A growth mechanism of the NR and NT arrays is proposed.


Input: Quantum dot-sensitized solar cells (QDSCs) are fabricated by coating CdSe QDs on to the TiO2 arrays.

CdSe


Input: After conversion from NRs to NTs, more QDs can be filled in the NTs and the energy conversion efficiency of the QDSCs almost double.


Input: Beyond Statins: Lipid Management to Reduce Cardiovascular Risk.

Statins


Input: The discovery that elevated total cholesterol levels and the subsequent understanding that low-density lipoprotein cholesterol levels are associated with higher risk for cardiovascular disease (CVD) has led to the development of lipid management strategies that seek to reduce the burden of CVD.

cholesterol

cholesterol


Input: Although substantive progress has been made in reducing death and cardiovascular events, questions remain regarding the optimal approach to further reduce CVD-associated death and disability.


Input: Based on current evidence, statins are the clear first-line agents for the management of hyperlipidemia in patients at high risk for cardiovascular events.

statins


Input: However, due to the failure of recent clinical trials evaluating antihyperlipidemic drugs, the most appropriate lipid management strategy in patients who cannot tolerate statin therapy or who warrant antihyperlipidemic therapies in addition to statins is a major therapeutic controversy.


Input: In this review, we summarize the clinical trial evidence evaluating the efficacy of second-line antihyperlipidemic drug classes for reducing cardiovascular risk, provide recommendations for appropriate use of nonstatin lipid-altering drugs, and identify key areas of future research to support evidence-based lipid management.


Input: Given the complexity, magnitude, and burden of CVD, opportunities to improve processes of care and identify new therapeutic options clearly exist.


Input: Microfluidic Surface-Enhanced Raman Scattering Sensors Based on Nanopillar Forests Realized by an Oxygen-Plasma-Stripping-of-Photoresist Technique.

Oxygen


Input: A novel surface-enhanced Raman scattering (SERS) sensor is developed for real-time and highly repeatable detection of trace chemical and biological indicators.


Input: The sensor consists of a polydimethylsiloxane (PDMS) microchannel cap and a nanopillar forest-based open SERS-active substrate.

polydimethylsiloxane

PDMS


Input: The nanopillar forests are fabricated based on a new oxygen-plasma-stripping-of-photoresist technique.

oxygen


Input: The enhancement factor (EF) of the SERS-active substrate reaches 6. 06 x 10 (6), and the EF of the SERS sensor is about 4 times lower due to the influence of the PDMS cap.


Input: However, the sensor shows much higher measurement repeatability than the open substrate, and it reduces the sample preparation time from several hours to a few minutes, which makes the device more reliable and facile for trace chemical and biological analysis.


Input: Reversal of Oral Anticoagulation.


Input: Although the use of dabigatran and rivaroxaban are increasing, data on the reversal of their effects are limited.

dabigatran

rivaroxaban


Input: The lack of reliable monitoring methods and specific reversal agents renders treatment strategies empirical, and as a result, treatment consists mainly of supportive measures.


Input: Therefore, we performed a systematic search of the PubMed database to find studies and reviews pertaining to oral anticoagulation reversal strategies.


Input: This review discusses current anticoagulation reversal recommendations for the oral anticoagulants warfarin, dabigatran, and rivaroxaban for patients at a heightened risk of bleeding, actively bleeding, or those in need of preprocedural anticoagulation reversal.

warfarin

dabigatran

rivaroxaban


Input: We highlight the literature that shaped these recommendations and provide directions for future research to address knowledge gaps.


Input: Although reliable recommendations are available for anticoagulation reversal in patients treated with warfarin, guidance on the reversal of dabigatran and rivaroxaban is varied and equivocal.

warfarin

dabigatran

rivaroxaban


Input: Given the increasing use of the newer agents, focused research is needed to identify effective reversal strategies and develop and implement an accurate method (assay) to guide reversal of the newer agents.


Input: Determining patient-specific factors that influence the effectiveness of reversal treatments and comparing the effectiveness of various treatment strategies are pertinent areas for future anticoagulation reversal research.


Input: Regulation of Conjugated Hemoglobin on Micelles through Copolymer Chain Sequences and the Protein' s Isoelectric Aggregation.


Input: Amphiphilic triblock copolymers with carbonyl groups located either in the middle segment or in the third side block are synthesized by adjusting feeding sequence of the comonomers.

carbonyl


Input: The conjugation of hemoglobin (Hb) on the copolymer micelles is realized by condensation reactions of carbonyl with the amino groups of Hb, and the gas-binding capacity of Hb is well preserved.

carbonyl

amino


Input: Interestingly, the reassembly behavior of Hb-conjugated micelles (HbM) is explored by adjusting the pH.


Input: As for triblock copolymers with a carbonyl-functionalized segment as the third block, Hb is rearranged into the inner core of micelles when the pH is adjusted close to the isoelectric point of Hb.

carbonyl


Input: Therefore, it may provide a new needed route for fabrication of protein carriers, which is different from the traditional encapsulation technique.


Input: Synthesis and Anti-herpetic Activity of Phosphoramidate ProTides.

Phosphoramidate


Input: Among the many prodrug approaches aimed at delivering nucleoside monophosphates into cells, the phosphoramidate ProTide approach is one that has shown success, which has made it possible for some of the phosphoramidates to enter into clinical trials.

nucleoside monophosphates

phosphoramidate

phosphoramidates


Input: Herein, we report the synthesis and antiviral activity of a series of phosphoramidate ProTides designed to bypass the thymidine kinase (TK) dependence of the parent nucleoside analogues.

phosphoramidate

thymidine

nucleoside


Input: Phosphoramidate derivatives of (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) that contain L-alanine or pivaloyloxymethyl iminodiacetate (IDA-POM) exhibit anti-HSV-1 and anti-VZV activity in cell cultures, but they largely lost antiviral potency against TK-deficient virus strains.

Phosphoramidate

BVDU

L-alanine

pivaloyloxymethyl iminodiacetate

IDA-POM


Input: Among deazapurine nucleosides and their phosphoramidate derivatives, the 7-deazaadenine containing nucleosides and their phosphoramidate triester derivatives showed weak antiviral activity against VZV.

nucleosides

phosphoramidate

nucleosides

phosphoramidate triester


Input: Apparently, intracellular nucleotide delivery with these phosphoramidates is partly successful.

nucleotide

phosphoramidates


Input: However, none of the compound prodrugs showed superior activity to their parent drugs.


Input: Genetic Insights into Pyralomicin Biosynthesis in Nonomuraea spiralis IMC A-0156.

Pyralomicin


Input: The biosynthetic gene cluster for the pyralomicin antibiotics has been cloned and sequenced from Nonomuraea spiralis IMC A-0156.

pyralomicin


Input: The 41 kb gene cluster contains 27 ORFs predicted to encode all of the functions for pyralomicin biosynthesis.

pyralomicin


Input: This includes nonribosomal peptide synthetases (NRPS) and polyketide synthases (PKS) required for the formation of the benzopyranopyrrole core unit, as well as a suite of tailoring enzymes (e. g., four halogenases, an O-methyltransferase, and an N-glycosyltransferase) necessary for further modifications of the core structure.

benzopyranopyrrole

O

N


Input: The N-glycosyltransferase is predicted to transfer either glucose or a pseudosugar (cyclitol) to the aglycone.

N

glucose

cyclitol


Input: A gene cassette encoding C7-cyclitol biosynthetic enzymes was identified upstream of the benzopyranopyrrole-specific ORFs.

cyclitol

benzopyranopyrrole


Input: Targeted disruption of the gene encoding the N-glycosyltransferase, prlH, abolished pyralomicin production, and recombinant expression of PrlA confirms the activity of this enzyme as a sugar phosphate cyclase involved in the formation of the C7-cyclitol moiety.

N

pyralomicin

sugar phosphate

cyclitol


Input: Fast Vortex-Assisted Self-Assembly of Carbon Nanoparticles on Air-Water Interface.

Carbon


Input: In this work a new self-assembly technique is presented, allowing the fast formation of carbon black thin films.

carbon black


Input: It consists in the controlled addition of a stable carbon material' s dispersion over the water surface, disturbed by a vortex.

carbon


Input: The vortex, although not essential for the film formation, was found to drastically improve film homogeneity.


Input: A physical chemical study concerning how several parameters could be used to tune film properties was also conducted.


Input: The self-assembled films, which can be picked up in any hydrophilic substrate, showed a good electrical conductivity and a high optical transparency.


Input: As an application example, films about 200 nm thick were employed as supercapacitor electrodes.


Input: Chiral dienes as " ligands " for borane-catalyzed metal-free asymmetric hydrogenation of imines.

dienes

borane

imines


Input: This paper describes a highly enantioselective metal-free hydrogenation of imines using chiral dienes as " ligands " for the generation of catalysts with HB (C6F5) 2 by hydroboration in situ to furnish a variety of chiral amines with up to 89% ee, which provides a practical strategy for the development of novel chiral frustrated Lewis pairs for asymmetric hydrogenation.

imines

dienes

HB (C6F5) 2

amines


Input: Pi-Pi Stacking Increases the Stability and Loading Capacity of Thermosensitive Polymeric Micelles for Chemotherapeutic Drugs.


Input: Thermosensitive amphiphilic block copolymers self-assemble into micelles above their lower critical solution temperature in water, however the micelles generally display mediocre physical stability.


Input: To stabilize such micelles and increase their loading capacity for chemotherapeutic drugs, block copolymers with novel aromatic monomers were synthesized by free radical polymerization of N-(2-benzoyloxypropyl methacrylamide (HPMAm-Bz) or the corresponding naphthoyl analogue (HPMAm-Nt), with N-(2-hydroxypropyl) methacrylamide monolactate, using a polyethylene glycol based macroinitiator.

N-(2-benzoyloxypropyl methacrylamide

naphthoyl

N-(2-hydroxypropyl) methacrylamide monolactate

polyethylene glycol


Input: The critical micelle temperatures and critical micelle concentrations decreased with increasing the HPMAm-Bz/Nt content.


Input: The micelles of 30 to 50 nm were prepared by heating the polymer aqueous solutions from 0 to 50 oC and were colloidally stable for at least 48 h at pH 7. 4 and 37 oC.


Input: Paclitaxel and docetaxel encapsulation was performed by mixing drug solutions in ethanol with polymer aqueous solutions and heating from 0 to 50 oC.

Paclitaxel

docetaxel

ethanol


Input: The micelles had a drug loading capacity up to 34 weight% for docetaxel, which is amongst the highest loadings reported for polymeric micelles, with loaded micelle sizes ranging from 60 to 80 nm.

docetaxel


Input: The micelles without aromatic groups almost completely released loaded paclitaxel in 10 days, whereas the HPMAm-Bz/Nt containing micelles released 50% of the paclitaxel at the same time, which showed a better retention for the drug of the latter micelles.

paclitaxel

paclitaxel


Input: 1H solid-state NMR spectroscopy data are compatible with pi-pi stacking between aromatic groups.


Input: The empty micelles demonstrated good cytocompatibility, and paclitaxel loaded micelles showed high cytotoxicity to tumor cells.

paclitaxel


Input: In conclusion, the pi-pi stacking effect introduced by aromatic groups increases the stability and loading capacity of polymeric micelles.


Input: Hierarchy of relative bond dissociation enthalpies and their use to efficiently compute accurate absolute bond dissociation enthalpies for C-h, C-C, and C-f bonds.

C-h

C-C

C-f


Input: We have used the high-level W1X-2 and G4 (MP2)-6X procedures to examine the performance of a variety of computationally less demanding quantum chemistry methods for the calculation of absolute bond dissociation enthalpies (BDEs) and a hierarchy of relative bond dissociation enthalpies.


Input: These include relative bond dissociation enthalpies (RBDEs), deviations from additivity of RBDEs (DARBDEs), and deviations from pairwise additivity of RBDEs (DPARBDEs).


Input: The absolute magnitudes of these quantities decrease in the order BDE > RBDE > DARBDE > DPARBDE, and overall, theoretical procedures are better able to describe these quantities in the same order.


Input: In general, the performance of the various types of procedures improves in the order pure DFT --> hybrid DFT --> double-hybrid DFT --> composite procedures, as expected.


Input: Overall, we find M06-L to be the best-performing pure DFT procedure and M06-2X to be the best among the hybrid DFT methods.


Input: A promising observation is that even many pure and hybrid DFT procedures give DARBDE and DPARBDE values that are reasonably accurate.


Input: This can be exploited by using reference BDEs calculated at a higher-level of theory, in combination with DARBDE or DPARBDE values obtained at a lower level, to produce BDEs and RBDEs with an accuracy that is close to the directly calculated higher-level values.


Input: Strongly pi-electron-withdrawing or pi-electron-donating groups, however, sometimes represent challenges to these approximation methods when the substrate contains several of these substituents.


Input: Novel therapeutic targets in non-small cell lung cancer.


Input: Oncogenic driver mutations frequently occur in lung cancer and play role in carcinogenesis.


Input: These mutations are usually associated with distinct clinical and histological features and are attractive targets for anticancer therapy.


Input: Recently, several molecularly distinct phenotypes of NSCLC based on specific and mutually exclusive genetic derangements have been described.


Input: Few targets like epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) gene rearrangements have successfully been targeted with EGFR tyrosine kinase inhibitors (TKIs) and crizotinib, respectively.

crizotinib


Input: Many more inhibitors of specific driver mutations involving genes like ROS, c-MET, FGFR, mTOR, IGFR and RET are currently under development.


Input: However, efforts to target some mutated genes like K-RAS have been unsuccessful.


Input: Moreover, the emerging challenge of acquired resistance to initially effective therapy is becoming another major concern.


Input: In this review recent data on novel molecular targets and their future prospects are discussed.


Input: Multiple origins for Hound' s tongues (Cynoglossum L.) and Navel seeds (Omphalodes Mill.)-The phylogeny of the borage family (Boraginaceae s. str.).


Input: Recent studies all indicated that both the affinities and subdivision of Boraginaceae s. str. are unsatisfactorily resolved.


Input: Major open issues are the placement and affinities of Boraginaceae s. str. in Boraginales and the major clades of the family, with especially the large tribes Cynoglosseae and Eritrichieae repeatedly retrieved as non-monophyletic groups, and the doubtful monophyly of several larger genera, especially Cynoglossum and Omphalodes.


Input: The present study addresses and solves these questions using two plastid markers (trnL-trnF, rps16) on the basis of a sampling including 16 outgroup taxa and 172 ingroup species from 65 genera.


Input: The phylogeny shows high statistical support for most nodes on the backbone and on the individual clades.


Input: Boraginaceae s. str. are sister to African Wellstediaceae, Wellstediaceae-Boraginaceae s. str.


Input: is sister to African Codonaceae.


Input: Echiochileae are retrieved as sister to the remainder of Boraginaceae s. str., which, in turn, fall into two major clades, the Boragineae-Lithospermeae (in a well-supported sister relationship) and the Cynoglosseae s. l.


Input: (including Eritrichieae).


Input: Cynoglosseae s. l.


Input: is highly resolved, with Trichodesmeae (incl. Microcaryum, Lasiocaryum) as sister to the remainder of the group.


Input: Eritrichieae s. str.


Input: (Eritrichium, Hackelia, Lappula) are resolved on a poorly supported polytomy together with the Omphalodes-clade (incl. Myosotidium, Cynoglossum p. p.), and the Mertensia-clade (incl. O. scorpioides, Asperugo).


Input: The Myosotideae (Myosotis, Trigonotis, Pseudomertensia) are retrieved in a well-supported sister-relationship to the core-Cynoglosseae, the latter comprising all other genera sampled.


Input: Cynoglossum is retrieved as highly para-and polyphyletic, with a large range of generic segregates embedded in Cynoglossum, but other species of Cynoglossum are sister to Microula or to the American " Eritrichieae " (Cryptantha and allied genera).


Input: Representatives of the genus Cynoglossum in its current definition are segregated onto six independent lineages, members of Omphalodes onto three independent lineages.


Input: At least 11 of the genera here sampled are deeply nested in other genera.


Input: The data show that individual details of nutlet morphology (e. g., winged margins, glochidia) are highly homoplasious.


Input: Conversely, a complex of nutlet characters (e. g., characters of the gynobase and cicatrix together with nutlet orientation and sculpturing) tends to circumscribe natural units.


Input: Geographical distribution of major clades suggests that the family originated in Africa and western Asia and radiated to eastern Eurasia, with several independent dispersal events into Australia and the New World.


Input: The effect of mitragynine on cAMP formation and mRNA expression of mu-opioid receptors mediated by chronic morphine treatment in SK-N-SH neuroblastoma cell.

mitragynine

cAMP


Input: ETHOPHARMACOLOGICAL RELEVANCE: Mitragynine is an indole alkaloid compound of Mitragyna speciosa (M. speciosa) Korth.

Mitragynine

indole alkaloid


Input: (Rubiaceae).


Input: This plant is native to the southern regions of Thailand and northern regions of Malaysia and is frequently used to manage the withdrawal symptoms in both countries.


Input: AIM OF STUDY: To investigate the effect of mitragynine after chronic morphine treatment on cyclic AMP (cAMP) level and mRNA expression of mu-opioid receptor (MOR) in human neuroblastoma SK-N-SH cell.

mitragynine

morphine

cyclic AMP

cAMP


Input: METHOD AND MATERIALS: Mitragynine was isolated from the Mitragyna speciosa plant using the acid-base extraction method.

Mitragynine


Input: The cAMP level upon forskolin stimulation in the cells was determined using the Calbiochem ((R)) Direct Immunoassay Kit.

cAMP

forskolin


Input: The mRNA expression of the MOR was carried out using quantitative RT-PCR.


Input: RESULT: Cotreatment and pretreatment of morphine and mitragynine significantly reduced the production of cAMP level at a lower concentration of nitrogen while the higher concentration of this compound could lead to the development of tolerance and dependence as shown by the increase of the cAMP level production in foskolin stimulation.

morphine

mitragynine

cAMP

nitrogen

cAMP

foskolin


Input: In MOR mRNA expression study, cotreatment of morphine with mitragynine significantly reduced the down-regulation of MOR mRNA expression as compared to morphine treatment only.

morphine

mitragynine

morphine


Input: CONCLUSION: These finding suggest that mitragynine could possibly avoid the tolerance and dependence on chronic morphine treatment by reducing the up-regulation of cAMP level as well as reducing the down-regulation of MOR at a lower concentration of mitragynine.

mitragynine

morphine

cAMP

mitragynine


Input: Evaluation and modification of commercial dry powder inhalers for the aerosolization of a submicrometer excipient enhanced growth (EEG) formulation.


Input: The aim of this study was to evaluate and modify commercial dry powder inhalers (DPIs) for the aerosolization of a submicrometer excipient enhanced growth (EEG) formulation.


Input: The optimized device and formulation was then tested in a realistic in vitro mouth-throat-tracheobronchial (MT-TB) model.


Input: An optimized EEG submicrometer powder formulation, consisting of albuterol sulfate (drug), mannitol (hygroscopic excipient), l-leucine (dispersion enhancer) and poloxamer 188 (surfactant) in a ratio of 30: 48: 20: 2 was prepared using a B u chi Nano spray dryer.

albuterol sulfate

mannitol

l-leucine

poloxamer 188


Input: The aerosolization performance of the EEG formulation was evaluated with five conventional DPIs: Aerolizer, Novolizer, HandiHaler, Exubera and Spiros.


Input: To improve powder dispersion, the HandiHaler was modified with novel mouth piece (MP) designs.


Input: The aerosol performance of each device was assessed using a next generation impactor (NGI) at airflow rates generating a pressure drop of 4kPa across the DPI.


Input: In silico and in vitro deposition and hygroscopic growth of formulations was studied using a MT-TB airway geometry model.


Input: Both HandiHaler and Aerolizer produced high emitted doses (EDs) together with a significant submicrometer aerosol fraction.


Input: A modified HandiHaler with a MP including a three-dimensional (3D) array of rods (HH-3D) produced a submicrometer particle fraction of 38. 8% with a conventional fine particle fraction (% < 5 mu m) of 97. 3%.


Input: The mass median diameter (MMD) of the aerosol was reduced below 1 mu m using this HH-3D DPI.


Input: The aerosol generated from the modified HandiHaler increased to micrometer size (2. 8 mu m) suitable for pulmonary deposition, when exposed to simulated respiratory conditions, with negligible mouth-throat (MT) deposition (2. 6%).


Input: Effects of 17 alpha-ethinylestradiol (EE2) on reproductive endocrine status in mummichog (Fundulus heteroclitus) under differing salinity and temperature conditions.

17 alpha-ethinylestradiol


Input: Exposure to 17 alpha-ethinylestradiol (EE2), a synthetic estrogen, has previously been shown to decrease reproductive endocrine status and egg production in northern mummichog (Fundulus heteroclitus macrolepidotus).

17 alpha-ethinylestradiol

estrogen


Input: The objective of this study was to evaluate if variations in salinity or temperature conditions of EE2-exposed mummichog modify the effect on whole organism reproductive endocrine status and gonadal steroidogenesis.


Input: Mummichog were exposed in vivo for 14 days to 0, 50 and 250ng/L EE2 in 0, 16 and 32ppt salinity at 18 degrees C and to 0 and 250ng/L EE2 at 10, 18 and 26 degrees C at 16ppt.


Input: There was a little overall effect of salinity on measured endpoints.


Input: In the salinity exposure, 250ng/L EE2-exposed females had significantly reduced 17 beta-estradiol (E2) levels.

17 beta-estradiol


Input: Increased temperature triggered gonadal growth in both sexes and increased plasma E2 and E2 production and decreased 11-KT (11-ketotestosterone) production.


Input: EE2 counteracted the effect of temperature by depressing gonadal growth in males.


Input: In both exposures, EE2 effects on testosterone (T) production were variable.

testosterone


Input: The use of steroidogenic precursors (25-OH-cholesterol, and/or pregnenolone and/or testosterone) in the in vitro gonadal incubations indicated decreased E2 production in females and 11-KT production in males were predominately due to suppression of the terminal conversion step between T and E2 or 11-KT.

pregnenolone

testosterone


Input: Ovarian aromatase A (cyp19a) gene expression at 16ppt and 18 degrees C was not affected by 250ng/L EE2 (the only treatment combinations tested).


Input: Overall, temperature is a factor regulating northern mummichog reproduction; EE2 overrides its effects and disrupts the terminal step of steroidogenesis.


Input: Our results should be considered in designing future estuarine fish bioassays and in understanding effects of estrogenic endocrine disruptors in estuaries.


Input: Three-dimensionally ordered macroporous Cu2O/Ni inverse opal electrodes for electrochemical supercapacitors.

Ni


Input: With an ordered polystyrene (PS) template-assisted electrochemical approach we synthesized three-dimensional ordered macroporous (3DOM) Cu2O/Ni inverse opals as electrodes for supercapacitors.

polystyrene

Ni


Input: The 3DOM Cu2O/Ni electrodes display superior kinetic performance, and satisfactory rate capability and cycling performance.

Ni


Input: Similarities and differences between sexes in regional loss of cortical and trabecular bone in the mid-femoral neck: The AGES-Reykjavik Longitudinal Study.


Input: The risk of hip fracture rises rapidly with age, and is notably higher in women.


Input: After falls and prior fragility fractures, the main clinically recognized risk factor for hip fracture is reduced bone density.


Input: To better understand the extent to which femoral neck density and structure change with age in each sex, we have carried out a longitudinal study in subjects not treated with agents known to influence bone mineral density to investigate changes in regional cortical thickness, as well as cortical and trabecular bone mineral density at the mid-femoral neck.


Input: Segmental QCT analysis was used to assess bone measurements in two anatomic sub-regions, the supero-lateral (superior) and infero-medial (inferior).


Input: A total of 400 older individuals (100 men and 300 women, aged 66-90 years) who were participants in the AGES-Reykjavik study, were studied.


Input: Participants had two QCT scans of the hip over a median follow-up of 5. 1 yr.


Input: (mean baseline age 74 yr.).


Input: Changes in bone values during follow-up were estimated from mixed effects regression models.


Input: At baseline women had lower bone values in the superior region than men.


Input: At follow-up all bone values were lower in women, except cortical vBMD inferiorly.


Input: The relative losses in all bone values estimated in the superior region were substantially (about threefold) and significantly greater compared to those estimated in the inferior region in both sexes.


Input: Women lost cortical thickness and cortical vBMD more rapidly than men in both regions; and this was only weakly reflected in total femoral neck DXA-like results.


Input: The higher rate of bone loss in women at critical locations may contribute materially to the greater femoral neck fracture incidence among women than men.


Input: Application of Medicinal Plants in Maternal Healthcare and Infertility: A South African Perspective.


Input: Plants have played significant roles as medicine during pregnancy, birth, and postpartum care in many rural areas of the world.


Input: In addition to this, plants have been used for centuries to treat infertility and related reproduction problems.


Input: The aim of this paper was to review the current status of plant species used in maternal healthcare, including infertility, in South Africa, in terms of scientific evaluation for efficacy and safety.


Input: In addition to this, the role of medicinal plants as a tool in achieving the MDG5 of reducing maternal mortality by 2015 was evaluated.


Input: A search was done with the aid of Google Scholar, PubMed, Science Direct, peer-reviewed papers, and books, using keywords such as child birth, labour pain, maternal health, maternal mortality, menstrual pains, and postpartum.


Input: The plants listed in the different research articles were classified according to their use and the target effect of a plant extract or compound on reproductive function.


Input: Eighty-four plant species were found to be used to treat infertility and related problems.


Input: Twenty plant species are used during pregnancy, while 26 plant species are used to ease childbirth.


Input: For postpartum healing and any problems after childbirth, nine plant species were recorded.


Input: Unhealthy pregnancy and birth complications are among the factors that contribute to the loss of cognitive potential in the developing world' s children, condemning them to impoverished lives.


Input: The best way to keep a country poor is to rob its children of their full developmental potential.


Input: In this respect, medicinal plants play a significant role in reducing maternal mortality and ensuring the birth of healthy children.


Input: Dynamics and structural changes of small water clusters on ionization.


Input: Despite utmost importance in understanding water ionization process, reliable theoretical results of structural changes and molecular dynamics (MD) of water clusters on ionization have hardly been reported yet.


Input: Here, we investigate the water cations [(H2 O) n = 2-6 (+)] with density functional theory (DFT), M o ller-Plesset second-order perturbation theory (MP2), and coupled cluster theory with single, double, and perturbative triple excitations [CCSD (T)].

(H2 O) n


Input: The complete basis set limits of interaction energies at the CCSD (T) level are reported, and the geometrical structures, electronic properties, and infrared spectra are investigated.


Input: The characteristics of structures and spectra of the water cluster cations reflect the formation of the hydronium cation moiety (H3 O (+)) and the hydroxyl radical.

hydronium

H3 O (+)

hydroxyl


Input: Although most density functionals fail to predict reasonable energetics of the water cations, some functionals are found to be reliable, in reasonable agreement with high-level ab initio results.


Input: To understand the ionization process of water clusters, DFT-and MP2-based Born-Oppenheimer MD (BOMD) simulations are performed on ionization.


Input: On ionization, the water clusters tend to have an Eigen-like form with the hydronium cation instead of a Zundel-like form, based on reliable BOMD simulations.

hydronium


Input: For the vertically ionized water hexamer, the relatively stable (H2 O) 5 (+) (5sL4A) cluster tends to form with a detached water molecule (H2 O).

(H2 O) 5 (+)

H2 O


Input: (c) 2013 Wiley Periodicals, Inc.


Input: Inhibition of the Proton-Coupled Folate Transporter (PCFT-SLC46A1) by Bicarbonate and Other Anions.

Folate

Bicarbonate


Input: The proton-coupled folate transporter (PCFT) plays a key role in intestinal folate absorption and loss-of-function mutations in the gene encoding this transporter are the molecular basis for hereditary folate malabsorption.

folate

folate

folate


Input: Using a stable transfectant with high expression of PCFT, physiological levels of bicarbonate produced potent and rapidly reversible inhibition of PCFT-mediated transport at neutral pH.

bicarbonate


Input: Bisulfite and nitrite also inhibited PCFT function at neutral pH, whereas sulfate, nitrate and phosphate had no impact at all.

Bisulfite

nitrite

sulfate

nitrate

phosphate


Input: At weakly acidic pH (6. 5), bisulfite and nitrite exhibited much stronger inhibition of PCFT-mediated transport while sulfate and nitrate remained non-inhibitory.

bisulfite

nitrite

sulfate

nitrate


Input: Inhibition by bisulfite and nitrite at pH 6. 5 was associated with a marked decrease in the influx Vmax and collapse of the transmembrane proton gradient attributed to the diffusion of the protonated forms into these cells.

bisulfite

nitrite


Input: Monocarboxylates such as pyruvate and acetate also collapsed the pH gradient and were also inhibitory, while citrate and glycine neither altered the proton gradient nor inhibited PCFT-mediated transport.

Monocarboxylates

pyruvate

acetate

citrate

glycine


Input: These observations add another dimension to the unfavorable pH environment for PCFT function in systemic tissues, the presence of high concentrations of bicarbonate.

bicarbonate


Input: Prospective observational study of physical functioning, physical activity and time outdoors and the risk of hip fracture: A population based cohort study of 158 057 older adults in the 45 and Up Study.


Input: Low levels of physical activity or sun exposure and limitations to physical functioning (or disability) have been identified as possible risk factors for hip fracture.


Input: However, these factors are closely related and data on their independent and joint association with risk of hip fracture are limited.


Input: A total of 158 057 individuals aged >= 45 years sampled from the general population of New South Wales, Australia, from the prospective 45 and Up Study completed a baseline postal questionnaire in 2006-9 including data on physical activity (Active Australia questionnaire); sun exposure (usual time outdoors); and physical functioning (Medical Outcomes Score-Physical Functioning; scored 0-100).


Input: Incident first hip fractures were ascertained by linkage to administrative hospital data (n = 293; average follow-up 2. 3 years).


Input: The Relative Risk (RR) of hip fracture was estimated using Cox proportional hazards.


Input: Poorer physical functioning, lower physical activity and less time outdoors were positively related to each other at baseline and individually associated with significantly increased hip fracture risk.


Input: However, physical activity and time outdoors were not significantly related to hip fracture risk after adjustment for baseline physical functioning or when analysis was restricted to those with no or mild baseline physical limitation.


Input: In contrast, physical functioning remained strongly related to hip fracture risk after adjustment for the other two factors; compared with the group without limitation (100) the RR of hip fracture among those with mild (75-95), moderate (50-70), severe (25-45) and greatest (0-20) level of physical limitation were 1. 38 (95% CI 0. 88-2. 14), 2. 14 (1. 29-3. 53), 3. 87 (2. 31-6. 44), and 5. 61 (3. 33-9. 42), respectively.


Input: The findings suggest that limitation in physical functioning, but not physical activity or time outdoors, is strongly related to hip fracture risk.


Input: The apparent increased risk of hip fracture previously described for low physical activity or sun exposure may be, at least in part, due to uncontrolled confounding.


Input: The Intermediate-conductance Calcium-activated Potassium Channel KCa3. 1 Regulates Vascular Smooth Muscle Cell Proliferation via Controlling Calcium-dependent Signaling.

Calcium

Potassium

Calcium


Input: The intermediate-conductance calcium-activated potassium channel KCa3. 1 contributes to a variety of cell activation processes in pathologies such as inflammation, carcinogenesis and vascular remodeling.

calcium

potassium


Input: We examined the electrophysiological and transcriptional mechanisms by which KCa3. 1 regulates vascular smooth muscle cell (VSMC) proliferation.


Input: Platelet-derived growth factor-BB (PDGF)-induced proliferation of human coronary artery VSMCs was attenuated by lowering intracellular Ca (2 +) concentration ([Ca (2 +)] i) and was enhanced by elevating [Ca (2 +)] i.

Ca (2 +)

Ca (2 +)

Ca (2 +)


Input: KCa3. 1 blockade or knockdown inhibited proliferation by suppressing the rise in [Ca (2 +)] i and attenuating the expression of phosphorylated cAMP response element binding protein (CREB), c-fos and neuron-derived orphan receptor-1 (NOR-1).

Ca (2 +)

cAMP


Input: This anti-proliferative effect was abolished by elevating [Ca (2 +)] i.

Ca (2 +)


Input: KCa3. 1 overexpression induced VSMC proliferation, and potentiated PDGF-induced proliferation, by inducing CREB phosphorylation, c-fos and NOR-1.


Input: Pharmacological stimulation of KCa3. 1 unexpectedly suppressed proliferation by inhibiting the rise in [Ca (2 +)] i and abolishing the expression and activity of KCa3. 1 and PDGF beta-receptors.

Ca (2 +)


Input: The stimulation also attenuated the levels of phosphorylated CREB, c-fos and cyclins expression.


Input: After KCa3. 1 blockade, the characteristic round shape of VSMCs expressing high l-caldesmon and low calponin-1 (dedifferentiation state) was maintained, whereas KCa3. 1 stimulation induced a spindle-shape cellular appearance, with low l-caldesmon and high calponin-1.


Input: In conclusion, KCa3. 1 plays an important role in VSMC proliferation via controlling Ca (2 +)-dependent signaling pathways and its modulation may therefore constitute a new therapeutic target for cell proliferative diseases such as atherosclerosis.

Ca (2 +)


Input: YidC occupies the lateral gate of the SecYEG translocon and is sequentially displaced by a nascent membrane protein.


Input: Most membrane proteins are co-translationally inserted into the lipid bilayer via the universally conserved SecY complex and they access the lipid phase presumably via a lateral gate in SecY.


Input: In bacteria, the lipid transfer of membrane proteins from the SecY channel is assisted by the SecY-associated protein YidC, but details on the SecY-YidC interaction are unknown.


Input: By employing an in vivo and in vitro site-directed cross-linking approach, we have mapped the SecY-YidC interface and found YidC in contact with all four transmembrane domains of the lateral gate.


Input: This interaction did not require the SecDFYajC complex and was not influenced by SecA binding to SecY.


Input: In contrast, ribosomes dissociated the YidC contacts to lateral gate helices 2b and 8.


Input: The major contact between YidC and the lateral gate was lost in the presence of ribosome-nascent chains and new SecY-YidC contacts appeared.


Input: These data demonstrate that the SecY-YidC interaction is influenced by nascent-membrane induced lateral gate movements.


Input: TIP60 Positively Regulates ThPOK-Mediated Repression of Eomesodermin in Human CD4 + T Cells.


Input: The abundant expression of IFN gamma in ThPOK-deficient CD4 + T cells requires the activation of Eomesodermin (Eomes); however, the underlying mechanism of this phenomenon remains unclear.


Input: Here we report that ThPOK directly binds to the promoter region of the Eomes gene to repress its expression in CD4 + T cells.


Input: We identified the histone acetyltransferase TIP60 as a corepressor of ThPOK-target genes, where ectopically expressed TIP60 increased ThPOK protein stability by promoting its acetylation at its K360 residue to then augment the transcriptional repression of Eomes.


Input: Moreover, knockdown of endogenous TIP60 abolished the stabilization of ThPOK in CD4 + T cells, which led to the transcriptional activation of Eomes and increased production of IFN gamma.


Input: Our results reveal a novel pathway by which TIP60 and ThPOK synergistically suppresses Eomes function and IFN gamma production, which could contribute to the regulation of inflammation.


Input: In vitro exploration of potential mechanisms of toxicity of the human hepatotoxic drug fenclozic acid.

fenclozic acid


Input: The carboxylic acid NSAID fenclozic acid exhibited an excellent preclinical safety profile and promising clinical efficacy, yet was withdrawn from clinical development in 1971 due to hepatotoxicity observed in clinical trials.

carboxylic acid

fenclozic acid


Input: A variety of modern in vitro approaches have been used to explore potential underlying mechanisms.


Input: Covalent binding studies were undertaken with [(14) C]-fenclozic acid to investigate the possible role of reactive metabolites.

[(14) C]-fenclozic acid


Input: Time-dependent covalent binding to protein was observed in NADPH-supplemented liver microsomes, although no metabolites were detected in these incubations or in reactive metabolite trapping experiments.

NADPH


Input: In human hepatocytes, covalent binding was observed at lower levels than in microsomes and a minor uncharacterizable metabolite was also observed.


Input: In addition, covalent binding was observed in incubations undertaken with dog and rat hepatocytes, where a taurine conjugate of the drug was detected.

taurine


Input: Although an acyl glucuronide metabolite was detected when liver microsomes from human, rat and dog were supplemented with UDPGA, there was no detectable UDPGA-dependent covalent binding.

acyl glucuronide

UDPGA

UDPGA


Input: No effects were observed when fenclozic acid was assessed for P450-dependent and P450-independent cytotoxicity to THLE cell lines, time-dependent inhibition of five major human cytochrome P450 enzymes, inhibition of the biliary efflux transporters BSEP and MRP2 or mitochondrial toxicity to THLE or HepG2 cells.

fenclozic acid


Input: These data suggest that Phase 1 bioactivation plays a role in the hepatotoxicity of fenclozic acid and highlight the unique insight into mechanisms of human drug toxicity that can be provided by investigations of biotransformation and covalent binding to proteins.

fenclozic acid


Input: Altered visual perception in long-term ecstasy (MDMA) users.

ecstasy

MDMA


Input: RATIONALE: The present study investigated the long-term consequences of ecstasy use on visual processes thought to reflect serotonergic functions in the occipital lobe.

ecstasy


Input: Evidence indicates that the main psychoactive ingredient in ecstasy (methylendioxymethamphetamine) causes long-term changes to the serotonin system in human users.

ecstasy

methylendioxymethamphetamine

serotonin


Input: Previous research has found that amphetamine-abstinent ecstasy users have disrupted visual processing in the occipital lobe which relies on serotonin, with researchers concluding that ecstasy broadens orientation tuning bandwidths.

amphetamine

serotonin

ecstasy


Input: However, other processes may have accounted for these results.


Input: OBJECTIVES: The aim of the present research was to determine if amphetamine-abstinent ecstasy users have changes in occipital lobe functioning, as revealed by two studies: a masking study that directly measured the width of orientation tuning bandwidths and a contour integration task that measured the strength of long-range connections in the visual cortex of drug users compared to controls.

amphetamine

ecstasy


Input: METHOD: Participants were compared on the width of orientation tuning bandwidths (26 controls, 12 ecstasy users, 10 ecstasy + amphetamine users) and the strength of long-range connections (38 controls, 15 ecstasy user, 12 ecstasy + amphetamine users) in the occipital lobe.

ecstasy

ecstasy

amphetamine

ecstasy

ecstasy

amphetamine


Input: RESULTS: Amphetamine-abstinent ecstasy users had significantly broader orientation tuning bandwidths than controls and significantly lower contour detection thresholds (CDTs), indicating worse performance on the task, than both controls and ecstasy + amphetamine users.

Amphetamine

ecstasy

ecstasy

amphetamine


Input: CONCLUSION: These results extend on previous research, which is consistent with the proposal that ecstasy may damage the serotonin system, resulting in behavioral changes on tests of visual perception processes which are thought to reflect serotonergic functions in the occipital lobe.

ecstasy

serotonin


Input: Acquisition of responding with a remifentanil-associated conditioned reinforcer in the rat.

remifentanil


Input: RATIONALE: Drug-associated environmental stimuli may serve as conditioned reinforcers to enhance drug self-administration behaviors in humans and laboratory animals.


Input: However, it can be difficult to distinguish experimentally the conditioned reinforcing effects of a stimulus from other behavioral processes that can change rates of responding.


Input: OBJECTIVES: To characterize the conditioned reinforcing effects of a stimulus paired with the mu-opioid agonist, remifentanil, using a new-response acquisition procedure in the rat.

remifentanil


Input: METHODS: First, in Pavlovian conditioning (PAV) sessions, rats received response-independent IV injections of remifentanil and presentations of a light-noise compound stimulus.

remifentanil


Input: In paired PAV groups, injections and stimulus presentations always co-occurred.


Input: In random PAV control groups, injections and stimulus presentations occurred with no consistent relationship.


Input: Second, in instrumental acquisition (ACQ) sessions, all animals could respond in an active nose-poke that produced the stimulus alone or in an inactive nose-poke that had no scheduled consequences.


Input: RESULTS: During ACQ, rats made significantly more active nose-pokes than inactive nose-pokes after paired PAV, but not after random PAV.


Input: Between groups, rats also made more active nose-pokes after paired PAV than after random PAV.


Input: After paired PAV, increased active responding was obtained under different schedules of reinforcement, persisted across multiple ACQ sessions, and depended on the number of PAV sessions conducted.


Input: CONCLUSIONS: The remifentanil-paired stimulus served as a conditioned reinforcer for nose-poking: responding depended on both the contingency between the stimulus and remifentanil and the contingency between the nose-poke and the stimulus.

remifentanil

remifentanil


Input: Generally, new-response acquisition procedures may provide valid, flexible models for studying opioid-based conditioned reinforcement.


Input: Drugs in Development for Relapsing Multiple Sclerosis.


Input: Drug development for multiple sclerosis (MS), as with any other neurological disease, faces numerous challenges, with many drugs failing at various stages of development.


Input: The disease-modifying therapies (DMTs) first introduced for MS are only moderately effective, but given the lack of competition, they have been widely accepted in clinical practice.


Input: Although safety and efficacy continue to be the two main metrics by which drugs will be judged, the newer agents in the market also face challenges of a more comparative nature-are they more efficacious than the currently available drugs on the market?


Input: Are they safer or better tolerated?


Input: Do they offer any practical advantages over current treatments?


Input: Fingolimod represented a milestone following its approval as an oral drug for MS in 2010, offering patients a far more convenient administration route.

Fingolimod


Input: However, association with cardiovascular complications has led to a more cautious approach in its initial prescribing, now requiring cardiac monitoring for the first 6 h as well as subsequent monitoring of blood pressure and for macular oedema.


Input: Natalizumab, amongst licensed drugs, represents the current benchmark for efficacy.


Input: The risk of progressive multifocal leukoencephalopathy during natalizumab treatment is now more quantifiable.


Input: Other monoclonal antibodies are in various phases of development.


Input: Marketing authorisation for alemtuzumab has been filed, and whilst trial data suggest that its efficacy outperforms both licensed drugs and others in development, there is a significant risk of secondary autoimmunity.


Input: Its once-yearly administration, however, seems particularly advantageous.


Input: Rituximab is unlikely to be developed further as its license will expire, but ocrelizumab, another monoclonal antibody directly targeting B cells, is currently in phase 2 development and looks promising.


Input: Daclizumab is also moderately efficacious but may struggle to establish itself given its monthly subcutaneous dosing.


Input: There are new oral drugs in development, and it is likely that BG-12 will be licensed this year.


Input: This has been licensed for psoriasis so there are good safety data in humans that may also hold true in MS; however, its three times daily dosage will probably impact on patient compliance.


Input: Laquinimod has lower efficacy than BG-12 but appears safe and could find a place as a first-line agent.

Laquinimod


Input: Teriflunomide has just been licensed by the US FDA and may challenge the current injectable first-line therapies as it has a similar efficacy but the advantage of being taken orally.

Teriflunomide


Input: However, risk of teratogenicity may caution against its use in some women of child-bearing potential.


Input: This review will examine drugs that have been recently approved as well as those that are in late phase 2 or 3 development as treatment for relapsing MS, highlighting their mechanism of action as well as the clinical trial and safety data before discussing their potential for success in an increasingly florid and complex DMT armamentarium.


Input: Fluorescent amino acids: modular building blocks for the assembly of new tools for chemical biology.

amino acids


Input: Fluorescence spectroscopy is a powerful tool for probing complex biological processes.


Input: The ubiquity of peptide-protein and protein-protein interactions in these processes has made them important targets for fluorescence labeling, and to allow sensitive readout of information concerning location, interactions with other biomolecules, and macromolecular dynamics.


Input: This review describes recent advances in design, properties and applications in the area of fluorescent amino acids (FlAAs).

amino acids


Input: The ability to site-selectively incorporate fluorescent amino acid building blocks into a protein or peptide of interest provides the advantage of closely retaining native function and appearance.

amino acid


Input: The development of an array of fluorescent amino acids with a variety of properties, such as environment sensitivity, chelation-enhanced fluorescence, and profluorescence, has allowed researchers to gain insights into biological processes, including protein conformational changes, binding events, enzyme activities, and protein trafficking and localization.

amino acids


Input: LIVER X RECEPTORS, NERVOUS SYSTEM AND LIPID METABOLISM.


Input: Lipids in the nervous system are represented by cholesterol and phospholipids as constituents of cell membranes and, in particular, of myelin.

cholesterol


Input: Therefore, lipids are finely regulated to guarantee physiological functions.


Input: In the central nervous system, cholesterol is locally synthesized due to the presence of the blood brain barrier.

cholesterol


Input: In the peripheral nervous system cholesterol is either uptaken by lipoproteins and/or produced by de novo biosynthesis.

cholesterol


Input: Defects in lipid homeostasis in these tissues lead to structural and functional changes that often result in different pathological conditions depending on the affected pathways (i. e. cholesterol biosynthesis, cholesterol efflux, fatty acid biosynthesis etc.).

cholesterol

cholesterol

fatty acid


Input: Alterations in cholesterol metabolism in the central nervous system are linked to several disorders such as Alzheimer' s disease, Huntington disease, Parkinson disease, Multiple Sclerosis, Smith-Lemli-Opitz syndrome, Niemann-Pick type C disease, and glioblastoma.

cholesterol


Input: In the peripheral nervous system changes in lipid metabolism are associated with the development of peripheral neuropathy that may be caused by metabolic disorders, injuries, therapeutics and autoimmune diseases.


Input: Transcription factors, such as the Liver X receptors (LXRs), regulate both cholesterol and fatty acid metabolism in several tissues including the nervous system.

cholesterol

fatty acid


Input: In the last few years several studies elucidated the biology of LXRs in nervous system due to the availability of knock-out mice and the development of synthetic ligands.


Input: Here, we review a survey of the literature focused on central and peripheral nervous system and in physiological and pathological settings with particular attention on the roles played by LXRs in both districts.


Input: In Vitro Evaluation of Combined Sulfated Silk Fibroin Scaffolds for Vascular Cell Growth.


Input: A combined sulfated silk fibroin scaffold is fabricated by modifying a knitted silk scaffold with sulfated silk fibroin sponges.


Input: In vitro hemocompatibility evaluation reveals that the combined sulfated silk fibroin scaffolds reduce platelet adhesion and activation, and prolong the activated partial thromboplastin time (APTT), thrombin time (TT), and prothrombin time (PT).


Input: The response of porcine endothelial cells (ECs) and smooth muscle cells (SMCs) on the scaffolds is studied to evaluate the cytocompatibility of the scaffolds.


Input: Vascular cells are seeded on the scaffolds and cultured for 2 weeks.


Input: The scaffolds demonstrate enhanced EC adhesion, proliferation, and maintenance of cellular functions.


Input: Moreover, the scaffolds inhibit SMC proliferation and induce expression of contractile SMC marker genes.


Input: Resistance to aerobic exercise training causes metabolic dysfunction and reveals novel exercise-regulated signaling networks.


Input: Low aerobic exercise capacity is a risk factor for diabetes and strong predictor of mortality; yet some individuals are " exercise resistant ", and unable to improve exercise capacity through exercise training.


Input: To test the hypothesis that resistance to aerobic exercise training underlies metabolic disease-risk, we used selective breeding for 15 generation to develop rat models of low-and high-aerobic response to training.


Input: Before exercise training, rats selected as low-and high-responders had similar exercise capacities.


Input: However, after 8-wks of treadmill training low-responders failed to improve their exercise capacity, while high-responders improved by 54%.


Input: Remarkably, low-responders to aerobic training exhibited pronounced metabolic dysfunction characterized by insulin resistance and increased adiposity, demonstrating that the " exercise resistant " phenotype segregates with disease risk.


Input: Low-responders had impaired exercise-induced angiogenes0is in muscle; however, mitochondrial capacity was intact and increased normally with exercise training, demonstrating that mitochondria are not limiting for aerobic adaptation or responsible for metabolic dysfunction in low-responders.


Input: Low-responders had increased stress/inflammatory signaling and altered TGF beta signaling, characterized by hyperphosphorylation of a novel exercise-regulated phosphorylation site on SMAD2.


Input: Using this powerful biological model system we have discovered key pathways for low exercise training response that may represent novel targets for the treatment of metabolic disease.


Input: Surface-Passivated SBA-15-Supported Gold Nanoparticles: Highly Improved Catalytic Activity and Selectivity toward Hydrophobic Substrates.


Input: Silanol groups on a silica surface affect the activity of immobilized catalysts because they can influence the hydrophilicity/hydrophobicity, matter transfer, or even transition state in a catalytic reaction.

Silanol

silica


Input: Previously, these silanol groups have usually been passivated by using surface-passivation reagents, such as alkoxysilanes, bis-silylamine reagents, chlorosilanes, etc., and surface passivation has typically been found in mesoporous-silicas-supported molecular catalysts and heteroatomic catalysts.

silanol

alkoxysilanes

bis-silylamine

chlorosilanes


Input: However, this property has rarely been reported in mesoporous-silicas-supported metal-nanoparticle catalysts.


Input: Herein, we prepared an almost-superhydrophobic SBA-15-supported gold-nanoparticle catalyst by using surface passivation, in which the catalytic activity increased more than 14 times for the reduction of nitrobenzene compared with non-passivated SBA-15.

nitrobenzene


Input: In addition, this catalyst can selectively catalyze hydrophobic molecules under our experimental conditions, owing to its high (almost superhydrophobic) hydrophobic properties.


Input: Reactive Metabolite Trapping Studies on Imidazo-and 2-Methylimidazo [2, 1-b] thiazole-based Inverse Agonists of the Ghrelin Receptor.

Imidazo-and 2-Methylimidazo [2, 1-b] thiazole


Input: The current study examined the bioactivation potential of ghrelin receptor inverse agonists, 1-(2-(2-chloro-4-(2H-1, 2, 3-triazol-2-yl) benzyl)-2, 7-diazaspiro [3. 5] nonan-7-yl)-2-(imidazo [2, 1-b] thiazol-6-yl) ethanone (1) and 1-(2-(2-chloro-4-(2H-1, 2, 3-triazol-2-yl) benzyl)-2, 7-diazaspiro [3. 5] nonan-7-yl)-2-(2-methylimidazo [2, 1-b] thiazol-6-yl) ethanone (2), containing a fused imidazo [2, 1-b] thiazole motif in the core structure.

1-(2-(2-chloro-4-(2H-1, 2, 3-triazol-2-yl) benzyl)-2, 7-diazaspiro [3. 5] nonan-7-yl)-2-(imidazo [2, 1-b] thiazol-6-yl) ethanone

1-(2-(2-chloro-4-(2H-1, 2, 3-triazol-2-yl) benzyl)-2, 7-diazaspiro [3. 5] nonan-7-yl)-2-(2-methylimidazo [2, 1-b] thiazol-6-yl) ethanone

imidazo [2, 1-b] thiazole


Input: Both compounds underwent oxidative metabolism in NADPH-and glutathione-supplemented human liver microsomes to yield glutathione conjugates, which was consistent with their bioactivation to reactive species.

NADPH

glutathione

glutathione


Input: Mass spectral fragmentation and NMR analysis indicated that the site of attachment of the glutathionyl moiety in the thiol conjugates was on the thiazole ring within the bicycle.

glutathionyl

thiol

thiazole


Input: Two glutathione conjugates were discerned with the imidazo [2, 1-b] thiazole derivative 1.

glutathione

imidazo [2, 1-b] thiazole


Input: One adduct was derived from the Michael addition of glutathione to a putative S-oxide metabolite of 1, whereas, the second adduct was formed via the reaction of a second glutathione molecule with the initial glutathione-S-oxide adduct.

glutathione

S-oxide

glutathione

glutathione-S-oxide


Input: In the case of the 2-methylimidazo [2, 1-b] thiazole analog 2, glutathione conjugation occurred via an oxidative desulfation mechanism, possibly involving thiazole ring epoxidation as the rate-limiting step.

2-methylimidazo [2, 1-b] thiazole

glutathione

thiazole


Input: Additional insights into the mechanism were obtained via 18O exchange and trapping studies with potassium cyanide.

potassium cyanide


Input: The mechanistic insights into the bioactivation pathways of 1 and 2 allowed the deployment of a rational chemical intervention strategy that involved replacement of the thiazole ring with a 1, 2, 4-thiadiazole group to yield-(2-(2-chloro-4-(2H-1, 2, 3-triazol-2-yl) benzyl)-2, 7-diazaspiro [3. 5] nonan-7-yl)-2-(2-methylimidazo [2, 1-b] [1, 3, 4] thiadiazol-6-yl) ethanone (3).

thiazole

1, 2, 4-thiadiazole

-(2-(2-chloro-4-(2H-1, 2, 3-triazol-2-yl) benzyl)-2, 7-diazaspiro [3. 5] nonan-7-yl)-2-(2-methylimidazo [2, 1-b] [1, 3, 4] thiadiazol-6-yl) ethanone


Input: These structural changes not only abrogated the bioactivation liability but also retained the attractive pharmacological attributes of the prototype agents.


Input: Rnf165/Ark2C Enhances BMP-Smad Signaling to Mediate Motor Axon Extension.


Input: Little is known about extrinsic signals required for the advancement of motor neuron (MN) axons, which extend over long distances in the periphery to form precise connections with target muscles.


Input: Here we present that Rnf165 (Arkadia-like; Arkadia2; Ark2C) is expressed specifically in the nervous system and that its loss in mice causes motor innervation defects that originate during development and lead to wasting and death before weaning.


Input: The defects range from severe reduction of motor axon extension as observed in the dorsal forelimb to shortening of presynaptic branches of the phrenic nerve, as observed in the diaphragm.


Input: Molecular functional analysis showed that in the context of the spinal cord Ark2C enhances transcriptional responses of the Smad1/5/8 effectors, which are activated (phosphorylated) downstream of Bone Morphogenetic Protein (BMP) signals.


Input: Consistent with Ark2C-modulated BMP signaling influencing motor axons, motor pools in the spinal cord were found to harbor phosphorylated Smad1/5/8 (pSmad) and treatment of primary MN with BMP inhibitor diminished axon length.


Input: In addition, genetic reduction of BMP-Smad signaling in Ark2C (+/-) mice caused the emergence of Ark2C (-/-)-like dorsal forelimb innervation deficits confirming that enhancement of BMP-Smad responses by Ark2C mediates efficient innervation.


Input: Together the above data reveal an involvement of BMP-Smad signaling in motor axon advancement.


Input: D-Glucose hydrogenation over Ru Nanoparticles Embedded in Mesoporous Hypercrosslinked Polystyrene.

D-Glucose

Ru

Polystyrene


Input: The kinetics of D-glucose hydrogenation on the catalyst containing Ru nanoparticles in the matrix of hypercrosslinked polystyrene was studied.

D-glucose

Ru

polystyrene


Input: Two routes of the hydrogenation reaction were revealed, their rates differ by several digits.


Input: The first route includes the interaction of D-glucose with the spilled-over hydrogen supplied by the catalyst; the second one includes classical interaction of the sorbed substrate with incident hydrogen from the reaction medium.

D-glucose

hydrogen

hydrogen


Input: Mathematical description of D-glucose conversion and the change of the catalyst activity by the fist way of D-glucose hydrogenation were obtained.

D-glucose

D-glucose


Input: The most probable scheme of the process flow was suggested.


Input: The main kinetic parameters were calculated.


Input: The role of hydrogen spillover phenomenon in the kinetics of the processes is discussed.

hydrogen


Input: Preliminary Structure-Activity Relationships and Biological Evaluation of Novel Antitubercular Indolecarboxamide Derivatives Against Drug-Susceptible and Drug-Resistant Mycobacterium tuberculosis Strains.

Indolecarboxamide


Input: Tuberculosis (TB) remains one of the leading causes of mortality and morbidity worldwide, with approximately one-third of the world' s population infected with latent TB.


Input: This is further aggravated by HIV coinfection and the emergence of multidrug-and extensively drug-resistant (MDR and XDR, respectively) TB; hence the quest for highly effective antitubercular drugs with novel modes of action is imperative.


Input: We report herein the discovery of an indole-2-carboxamide analogue, 3, as a highly potent antitubercular agent, and the subsequent chemical modifications aimed at establishing a preliminary body of structure-activity relationships (SARs).


Input: These efforts led to the identification of three molecules (12-14) possessing an exceptional activity in the low nanomolar range against actively replicating Mycobacterium tuberculosis, with minimum inhibitory concentration (MIC) values lower than those of the most prominent antitubercular agents currently in use.


Input: These compounds were also devoid of apparent toxicity to Vero cells.


Input: Importantly, compound 12 was found to be active against the tested XDR-TB strains and orally active in the serum inhibition titration assay.


Input: Reaction between peroxynitrite and triphenylphosphonium-substituted arylboronic acid isomers-Identification of diagnostic marker products and biological implications.

peroxynitrite

triphenylphosphonium-substituted arylboronic acid


Input: </i > Aromatic boronic acids react rapidly with peroxynitrite (ONOO < sup >-</sup >) to yield phenols as major products.

Aromatic boronic acids

peroxynitrite

ONOO < sup >-</sup >

phenols


Input: This reaction was used to monitor ONOO < sup >-</sup > formation in cellular systems.

ONOO < sup >-</sup >


Input: Previously, we proposed that the reaction between ONOO - and arylboronates (PhB (OH)  2 ) yields a phenolic product (major pathway) and a radical pair PhB (OH)  2  O  *- ...  *  NO  2  (minor pathway).

ONOO < sup >-</sup >

arylboronates

PhB (OH) < sub > 2 </sub >

phenolic

PhB (OH) < sub > 2 </sub > O < sup > *-</sup >

< sup > * </sup > NO < sub > 2 </sub >


Input: [Sikora A. < i > et al., Chem Res Toxicol </i > 24, 687-97].


Input: In this study, we investigated the influence of a bulky triphenylphosphonium (TPP) group on the reaction between ONOO < sup >-</sup > and mitochondria-targeted arylboronate isomers (< i > o </i >-, < i > m </i >-, and < i > p </i >-MitoPhB (OH) < sub > 2 </sub >).

triphenylphosphonium

TPP

ONOO < sup >-</sup >

arylboronate

< i > o </i >-, < i > m </i >-, and < i > p </i >-MitoPhB (OH) < sub > 2 </sub >


Input: Results from the electron paramagnetic resonance (EPR) spin-trapping experiments unequivocally showed the presence of a phenyl radical intermediate from < i > meta </i > and < i > para </i > isomers, and not from the < i > ortho </i > isomer.

phenyl


Input: The yield of  o -MitoPhNO  2  formed from the reaction between  o -MitoPhB (OH)  2  and ONOO - was not diminished by phenyl radical scavengers, suggesting a rapid fragmentation of the  o -MitoPhB (OH)  2  O  *- radical anion with subsequent reaction of the resulting phenyl radical with  *  NO  2  in the solvent cage.

< i > o </i >-MitoPhNO < sub > 2 </sub >

< i > o </i >-MitoPhB (OH) < sub > 2 </sub >

ONOO < sup >-</sup >

phenyl

< i > o </i >-MitoPhB (OH) < sub > 2 </sub > O < sup > *-</sup >

phenyl

< sup > * </sup > NO < sub > 2 </sub >


Input: The DFT quantum mechanical calculations showed that the energy barrier for the dissociation of  o -MitoPhB (OH)  2  O  *- radical anion is significantly lower than that of  m -MitoPhB (OH)  2  O  *- and  p -MitoPhB (OH)  2  O  *- radical anions.

< i > o </i >-MitoPhB (OH) < sub > 2 </sub > O < sup > *-</sup >

< i > m </i >-MitoPhB (OH) < sub > 2 </sub > O < sup > *-</sup >

< i > p </i >-MitoPhB (OH) < sub > 2 </sub > O < sup > *-</sup >


Input: We conclude that the reaction of ONOO - with  ortho -MitoPhB (OH)  2  forming the minor nitrated product,  o -MitoPhNO  2 , and the corresponding major phenolic product ( o -MitoPhOH) can be employed as a diagnostic tool to specifically detect ONOO - in biological systems.

ONOO < sup >-</sup >

< i > ortho </i >-MitoPhB (OH) < sub > 2 </sub >

< i > o </i >-MitoPhNO < sub > 2 </sub >

phenolic

< i > o </i >-MitoPhOH

ONOO < sup >-</sup >


Input: Links between obesity, diabetes and ethnic disparities in breast cancer among Hispanic populations.


Input: Breast cancer is the most prevalent malignancy in women worldwide and is a growing concern due to rising incidence and ongoing ethnic disparities in both incidence and mortality.


Input: A number of factors likely contribute to these trends including rising rates of obesity and diabetes across the globe and differences in genetic predisposition.


Input: Here, we emphasize Hispanic populations and summarize what is currently known about obesity, diabetes and individual genetic predisposition as they relate to ethnic disparities in breast cancer incidence and mortality.


Input: In addition, we discuss potential contributions to breast cancer aetiology from molecular mechanisms associated with obesity and diabetes including dyslipidemia, hyperglycaemia, hyperinsulinaemia, endocrine dysfunction and inflammation.


Input: We propose that unique differences in diet and lifestyle coupled with individual genetic predisposition and endocrine/immune dysfunction explain most of the ethnic disparities seen in breast cancer incidence and mortality.


Input: Cross-Sectional Tracking of Particle Motion in Evaporating Drops: Flow Fields and Interfacial Accumulation.


Input: The lack of an effective technique for three-dimensional flow visualization has limited the experimental exploration of the " coffee ring effect " to the two dimensional, top-down viewpoint.


Input: In this report, high-speed, cross-sectional imaging of the flow fields was obtained by using optical coherence tomography to track particle motion in an evaporating colloidal water drop.


Input: This approach enables z-dimensional mapping of primary and secondary flow fields and changes in these fields over time.


Input: These sectional images show that 1 mu m diameter polystyrene particles have a highly non-uniform vertical distribution with particles accumulating at both the air-water interface and water-glass interface during drop evaporation.

polystyrene


Input: Particle density and relative humidity are shown to influence interfacial entrapment, which suggests that both sedimentation rate and evaporation rate affect the dynamic changes in the cross-sectional distribution of particles.


Input: Furthermore, entrapment at the air-water interface delays the time at which particles reach the ring structure.


Input: These results suggest that the organization of the ring structure can be controlled based on the ratio of different density particles in a colloidal solution.


Input: Toward the Molecular Mechanism (s) by Which EGCG Treatment Remodels Mature Amyloid Fibrils.

EGCG


Input: Protein misfolding and/or aggregation has been implicated as the cause of several human diseases, such as Alzheimer' s and Parkinson' s diseases and familial amyloid polyneuropathy.


Input: These maladies are referred to as amyloid diseases, named after the cross-beta-sheet amyloid fibril aggregates or deposits common to these disorders.


Input: Epigallocatechin-3-gallate (EGCG), the principal polyphenol present in green tea, has been shown to be effective at preventing aggregation and is able to remodel amyloid fibrils comprising different amyloidogenic proteins, although the mechanistic underpinnings are unclear.

EGCG

polyphenol


Input: Herein, we work toward an understanding of the molecular mechanism (s) by which EGCG remodels mature amyloid fibrils made up of A beta 1-40, IAPP8-24, or Sup35NM7-16.

EGCG


Input: We show that EGCG amyloid remodeling activity in vitro is dependent on auto-oxidation of the EGCG.

EGCG

EGCG


Input: Oxidized and unoxidized EGCG binds to amyloid fibrils, preventing the binding of thioflavin T.

EGCG

thioflavin T


Input: This engagement of the hydrophobic binding sites in A beta 1-40, IAPP8-24, or Sup35NMAc7-16 Y --> F amyloid fibrils seems to be sufficient to explain the majority of the amyloid remodeling observed by EGCG treatment, although how EGCG oxidation drives remodeling remains unclear.

EGCG

EGCG


Input: Oxidized EGCG molecules react with free amines within the amyloid fibril through the formation of Schiff bases, cross-linking the fibrils, which may prevent dissociation and toxicity, but these aberrant post-translational modifications do not appear to be the major driving force for amyloid remodeling by EGCG treatment.

EGCG

amines

Schiff bases

EGCG


Input: These insights into the molecular mechanism of action of EGCG provide boundary conditions for exploring amyloid remodeling in more detail.

EGCG


Input: Human UGT2B10 in Drug N-glucuronidations: Substrate Screening and Comparison with UGT1A3 and UGT1A4.


Input: Recent observations revealed that human UDP-glucuronosyltransferase (UGT) 2B10 catalyzes N-glucuronidation of amine-containing compounds.

UDP

amine


Input: Knowledge of the substrate specificity and clinical significance of UGT2B10 is still limited.


Input: The purpose of this study was to expand the knowledge of UGT2B10 substrates and to evaluate its significance in drug clearance.


Input: Using recombinant UGT2B10, we found that it catalyzes the N-glucuronidation of amitriptyline, imipramine, ketotifen, pizotifen, olanzapine, diphenhydramine, tamoxifen, ketoconazole and midazolam.

amitriptyline

imipramine

ketotifen

pizotifen

olanzapine

diphenhydramine

tamoxifen

ketoconazole

midazolam


Input: These are drugs that were previously reported to be substrates for UGT1A4 or UGT1A3 and that contain in their structure either tertiary aliphatic amines, cyclic amines, or an imidazole group.

tertiary aliphatic amines

cyclic amines

imidazole


Input: UGT2B10 was inactive in the glucuronidation of desipramine, nortriptyline, carbamazepine and afloqualone.

desipramine

nortriptyline

carbamazepine

afloqualone


Input: This group of drugs contains secondary or primary amines, and these results suggest that UGT2B10 preferably conjugates tertiary amines.

secondary or primary amines

tertiary amines


Input: This preference is partial because UGT2B10 did not conjugate the tertiary cyclic amine in trifluoperazine.

tertiary cyclic amine

trifluoperazine


Input: Kinetic analyses revealed that the affinity and clearance of UGT2B10 for amitriptyline, imipramine, and diphenhydramine are significantly higher than the corresponding values of UGT1A4 and UGT1A3, although the Vmax values of UGT1A4 toward these drugs are considerably higher.

amitriptyline

imipramine

diphenhydramine


Input: These findings suggest that UGT2B10 plays a major role in the N-glucuronidation of these drugs at therapeutic concentrations.


Input: These results are also supported by inhibition studies with nicotine and hecogenin.

nicotine

hecogenin


Input: In conclusion, this study expands the understanding of the substrate specificity of UGT2B10, highlighting its preference for tertiary amines with higher affinities and clearance values than those of UGT1A4 and UGT1A3.

tertiary amines


Input: Transcriptional and catalytic responses of antioxidant and biotransformation pathways in mussels, Mytilus galloprovincialis, exposed to chemical mixtures.


Input: Antioxidant and biotransformation pathways are widely studied in marine organisms exposed to environmental stressors.


Input: However, mechanisms of responses and links between different intracellular levels are not always easy to elucidate and conflicting results are frequently observed between molecular and enzymatic data.


Input: In this study, transcriptional and catalytic responses of antioxidant and biotransformation parameters were analyzed after a 4-week exposure of a marine invertebrate, Mytilus galloprovincialis, to chemical mixtures from low polluted and highly polluted sediments.


Input: A significant, dose-dependent bioaccumulation was observed for polycyclic aromatic hydrocarbons, especially low molecular weight compounds.

polycyclic aromatic hydrocarbons


Input: Among antioxidant defences, catalase and glutathione peroxidases did not exhibit variations in enzymatic activity, while the corresponding gene transcriptions were up-and down-regulated, respectively; unchanged mRNA levels of superoxide dismutase confirmed the non-synchronous pathways of variations for such antioxidants.

glutathione

superoxide


Input: Biotransformation responses also revealed inconsistent trends between transcriptional and catalytic variations of glutathione S-transferases, and a significant increase in mRNA levels for cytochrome P450 3A1.

glutathione S


Input: The overall results indicated that transcriptional responses might be sensitive but do not necessarily correspond to functional changes, being more useful as " exposure " rather than " effect " biomarkers.


Input: Data on gene transcription and catalytic activities should be carefully interpreted when assessing the impact of chemical pollutants and additional studies are needed on modulation of post-transcriptional mechanisms by environmental stressors.


Input: Traditional and alternative natural therapeutic products used in the treatment of respiratory tract infectious diseases in the eastern Catalan Pyrenees (Iberian Peninsula).


Input: ETHNOPHARMACOLOGICAL RELEVANCE: Respiratory tract diseases, including mild troubles, such as the common cold, and also life-threatening ones such as bacterial pneumonia and lung cancer, are very important in terms of mortality, incidence, prevalence and costs.


Input: Classical medicine has undoubtedly addressed these illnesses, but the body of knowledge generated by alternative approaches, among which folk medicine plays an important role, is not at all negligible.


Input: AIMS OF THE STUDY: In this context, we performed an ethnobotanical study in a Catalan region of the eastern Pyrenees, northeast Iberian Peninsula, in order to assess the popular knowledge on useful plants.


Input: We present here the data concerning pharmaceutical uses of plants devoted to respiratory illnesses.


Input: METHODOLOGY: A total of 160 informants (94 women and 66 men, born between 1915 and 1988) were interviewed during 102 semi-structured interviews.


Input: Voucher specimens were collected, and then processed and deposited in the herbarium BCN.


Input: RESULTS: We collected information about 99 plant taxa (94 species-some of them with subspecies-of 85 genera belonging to 50 families) popularly employed to prevent or treat respiratory troubles.


Input: The degree of reliability of uses is high, as indicated for instance by an informant consensus factor of 0. 83 and by high medicinal importance indexes for many taxa.


Input: In addition, we have recorded information on 14 animal and four mineral products also used against respiratory ailments, this constituting the first ethnopharmacological work in the Catalan linguistic area to report plant, animal and mineral remedies, and one of the very few in the Iberian Peninsula involving the study of ethnozoological medicines.


Input: CONCLUSIONS: The data collected show a high degree of consistency and indicate a remarkable persistence of folk knowledge on plant uses.


Input: The anticatarrhal, antitussive and for sore throat are the most valuable uses.


Input: This research could be the starting point for further research aiming to obtain products that may generalise the alternative medical uses here raised at a local level.


Input: Phytochemical and pharmacological studies on some of the plants quoted here-of which we could provide material to potentially interested researchers-would be useful first steps in this process.


Input: Urinary metabonomic study of the surface layer of poria cocos as an effective treatment for chronic renal injury in rats.


Input: ETHNOPHARMACOLOGICAL RELEVANCE: Poria cocos Wolf (Polyporaceae) is a well-known medicinal fungus. the epidermis of the sclerotia (" Fu-Ling-Pi " in Chinese) is used as a diuretic and traditionally used for promoting urination and reduce edema.


Input: AIM OF THE STUDY: Traditional Chinese medicines (TCM) treat many diseases through multi-components, multi-ways and multi-targets.


Input: However, the molecular mechanisms of TCM are not yet well understood.


Input: In the present work, ultra performance liquid chromatography-based metabonomics analysis was applied to investigate the urinary metabolite profiling of the renoprotective effect of FLP on adenine-induced chronic kidney disease (CKD) rat model and involved possible mechanism.

adenine


Input: MATERIAL AND METHODS: A metabonomic approach based on ultra performance liquid chromatography coupled with quadrupole time-of-flight high-sensitivity mass spectrometry and a novel mass spectrometry (Elevated Energy) data collection technique was developed.


Input: The resulting dataset was analyzed by principal component analysis and partial least squares discriminant analysis.


Input: The identification of all potential biomarkers was performed using reference standard by comparing their mass spectra, MS (E) fragments information, isotopic pattern and MassLynx i-FIT algorithm.


Input: RESULTS: By partial least squares-discriminate analysis analyses, 15 biomarkers in rat urine were identified and 11 of them were related to the pathway of adenine metabolism and amino acid metabolism.

adenine

amino acid


Input: Among these biomarkers, eight biomarkers like adenine, L-acetylcarnitine, 8-hydroxyadenine, hypoxanthine, creatine, methionine, phytosphingosine and phenylalanine were reversed to the control level in FLP-treated groups and six biomarkers like 2, 8-dihydroxyadenine, indole-3-carboxylic acid, 3-methyldioxyindole, ethyl-N2-acetyl-L-argininate, 3-O-methyldopa and xanthurenic acid were reversed to high normal group by FLP, which indicates that the urinary metabolic pattern significantly changed after FLP treatment.

adenine

L-acetylcarnitine

hypoxanthine

creatine

methionine

phytosphingosine

phenylalanine

2, 8-dihydroxyadenine

indole-3-carboxylic acid

3-methyldioxyindole, ethyl-N2-acetyl-L-argininate, 3-O-methyldopa

xanthurenic acid


Input: CONCLUSIONS: Our study indicates that FLP treatment can ameliorate CKD by intervening in some dominating metabolic pathways, such as adenine metabolism and amino acid metabolism.

adenine

amino acid


Input: The metabonomic results not only supplied a systematic view of the development and progression of CKD and mechanism studies of FLP but also provided the theoretical basis for the prevention or treatment of CKD.


Input: Gastroprotective mechanism of Bauhinia thonningii Schum.


Input: ETHNOPHARMACOLOGICAL RELEVANCE: Bauhinia thonningii Schum.


Input: (Cesalpiniaceae) is locally known as Tambarib and used to treat various diseases including gastric ulcer.


Input: AIM OF THE STUDY: The current study aims to evaluate the gastroprotecive mechanism (s) of methanolic (MEBT) and chloroform (CEBT) extracts of Bauhinia thonningii leaves on ethanol-induced gastric ulceration.

chloroform

ethanol


Input: MATERIALS AND METHODS: Gastric acidity, quantification and histochemistry of mucus, gross and microscopic examination, nitric oxide, lipid peroxidation, 2D gel electrophoresis, mass spectroscopy and biochemical tests were utilized to assess the mechanism (s) underlying the gastroprotective effects of MEBT and CEBT.

nitric oxide


Input: Effect of these extracts into lipopolysaccharide/interferon-gamma stimulated rodent cells were done in vitro.


Input: In vitro and in vivo toxicity studies were also conducted.


Input: Antioxidant activities of MEBT and CEBT were examined using DPPH, FRAP and ORAC assays.

DPPH


Input: Phytochemical analyses of MEBT and CEBT were conducted using chemical and spectroscopic methods.


Input: RESULTS: Gross and histological features confirmed the anti-ulcerogenic properties of Bauhinia thonningii.


Input: Gastroprotective mechanism of MEBT was observed to be mediated through the modulation of PAS-reactive substances, MDA and proteomics biomarkers (creatine kinase, malate dehydrogenase, ATP synthase, actin and thioredoxin).

MDA

creatine

malate

ATP


Input: MEBT and CEBT showed no significant in vitro and in vivo effects on nitric oxide.

nitric oxide


Input: Methanolic extract (MEBT) showed superior gastroprotective effects, polyphenolic content and antioxidant activities compared to CEBT.


Input: The plant extracts showed no in vitro or in vivo toxicity.


Input: CONCLUSION: It could be concluded that MEBT possesses anti-ulcer activity, which could be attributed to the inhibition of ethanol-induced oxidative damage and the intervention in proteomic pathways but not the nitric oxide pathway.

ethanol

nitric oxide


Input: Sphingosine-1-phosphate promotes the nuclear translocation of beta-catenin and thereby induces osteoprotegerin gene expression in osteoblast-like cell lines.


Input: Sphingosine-1-phosphate (S1P) is a well-known signaling sphingolipid and bioactive lipid mediator.

sphingolipid


Input: Recently, it was reported that S1P inhibits osteoclast differentiation and bone resorption.


Input: On the other hand, S1P effects on osteoblasts and bone formation are little known.


Input: In this study, we investigated the effects of S1P on osteoblasts, using two osteoblast-like cell lines, SaOS-2 and MC3T3-E1.


Input: S1P activated phosphatidylinositol 3-kinase (PI3K)/Akt signaling, leading to the inhibition of glycogen synthase kinase-3 beta and the nuclear translocation of beta-catenin, followed by the increase of the transcriptional activity by beta-catenin/T-cell factor complex formation in both SaOS-2 cells and MC3T3-E1 cells.

phosphatidylinositol


Input: The inhibitors of PI3K and Akt suppressed S1P-induced nuclear localization of beta-catenin.


Input: We further investigated the effects of PI3K/Akt signaling on the Wnt/beta-catenin signaling pathway, since beta-catenin takes a central role in this signaling pathway.


Input: Both inhibitors for PI3K and Akt suppressed the nuclear localization of beta-catenin and T-cell factor transcriptional activity induced by Wnt-3a.


Input: S1P increased the amount of osteoprotegerin at both mRNA and protein levels, and increased the activity of alkaline phosphatase, leading to the mineralization.


Input: These findings suggest that S1P activates the PI3K/Akt signaling pathway leading to the promotion of nuclear translocation of beta-catenin in osteoblast-like cells, resulting in the upregulation of osteoptotegerin and osteoblast differentiation markers including alkaline phosphatase, probably relating to the inhibition of osteoclast formation and the mineralization, respectively.


Input: Noncanonical NF-kappa B Activation by the Oncoprotein Tio Occurs Through a Nonconserved TRAF3-Binding Motif.


Input: Members of the nuclear factor kappa B (NF-kappa B) family of transcription factors regulate many cellular functions.


Input: Activation of NF-kappa B signaling is commonly classified as occurring through canonical or noncanonical pathways.


Input: Most NF-kappa B-inducing stimuli, including the viral oncoprotein Tio, lead to a concerted activation of both NF-kappa B pathways; however, extensive crosstalk at multiple levels between these signaling cascades restricts the ability to discriminate between the canonical and the noncanonical effects.


Input: We showed that noncanonical NF-kappa B activation by Tio depends on a distinct sequence motif that directly recruits tumor necrosis factor receptor-associated factor 3 (TRAF3).


Input: Through its TRAF3-binding motif, Tio triggered a ubiquitin-independent depletion of TRAF3 from the cytosol, which prevented TRAF3 from inhibiting signaling through the noncanonical NF-kappa B cascade.


Input: Furthermore, the Tio-TRAF3 interaction did not affect components of the canonical NF-kappa B signaling pathway or the expression of target genes; thus, Tio induced noncanonical NF-kappa B independently of crosstalk with the canonical pathway.


Input: Together, these data identify a distinct molecular mechanism of noncanonical NF-kappa B activation that should enable studies into the particular functions of this pathway.


Input: Signaling mechanisms in Mammalian myoblast fusion.


Input: Myoblast fusion is a critical process that contributes to the growth of muscle during development and to the regeneration of myofibers upon injury.


Input: Myoblasts fuse with each other as well as with multinucleated myotubes to enlarge the myofiber.


Input: Initial studies demonstrated that myoblast fusion requires extracellular calcium and changes in cell membrane topography and cytoskeletal organization.

calcium


Input: More recent studies have identified several cell-surface and intracellular proteins that mediate myoblast fusion.


Input: Furthermore, emerging evidence suggests that myoblast fusion is also regulated by the activation of specific cell-signaling pathways that lead to the expression of genes whose products are essential for the fusion process and for modulating the activity of molecules that are involved in cytoskeletal rearrangement.


Input: Here, we review the roles of the major signaling pathways in mammalian myoblast fusion.