Input: The nanogels did have an influential role, in that modulation of DC functional activity owed more to the nanogel structure.


Input: Using an in vitro restimulation assay with ova-specific lymphocytes, nanogel-delivered and free ova were similarly effective at inducing specific antibody.


Input: Nanogel-delivered ova with mannose surface decoration was superior to free ova for inducing interferon-gamma production by T-lymphocytes.

mannose


Input: Together, the data demonstrates that particle-based vaccine delivery should consider the influences of both the surface decoration and the vaccine cargo; each can influence different aspects of the interaction with DCs.


Input: Such combined influences are likely to impinge on the characteristics of the immune response induced.


Input: Treating epilepsy in Italy between XIX and XX century.


Input: Epilepsy is a neurological disorder which has been recognized since antiquity.


Input: This paper evaluates the prophylactic and therapeutic remedies used by folk medicine to cure epilepsy in Italy.


Input: The data has been collected by reviewing written sources of physicians, ethnographers, folklorists between the late nineteenth and mid twentieth century.


Input: This approach leads to unearthing of 78 heterogeneous healing methods that have been divided into 16 (20%) magical, 20 (26%) religious and 42 (54%) natural remedies.


Input: The latter has been subdivided into 18 (43%) animal remedies, 17 (40%) plant remedies and 7 (17%) other remedies.


Input: Religious and magical remedies were used with the conviction that they would be able to provide recovery from epilepsy and to ward off evil spirits which had taken possession of the sick.


Input: Interestingly, the herbal remedies highlighted 12 (70%) plants that play or might play an important role with respect to the mechanisms that generate the epileptic seizures.


Input: This leads us to reconsider the historical significance of folk medicine, too often it is underestimated owing to its use of ineffective remedies, born of incompetence and superstition.


Input: Food reward-sensitive interaction of ghrelin and opioid receptor pathways in mesolimbic dopamine system.

dopamine


Input: Ghrelin is a stomach-derived orexigenic peptide.


Input: The goal of the study was to investigate the roles of mu and kappa opioid receptors in systemic ghrelin-mediated regulation of the mesolimbic dopamine system.

dopamine


Input: To evaluate the interaction of systemic ghrelin with values of food reward, rats were exposed to food removal, regular food or palatable food after systemic ghrelin administration.


Input: Extracellular dopamine levels were quantified in the nucleus accumbens (NAc) and receptor-specific compounds were infused into the ventral tegmental area (VTA) using dual-probe microdialysis.

dopamine


Input: Consumption of regular or palatable food without systemic ghrelin administration induced an increase in dopamine levels in the NAc via activation of mu opioid receptors in the VTA.

dopamine


Input: Systemic ghrelin administration (3 nmol, i. v.) followed by no food induced a decrease in dopamine levels via activation of kappa opioid receptors in the VTA.

dopamine


Input: Systemic ghrelin administration followed by consumption of regular food induced an increase in dopamine levels via preferential activation of mu opioid receptors, whereas systemic ghrelin administration followed by consumption of palatable food suppressed the increase in dopamine levels via preferential activation of kappa opioid receptors.

dopamine

dopamine


Input: Thus, natural food reward and systemic ghrelin activate mu and kappa opioid receptor pathways in the VTA, respectively, resulting in opposite influences on dopamine release in the NAc.

dopamine


Input: Furthermore, systemic ghrelin induces switching of the dominant opioid receptor pathway for highly rewarding food from mu to kappa, resulting in suppression of the mesolimbic dopamine system.

dopamine


Input: These novel findings might provide insights into the neural pathways involved in eating disorders.


Input: Characterisation of an mGlu8 receptor-selective agonist and antagonist in the lateral and medial perforant path inputs to the dentate gyrus.


Input: Since its characterisation in 2001, the mGlu8-selective agonist DCPG has been widely used to explore the potential functional role of this group III mGlu receptor within the central nervous system.

DCPG


Input: This research has implicated mGlu8 receptors in a number of disease states and conditions such as epilepsy and anxiety, suggesting that mGlu8-selective ligands may hold important therapeutic potential.


Input: However, there is evidence that DCPG exerts off-target effects at higher concentrations, limiting its use as an mGlu8-selective agonist.

DCPG


Input: Here, we have used field recordings in rat hippocampal slices to investigate the effects of DCPG in the lateral perforant path (LPP), a pathway known to express high levels of mGlu8.

DCPG


Input: We show that DCPG does inhibit excitatory transmission in this pathway, but produces a biphasic concentration-response curve suggesting activation of two distinct receptor types.

DCPG


Input: The putative mGlu8-selective antagonist MDCPG antagonises the high, but not the low, potency component of this concentration-response curve.

MDCPG


Input: In addition, higher concentrations of DCPG also depress excitatory transmission in the medial perforant path (MPP), a pathway expressing very low levels of mGlu8 receptors.

DCPG


Input: Experiments in slices from mice lacking mGlu8 receptors indicate that concentrations of DCPG > 1 mu M produce large non-selective effects in both the LPP and MPP.

DCPG


Input: Further experiments in slices from mGlu2, 4 and 7 knock-out mice, as well as in an mGlu2-deficient substrain of Wistar rat, reveal that these non-selective effects are mediated primarily by mGlu2 receptors.


Input: Taken together, our results confirm the mGlu8-selectivity of DCPG at submicromolar concentrations, but suggest that care must be taken when employing higher concentrations of the agonist, which may additionally activate mGlu2 receptors, especially at synapses where their expression is high.

DCPG


Input: MDCPG may be a useful tool in determining whether observable DCPG effects are attributable to mGlu8, versus mGlu2, receptor activation.

MDCPG

DCPG


Input: Organochlorines and metals induce changes in the mitochondria-rich cells of fish gills: an integrative field study involving chemical, biochemical and morphological analyses.

Organochlorines


Input: Through integrating chemical, biochemical and morphological analyses, this study investigated the effects of multiple pollutants on the gill mitochondria-rich cells (MRCs) in two fish species, Astyanax fasciatus and Pimelodus maculatus, collected from five sites (FU10, FU20, FU30, FU40 and FU50) in the Furnas Hydroelectric Power Station reservoir.


Input: Water analyses revealed aluminum, iron and zinc as well as organochlorine (aldrin/dieldrin, endosulfan, heptachlor/heptachlor epoxide and metolachlor) contamination at all of the sites, with the exception of FU10.

aluminum

iron

zinc

organochlorine

aldrin

dieldrin

endosulfan

heptachlor

heptachlor epoxide

metolachlor


Input: Copper, chrome, iron and zinc were detected in the gills of both species, and aldrin/dieldrin, endosulfan and heptachlor/heptachlor epoxide were detected in the gills of fish from all of the sites, with the exception of FU10.

Copper

chrome

iron

zinc

aldrin

dieldrin

endosulfan

heptachlor

heptachlor epoxide


Input: Fish collected at FU20, FU30 and FU50 exhibited numerous alterations in the surface architecture of their pavement cells and MRCs.


Input: The surface MRC density and MRC fractional area were lower in fish from FU20, FU30, FU40 and FU50 than in those from the reference site (FU10) in the winter, and some variability between the sites was observed in the summer.


Input: The organochlorine contamination at FU20 and FU50 was associated with variable changes in the MRCs and inhibition of Na (+)/K (+)-ATPase (NKA) activity, especially in P. maculatus.

organochlorine

Na (+)

K (+)


Input: At FU30, the alterations in the MRCs were associated with the contaminants present, especially metals.


Input: A multivariate analysis demonstrated a positive association between the biological responses of both species and environmental contamination, indicating that under realistic conditions, a mixture of organochlorines and metals affected the MRCs by inhibiting NKA activity and inducing morphological changes, which may cause an ionic imbalance.

organochlorines


Input: Identification and discrimination of snake venoms from Egyptian elapids.


Input: The avidity to the corresponding antigens is often higher than to the cross-reactive antigens.


Input: This was demonstrated with the highly cross-reactive elapid Egyptian snake venoms Naja haje (Nh), Naja nigricollis (Nn) and Walterinnesia aegyptia (Wa), and used for the differentiation among the three species in a simple ELISA-based assay.


Input: A three-step immuno-affinity protocol was followed and the titer and avidity of the different antibody (Ab) preparations were assessed and evaluated.


Input: The advantages offered by the avidity power of the venom specific antibodies (VS-Abs) obtained after one step purification, outweigh the specificity of the species-specific antibodies (SS-Abs) obtained after further purification.


Input: The efficiency of the VS-Abs as special immunodiagnostics was validated using 16 venom samples collected from individual snakes of different size and age at different time intervals.


Input: The avidities of the VS-Abs to the homologous venoms were 2. 53 +/- 0. 4, 2. 66 +/- 0. 31 and 2. 8 +/- 0. 06 for Nh, Nn and Wa venoms respectively; whereas the avidity of the same Abs to the heterologous venoms could hardly exceed 1.


Input: Venom concentrations in the range between 10-1250 ng/well were detected with almost the same efficiency, an extra advantage that could be added to the assay to assure equal sensitivity allover the mentioned venom concentration range.


Input: Effects of the natural endocrine disruptor equol on the pituitary function in adult male rats.

equol


Input: Equol (EQ), a potent biologically active metabolite of the soy isoflavone daidzein, interacts with estrogen receptors (ERs), however, as suggested recently, EQ may also exert anti-androgenic actions in androgen regulated tissues like prostate and seminal vesicles in adult male rats.

Equol

isoflavone daidzein

estrogen

androgenic


Input: However, data regarding a putative anti-androgenic activity of EQ on pituitary function in male individuals are still lacking.


Input: Therefore, we investigated the effects of EQ on androgen-and estrogen-regulated gene expressions in the pituitary and circulating luteinizing hormone (LH) and prolactin (PRL) levels in adult male rats.

androgen

estrogen


Input: 3-Month-old male Sprague-Dawley rats (n = 12 per group) were treated by gavage for 5 days with either EQ (100 and 250 mg/kg BW/day) or vehicle olive oil (1 ml/rat/day).


Input: As reference compound, the pure anti-androgenic drug flutamide (FLUT) was employed at a dose of 100 mg/kg BW/day.

flutamide

FLUT


Input: At day 5, animals were sacrificed.


Input: Levels of pituitary hormones and gene expression were measured by radioimmunoassays and quantitative TaqMan ((R)) real-time reverse transcription polymerase chain reaction, respectively.


Input: The present findings revealed that the pituitary mechanisms involved in the effects of EQ and FLUT were different due to the opposite changes in the mRNA expression levels of estrogen receptor subtype alpha (ER alpha)-, truncated estrogen receptor product-1 (TERP-1)-and-2 (TERP-2)-, gonadotropin releasing hormone receptor (GnRH receptor)-, beta-subunit of LH (LH beta)-, and gonadotropin alpha subunit (alpha-subunit) genes.

FLUT

estrogen

estrogen

gonadotropin releasing hormone

GnRH


Input: EQ displayed typical ER-agonistic actions as shown by the significant increases in ER alpha-, TERP-1/-2 mRNA expressions and serum PRL levels along with the significant reduction in serum LH levels, whereas FLUT exerted opposite effects on gonadotropin secretion and expression.

FLUT


Input: Taken together, our findings are the first in vivo data that upon sub-acute oral exposure of EQ show an estrogenic effect on reproductive endocrine activity of the pituitary in adult male rats.


Input: However, EQ did not exert anti-androgenic effects on male rat pituitary function as observed at the levels of mRNA expression of androgen-and estrogen-regulated genes and circulating pituitary hormones.

androgenic

estrogen


Input: Retinoic acid biosynthesis catalyzed by retinal dehydrogenases relies on a rate-limiting conformational transition associated with substrate recognition.

Retinoic acid

retinal


Input: Retinoic acid (RA), a metabolite of vitamin A, exerts pleiotropic effects throughout life in vertebrate organisms.

Retinoic acid

vitamin A


Input: Thus, RA action must be tightly regulated through the coordinated action of biosynthetic and degrading enzymes.


Input: The last step of retinoic acid biosynthesis is irreversibly catalyzed by the NAD-dependent retinal dehydrogenases (RALDH), which are members of the aldehyde dehydrogenase (ALDH) superfamily.

retinoic acid

NAD

retinal

aldehyde


Input: Low intracellular retinal concentrations imply efficient substrate molecular recognition to ensure high affinity and specificity of RALDHs for retinal.

retinal

retinal


Input: This study addresses the molecular basis of retinal recognition in human ALDH1A1 (or RALDH1) and rat ALDH1A2 (or RALDH2), through the comparison of the catalytic behavior of retinal analogs and use of the fluorescence properties of retinol.

retinal

retinal

retinol


Input: We show that, in contrast to long chain unsaturated substrates, the rate-limiting step of retinal oxidation by RALDHs is associated with acylation.

retinal


Input: Use of the fluorescence resonance energy transfer upon retinol interaction with RALDHs provides evidence that retinal recognition occurs in two steps: binding into the substrate access channel, and a slower structural reorganization with a rate constant of the same magnitude as the kcat for retinal oxidation: 0. 18 vs. 0. 07 and 0. 25 vs. 0. 1 s (-1) for ALDH1A1 and ALDH1A2, respectively.

retinol

retinal

retinal


Input: This suggests that the conformational transition of the RALDH-retinal complex significantly contributes to the rate-limiting step that controls the kinetics of retinal oxidation, as a prerequisite for the formation of a catalytically competent Michaelis complex.

retinal

retinal


Input: This conclusion is consistent with the general notion that structural flexibility within the active site of ALDH enzymes has been shown to be an integral component of catalysis.


Input: Inhibition of human alcohol and aldehyde dehydrogenases by cimetidine and assessment of its effects on ethanol metabolism.

alcohol

aldehyde

cimetidine

ethanol


Input: Previous studies have reported that cimetidine, an H2-receptor antagonist used to treat gastric and duodenal ulcers, can inhibit alcohol dehydrogenases (ADHs) and ethanol metabolism.

cimetidine

alcohol

ethanol


Input: Human alcohol dehydrogenases and aldehyde dehydrogenases (ALDHs), the principal enzymes responsible for metabolism of ethanol, are complex enzyme families that exhibit functional polymorphisms among ethnic groups and distinct tissue distributions.

alcohol

aldehyde

ethanol


Input: We investigated the inhibition by cimetidine of alcohol oxidation by recombinant human ADH1A, ADH1B1, ADH1B2, ADH1B3, ADH1C1, ADH1C2, ADH2, and ADH4, and aldehyde oxidation by ALDH1A1 and ALDH2 at pH 7. 5 and a cytosolic NAD (+) concentration.

cimetidine

alcohol

aldehyde

NAD (+)


Input: Cimetidine acted as competitive or noncompetitive inhibitors for the ADH and ALDH isozymes/allozymes with near mM inhibition constants.

Cimetidine


Input: The metabolic interactions between cimetidine and ethanol/acetaldehyde were assessed by computer simulation using the inhibition equations and the determined kinetic constants.

cimetidine

ethanol

acetaldehyde


Input: At therapeutic drug levels (0. 015 mM) and physiologically relevant concentrations of ethanol (10 mM) and acetaldehyde (10 mu M) in target tissues, cimetidine could weakly inhibit (< 5%) the activities of ADH1B2 and ADH1B3 in liver, ADH2 in liver and small intestine, ADH4 in stomach, and ALDH1A1 in the three tissues, but not significantly affect ADH1A, ADH1B1, ADH1C1/2, or ALDH2.

ethanol

acetaldehyde

cimetidine


Input: At higher drug levels, which may accumulate in cells (0. 2 mM), the activities of the weakly-inhibited enzymes may be decreased more significantly.


Input: The quantitative effects of cimetidine on metabolism of ethanol and other physiological substrates of ADHs need further investigation.

cimetidine

ethanol


Input: Anti-inflammatory properties of fruit juices enriched with pine bark extract in an in vitro model of inflamed human intestinal epithelium: the effect of gastrointestinal digestion.


Input: Enrichment of fruit juices with pine bark extract (PBE) could be a strategy to compensate for phenolic losses during the gastrointestinal digestion.

phenolic


Input: A coculture system with Caco-2 cells and RAW 264. 7 macrophages was established as an in vitro model of inflamed human intestinal epithelium for evaluating the anti-inflammatory capacity of fruit juices enriched with PBE (0. 5 g L (-1)) before and after in vitro digestion.


Input: The digestion of both PBE-enriched pineapple and red fruit juice led to significant changes in most of the analysed phenolic compounds.

phenolic


Input: The in vitro inflammatory state showed cell barrier dysfunction and overproduction of IL-8, nitric oxide (NO) and reactive oxygen species (ROS).

nitric oxide

NO

oxygen


Input: In the inflamed cells, incubation with nondigested samples reduced (P < 0. 05) the production of IL-8 and NO compared with digested samples.

NO


Input: ROS production increased in the inflamed cells exposed to digested commercial red fruit juice (86. 8 +/- 1. 3%) compared with fresh juice (77. 4 +/- 0. 8%) and increased in the inflamed cells exposed to digested enriched red fruit juice (82. 6 +/- 1. 6%) compared with the fresh enriched juice (55. 8 +/- 6%).


Input: The anti-inflammatory properties of PBE-enriched fruit juices decreased after digestion; further research on the bioavailability of the assayed compounds is needed to properly assess their usefulness for the treatment of gut inflammation.


Input: New mycotoxins from marine-derived fungus Aspergillus sp.


Input: Nine mycotoxins including six aspergillic acid group toxins, aluminiumneoaspergillin (1), zirconiumneoaspergillin (2), aspergilliamide (3), ferrineoaspergillin (5), flavacol (6), neoaspergillic acid (7), and three ochratoxins, ochratoxin A n-butyl ester (4), ochratoxin A (8), ochratoxin A methyl ester (9), were isolated from the fermentation broth of marine gorgonian derived fungus Aspergillus sp.

aspergillic acid

aluminiumneoaspergillin

zirconiumneoaspergillin

aspergilliamide

ferrineoaspergillin

flavacol

neoaspergillic acid

ochratoxins

ochratoxin A n-butyl ester

ochratoxin A

ochratoxin A methyl ester


Input: Four of them (1-4) were new mycotoxins, and their structures were elucidated on the basis of spectroscopic analysis and chemical evidence.


Input: The bio-toxicity of compounds 1-9 were determined by brine shrimp lethality bioassay with median lethal concentration (LC (50)) values of 2. 59-205. 67 mu M.


Input: This was the first report about zirconium complex obtained from nature and ochratoxins isolated from marine environment.

zirconium

ochratoxins


Input: The selective SYK inhibitor P505-15 (PRT062607) inhibits B cell signaling and function in vitro and in vivo and augments the activity of fludarabine in chronic lymphocytic leukemia.

fludarabine


Input: B-cell receptor (BCR) associated kinases including spleen tyrosine kinase (SYK) contribute to the pathogenesis of B-cell malignancies.

tyrosine


Input: SYK is persistently phosphorylated in a subset of non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL), and SYK inhibition results in abrogation of downstream kinase activity and apoptosis.


Input: P505-15 (also known as PRT062607) is a novel, highly selective, and orally bioavailable small molecule SYK inhibitor (SYK IC (50) = 1 nM) with anti-SYK activity that is at least 80-fold greater than its affinity for other kinases.


Input: We evaluated the preclinical characteristics of P505-15 in models of NHL and CLL.


Input: P505-15 successfully inhibited SYK-mediated B-cell receptor signaling and decreased cell viability in NHL and CLL.


Input: Oral dosing in mice prevented BCR-mediated splenomegaly and significantly inhibited NHL tumor growth in a xenograft model.


Input: In addition, combination treatment of primary CLL cells with P505-15 plus fludarabine produced synergistic enhancement of activity at nanomolar concentrations.

fludarabine


Input: Our findings support the ongoing development of P505-15 as a therapeutic agent for B-cell malignancies.


Input: A dose finding study in healthy volunteers has been completed.


Input: Ticlopidine, a cholestatic liver injury-inducible drug, causes dysfunction of bile formation via diminished biliary secretion of phospholipids: involvement of biliary-excreted glutathione-conjugated ticlopidine metabolites.

Ticlopidine

glutathione

ticlopidine


Input: The antiplatelet drug, ticlopidine (TIC), reportedly causes cholestatic liver injuries.

ticlopidine

TIC


Input: The present study analyzed the effect of TIC on bile formation, revealing that the biliary secretion of phospholipids was significantly decreased in TIC-administered Sprague Dawley (SD) rats.

TIC

TIC


Input: However, the effect of TIC on biliary phospholipids was not observed in SD rats pretreated with diethylaminoethyl diphenylpropylacetate that inhibits cytochrome P450s (P450), or in Eisai hyperbilirubinemic rats (EHBR) lacking functional multidrug resistance-associated protein 2 (MRP2/ABCC2).

TIC

diethylaminoethyl diphenylpropylacetate


Input: These results suggest that glutathione-conjugated TIC metabolites (TIC-SGs), which were formed in the liver after P450s-mediated metabolism and were excreted extensively into bile by MRP2, mediated the observed alterations of the bile composition.

glutathione

TIC

TIC


Input: Administration of TIC caused significant liver injuries in SD rats, with decreased biliary phospholipids, but not in EHBR, consistent with the in vitro observation that phospholipid-bile acid-mixed micelles moderated the cytotoxic effects of bile acids.

TIC

bile acid

bile acids


Input: Further analyses revealed that TIC-SGs did not directly inhibit multidrug resistance 3 P-glycoprotein (MDR3/ABCB4)-mediated phosphatidylcholine efflux in vitro.

TIC

phosphatidylcholine


Input: Because the diminished biliary secretion of phospholipids with TIC administration was restored by taurocholate infusion in SD rats, the decreased biliary concentration of bile acids, due to the stimulation of bile acid-independent bile flow driven by TIC-SGs, might have indirectly attenuated phospholipid secretion.

TIC

taurocholate

bile acids

bile acid

TIC


Input: In conclusion, extensive biliary excretion of TIC-SGs decreased the biliary secretion of phospholipids, which might have increased the risk of TIC-induced cholestatic liver injury.

TIC

TIC


Input: Apomorphine is a bimodal modulator of TRPA1 channels.

Apomorphine


Input: Apomorphine is a non-narcotic derivative of morphine, which acts as a dopamine agonist and is clinically used to treat " off-states " in patients suffering from Parkinson' s disease.

Apomorphine

morphine

dopamine


Input: Adverse effects of apomorphine treatment include severe emesis and nausea, and ulceration and pain at the injection site.

apomorphine


Input: We wanted to test whether sensory transient receptor potential (TRP) channels are a molecular target for apomorphine.

apomorphine


Input: Here, we show that rTRPV1, rTRPV2, rTRPV3, and mTRPV4, as well as hTRPM8, and rTRPM3, which are expressed in dorsal root ganglion neurons, are insensitive toward apomorphine treatment.

apomorphine


Input: This also applied to the cellular redox sensor hTRPM2.


Input: On the contrary, human TRPA1 could be concentration-dependently modulated by apomorphine.

apomorphine


Input: Whereas the addition of apomorphine in the low micromolar range produced an irreversible activation of the channel, application of higher concentrations caused a reversible voltage-dependent inhibition of heterologously expressed TRPA1 channels, resulting from a reduction of single-channel open times.

apomorphine


Input: In addition, we provide evidence that apomorphine also acts on endogenous TRPA1 in cultured dorsal root ganglion neurons from rats and in the enterochromaffin model cell line QGP-1, from which serotonin is released upon activation of TRPA1.

apomorphine

serotonin


Input: Our study shows that human TRPA1 is a target for apomorphine, suggesting that an activation of TRPA1 might contribute to adverse side effects such as nausea and painful injections, which can occur during treatment with apomorphine.

apomorphine

apomorphine


Input: Human stearoyl-CoA desaturase 1 (SCD-1) gene expression is negatively regulated by thyroid hormone without direct binding of thyroid hormone receptor to the gene promoter.

stearoyl-CoA

thyroid hormone

thyroid hormone


Input: Stearoyl-CoA desaturase-1 (SCD-1) plays a pivotal role in an increase of triglyceride by an excess of dietary carbohydrate intake.

Stearoyl-CoA

triglyceride

carbohydrate


Input: Dietary carbohydrates increase SCD-1 gene expression in liver by sterol response element binding protein (SREBP)-1c-dependent and SREBP-1c-independent pathways.

carbohydrates

sterol


Input: Previous report demonstrated that thyroid hormone (TH) negatively regulates mouse SCD-1 gene promoter before SREBP-1c was revealed.

thyroid hormone


Input: We reported that TH negatively regulates SREBP-1c recently.


Input: Therefore, in the current study, we examined whether and how TH regulates human SCD-1 gene expression and evaluated SREBP-1c effect on the negative regulation.


Input: Luciferase assays revealed that TH suppresses both mouse and human SCD-1 gene promoter activity.


Input: In SREBP-1 knockdown HepG2 cells, TH still suppresses SCD-1 gene promoter activity, and it also exerted the negative regulation under cotransfection of a small amount of SREBP-1c.


Input: These data indicated that SREBP-1c does not play the decisive role for the negative regulation by TH.


Input: The responsible region for the negative regulation in human SCD-1 gene promoter turned out to be between-124 and-92 bp, referred to as site A.


Input: Chromatin immunoprecipitation assays demonstrated that TH receptor-beta is recruited to the region upon T (3) administration, although TR-beta does not bind directly to site A.


Input: In conclusion, TH negatively regulates human SCD-1 gene expression in without direct binding of the TH receptor to the SCD-1 gene promoter.


Input: An in vitro network of intermolecular interactions between viral RNA segments of an avian H5N2 influenza A virus: comparison with a human H3N2 virus.


Input: The genome of influenza A viruses (IAV) is split into eight viral RNAs (vRNAs) that are encapsidated as viral ribonucleoproteins.


Input: The existence of a segment-specific packaging mechanism is well established, but the molecular basis of this mechanism remains to be deciphered.


Input: Selective packaging could be mediated by direct interaction between the vRNA packaging regions, but such interactions have never been demonstrated in virions.


Input: Recently, we showed that the eight vRNAs of a human H3N2 IAV form a single interaction network in vitro that involves regions of the vRNAs known to contain packaging signals in the case of H1N1 IAV strains.


Input: Here, we show that the eight vRNAs of an avian H5N2 IAV also form a single network of interactions in vitro, but, interestingly, the interactions and the regions of the vRNAs they involve differ from those described for the human H3N2 virus.


Input: We identified the vRNA sequences involved in five of these interactions at the nucleotide level, and in two cases, we validated the existence of the interaction using compensatory mutations in the interacting sequences.

nucleotide


Input: Electron tomography also revealed significant differences in the interactions taking place between viral ribonucleoproteins in H5N2 and H3N2 virions, despite their canonical' 7 + 1' arrangement.


Input: Chromatin-dependent and-independent regulation of DNA replication origin activation in budding yeast.


Input: To elucidate the role of the chromatin environment in the regulation of replication origin activation, autonomously replicating sequences were inserted into identical locations in the budding yeast genome and their activation times in S phase determined.


Input: Chromatin-dependent origins adopt to the firing time of the surrounding locus.


Input: In contrast, the origins containing two binding sites for Forkhead transcription factors are activated early in the S phase regardless of their location in the genome.


Input: Our results also show that genuinely late-replicating parts of the genome can be converted into early-replicating loci by insertion of a chromatin-independent early replication origin, ARS607, whereas insertion of two Forkhead-binding sites is not sufficient for conversion.


Input: HLA-DO acts as a substrate mimic to inhibit HLA-DM by a competitive mechanism.


Input: Mammalian class II major histocompatibility (MHCII) proteins bind peptide antigens in endosomal compartments of antigen-presenting cells.


Input: The nonclassical MHCII protein HLA-DM chaperones peptide-free MHCII, protecting it against inactivation, and catalyzes peptide exchange on loaded MHCII.


Input: Another nonclassical MHCII protein, HLA-DO, binds HLA-DM and influences the repertoire of peptides presented by MHCII proteins.


Input: However, the mechanism by which HLA-DO functions is unclear.


Input: Here we have used X-ray crystallography, enzyme kinetics and mutagenesis approaches to investigate human HLA-DO structure and function.


Input: In complex with HLA-DM, HLA-DO adopts a classical MHCII structure, with alterations near the alpha subunit' s 3 1 0 helix.


Input: HLA-DO binds to HLA-DM at the same sites implicated in MHCII interaction, and kinetic analysis showed that HLA-DO acts as a competitive inhibitor.


Input: These results show that HLA-DO inhibits HLA-DM function by acting as a substrate mimic, and the findings also limit the possible functional roles for HLA-DO in antigen presentation.


Input: DAXX-dependent supply of soluble (H3. 3-H4) dimers to PML bodies pending deposition into chromatin.


Input: Replication-independent chromatin deposition of histone variant H3. 3 is mediated by several chaperones.


Input: We report a multistep targeting of newly synthesized epitope-tagged H3. 3 to chromatin via PML bodies.


Input: H3. 3 is recruited to PML bodies in a DAXX-dependent manner, a process facilitated by ASF1A.


Input: DAXX is required for enrichment of ATRX, but not ASF1A or HIRA, with PML.


Input: Nonetheless, the chaperones colocalize with H3. 3 at PML bodies and are found in one or more complexes with PML.


Input: Both DAXX and PML are necessary to prevent accumulation of a soluble, nonincorporated pool of H3. 3.


Input: H3. 3 targeting to PML is enhanced with an (H3. 3-H4) 2 tetramerization mutant of H3. 3, suggesting H3. 3 recruitment to PML as an (H3. 3-H4) dimer rather than as a tetramer.


Input: Our data support a model of DAXX-mediated recruitment of (H3. 3-H4) dimers to PML bodies, which may function as triage centers for H3. 3 deposition into chromatin by distinct chaperones.


Input: Cell-based screening identifies paroxetine as an inhibitor of diabetic endothelial dysfunction.

paroxetine


Input: We have conducted a phenotypic screening in endothelial cells exposed to elevated extracellular glucose (an in vitro model of hyperglycemia) to identify compounds that prevent hyperglycemia-induced reactive oxygen species (ROS) formation without adversely affecting cell viability.

glucose

oxygen


Input: From a focused library of > 6, 000 clinically used drug-like and pharmacologically active compounds, several classes of active compounds emerged, with a confirmed hit rate of < 0. 5%.


Input: Follow-up studies focused on paroxetine, a clinically used antidepressant compound that has not been previously implicated in the context of hyperglycemia or diabetes.

paroxetine


Input: Paroxetine reduced hyperglycemia-induced mitochondrial ROS formation, mitochondrial protein oxidation, and mitochondrial and nuclear DNA damage, without interfering with mitochondrial electron transport or cellular bioenergetics.

Paroxetine


Input: The ability of paroxetine to improve hyperglycemic endothelial cell injury was unique among serotonin reuptake blockers and can be attributed to its antioxidant effect, which primarily resides within its sesamol moiety.

paroxetine

serotonin

sesamol


Input: Paroxetine maintained the ability of vascular rings to respond to the endothelium-dependent relaxant acetylcholine, both during in vitro hyperglycemia and ex vivo, in a rat model of streptozotocin-induced diabetes.

Paroxetine

acetylcholine

streptozotocin


Input: Thus, the current work identifies a novel pharmacological action of paroxetine as a protector of endothelial cells against hyperglycemic injury and raises the potential of repurposing of this drug for the experimental therapy of diabetic cardiovascular complications.

paroxetine


Input: Gamma-radiolysis-assisted cobalt oxide nanoparticle formation.

cobalt oxide


Input: The formation of Co (3) O (4) nano-scale colloid particles by gamma irradiation of CoSO (4) solutions was investigated.

Co (3) O (4)

CoSO (4)


Input: Solutions of 0. 2-0. 3 mM CoSO (4) at pH 6. 0 and 10. 6 (air-saturated and Ar-purged) were irradiated at an absorbed dose rate of 5. 5 kGy h (-1).

CoSO (4)


Input: The resulting concentrations of H (2), H (2) O (2), Co (II) and Co (III) species in solution and the chemical composition and sizes of particles that were formed were measured as a function of irradiation time.

H (2)

H (2) O (2)

Co (II)

Co (III)


Input: Particle formation was observed only for initially air-saturated CoSO (4) solutions at pH 10. 6.

CoSO (4)


Input: Analysis of the particle formation as a function of irradiation time shows that the particles evolve from Co (OH) (2) to CoOOH and then to Co (3) O (4).

Co (OH) (2)

CoOOH

Co (3) O (4)


Input: The radiolytic oxidation of Co (II) to Co (III) was completed in 100 min and the chemical composition of the final particles was identified as Co (3) O (4) by XPS, Raman and UV-Vis spectroscopy.

Co (II)

Co (III)

Co (3) O (4)


Input: Transmission electron microscopy (TEM) images show the final particles are approximately uniform in size, ranging from 8 to 20 nm.


Input: A mechanism is proposed to explain the particle formation.


Input: A key factor is the low solubility of Co (OH) (2) in air-saturated solutions at high pH.

Co (OH) (2)


Input: This mechanism for particle formation is compared with the mechanism previously reported for the radiolytic formation of gamma-FeOOH nanoparticles.

gamma-FeOOH


Input: Plasma electrochemistry: voltammetry in a flame plasma electrolyte.


Input: In this paper we present detailed dynamic electrochemical measurements in a flame plasma electrolyte in the presence of tungsten oxide salts.

tungsten oxide salts


Input: Defined reproducible redox processes are measured using conventional cyclic voltammetry in an operational potential window between 1 and-9 V.


Input: This wide potential window is possible due to the absence of solvent and its associated limits due to solvent electrolysis at high over potentials.


Input: The measurements were enabled through the development of a new reference electrode, composed of yttria stabilised zirconia (YSZ) which maintains a stable potential at 1100 K.

yttria

zirconia


Input: In this paper we focus on developing a phenomenological understanding of electron transfer at the solid-gas interface, using cyclic voltammetry.


Input: The effect of working electrode surface area and material, as well as potential scan rate on the voltammetric redox features is presented.


Input: We discuss the physical origin of the observed Faradaic current peaks measured in a flame plasma electrolyte, and propose a simple model to describe the redox processes occurring.


Input: We conclude that redox processes at the solid-gas interface are actually similar to the analogous processes at the solid-liquid interface described by conventional electrochemical theory; the departures are mainly due to the mass transport processes that dominate in the gas phase.


Input: We associate migration effects with the total absence of any oxidation processes.


Input: Parenteral nutrition-associated hyperglycemia in non-critically ill inpatients increases the risk of in-hospital mortality (multicenter study).


Input: OBJECTIVE Hyperglycemia may increase mortality in patients who receive total parenteral nutrition (TPN).


Input: However, this has not been well studied in noncritically ill patients (i. e., patients in the nonintensive care unit setting).


Input: The aim of this study was to determine whether mean blood glucose level during TPN infusion is associated with increased mortality in noncritically ill hospitalized patients.

glucose


Input: RESEARCH DESIGN AND METHODS This prospective multicenter study involved 19 Spanish hospitals.


Input: Noncritically ill patients who were prescribed TPN were included prospectively, and data were collected on demographic, clinical, and laboratory variables as well as on in-hospital mortality.


Input: RESULTS The study included 605 patients (mean age 63. 2 +/- 15. 7 years).


Input: The daily mean TPN values were 1. 630 +/- 323 kcal, 3. 2 +/- 0. 7 g carbohydrates/kg, 1. 26 +/- 0. 3 g amino acids/kg, and 0. 9 +/- 0. 2 g lipids/kg.

carbohydrates

amino acids


Input: Multiple logistic regression analysis showed that the patients who had mean blood glucose levels > 180 mg/dL during the TPN infusion had a risk of mortality that was 5. 6 times greater than those with mean blood glucose levels < 140 mg/dL (95% CI 1. 47-21. 4 mg/dL) after adjusting for age, sex, nutritional state, presence of diabetes or hyperglycemia before starting TPN, diagnosis, prior comorbidity, carbohydrates infused, use of steroid therapy, SD of blood glucose level, insulin units supplied, infectious complications, albumin, C-reactive protein, and HbA1c levels.

glucose

glucose

carbohydrates

steroid

glucose


Input: CONCLUSIONS Hyperglycemia (mean blood glucose level > 180 mg/dL) in noncritically ill patients who receive TPN is associated with a higher risk of in-hospital mortality.

glucose


Input: Effect of nuclear vibrations, temperature, co-adsorbed water, and dye orientation on light absorption, charge injection and recombination conditions in organic dyes on TiO2.


Input: We study the effect of nuclear motions at different temperatures, including the effect of a dye molecule' s orientation with respect to the oxide surface, on factors determining the performance of dye sensitized solar cells: light absorption, electron injection, and back-donation.

oxide


Input: We perform ab initio molecular dynamics simulations of aminophenyl acid dyes NK1 and NK7, differing by the electron donating group, in a vacuum and adsorbed in mono-and bi-dentate modes on a dry and a water-covered anatase (101) surface of TiO (2), at 300 and 350 K.

aminophenyl acid

anatase (101)

TiO (2)


Input: Nuclear vibrations and an increase of temperature cause a red shift in the absorption spectra of free dyes.


Input: This effect is preserved in dyes on dry TiO (2) but largely disappears in the presence of water.

TiO (2)


Input: Averaged over nuclear vibrations, the driving force to injection, Delta G, differs from the static estimate.


Input: It depends on the adsorption mode and the presence of H (2) O but is almost the same for 300 and 350 K.

H (2) O


Input: Recombination to the dye cation is expected to be much enhanced by the approach of the dye oxidation equivalent hole to the surface during dye wagging around TiO (2).

TiO (2)


Input: This effect is somewhat mitigated by the co-adsorbed water.


Input: The dynamics of Delta G (t) are explained by uncorrelated evolution of the energies of the dye excited state and the conduction band minimum of the oxide due to their respective vibrations, and are almost independent of dye orientation.

oxide


Input: It may therefore be possible to independently control the conditions of recombination and of injection.


Input: Loss of LARGE2 disrupts functional glycosylation of alpha-dystroglycan in prostate cancer.


Input: Dystroglycan (DG) is a cell surface receptor for extracellular matrix proteins and is involved in cell polarity, matrix organization, and mechanical stability of tissues.


Input: Previous studies documented loss of DG protein expression and glycosylation in a variety of cancer types, but the underlying mechanisms and the functional consequences with respect to cancer progression remain unclear.


Input: Here, we show that the level of expression of the beta DG subunit as well as the glycosylation status of the alpha DG subunit inversely correlate with the Gleason scores of prostate cancers; furthermore, we show that the functional glycosylation of alpha DG is substantially reduced in prostate cancer metastases.


Input: Additionally, we demonstrate that LARGE2 (GYLTL1B), a gene not previously implicated in cancer, regulates functional alpha DG glycosylation in prostate cancer cell lines; knockdown of LARGE2 resulted in hypoglycosylation of alpha DG and loss of its ability to bind laminin-111 while overexpression restored ligand binding and diminished growth and migration of an aggressive prostate cancer cell line.


Input: Finally, our analysis of LARGE2 expression in human cancer specimens reveals that LARGE2 is significantly down-regulated in the context of prostate cancer, and that its reduction correlates with disease progression.


Input: Our results describe a novel molecular mechanism to account for the commonly observed hypoglycosylation of alpha DG in prostate cancer.


Input: Prolyl 4-hydroxlase activity is essential for development and cuticle formation in the human infective parasitic nematode Brugia malayi.


Input: Collagen prolyl 4-hydroxylases (C-P4H) are required for formation of extracellular matrices in higher eukaryotes.


Input: These enzymes convert proline residues within the repeat regions of collagen polypeptides to 4-hydroxyproline, a modification essential for the stability of the final triple helix.

proline


Input: C-P4H are most often oligomeric complexes, with enzymatic activity contributed by the alpha subunits, and the beta subunits formed by protein disulfide isomerase (PDI).

disulfide


Input: Here, we characterize this enzyme class in the important human parasitic nematode Brugia malayi.


Input: All potential C-P4H subunits were identified by detailed bioinformatic analysis of sequence databases, function was investigated both by RNAi in the parasite and heterologous expression in Caenorhabditis elegans, whereas biochemical activity and complex formation were examined via co-expression in insect cells.


Input: Simultaneous RNAi of two B. malayi C-P4H alpha subunit-like genes resulted in a striking, highly penetrant body morphology phenotype in parasite larvae.


Input: This was replicated by single RNAi of a B. malayi C-P4H beta subunit-like PDI.


Input: Surprisingly, however, the B. malayi proteins were not capable of rescuing a C. elegans alpha subunit mutant, whereas the human enzymes could.


Input: In contrast, the B. malayi PDI did functionally complement the lethal phenotype of a C. elegans beta subunit mutant.


Input: Comparison of recombinant and parasite derived material indicates that enzymatic activity may be dependent on a non-reducible covalent link, present only in the parasite.


Input: We therefore demonstrate that C-P4H activity is essential for development of B. malayi and uncover a novel parasite-specific feature of these collagen biosynthetic enzymes that may be exploited in future parasite control.


Input: Alteration of the expression of pesticide-metabolizing enzymes in pregnant mice: potential role in the increased vulnerability of the developing brain.


Input: Studies on therapeutic drug disposition in humans have shown significant alterations as the result of pregnancy.


Input: However, it is not known whether pesticide metabolic capacity changes throughout pregnancy, which could affect exposure of the developing brain.


Input: We sought to determine the effect of pregnancy on the expression of hepatic enzymes involved in the metabolism of pesticides.


Input: Livers were collected from virgin and pregnant C57BL/6 mice at gestational days (GD) 7, GD11, GD14, GD17, and postpartum days (PD) 1, PD15, and PD30.


Input: Relative mRNA expression of several enzymes involved in the metabolism of pesticides, including hepatic cytochromes (Cyp) P450s, carboxylesterases (Ces), and paraoxonase 1 (Pon1), were assessed in mice during gestation and the postpartum period.


Input: Compared with virgin mice, alterations in the expression occurred at multiple time points, with the largest changes observed on GD14.


Input: At this time point, the expression of most of the Cyps involved in pesticide metabolism in the liver (Cyp1a2, Cyp2d22, Cyp2c37, Cyp2c50, Cyp2c54, and Cyp3a11) were downregulated by 30% or more.


Input: Expression of various Ces isoforms and Pon1 were also decreased along with Pon1 activity.


Input: These data demonstrate significant alterations in the expression of key enzymes that detoxify pesticides during pregnancy, which could alter exposure of developing animals to these chemicals.


Input: Altered UDP-glucuronosyltransferase and sulfotransferase expression and function during progressive stages of human nonalcoholic fatty liver disease.

UDP


Input: The UDP-glucuronosyltransferases (UGTs) and sulfotransferases (SULTs) represent major phase II drug-metabolizing enzymes that are also responsible for maintaining cellular homeostasis by metabolism of several endogenous molecules.

UDP


Input: Perturbations in the expression or function of these enzymes can lead to metabolic disorders and improper management of xenobiotics and endobiotics.


Input: Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of liver damage ranging from steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis.


Input: Because the liver plays a central role in the metabolism of xenobiotics, the purpose of the current study was to determine the effect of human NAFLD progression on the expression and function of UGTs and SULTs in normal, steatosis, NASH (fatty), and NASH (not fatty/cirrhosis) samples.


Input: We identified upregulation of UGT1A9, 2B10, and 3A1 and SULT1C4 mRNA in both stages of NASH, whereas UGT2A3, 2B15, and 2B28 and SULT1A1, 2B1, and 4A1 as well as 3'-phosphoadenosine-5'-phosphosulfate synthase 1 were increased in NASH (not fatty/cirrhosis) only.


Input: UGT1A9 and 1A6 and SULT1A1 and 2A1 protein levels were decreased in NASH; however, SULT1C4 was increased.


Input: Measurement of the glucuronidation and sulfonation of acetaminophen (APAP) revealed no alterations in glucuronidation; however, SULT activity was increased in steatosis compared with normal samples, but then decreased in NASH compared with steatosis.

acetaminophen

APAP


Input: In conclusion, the expression of specific UGT and SULT isoforms appears to be differentially regulated, whereas sulfonation of APAP is disrupted during progression of NAFLD.

APAP


Input: SERS performance of gold nanotubes obtained by sputtering onto polycarbonate track-etched membranes.

polycarbonate


Input: Surface-enhanced Raman scattering (SERS) is a powerful and versatile tool for studying molecules on metallic surfaces with great impact on areas such as electrochemistry, catalysis and related subjects.


Input: The search for new SERS-active substrates with high performance, namely high enhancement factors and reproducibility, is currently the main focus of several research groups.


Input: Here is shown an alternative easy and inexpensive synthetic approach to a SERS-substrate comprised of gold nanotubes obtained by the sputtering onto polycarbonate track-etched membranes used as template.

polycarbonate


Input: Its SERS performance was evaluated by mapping (10 x 10) mu m (2) areas and resulted in average enhancement factors that span from 2. 3 x 10 (3) to 1. 2 x 10 (5) with a maximum enhancement factor of 2. 5 x 10 (5).


Input: The enhancement depended strongly on the template pore diameter, with the best performance obtained when membranes with pore diameters of 400 nm were used as template.


Input: Further analysis showed that the larger enhancements came from coalesced gold nanotubes and detection of the dye rhodamine 6G at concentrations as low as 0. 1 nM was possible.

rhodamine 6G


Input: These results put this substrate as a valuable and easy-to-fabricate tool for studying and detecting molecules on surfaces.


Input: The proposed methodology could be easily adapted to other metals, such as silver and copper.

silver

copper


Input: Advanced gecko-foot-mimetic dry adhesives based on carbon nanotubes.

carbon


Input: Geckos can run freely on vertical walls and even ceilings.


Input: Recent studies have discovered that gecko' s extraordinary climbing ability comes from a remarkable design of nature with nanoscale beta-keratin elastic hairs on their feet and toes, which collectively generate sufficiently strong van der Waals force to hold the animal onto an opposing surface while at the same time disengaging at will.


Input: Vertically aligned carbon nanotube (VA-CNT) arrays, resembling gecko' s adhesive foot hairs with additional superior mechanical, chemical and electrical properties, have been demonstrated to be a promising candidate for advanced fibrillar dry adhesives.

carbon


Input: The VA-CNT arrays with tailor-made hierarchical structures can be patterned and/or transferred onto various flexible substrates, including responsive polymers.


Input: This, together with recent advances in nanofabrication techniques, could offer' smart' dry adhesives for various potential applications, even where traditional adhesives cannot be used.


Input: A detailed understanding of the underlying mechanisms governing the material properties and adhesion performances is critical to the design and fabrication of gecko inspired CNT dry adhesives of practical significance.


Input: In this feature article, we present an overview of recent progress in both fundamental and applied frontiers for the development of CNT-based adhesives by summarizing important studies in this exciting field, including our own work.


Input: Factors limiting device efficiency in organic photovoltaics.


Input: The power conversion efficiency of the most efficient organic photovoltaic (OPV) cells has recently increased to over 10%.


Input: To enable further increases, the factors limiting the device efficiency in OPV must be identified.


Input: In this review, the operational mechanism of OPV cells is explained and the detailed balance limit to photovoltaic energy conversion, as developed by Shockley and Queisser, is outlined.


Input: The various approaches that have been developed to estimate the maximum practically achievable efficiency in OPV are then discussed, based on empirical knowledge of organic semiconductor materials.


Input: Subsequently, approaches made to adapt the detailed balance theory to incorporate some of the fundamentally different processes in organic solar cells that originate from using a combination of two complementary, donor and acceptor, organic semiconductors using thermodynamic and kinetic approaches are described.


Input: The more empirical formulations to the efficiency limits provide estimates of 10-12%, but the more fundamental descriptions suggest limits of 20-24% to be reachable in single junctions, similar to the highest efficiencies obtained for crystalline silicon p-n junction solar cells.

silicon


Input: Closing this gap sets the stage for future materials research and development of OPV.


Input: Exploring the polyamine regulatory site of the NMDA receptor: a parallel synthesis approach.

polyamine

NMDA


Input: The elongated structures of polyamine inverse agonists such as 1, 12-diaminododecane (N12N) and 5-(4-aminobutyl)-2-thiopheneoctanamine (N4T8N) lend themselves to a combinatorial chemistry approach to explore a potential polyamine pharmacophore at the NMDA receptor.

polyamine

1, 12-diaminododecane

polyamine

NMDA


Input: Herein we describe more than 100 new analogues of N4T8N obtained by breaking up the long octanamine arm into a dipeptide chain of equivalent length.

octanamine


Input: Solid-phase parallel synthesis based on cross-linked polystyrene and a Wang anchor allowed the low-scale preparation of four small libraries based on the combination of two amino acid residues (out of Gly, Leu, Phe, Lys, phenylglycine, Tyr, Trp, His, and Arg).

polystyrene

amino acid

Gly

Leu

Phe

Lys

phenylglycine

Tyr

Trp

His

Arg


Input: The obtained compounds were tested as modulators of [(3) H] MK-801 binding to rat brain membranes and of NMDA-induced currents in cultured rat hippocampal neurons.

[(3) H] MK-801

NMDA


Input: Compounds with two aromatic residues acted as binding inhibitors (inverse agonists).


Input: Compounds with two Lys residues acted as binding stimulators (agonists) and had stimulatory and inhibitory effects on NMDA-induced currents, depending on the holding potential.

Lys

NMDA


Input: High sensitivity of binding inhibition to spermine was conferred by a Tyr residue, whereas a His residue favored high potency at acidic pH.

spermine

Tyr

His


Input: Design strategies and applications of tissue bioadhesives.


Input: In the past two decades tissue adhesives and sealants have revolutionized bleeding control and wound healing.


Input: This paper focuses on existing tissue adhesive design, their structure, functioning mechanism, and their pros and cons in wound management.


Input: It also includes the latest advances in the development of new tissue adhesives as well as the emerging applications in regenerative medicine.


Input: We expect that this paper will provide insightful discussion on tissue bioadhesive design and lead to innovations for the development of the next generation of tissue bioadhesives and their related biomedical applications.


Input: Microbial transformation of asiatic acid.

asiatic acid


Input: Asiatic acid (1), a major pentacyclic triterpene of Centella asiatica, was subjected to transformation by Penicillium lilacinum ACCC 31890, Fusarium equiseti CGMCC 3. 3658, and Streptomyces griseus CGMCC 4. 18 strains.

Asiatic acid

pentacyclic triterpene


Input: Incubation of asiatic acid with P. lilacinum ACCC 31890 and F. equiseti CGMCC 3. 3658 gave an identical product: 2 alpha, 3 beta, 15 alpha, 23-tetrahydroxyurs-12-en-28-oic acid (2).

asiatic acid

2 alpha, 3 beta, 15 alpha, 23-tetrahydroxyurs-12-en-28-oic acid


Input: Biotransformation of asiatic acid by S. griseus CGMCC 4. 18 resulted in three derivatives: 2 alpha, 3 beta, 21 beta, 23-tetrahydroxyurs-12-en-28-oic acid (3), 2 alpha, 3 beta, 23-trihydroxyurs-12-en-28, 30-dioic acid (4), and 2 alpha, 3 beta, 23, 30-tetrahydroxyurs-12-en-28-oic acid (5).

asiatic acid

2 alpha, 3 beta, 21 beta, 23-tetrahydroxyurs-12-en-28-oic acid

2 alpha, 3 beta, 23-trihydroxyurs-12-en-28, 30-dioic acid

2 alpha, 3 beta, 23, 30-tetrahydroxyurs-12-en-28-oic acid


Input: The structures of those derivatives were deduced from their spectral data.


Input: Products (2), (3), and (4) were new compounds.


Input: In addition, the in vitro cytotoxicities of those derivatives along with 1 were evaluated with several human cancer cell lines.


Input: Predicting dislocations and grain boundaries in two-dimensional metal-disulfides from the first principles.

metal-disulfides


Input: Guided by the principles of dislocation theory, we use the first-principles calculations to determine the structure and properties of dislocations and grain boundaries (GB) in single-layer transition metal disulfides MS (2) (M = Mo or W).

transition metal disulfides MS (2)

Mo

W


Input: In sharp contrast to other two-dimensional materials (truly planar graphene and h-BN), here the edge dislocations extend in third dimension, forming concave dreidel-shaped polyhedra.

graphene

h-BN


Input: They include different number of homoelemental bonds and, by reacting with vacancies, interstitials, and atom substitutions, yield families of the derivative cores for each Burgers vector.


Input: The overall structures of GB are controlled by both local-chemical and far-field mechanical energies and display different combinations of dislocation cores.


Input: Further, we find two distinct electronic behaviors of GB.


Input: Typically, their localized deep-level states act as sinks for carriers but at large 60 degrees-tilt the GB become metallic.


Input: The analysis shows how the versatile GB in MS (2) (if carefully engineered) should enable new developments for electronic and opto-electronic applications.

MS (2)


Input: Terpenoids from Incarvillea arguta.

Terpenoids


Input: One new monoterpenoid, (+)-argutoid A (1), three new iridoids, (-)-incarvoid A (2), (+)-incarvoid B (3), and incarvoid C (4), and five known compounds were isolated from Incarvillea arguta.

monoterpenoid

(+)-argutoid A

iridoids

(-)-incarvoid A

(+)-incarvoid B

incarvoid C


Input: Their structures were characterized by means of spectroscopic methods.


Input: Amino acid-based zwitterionic poly (serine methacrylate) as an antifouling material.

Amino acid

zwitterionic poly (serine methacrylate)


Input: A serine-based zwitterionic poly (serine methacrylate) (pSerMA) was developed in this work to be used as a potential antifouling material.

serine

zwitterionic poly (serine methacrylate)

pSerMA


Input: A surface-initiated photoiniferter-mediated polymerization (SI-PIMP) method was used to graft polymer brushes on gold surfaces.


Input: The pSerMA-grafted samples with different polymer film thicknesses were readily prepared by varying the UV-irradiation time.

pSerMA


Input: With the optimal film thickness, the adsorptions from bovine serum albumin, human serum, and human plasma onto the pSerMA-grafted surfaces, as evaluated by a surface plasmon resonance (SPR) biosensor, were 1. 8, 9. 2, and 12. 9 ng/cm (2), respectively, comparable to the traditional antifouling material such as poly (ethylene glycol).

pSerMA

poly (ethylene glycol)


Input: The pSerMA-grafted surfaces also strongly resisted adhesion from bovine aortic endothelial cells.

pSerMA


Input: This is the first work to develop an amino acid-based zwitterionic polymer as an antifouling material, demonstrating that pSerMA is a promising alternative to the traditional ethylene glycol-based antifouling materials.

amino acid

pSerMA

ethylene glycol


Input: Discriminating the endogenous and exogenous urinary estrogens in human by isotopic ratio mass spectrometry and its potential clinical value.

estrogens


Input: Estrogens were prohibited in the food producing animals by European Union (96/22/EC directive) and added to the Report on Carcinogens in United States since 2002.

Estrogens


Input: Due to very low concentration in serum or urine (~ pg/mL), the method of control its abuse had not been fully developed.


Input: The endogenous estrogens were separated from urines of 18 adult men and women.

estrogens


Input: The exogenous estrogens were chemical reference standards and over the counter preparations.

estrogens


Input: Two patients of dysfunctional uterine bleeding (DUB) administered exogenous estradiol and the urines were collected for 72 h.

estradiol


Input: The urinary estrogens were separated by high-performance liquid chromatography (HPLC) and confirmed.

estrogens


Input: The exogenous and exogenous estrogens were analyzed by gas chromatography combustion isotope ratio mass spectrometry (GC-C-IRMS) to determine the (13) C/(12) C ratio (delta (13) C /1000).

estrogens

(13) C

(12) C

(13) C


Input: The delta (13) C /1000 values of reference standard of E1, E2, and E3 were-29. 36 +/- 0. 72,-27. 98 +/- 0. 35,-27. 62 +/- 0. 51, respectively.

(13) C


Input: The delta (13) C /1000 values of the endogenous E1, E2, and E3 were-21. 62 +/- 1. 07,-22. 14 +/- 0. 98, and-21. 88 +/- 1. 16, with P < 0. 01 (t-test).

(13) C


Input: Two DUB patients' urinary estradiol delta (13) C /1000 values was depleted to-28. 02 +/- 0. 33 after the administration.

estradiol

(13) C


Input: The progesterone, 17 alpha-hydroxyprogesterone, pregnanediol, as well as desogestrel and ethinylestradiol from contraceptives were also determined.

progesterone

17 alpha-hydroxyprogesterone

pregnanediol

desogestrel

ethinylestradiol


Input: Stable carbon isotope analysis can distinguish the endogenous and exogenous urinary estrogen in human.

carbon

estrogen


Input: Identification and characterization of MIP-1 alpha/CCL3 isoform 2 from bovine serum as a potent monocyte/dendritic cell chemoattractant.


Input: Bovine serum is a rich source of cytokines and growth factors supporting in vitro cell culture.


Input: Here, a novel bovine monocyte chemotactic factor (boMCF-1) was isolated from commercial bovine serum by a four step purification procedure including adsorption to silicic acid, heparin affinity and cation-exchange chromatography and reversed phase HPLC.

silicic acid


Input: Homogeneous boMCF-1 was characterized as a 7717Da protein by mass spectrometry and identified by Edman degradation as the predicted product of bovine macrophage inflammatory protein-1 alpha gene (boMIP-1 alpha/CCL3) isoform 2 (lacking three NH 2-terminal amino acids), belonging to the MIP subfamily of CC chemokines.

NH 2

amino acids


Input: Monocyte chemotactic activity of boCCL3 isoform 2 was completely desensitized by human CCL3 and CCL5, partially by CCL7 and not by CCL2.


Input: Its activity was better inhibited by CCR1 than by CCR5 blockade.


Input: BoCCL3 isoform 2, present in bovine serum at about 10 ng/ml, functioned as a most potent chemoattractant for immature (but not mature) dendritic cells with a minimal effective concentration of 0. 03 ng/ml and a maximal chemotactic index of 30 at 0. 3 ng/ml.


Input: Its chemotactic activity on immature dendritic cells was significantly desensitized by human CCL3, CCL5 and CCL7.


Input: Blockade of CCR5 rather than CCR1 partially prevented chemotactic activity, whereas blockade of both further enhanced this inhibition.


Input: BoCCL3 isoform 2 was not chemokinetic but, like human CCL3, synergized with CXCL12 in monocytic cell chemotaxis.


Input: Since it cannot be deduced which is the exact human homolog of boCCL3 isoform 2, further research is required to study the biology of other boCCL3 family members.


Input: A naonoporous cell-therapy device with controllable biodegradation for long-term drug release.


Input: Herein we describe the development and implementation of a nanoporous cell-therapy device with controllable biodegradation.


Input: Dopamine-secreting PC12 cells were housed within newly formulated alginate-glutamine degradable polylysine (A-GD-PLL) microcapsules.

Dopamine

glutamine

polylysine

PLL


Input: The A-GD-PLL microcapsules provided a 3-D microenvironment for good spatial cell growth, viability and proliferation.

PLL


Input: The microcapsules were subsequently placed within a poly (ethylene glycol) (PEG)-coated poly (epsilon-caprolactone) (PCL) chamber covered with a PEG-grafted PCL nanoporous membrane formed by phase inversion.

poly (ethylene glycol)

PEG

poly (epsilon-caprolactone)

PCL

PEG-grafted PCL


Input: To enhance PC12 cell growth and to assist in controlled degradation of both the PC12 cells and the device construct, small PCL capsules containing neural growth factor (PCL-NGF) and a poly (lactic-co-glycolic acid) pellet containing glutamine (PLGA-GLN) were also placed within the PCL chamber.

PCL

PCL

poly (lactic-co-glycolic acid)

glutamine

PLGA

GLN

PCL


Input: Release of NGF from the PCL-NGF capsules facilitated cell proliferation and viability, while the controlled release of GLN from the PLGA-GLN pellet resulted in A-GD-PLL microcapsule degradation and eventual PC12 cell death following a pre-specified period of time (4 weeks in this study).

PCL

GLN

PLGA

GLN

PLL


Input: In vivo, our device was found to be well tolerated and we successfully demonstrated the controlled release of dopamine over a period of four weeks.

dopamine


Input: This integrated biodegradable device holds great promise for the future treatment of a variety of diseases.


Input: Metals loads into the Mediterranean Sea: estimate of Sarno River inputs and ecological risk.


Input: The metals pollution in the Sarno River and its environmental impact on the Gulf of Naples (Tyrrhenian Sea, Central Mediterranean Sea) were estimated.


Input: Eight selected metals (As, Hg, Cd, Cr, Cu, Ni, Pb and Zn) were determined in the water dissolved phase (DP), suspended particulate matter (SPM) and sediment samples.

As

Hg

Cd

Cr

Cu

Ni

Pb

Zn


Input: Selected metals concentrations ranged from 0. 32 to 1, 680. 39 mu g l (-1) in water DP, from 103. 6 to 7, 734. 6 mu g l (-1) in SPM and from 90. 7 to 2, 470. 3 mg kg (-1) in sediment samples.


Input: Contaminant discharges of selected metals into the sea were calculated in about 13, 977. 6 kg year (-1) showing that this river should account as one of the main contribution sources of metals to the Tyrrhenian Sea.


Input: Dynamic bioavailability of copper in soil estimated by uptake and elimination kinetics in the springtail Folsomia candida.

copper


Input: This study aimed to assess the bioavailability of copper in soil, by measuring its uptake kinetics into a representative soil invertebrate, the collembolan Folsomia candida.

copper


Input: The animals were exposed to 25 or 100 mu g Cu g (-1) dry LUFA 2. 2 soil at nominal pH (CaCl2) 4. 5, 5. 5, or 6. 5 during 14 days after which they were transferred to clean soil for 14 days elimination.

Cu


Input: Uptake and elimination rate constants were calculated based on total and extractable soil concentrations and porewater concentrations using one-compartment first-order kinetics modelling.


Input: Copper was present in the animals at a basal physiological level of 40-90 mu g g (-1) dry weight, on top of this uptake and elimination kinetics were observed.

Copper


Input: Uptake rates constants varied between 0. 02 and 0. 17 g (soil) g (animal) (-1) day (-1), being higher at lower exposure level, but did not differ significantly between different soil pH levels.


Input: Elimination rate constants ranged between 0. 04 and 0. 20 day (-1) and were negligible (k (2) < 0. 001 day (-1)) at pH 4. 5 and 6. 5.


Input: Multiple linear regressions showed that the pH effect on copper uptake was only significant when taking into account cation exchange capacity, or calcium and dissolved organic carbon levels in the pore water.

copper

calcium

carbon


Input: Copper concentrations in the animals however, never were higher than 185 mu g g (-1) dry weight, independent of exposure level and pH, suggesting homeostatic regulation.

Copper


Input: These results show that the chemical composition of the pore water does affect bioavailability of copper in soil, but that copper uptake in collembolans is dominated by homeostatic regulation rather than by soil properties like pH.

copper

copper


Input: A photoinduced charge transfer composite of graphene oxide and ferrocene.

graphene oxide

ferrocene


Input: We demonstrate the formation of a photoinduced charge transfer composite with graphene oxide (GO) and ferrocene (Fc) molecules.

graphene oxide

ferrocene


Input: Derived insulating GO was partially reduced to improve the conductivity and modified with the Fc molecules.


Input: Transmission electron microscopy (TEM), elemental mapping, X-ray photoelectron and UV-visible spectroscopy studies confirm that the Fc molecules were well grafted to the surface of a GO sheet.


Input: Photoresponsivity of the prepared GO-Fc composite was investigated by fabricating a metal/GO-Fc/metal device.

GO-Fc

GO-Fc


Input: The fabricated device shows enhanced current density under light illumination, suggesting a photo-induced charge transfer process in the developed GO-Fc composite.

GO-Fc


Input: Phase transition-induced elasticity of alpha-helical bioelastomeric fibres and networks.


Input: Natural elastomeric fibres play central structural and functional roles in a variety of tissues produced by many organisms from diverse Phyla.


Input: Most of these fibres feature amorphous structure and their long-range elastic response is well described within the framework of entropic (rubber-like) elasticity.


Input: Recently, it has been recognized that long-range reversible deformation can also occur in biomacromolecular fibres or networks that feature significant secondary structure and long-range order.


Input: Their elastomeric response is then associated with conformational changes of the backbone of the constitutive protein-based polymers.


Input: Under axially imposed loads, several groups of proteins whose structure is dominated by alpha-helical coiled-coil structures can undergo unfolding transitions and secondary structure transformations, for example from coiled-coil alpha-helices to beta-sheet strands.


Input: In contrast to rubber-like biopolymers, the retractive elastic force in these biomacromolecular materials is not dominated by a return to a maximum entropic state, but is mostly the result of variations in internal energy associated with the conformational changes.


Input: Here, a review of alpha-helix based elastomeric materials is presented that encompasses examples and experimental evidence across multiple length scales, from the molecular to the macroscopic scale.


Input: We begin by summarizing the basic thermodynamic formalism of thermoelasticity.


Input: While this formalism is well established for amorphous (entropically-dominated) fibres under tensile loading, its extension towards conformational (internal energy-dominated) elasticity is less known.


Input: Recent experimental evidence as well as corroborating computer simulations are then reviewed and discussed in the light of secondary structure and nano-scale features of these biopolymers.


Input: Comparisons are also drawn with physiologically important structural fibres that share common characteristics at the molecular and the nano-scale, including intermediate filament (IF) proteins from the cell cytoskeleton, myosins from motor proteins, and fibrin from blood clot.


Input: We conclude with a discussion on future directions and opportunities for these materials from a biomimetics engineering perspective.


Input: Regions on adenylyl cyclase VII required for selective regulation by the G13 pathway.

adenylyl


Input: Regulation of multiple adenylyl cyclases (AC) provides unique inputs to mediate the synthesis of cAMP, a ubiquitous second messenger that controls many aspects of cellular function.

adenylyl

cAMP


Input: On stimulation by G (s), the activities of ACs can be further selectively modulated by other pathways to ensure precise control of intracellular cAMP responses to specific stimuli.

cAMP


Input: Recently, we reported that one of the AC isoforms, AC7, is uniquely regulated by the G (13) pathway.


Input: To understand more fully the molecular mechanism of this regulation, we compared the regulation of AC7 with that of AC2 in bone marrow-derived macrophages devoid of AC7.


Input: Although both enzymes could fully restore regulation of cAMP by G beta gamma, activation of the G (13) pathway preferentially synergized with AC7.

cAMP


Input: Exchange of domains between the two isoforms indicates that the C1b domain and the N-terminus of the C1a domain are important for directing selective regulation of AC7 by the G (13) pathway.

N


Input: A mutagenesis screen identified more specific regions of AC7 that differentially mediate its regulation by distinct pathways.


Input: Vitamin K2 covalently binds to Bak and induces Bak-mediated apoptosis.

Vitamin K2


Input: Vitamin K2 (VK2, menaquinone) is known to have anticancer activity in vitro and in vivo.

Vitamin K2

menaquinone


Input: Although its effect is thought to be mediated, at least in part, by the induction of apoptosis, the underlying molecular mechanism remains elusive.


Input: Here, we identified Bcl-2 antagonist killer 1 (Bak) as a molecular target of VK2-induced apoptosis.


Input: VK2 directly interacts with Bak and induces mitochondrial-mediated apoptosis.


Input: Although Bak and Bcl-2-associated X protein (Bax), another member of the Bcl-2 family, are generally thought to be functionally redundant, only Bak is necessary and sufficient for VK2-induced cytochrome c (cyt c) release and cell death.


Input: Moreover, VK2-2, 3 epoxide, an intracellular metabolite of VK2, was shown to covalently bind to the cysteine-166 residue of Bak.

VK2-2, 3 epoxide

cysteine


Input: Several lines of evidence suggested that the covalent attachment of VK2 is critical for apoptosis induction.


Input: Thus this study reveals a specific role for Bak in mitochondria-mediated apoptosis.


Input: This study also provides insight into the anticancer effects of VK2 and suggests that Bak may be a potential target of cancer therapy.


Input: Relative oral bioavailability of 3-MCPD from 3-MCPD fatty acid esters in rats.

3-MCPD fatty acid esters


Input: In order to quantify the relative oral bioavailability of 3-chloropropane-1, 2-diol (3-MCPD) from 3-MCPD fatty acid diesters in vivo, 1, 2-dipalmitoyl-3-chloropropane-1, 2-diol (3-MCPD diester) and 3-MCPD were orally applied to rats in equimolar doses.

3-chloropropane-1, 2-diol

3-MCPD fatty acid diesters

1, 2-dipalmitoyl-3-chloropropane-1, 2-diol

3-MCPD diester


Input: In both cases, the time courses of 3-MCPD concentrations were measured in blood, various organs, tissues and intestinal luminal contents.


Input: The results show that 3-MCPD is released by enzymatic hydrolysis from the 3-MCPD diester in the gastrointestinal tract and distributed to blood, organs and tissues.

3-MCPD diester


Input: Based on the measurements in blood, the areas under the curve (AUC) for 3-MCPD were calculated.


Input: By comparing both AUC, the relative amount of 3-MCPD bioavailable from the 3-MCPD diester was calculated to be 86% on average of the amount bioavailable following administration of 3-MCPD.

3-MCPD diester


Input: In view of limited experimental data, it is justified for the purpose of risk assessment to assume complete hydrolysis of the diesters in the gastro-intestinal tract.


Input: Therefore, assessment of the extent of exposure to 3-MCPD released from its fatty acid esters should be performed in the same way as exposure to the same molar quantity of 3-MCPD.

fatty acid esters


Input: Enantioresolution of chiral derivatives of xanthones on (S, S)-Whelk-O1 and L-phenylglycine stationary phases and chiral recognition mechanism by docking approach for (S, S)-Whelk-O1.

xanthones

L-phenylglycine


Input: The resolution of seven enantiomeric pairs of chiral derivatives of xanthones (CDXs) on (S, S)-Whelk-O1 and L-phenylglycine chiral stationary phases (CSPs) was systematically investigated using multimodal elution conditions (normal-phase, polar-organic, and reversed-phase).

xanthones

L-phenylglycine


Input: The (S, S)-Whelk-O1 CSP, under polar-organic conditions, demonstrated a very good power of resolution for the CDXs possessing an aromatic moiety linked to the stereogenic center with separation factor and resolution factor ranging from 1. 91 to 7. 55 and from 6. 71 to 24. 16, respectively.


Input: The chiral recognition mechanisms were also investigated for (S, S)-Whelk-O1 CSP by molecular docking technique.


Input: Data regarding the CSP-CDX molecular conformations and interactions were retrieved.


Input: These results were in accordance with the experimental chromatographic parameters regarding enantioselectivity and enantiomer elution order.


Input: The results of the present study fulfilled the initial objectives of enantioselective studies of CDXs and elucidation of intermolecular CSP-CDX interactions.


Input: The Midregional Fragment of Pro-A-Type Natriuretic Peptide, Blood Pressure, and Mortality in a Prospective Cohort Study of Patients With Type 2 Diabetes (ZODIAC-25).


Input: OBJECTIVE Evidence that midregional fragment of pro-A-type natriuretic peptide (MR-proANP) is a marker of mortality in patients with type 2 diabetes is limited.


Input: Therefore, we aimed to investigate the capabilities of MR-proANP in predicting mortality.


Input: We also investigated whether MR-proANP influences the relationship between blood pressure and mortality in old age.


Input: RESEARCH DESIGN AND METHODS In 1998, 1, 143 primary care patients with type 2 diabetes participated in the ZODIAC study.


Input: Because blood was drawn for 867 patients (76%) and confounders were missing for 19 patients, the final study sample comprised 848 patients.


Input: After a follow-up time of 10 years, we used Cox proportional hazard models to evaluate the relationship between MR-proANP and (cardiovascular) mortality.


Input: Harrell C statistic was used to compare models with and without MR-proANP.


Input: The regression analyses were repeated without MR-proANP for patients aged older than 75 years.


Input: RESULTS Median MR-proANP in the total study sample was 75 pmol/L (interquartile range, 48-124 pmol/L).


Input: During follow-up, 354 (42%) out of 848 patients had died, of whom 152 (43%) deaths were attributable to cardiovascular factors.


Input: MR-proANP was independently associated with all-cause and cardiovascular mortality, irrespective of age.


Input: During old age, there was a significant inverse relationship between blood pressure and mortality.


Input: This relationship did not change after adjustment for MR-proANP.


Input: CONCLUSIONS MR-proANP is independently associated with mortality in patients with type 2 diabetes.


Input: MR-proANP did not influence the inverse relationship between blood pressure and mortality in elderly patients.


Input: Involvement of UDP-glucuronosyltransferases UGT1A9 and UGT2B7 in ethanol glucuronidation, and interactions with common drugs of abuse.

UDP

ethanol


Input: Ethyl glucuronide (EtG) determination is increasingly used in clinical and forensic toxicology to document ethanol consumption.

Ethyl glucuronide

EtG

ethanol


Input: The enzymes involved in EtG production, as well as potential interactions with common drugs of abuse, have not been extensively studied.

EtG


Input: Activities of human liver (HLM), kidney (HKM), and intestinal (HIM) microsomes, as well as of 12 major human recombinant UDP-glucuronosyltransferases (UGTs), toward ethanol (50 and 500 mM) were evaluated in vitro using liquid chromatography-tandem mass spectrometry.

UDP

ethanol


Input: Enzyme kinetic parameters were determined for pooled microsomes and recombinant UGTs with significant activity.


Input: Individual contributions of UGTs were estimated using the relative activity factor approach, proposed for scaling activities obtained with cDNA-expressed enzymes to HLM.


Input: Interaction of morphine, codeine, lorazepam, oxazepam, nicotine, cotinine, cannabinol, and cannabidiol (5, 10, 15 mg/l) with ethanol (1. 15, 4. 6, 11. 5 g/l; i. e., 25, 100, 250 mM) glucuronidation was assessed using pooled HLM.

morphine

codeine

lorazepam

oxazepam

nicotine

cotinine

cannabinol

cannabidiol

ethanol


Input: Ethanol glucuronidation intrinsic clearance (Cl (int)) was 4 and 12. 7 times higher for HLM than for HKM and HIM, respectively.

Ethanol


Input: All recombinant UGTs, except UGT1A1, 1A6, and 1A10, produced EtG in detectable amounts.

EtG


Input: UGT1A9 and 2B7 were the most active enzymes, each accounting for 17 and 33% of HLM Cl (int), respectively.


Input: Only cannabinol and cannabidiol significantly affected ethanol glucuronidation.

cannabinol

cannabidiol

ethanol


Input: Cannabinol increased ethanol glucuronidation in a concentration-dependent manner, whereas cannabidiol significantly inhibited EtG formation in a noncompetitive manner (IC (50) = 1. 17 mg/l; inhibition constant (K (i)) = 3. 1 mg/l).

Cannabinol

ethanol

cannabidiol

EtG


Input: UGT1A9 and 2B7 are the main enzymes involved in ethanol glucuronidation.

ethanol


Input: In addition, our results suggest that cannabinol and cannabidiol could significantly alter ethanol glucuronidation.

cannabinol

cannabidiol

ethanol


Input: Mutation of a zinc-binding residue in the glycine receptor alpha 1 subunit changes ethanol sensitivity in vitro and alcohol consumption in vivo.

zinc

glycine

ethanol

alcohol


Input: Ethanol is a widely used drug, yet an understanding of its sites and mechanisms of action remains incomplete.

Ethanol


Input: Among the protein targets of ethanol are glycine receptors (GlyRs), which are potentiated by millimolar concentrations of ethanol.

ethanol

glycine

ethanol


Input: In addition, zinc ions also modulate GlyR function, and recent evidence suggests that physiologic concentrations of zinc enhance ethanol potentiation of GlyRs.

zinc

zinc

ethanol


Input: Here, we first built a homology model of a zinc-bound GlyR using the D80 position as a coordination site for a zinc ion.

zinc

zinc


Input: Next, we investigated in vitro the effects of zinc on ethanol action at recombinant wild-type (WT) and mutant alpha 1 GlyRs containing the D80A substitution, which eliminates zinc potentiation.

zinc

ethanol

zinc


Input: At D80A GlyRs, the effects of 50 and 200 mM ethanol were reduced as compared with WT receptors.

ethanol


Input: Also, in contrast to what was seen with WT GlyRs, neither adding nor chelating zinc changed the magnitude of ethanol enhancement of mutant D80A receptors.

zinc

ethanol


Input: Next, we evaluated the in vivo effects of the D80A substitution by using heterozygous Glra1 (D80A) knock-in (KI) mice.


Input: The KI mice showed decreased ethanol consumption and preference, and they displayed increased startle responses compared with their WT littermates.

ethanol


Input: Other behavioral tests, including ethanol-induced motor incoordination and strychnine-induced convulsions, revealed no differences between the KI and WT mice.

ethanol

strychnine


Input: Together, our findings indicate that zinc is critical in determining the effects of ethanol at GlyRs and suggest that zinc binding at the D80 position may be important for mediating some of the behavioral effects of ethanol action at GlyRs.

zinc

ethanol

zinc

ethanol


Input: Expression and activity of nitric oxide synthase isoforms in methamphetamine-induced striatal dopamine toxicity.

nitric oxide

methamphetamine

dopamine


Input: Nitric oxide is implicated in methamphetamine (METH)-induced neurotoxicity; however, the source of the nitric oxide has not been identified.

Nitric oxide

methamphetamine

METH

nitric oxide


Input: Previous work has also revealed that animals with partial dopamine loss induced by a neurotoxic regimen of methamphetamine fail to exhibit further decreases in striatal dopamine when re-exposed to methamphetamine 7-30 days later.

dopamine

methamphetamine

dopamine

methamphetamine


Input: The current study examined nitric oxide synthase expression and activity and protein nitration in striata of animals administered saline or neurotoxic regimens of methamphetamine at postnatal days 60 and/or 90, resulting in four treatment groups: Saline: Saline, METH: Saline, Saline: METH, and METH: METH.

nitric oxide

methamphetamine

METH

METH

METH

METH


Input: Acute administration of methamphetamine on postnatal day 90 (Saline: METH and METH: METH) increased nitric oxide production, as evidenced by increased protein nitration.

methamphetamine

METH

METH

METH

nitric oxide


Input: Methamphetamine did not, however, change the expression of endothelial or inducible isoforms of nitric oxide synthase, nor did it change the number of cells positive for neuronal nitric oxide synthase mRNA expression or the amount of neuronal nitric oxide synthase mRNA per cell.

Methamphetamine

nitric oxide

nitric oxide

nitric oxide


Input: However, nitric oxide synthase activity in striatal interneurons was increased in the Saline: METH and METH: METH animals.

nitric oxide

METH

METH

METH


Input: These data suggest that increased nitric oxide production after a neurotoxic regimen of methamphetamine results from increased nitric oxide synthase activity, rather than an induction of mRNA, and that constitutively expressed neuronal nitric oxide synthase is the most likely source of nitric oxide after methamphetamine administration.

nitric oxide

methamphetamine

nitric oxide

nitric oxide

nitric oxide

methamphetamine


Input: Of interest, animals rendered resistant to further methamphetamine-induced dopamine depletions still show equivalent degrees of methamphetamine-induced nitric oxide production, suggesting that nitric oxide production alone in response to methamphetamine is not sufficient to induce acute neurotoxic injury.

methamphetamine

dopamine

methamphetamine

nitric oxide

nitric oxide

methamphetamine


Input: The yeast cap binding complex modulates transcription factor recruitment and establishes proper histone H3K36 trimethylation during active transcription.


Input: Recent studies have revealed a close relationship between transcription, histone modification, and RNA processing.


Input: In fact, genome-wide analyses that correlate histone marks with RNA processing signals raise the possibility that specific RNA processing factors may modulate transcription and help to " write " chromatin marks.


Input: Here we show that the nuclear cap binding complex (CBC) directs recruitment of transcription elongation factors and establishes proper histone marks during active transcription.


Input: A directed genetic screen revealed that deletion of either subunit of the CBC confers a synthetic growth defect when combined with deletion of genes encoding either Ctk2 or Bur2, a component of the Saccharomyces cerevisiae ortholog of P-TEFb.


Input: The CBC physically associates with these complexes to recruit them during transcription and mediates phosphorylation at Ser-2 of the C-terminal domain (CTD) of RNA polymerase II.

Ser

C


Input: To understand how these interactions influence downstream events, histone H3K36me3 was examined, and we demonstrate that CBC Delta affects proper Set2-dependent H3K36me3.


Input: Consistent with this, the CBC and Set2 have similar effects on the ability to rapidly induce and sustain activated gene expression, and these effects are distinct from other histone methyltransferases.


Input: This work provides evidence for an emerging model that RNA processing factors can modulate the recruitment of transcription factors and influence histone modification during elongation.


Input: Continuum-and particle-based modeling of shapes and dynamics of red blood cells in health and disease.


Input: We review recent advances in multiscale modeling of the mechanics of healthy and diseased red blood cells (RBCs), and blood flow in the microcirculation.


Input: We cover the traditional continuum-based methods but also particle-based methods used to model both the RBCs and the blood plasma.


Input: We highlight examples of successful simulations of blood flow including malaria and sickle cell anemia.


Input: Surfactant-free microemulsion composed of oleic acid, n-propanol, and H2O.

oleic acid

n-propanol


Input: Generally, a microemulsion consists of oil, water, surfactant, and sometimes cosurfactant.


Input: Herein, we report a surfactant-free microemulsion (denoted as SFME), consisting of oleic acid (oil phase), water, and n-propanol without the amphiphilic molecular structure of a traditional surfactant.

oleic acid

n-propanol


Input: The phase behavior of the ternary system was investigated, showing that there were a single-phase microemulsion region and a multiphase region in the ternary phase diagram.


Input: The electrical conductivity measurement was employed to investigate the microregions of the single-phase microemulsion region, and three different microregions, that is, water-in-oleic acid (W/O), a bicontinuous (B. C.) region, and oleic acid-in-water (O/W), were identified, which were further confirmed by freeze-fracture and cryogenic transmission electron microscopy (FF-TEM and Cryo-TEM) observations.

oleic acid

oleic acid


Input: The polarity and the salt solubility of water domains in the W/O SFME were investigated by UV-visible spectroscopy using methyl orange and potassium ferricyanide as probes, respectively.

methyl orange

potassium ferricyanide


Input: Experimental results showed that the water domains in the W/O microemulsion had a lower polarity than bulk water and a normal solubility for salt species, indicating that the SFMEs have much significance in the preparation of various nanomaterials.


Input: An optimized RAD51 inhibitor that disrupts homologous recombination without requiring Michael acceptor reactivity.


Input: Homologous recombination (HR) is an essential process in cells that provides repair of DNA double-strand breaks and lesions that block DNA replication.


Input: RAD51 is an evolutionarily conserved protein that is central to HR.


Input: Overexpression of RAD51 protein is common in cancer cells and represents a potential therapeutic target in oncology.


Input: We previously described a chemical inhibitor of RAD51, called RI-1 (referred to as compound 1 in this report).


Input: The chloromaleimide group of this compound is thought to act as a Michael acceptor and react with the thiol group on C319 of RAD51, using a conjugate addition-elimination mechanism.

chloromaleimide

thiol


Input: In order to reduce the likelihood of off-target effects and to improve compound stability in biological systems, we developed an analogue of compound 1 that lacks maleimide-based reactivity but retains RAD51 inhibitory activity.

maleimide


Input: This compound, 1-(3, 4-dichlorophenyl)-3-(4-methoxyphenyl)-4-morpholino-1H-pyrrole-2, 5-dione, named RI-2 (referred to as compound 7a in this report), appears to bind reversibly to the same site on the RAD51 protein as does compound 1.

1-(3, 4-dichlorophenyl)-3-(4-methoxyphenyl)-4-morpholino-1H-pyrrole-2, 5-dione


Input: Like compound 1, compound 7a specifically inhibits HR repair in human cells.


Input: Tilting the balance between canonical and noncanonical conformations for the H1 hypervariable loop of a llama VHH through point mutations.


Input: Nanobodies are single-domain antibodies found in camelids.


Input: These are the smallest naturally occurring binding domains and derive functionality via three hypervariable loops (H1-H3) that form the binding surface.


Input: They are excellent candidates for antibody engineering because of their favorable characteristics like small size, high solubility, and stability.


Input: To rationally engineer antibodies with affinity for a specific target, the hypervariable loops can be tailored to obtain the desired binding surface.


Input: As a first step toward such a goal, we consider the design of loops with a desired conformation.


Input: In this study, we focus on the H1 loop of the anti-hCG llama nanobody that exhibits a noncanonical conformation.


Input: We aim to " tilt " the stability of the H1 loop structure from a noncanonical conformation to a (humanized) type 1 canonical conformation by studying the effect of selected mutations to the amino acid sequence of the H1, H2, and proximal residues.

amino acid


Input: We use all-atomistic, explicit-solvent, biased molecular dynamic simulations to simulate the wild-type and mutant loops in a prefolded framework.


Input: We thus find mutants with increasing propensity to form a stable type 1 canonical conformation of the H1 loop.


Input: Free energy landscapes reveal the existence of conformational isomers of the canonical conformation that may play a role in binding different antigenic surfaces.


Input: We also elucidate the approximate mechanism and kinetics of transitions between such conformational isomers by using a Markovian model.


Input: We find that a particular three-point mutant has the strongest thermodynamic propensity to form the H1 type 1 canonical structure but also to exhibit transitions between conformational isomers, while a different, more rigid three-point mutant has the strongest propensity to be kinetically trapped in such a canonical structure.


Input: Peptidyl-prolyl cis/trans-isomerase A1 (Pin1) is a target for modification by lipid electrophiles.

prolyl


Input: Oxidation of membrane phospholipids is associated with inflammation, neurodegenerative disease, and cancer.


Input: Oxyradical damage to phospholipids results in the production of reactive aldehydes that adduct proteins and modulate their function.

aldehydes


Input: 4-Hydroxynonenal (HNE), a common product of oxidative damage to lipids, adducts proteins at exposed Cys, His, or Lys residues.

HNE

Cys

His

Lys


Input: Here, we demonstrate that peptidyl-prolyl cis/trans-isomerase A1 (Pin1), an enzyme that catalyzes the conversion of the peptide bond of pSer/pThr-Pro moieties in signaling proteins from cis to trans, is highly susceptible to HNE modification.

prolyl

pSer

pThr

Pro

HNE


Input: Incubation of purified Pin1 with HNE followed by MALDI-TOF/TOF mass spectrometry resulted in detection of Michael adducts at the active site residues His-157 and Cys-113.

HNE

His

Cys


Input: Time and concentration dependencies indicate that Cys-113 is the primary site of HNE modification.

Cys

HNE


Input: Pin1 was adducted in MDA-MB-231 breast cancer cells treated with 8-alkynyl-HNE as judged by click chemistry conjugation with biotin followed by streptavidin-based pulldown and Western blotting with anti-Pin1 antibody.

biotin


Input: Furthermore, orbitrap MS data support the adduction of Cys-113 in the Pin1 active site upon HNE treatment of MDA-MB-231 cells.

Cys

HNE


Input: siRNA knockdown of Pin1 in MDA-MB-231 cells partially protected the cells from HNE-induced toxicity.

HNE


Input: Recent studies indicate that Pin1 is an important molecular target for the chemopreventive effects of green tea polyphenols.

polyphenols


Input: The present study establishes that it is also a target for electrophilic modification by products of lipid peroxidation.


Input: New iridoid glycoside and triterpenoid glycoside from Premna fulva.

iridoid glycoside

triterpenoid glycoside


Input: Liquid chromatography-photodiode array detector-mass spectrometry-based chemical investigation of the leaves and stems of Premna fulva yielded one new iridoid glycoside (1), one new triterpenoid glycoside (2) along with six known compounds isolated for the first time from the genus.

iridoid glycoside

triterpenoid glycoside


Input: Their structures were established on the basis of extensive spectroscopic data analyses and chemical methods.


Input: Acetazolamide impairs fear memory consolidation in rodents.

Acetazolamide


Input: Acetazolamide (AZ) is an carbonic anhydrase inhibitor, which has been used in the treatment of seizures, mountain sickness and glaucoma.

Acetazolamide


Input: Memory impairment by AZ has been reported in patient interviews; however, the related mechanism is unclear.


Input: We applied two fear conditioning paradigms, shuttle avoidance and passive avoidance, in both rats and mice to investigate this clinical anecdote.


Input: Adult Wistar rats receiving AZ 1 h before the shuttle avoidance test showed decreased avoidance rates, especially at high dosage.


Input: Adult ICR mice receiving AZ both before and after acquisition trials showed the decreased step-through latencies during the passive avoidance test.


Input: This impairment of fear memory was corroborated with decreased LTP by AZ in the amygdala.


Input: AZ only inhibited fear conditioning-induced ERK phosphorylation and had no effect on Akt phosphorylation.


Input: In conclusion, our study confirmed the adverse cognitive effect of AZ in animal and electrophysiological studies.


Input: In clinical practice, clinicians should be aware of this side effect in patients taking AZ.


Input: In addition, this inhibition of fear memory by AZ could potentially be applied to patients with posttraumatic stress disorder.


Input: Structure-based optimization of angiostatic agent 6DBF7, an allosteric antagonist of galectin-1.


Input: Galectin-1 (gal-1), which binds beta-galactoside groups on various cell surface receptors, is crucial to cell adhesion and migration, and is found to be elevated in several cancers.


Input: Previously, we reported on 6DBF7, a dibenzofuran (DBF)-based peptidomimetic of the gal-1 antagonist anginex.

dibenzofuran

DBF


Input: In the present study, we used a structure-based approach to optimize 6DBF7.


Input: Initial NMR studies showed that 6DBF7 binds to gal-1 on one side of the beta-sandwich away from the lectin' s carbohydrate binding site.

carbohydrate


Input: Although an alanine scan of 6DBF7 showed that the two cationic groups (lysines) in the partial peptide are crucial to its angiostatic activity, it is the hydrophobic face of the amphipath that appears to interact directly with the surface of gal-1.

alanine

lysines


Input: Based on this structural information, we designed and tested additional DBF analogs.

DBF


Input: In particular, substitution of the C-terminal Asp for alanine and branched alkyl side chains (Val, Leu, Ile) for linear ones (Nle, Nva) rendered the greatest improvements in activity.

C

Asp

alanine

alkyl

Val

Leu

Ile

Nle

Nva


Input: Flow cytometry with gal-1 (-/-) splenocytes showed that 6DBF7 and two of its more potent analogs (DB16 and DB21) can fully inhibit fluorescein isothiocyanate-gal-1 binding.

fluorescein isothiocyanate


Input: Moreover, heteronuclear single-quantum coherence NMR titrations showed that the presence of DB16 decreases gal-1 affinity for lactose, indicating that the peptidomimetic targets gal-1 as a noncompetitive, allosteric inhibitor of glycan binding.

lactose