Input: The oxidative damage of liver tissue was evaluated by lipid peroxidation and antioxidant enzymes.


Input: Oxidative stress related genes were detected to reflect the liver stress state at the molecular level.


Input: Compared to the control and Na2SeO3 groups, the MDA content in liver tissue was decreased and the activities of antioxidant enzymes were increased in the Na2SeO3 intervention group.

MDA


Input: The mRNA levels of SOD1, CAT, GPx and Txnrd1 were increased significantly (P < 0. 05) in the combined Na2SeO3 + NaAsO2 treatment group.


Input: The expressions of HSP70 and HO-1 were significantly (P < 0. 05) increased in the NaAsO2 group and reduced in the combined treatment group.


Input: The results indicate that long-term intake of NaAsO2 causes oxidative damage in the rat liver, and Na2SeO3 protects liver cells by adjusting the expression of oxidative stress related genes to improve the activities of antioxidant enzymes.


Input: Juniperus oxycedrus L. subsp.


Input: oxycedrus and Juniperus oxycedrus L. subsp.


Input: macrocarpa (Sibth. & Sm.) Ball.


Input: " berries " from Turkey: Comparative evaluation of phenolic profile, antioxidant, cytotoxic and antimicrobial activities.


Input: This work aimed to evaluate and compare the phenolic profile and some biological properties of the ripe " berries " methanol extracts of Juniperus oxycedrus L. subsp.

methanol


Input: oxycedrus (Joo) and Juniperus oxycedrus L. subsp.


Input: macrocarpa (Sibth. & Sm.) Ball.


Input: (Jom) from Turkey.


Input: The total phenolic content resulted about 3-fold higher in Jom (17. 89 +/- 0. 23mg GAE/g extract) than in Joo (5. 14 +/- 0. 06mg GAE/g extract).

phenolic


Input: The HPLC-DAD-ESI-MS analysis revealed a similar flavonoid fingerprint in Joo and Jom, whereas a difference in their quantitative content was found (4632 mu g/g extract and 12, 644 mu g/g extract).

flavonoid


Input: In addition, three phenolic acids were detected in Jom only (5765 mu g/g extract), and protocatechuic acid was the most abundant one.

phenolic acids

protocatechuic acid


Input: The antioxidant capacity of the extracts was evaluated by different in vitro assays: in the DPPH and in the TBA tests a stronger activity in Jom was highlighted, while Joo exhibited higher reducing power and metal chelating activity.

DPPH

TBA


Input: Joo and Jom did not affect HepG2 cell viability and both extracts resulted virtually non-toxic against Artemia salina.


Input: The extracts were also studied for their antimicrobial potential, displaying efficacy against Gram-positive bacteria.


Input: The molecular basis of simple relationships between exposure concentration and toxic effects with time.


Input: Understanding the toxicity of chemicals to organisms requires considering the molecular mechanisms involved as well as the relationships between exposure concentration and toxic effects with time.


Input: Our current knowledge about such relationships is mainly explained from a toxicodynamic and toxicokinetic perspective.


Input: This paper re-introduces an old approach that takes into account the biochemical mode of action and their resulting biological effects over time of exposure.


Input: Empirical evidence demonstrates that the Druckrey-K u pfm u ller toxicity model, which was validated for chemical carcinogens in the early 1960s, is also applicable to a wide range of toxic compounds in ecotoxicology.


Input: According to this model, the character of a poison is primarily determined by the reversibility of critical receptor binding.


Input: Chemicals showing irreversible or slowly reversible binding to specific receptors will produce cumulative effects with time of exposure, and whenever the effects are also irreversible (e. g. death) they are reinforced over time; these chemical have time-cumulative toxicity.


Input: Compounds having non-specific receptor binding, or involving slowly reversible binding to some receptors that do not contribute to toxicity, may also be time-dependent; however, their effects depend primarily on the exposure concentration, with time playing a minor role.


Input: Consequently, the mechanism of toxic action has important implications for risk assessment.


Input: Traditional risk approaches cannot predict the impacts of toxicants with time-cumulative toxicity in the environment.


Input: New assessment procedures are needed to evaluate the risk that the latter chemicals pose on humans and the environment.


Input: An example is shown to explain how the risk of time-dependent toxicants is underestimated when using current risk assessment protocols.


Input: Cognitive effects of variations in pubertal timing: Is puberty a period of brain organization for human sex-typed cognition?


Input: There is considerable interest in the organizational effects of pubertal sex hormones on human sex-related characteristics.


Input: Recent evidence from rodents suggests that there is a decreasing window of sensitivity to sex hormones throughout adolescence.


Input: If adolescence also represents a period of brain organization in human beings, then the timing of exposure to sex-typical hormones at puberty should have long-term effects on sex-typed characteristics: individuals with early timing should be more sex-typed than individuals with late timing.


Input: We tested this hypothesis in 320 young adults by relating their pubertal timing (retrospective comparison to peers) to cognitive abilities that show sex differences.


Input: Results provide partial support for the hypothesis.


Input: For men, pubertal timing was inversely related to scores on a test of three-dimensional mental rotations.


Input: Effects do not appear to be due to duration of hormone exposure (time since puberty), but other potential influences need further study.


Input: New anticancer active and selective phenylene-bisbenzothiazoles: Synthesis, antiproliferative evaluation and DNA binding.

phenylene-bisbenzothiazoles


Input: Novel amidino-derivatives of phenylene-bisbenzothiazoles were synthesized and tested for their antiproliferative activity against several human cancer cell lines, as well as DNA-binding properties.

amidino

phenylene-bisbenzothiazoles


Input: The synthetic approach used for preparation of isomeric amidino substituted-phenylene-bis-benzothyazoles 3a-3f was achieved by condensation reaction of isophthaloyl dichloride 1a and terephthaloyl dichloride 1b or with phthalic acid 1c with 5-amidinium-2-aminobenzothiolate 2a and 5-(imidazolinium-2-yl)-2-aminobenzothiolate 2b in good yields.

amidino substituted-phenylene-bis-benzothyazoles

isophthaloyl dichloride

terephthaloyl dichloride

phthalic acid

5-(imidazolinium-2-yl)-2-aminobenzothiolate


Input: The targeted compounds were converted in the desired water soluble dihydrochloride salts by reaction of appropriate free base with concd HCl in ethanol or acetic acid.

dihydrochloride

HCl

ethanol

acetic acid


Input: All tested compounds (3a-3f) showed antiproliferative effects on tumour cells in a concentration-dependant manner.


Input: The strongest activity and cytotoxicity was observed for diimidazolinyl substituted phenylene-bisbenzothiazole compound 3b.

diimidazolinyl substituted phenylene-bisbenzothiazole


Input: These effects were shown to be related to DNA-binding properties, topoisomerase I and II poisoning effects and apoptosis induction.


Input: The highest tested selectivity towards tumour cells was observed for the imidazolyl substituted phenylene-benzothiazole 3d that showed no cytotoxic effects on normal fibroblasts making it an excellent candidate for further chemical optimization and preclinical evaluation.

imidazolyl substituted phenylene-benzothiazole


Input: A Bioluminescent Assay System for Whole-Cell Determination of Hormones.


Input: A bioluminescent-assay system was fabricated for an efficient determination of bioactive small molecules in physiological samples.


Input: The following three components were newly created for this assay system: (i) a single-chain probe exerting a 7. 2-times stronger optical intensity than conventional ones, (ii) a high throughput assay device uniquely designed for the assay system with ca. one-fourth smaller standard deviation (SD) to samples than without the device, (iii) a buffer cocktail optimized for the assay system.


Input: The advantages of the assay system were evaluated by determining (i) the stress hormone levels in human saliva and (ii) multicolor imaging of genomic and nongenomic effects of woman sex hormones.


Input: This study guides on how to fabricate an efficient assay system for bioactive small molecules with convenience and high precision.


Input: Large networks of vertical multi-layer graphenes with morphology-tunable magnetoresistance.

graphenes


Input: We report on the comparative study of magnetotransport properties of large-area vertical few-layer graphene networks with different morphologies, measured in a strong (up to 10 T) magnetic field over a wide temperature range.

graphene


Input: The petal-like and tree-like graphene networks grown by a plasma enhanced CVD process on a thin (500 nm) silicon oxide layer supported by a silicon wafer demonstrate a significant difference in the resistance-magnetic field dependencies at temperatures ranging from 2 to 200 K.

graphene

silicon oxide

silicon


Input: This behaviour is explained in terms of the effect of electron scattering at ultra-long reactive edges and ultra-dense boundaries of the graphene nanowalls.

graphene


Input: Our results pave a way towards three-dimensional vertical graphene-based magnetoelectronic nanodevices with morphology-tuneable anisotropic magnetic properties.

graphene


Input: The structure of the biliverdin cofactor in the Pfr state of bathy and prototypical phytochromes.

biliverdin


Input: The structures of the chromophore binding pockets in the Pfr states of various bathy and prototypical biliverdin-binding phytochromes were analysed by using a combined spectroscopic-theoretical approach.

biliverdin


Input: For the Pfr state of the bathy phytochrome from Pseudomonas aeruginosa (PaBphP) the very good agreement between calculated Raman spectra of the tetrapyrrole cofactor, obtained by quantum-mechanical/molecular-mechanical hybrid methods, and the experimental resonance Raman (RR) spectra confirms important conclusions derived from the previous crystallographic analyses, particularly the ZZEssa configuration of the chromophore and its attachment to the thiol side chain of Cys12 via the exocyclic vinyl group of ring A.

tetrapyrrole

thiol

vinyl


Input: The match between the RR spectra of the Pfr states of PaBphP and the bathy phytochrome Agp2 from Agrobacterium tumefaciens indicates very similar structures of the chromophore binding pockets.


Input: The homogeneous chromophore conformation in bathy phytochromes is in sharp contrast to the Pfr states of prototypical phytochromes as demonstrated by comparative RR spectroscopic analyses.


Input: The Pfr states of prototypical phytochromes, thoroughly studied for Agp1 (A. tumefaciens), display conformational equilibria between two sub-states differing with respect to the CD methine bridge torsional angle and the AB methine bridge geometry.

methine

methine


Input: These differences may mainly root in the interactions of the cofactor with the highly conserved Asp194 (PaBphP) that occur via its carboxylate function in bathy phytochromes.

carboxylate


Input: The weaker interactions via the carbonyl function in prototypical phytochromes may lead to a higher structural flexibility of the chromophore binding pocket that opens the reaction channel for the thermal (ZZE --> ZZZ) Pfr-to-Pr back-conversion.

carbonyl


Input: Genetic Information and the Prediction of Incident Type 2 Diabetes in a High-Risk Multi-Ethnic Population: The EpiDREAM Genetic Study.


Input: OBJECTIVESTo determine if 16 single nucleotide polymorphisms (SNPs) associated with type 2 diabetes (T2DM) in Europeans are also associated with T2DM in South Asians and Latinos, and if they can add to the prediction of incident T2DM in a high-risk population. RESEARCH DESIGN AND METHODSIn the EpiDREAM prospective cohort study, physical measures, questionnaires, and blood samples were collected from 25, 063 individuals at risk for dysglycemia.


Input: Sixteen SNPs that have been robustly associated with T2DM in Europeans were genotyped.


Input: Among 15, 466 European, South Asian, and Latino subjects, we examined the association of these 16 SNPs alone and combined in a gene score with incident cases of T2DM (n = 1, 016) that developed during 3. 3 years of follow-up. RESULTSNine of the 16 SNPs were significantly associated with T2DM, and their direction of effect was consistent across the three ethnic groups.


Input: The gene score was significantly higher among subjects who developed incident T2DM (cases vs. noncases: 16. 47 [2. 50] vs. 15. 99 [2. 56]; P = 0. 00001).


Input: The gene score remained an independent predictor of incident T2DM with an odds ratio of 1. 08 (95% CI, 1. 05-1. 11) per additional risk allele after adjustment for T2DM risk factors.


Input: The gene score in those with no family history of T2DM was 16. 02, whereas it was 16. 19 in those with one parent with T2DM and it was 16. 32 in those with two parents with T2DM (P trend = 0. 0004).


Input: The C statistic of T2DM risk factors was 0. 708 (0. 691-0. 725) and increased only marginally to 0. 714 (0. 698-0. 731) with the addition of the gene score (P for C statistic change = 0. 0052). CONCLUSIONT2DM genetic associations are generally consistent across ethnic groups, and a gene score only adds marginal information to clinical factors for T2DM prediction.


Input: Strain-induced Dirac cone-like electronic structures and semiconductor-semimetal transition in graphdiyne.

graphdiyne


Input: By means of first-principles calculations combined with the tight-binding approximation, the strain-induced semiconductor-semimetal transition in graphdiyne is discovered.

graphdiyne


Input: It is shown that the band gap of graphdiyne increases from 0. 47 eV to 1. 39 eV with increasing the biaxial tensile strain, while the band gap decreases from 0. 47 eV to nearly zero with increasing the uniaxial tensile strain, and Dirac cone-like electronic structures are observed.

graphdiyne


Input: The uniaxial strain-induced changes of the electronic structures of graphdiyne come from the breaking of geometrical symmetry that lifts the degeneracy of energy bands.

graphdiyne


Input: The properties of graphdiyne under strains are found to differ remarkably from that of graphene.

graphdiyne

graphene


Input: The nascent polypeptide-associated complex is a key regulator of proteostasis.


Input: The adaptation of protein synthesis to environmental and physiological challenges is essential for cell viability.


Input: Here, we show that translation is tightly linked to the protein-folding environment of the cell through the functional properties of the ribosome bound chaperone NAC (nascent polypeptide-associated complex).


Input: Under non-stress conditions, NAC associates with ribosomes to promote translation and protein folding.


Input: When proteostasis is imbalanced, NAC relocalizes from a ribosome-associated state to protein aggregates in its role as a chaperone.


Input: This results in a functional depletion of NAC from the ribosome that diminishes translational capacity and the flux of nascent proteins.


Input: Depletion of NAC from polysomes and re-localisation to protein aggregates is observed during ageing, in response to heat shock and upon expression of the highly aggregation-prone polyglutamine-expansion proteins and A beta-peptide.

polyglutamine


Input: These results demonstrate that NAC has a central role as a proteostasis sensor to provide the cell with a regulatory feedback mechanism in which translational activity is also controlled by the folding state of the cellular proteome and the cellular response to stress.


Input: Antifungal Azoles: Structural Insights into Undesired Tight Binding to Cholesterol-Metabolizing CYP46A1.

Azoles

Cholesterol


Input: Although there are currently three generations of antifungal azoles on the market, even the third generation agents show undesired interactions with human cytochrome P450 enzymes.

azoles


Input: CYP46A1 is a cholesterol-metabolizing P450 in the brain tightly binding a number of structurally distinct azoles.

cholesterol

azoles


Input: Previously, we determined the crystal structures of CYP46A1 in complex with voriconazole and clotrimazole, and in the present work we co-crystallized the P450 with posaconazole at 2. 5 A resolution.

voriconazole

clotrimazole

posaconazole


Input: This long antifungal drug coordinates the P450 heme iron with the nitrogen atom of its terminal azole ring and adopts a linear configuration occupying the whole length of the substrate access channel and extending beyond the protein surface.

heme iron

nitrogen

azole


Input: Numerous drug-protein interactions determine the submicromolar Kd of posaconazole for CYP46A1.

posaconazole


Input: We compared the crystal structure of posaconazole-bound CYP46A1 with those of the P450 in complex with other drugs including the antifungal voriconazole and clotrimazole.

posaconazole

voriconazole

clotrimazole


Input: We also analyzed the accommodation of posaconazole in the active site of the target enzymes, CYPs 51, from several pathogenic species.

posaconazole


Input: These and the solution studies with different marketed azoles, collectively, allowed us to identify the determinants of tight azole binding to CYP46A1 and generate an overall picture of azole binding to this important P450.

azoles

azole

azole


Input: The data obtained suggest that development of CYP51-specific antifungal agents will continue to be a challenge.


Input: Therefore, structural understanding of the azole binding not only to CYPs 51 from the pathogenic species but also to different human P450s is required to deal efficiently with this challenge.

azole


Input: Pharmacological activation of kappa opioid receptors: aversive effects in adolescent and adult male rats.


Input: RATIONALE: The dynorphin (DYN)/kappa opioid receptor (KOR) system is involved in the dysphoric properties of drugs of abuse.


Input: Given that adolescents show reduced sensitivity to aversive effects of many drugs, alterations in the DYN/KOR system may contribute to the prevalence of drug use during adolescence.


Input: OBJECTIVES: The present study was designed to assess dysphoric properties of a selective kappa agonist, U62, 066, in adolescent and adult rats using both conditioned taste aversion (CTA) and conditioned place aversion (CPA) paradigms.

U62, 066


Input: METHODS: For CTA, water-restricted rats were administered U62, 066 following 30 min access to a saccharin solution, with subsequent saccharin consumption used to index aversion.

U62, 066

saccharin

saccharin


Input: For CPA, animals were allowed access to both compartments of a two-compartment chamber for a 15-min pre-and post-conditioning test.


Input: For conditioning, subjects were administered U62, 066 prior to confinement to one side of the chamber and saline prior to confinement to the other side for a total of four pairings.

U62, 066


Input: RESULTS: Overall, adolescents displayed reduced sensitivity to the kappa agonist relative to adults.


Input: Adults demonstrated taste aversions to the 0. 2 and 0. 3 mg/kg doses of U62, 066, whereas adolescents did not display aversions to any tested doses.

U62, 066


Input: Adults demonstrated a place aversion to the 0. 1 and 0. 2 mg/kg dose of U62, 066 when paired with the preferred side of the conditioning chamber.

U62, 066


Input: Adolescents did not display aversions to any of the doses tested.


Input: CONCLUSIONS: Reduced sensitivity to DYN/KOR system activation during adolescence may be a contributing factor to the age-typical insensitivity to aversive properties of drugs commonly abused by adolescents.


Input: Automatic approach bias towards smoking cues is present in smokers but not in ex-smokers.


Input: RATIONALE: Drug-addicted individuals show automatic approach tendencies towards drug-related cues, i. e., an approach bias (ApB).


Input: Nevertheless, little is known about ApB in tobacco smokers and about the presence of ApB after smoking abstinence.


Input: OBJECTIVES: We investigated ApB to smoking cues in heavy tobacco smokers versus never-smokers and studied its relation to smoking characteristics and craving.


Input: Second, we compared ApBs of heavy smokers with biases of abstinent heavy smokers.


Input: METHOD: A group of current heavy smokers (n = 24), ex-smokers who were abstinent for at least 5 years (n = 20), and never-smokers (n = 20) took part in the experiment.


Input: An indirect smoking approach avoidance task was performed, in which participants were required to respond to pictures of smoking and neutral cues by pulling (approach) or pushing (avoid) on a joystick, according to the content-irrelevant format of the picture (landscape or portrait).


Input: Craving scores were examined using the Questionnaire of Smoking Urges.


Input: RESULTS: Heavy smokers showed an ApB for smoking cues compared to ex-smokers and never-smokers, which correlated positively to craving scores.


Input: There were no group differences in ApB scores for ex-smokers and never-smokers.


Input: CONCLUSION: These results suggest that ApBs for smoking cues are present in heavy smokers and decrease after long-term successful smoking cessation.


Input: Methylphenidate reduces functional connectivity of nucleus accumbens in brain reward circuit.

Methylphenidate


Input: Release of dopamine in the nucleus accumbens (NAcc) is essential for acute drug reward.

dopamine


Input: The present study was designed to trace the reinforcing effect of dopamine release by measuring the functional connectivity (FC) between the NAcc and brain regions involved in a limbic cortical-subcortical circuit during a dopaminergic challenge.

dopamine


Input: Twenty healthy volunteers received single doses of methylphenidate (40 mg) and placebo on separate test days according to a double-blind, cross-over study design.

methylphenidate


Input: Resting state functional magnetic resonance imaging (fMRI) was measured between 1. 5 and 2 h postdosing.


Input: FC between regions of interest (ROI) in the NAcc, the medial dorsal nucleus (MDN) of the thalamus and remote areas within the limbic circuit was explored.


Input: Methylphenidate significantly reduced FC between the NAcc and the basal ganglia (i. e., subthalamic nucleus and ventral pallidum (VP)), relative to placebo.

Methylphenidate

pallidum


Input: Methylphenidate also decreased FC between the NAcc and the medial prefrontal cortex (mPFC) as well as the temporal cortex.

Methylphenidate


Input: Methylphenidate did not affect FC between MDN and the limbic circuit.

Methylphenidate


Input: It is concluded that methylphenidate directly affects the limbic reward circuit.

methylphenidate


Input: Drug-induced changes in FC of the NAcc may serve as a useful marker of drug activity in in the brain reward circuit.


Input: Balancing power density based quantum yield characterization of upconverting nanoparticles for arbitrary excitation intensities.


Input: Upconverting nanoparticles (UCNPs) have recently shown great potential as contrast agents in biological applications.


Input: In developing different UCNPs, the characterization of their quantum yield (QY) is a crucial issue, as the typically drastic decrease in QY for low excitation power densities can either impose a severe limitation or provide an opportunity in many applications.


Input: The power density dependence of the QY is governed by the competition between the energy transfer upconversion (ETU) rate and the linear decay rate in the depopulation of the intermediate state of the involved activator in the upconversion process.


Input: Here we show that the QYs of Yb (3 +) sensitized two-photon upconversion emissions can be well characterized by the balancing power density, at which the ETU rate and the linear decay rate have equal contributions, and its corresponding QY.

Yb (3 +)


Input: The results in this paper provide a method to fully describe the QY of upconverting nanoparticles for arbitrary excitation power densities, and is a fast and simple approach for assessing the applicability of UCNPs from the perspective of energy conversion.


Input: Sparstolonin B suppresses lipopolysaccharide-induced inflammation in human umbilical vein endothelial cells.

Sparstolonin B


Input: Sparstolonin B (SsnB) is an isocoumarin compound isolated from the tubers of both Sparganium stoloniferum and Scirpus yagara.

Sparstolonin B

SsnB

isocoumarin


Input: We previously demonstrated that SsnB blocked the Toll-like receptor (TLR) 2-and TLR4-triggered inflammatory signaling in macrophages by inhibiting the recruitment of MyD88 to the TIR domains of TLR2 and TLR4.

SsnB


Input: The present study was designed to examine the effects of SsnB on vascular inflammatory responses in human umbilical vein endothelial cells (HUVECs) challenged by lipopolysaccharide (LPS, a TLR4 ligand).

SsnB


Input: We found that SsnB dose-dependently attenuated the LPS-induced expression of interleukin (IL)-1 beta and monocyte chemoattractant protein 1 both at the transcription and translation levels in HUVEC.

SsnB


Input: LPS-induced endothelial cell adhesion molecules, intercellular adhesion molecular-1 and vascular cell adhesion molecule-1 expressions were also reduced by treatment with SsnB.

SsnB


Input: In addition, co-incubation with SsnB attenuated THP-1 monocyte adhesion to LPS-activated HUVECs.

SsnB


Input: Furthermore, SsnB efficiently suppressed LPS-induced phosphorylation of extracellular-signal-regulated kinase (Erk1/2) and Akt in HUVECs.

SsnB


Input: These findings show that SsnB can suppress endothelial cell inflammation, suggesting that SsnB might be suitable for development as a therapeutic agent for inflammatory cardiovascular disease.

SsnB

SsnB


Input: Cytochrome p450-mediated changes in oxycodone pharmacokinetics/pharmacodynamics and their clinical implications.

oxycodone


Input: In recent years the use of the opioid oxycodone has increased markedly and replacing morphine as the first-line choice of opioid in several countries.

oxycodone

morphine


Input: There are formulations for oral immediate, oral extended release and intravenous use.


Input: The bioavailability is higher than for morphine and less variable.

morphine


Input: Oxycodone is primarily metabolized in the liver by the cytochrome P450 (CYP) enzymes with CYP3A as the major metabolic pathway and CYP2D6 as the minor metabolic pathway to noroxycodone, oxymorphone and noroxymorphone.

Oxycodone

noroxycodone

oxymorphone

noroxymorphone


Input: Oxycodone exerts its analgesic effect via the micro-opioid receptor.

Oxycodone


Input: The metabolism of CYP2D6 substrates varies to a large degree between individuals as a result of allele functionality.


Input: Poor metabolizers (PM) have two non-functional alleles, extensive metabolizers (EM) are homozygous with two functional alleles or heterozygous with one functional allele and ultrarapid metabolizers (UM) have more than two functional alleles.


Input: There are pronounced interethnic differences in the allele distribution.


Input: On the basis of studies performed thus far, oxycodone concentrations in comparison with EM are similar in PM and reduced in UM.

oxycodone


Input: The pharmacokinetics in UM are insufficiently investigated.


Input: Simultaneous inhibition of both CYP3A and CYP2D6 results in increased oxycodone concentrations and such a combination should be avoided.

oxycodone


Input: A similar effect is to be expected with use of a CYP3A inhibitor in CYP2D6 PM.


Input: Concomitant use of enzyme inducers such as rifampicin, St John' s wort and carbamazepine should be avoided because of the risk of subtherapeutic concentrations of oxycodone.

rifampicin

carbamazepine

oxycodone


Input: When the dosage of morphine may result in unpredictable bioavailability, like in patients with severe hepatic cirrhosis, oxycodone might be beneficial because it has higher and less variability in bioavailability between patients than morphine.

morphine

oxycodone

morphine


Input: Using multiple targeted therapies in oncology: considerations for use, and progress to date in breast cancer.


Input: There has been significant progress in our basic understanding of drugs and targets in the management of breast cancer.


Input: Recent breast cancer clinical trials have examined whether combinations of drugs targeting transmembrane receptors or their downstream effectors involved in cell signal transduction can increase response rates and overcome acquired and/or de novo drug resistance compared to a single targeted agent with or without systemic chemotherapy.


Input: We reviewed published clinical trials and conference proceedings examining combinations of targeted therapies across different breast cancer subtypes.


Input: Improvements in pathological complete response (pCR) rates and progression free survival (PFS) in preoperatively treated and metastatic human epidermal growth factor 2 (HER2)-positive breast cancer, respectively, have been observed with combinations of anti-HER2 therapies given concomitantly.


Input: Promising results were also observed in estrogen receptor (ER)-positive, HER2-negative breast cancer using a mammalian target of rapamycin inhibitor with tamoxifen or an aromatase inhibitor (AI) in the preoperative setting and for patients with metastatic breast cancer that had previously progressed on endocrine therapy alone.

estrogen

rapamycin

tamoxifen


Input: A recent phase II trial reported a statistically significant improvement in PFS with the addition of an oral inhibitor of cyclin-dependent kinase 4/6 to letrozole compared to letrozole alone (26. 1 versus 7. 5 months).

letrozole

letrozole


Input: A phase III study is planned for early 2013.


Input: On the basis of preclinical data, clinical trials have examined combinations of hormonal agents such as fulvestrant with an AI.

fulvestrant


Input: However, the results are conflicting.


Input: Early data indicated that poly (ADP-ribose) polymerase (PARP) inhibitors exploiting the concept of synthetic lethality would offer improved outcomes for patients with ER-negative, progesterone receptor (PR)-negative, HER2-negative breast cancer often referred to as triple negative breast cancer (TNBC); however, data in the phase III setting failed to confirm these findings but this may be because the drug was not a true PARP inhibitor.

poly (ADP-ribose)

progesterone


Input: Chemotherapy continues to be the mainstay of treatment for TNBC until specific drugs and their associated targets are identified.


Input: As advances in medical technologies continue to identify multiple molecularly distinct breast cancer subgroups that are predicted to respond to combinations of targeted agents new challenges have arisen.


Input: In particular, how do we evaluate the safety and efficacy of these new drug combinations in relatively small subgroups of patients?


Input: Novel clinical trial designs will be required and increasingly regulatory agencies will require companion diagnostic tests that can identify the subgroups likely to respond to these therapies.


Input: The US Food and Drug Administration is assessing the role of pCR in breast cancer studies as a surrogate endpoint to predict clinical benefit in the accelerated drug approval process.


Input: Hedgehog Signaling Pathway and Cancer Therapeutics: Progress to Date.


Input: The Hedgehog (Hh) pathway is a developmental signaling pathway involved in numerous developmental processes, including determination of cell fate, patterning, proliferation, survival, and differentiation.


Input: While this pathway is silenced in most adult tissues, aberrant activation of it has been documented in a variety of malignancies.


Input: In cancers such as basal cell carcinoma (BCC), ligand-independent mechanisms lead to constitutive Hh pathway activation through mutations in components of the pathway, including patched-1 (PTCH1) or smoothened (SMO).


Input: On the contrary, numerous other solid and hematologic tumors have been shown to harbor ligand-dependent activation of the Hh pathway by autocrine or paracrine mechanisms.


Input: Given that aberrant Hh pathway signaling has been seen in a number of malignancies, this pathway has been an attractive target for drug development.


Input: While the best-characterized approach is to target the SMO receptor, other rational approaches for inhibiting the Hh pathway include inhibiting downstream components or directly binding Hh ligands.


Input: In January of 2012, vismodegib, a SMO antagonist, became the first agent to target the Hh pathway to receive approval by the United States Food and Drug Administration (FDA) after this agent showed remarkable activity in phase I and II trials for the treatment of BCC.

vismodegib


Input: Despite promising preclinical studies with Hh pathway inhibitors in other malignancies that have suggested a potential role for these agents, attempts to translate this potential to clinical benefit has been disappointing.


Input: Future efforts will require further careful interpretation and analysis to determine the potential determinants and predictors of efficacy.


Input: Currently, several phase I and II trials evaluating Hh inhibitors in a variety of tumor settings are underway.


Input: Morphological Change and Mobility Enhancement in PEDOT: PSS by Adding Co-solvents.

PEDOT

PSS


Input: Adding ethylene glycol (EG) to poly (3, 4-ethylenedioxythiophene): poly (styrenesulfonate) (PEDOT: PSS) solution improves the crystallinity of the PEDOT and the ordering of the PEDOT nanocrystals in solid films.

ethylene glycol

poly (3, 4-ethylenedioxythiophene)

poly (styrenesulfonate)

PEDOT

PSS

PEDOT

PEDOT


Input: The carrier-mobility enhancement is confirmed by using ion-gel transistors combined with in situ UV-vis-NIR spectroscopy.


Input: A Generic Micropatterning Platform to Direct Human Mesenchymal Stem Cells from Different Origins Towards Myogenic Differentiation.


Input: Human mesenchymal stem cells (MSCs) derived from various origins show varied differentiation capability.


Input: Recent work shows that cell shape manipulation via micropatterning can modulate the differentiation of bone-marrow-derived MSCs.


Input: Herein, the effect of micropatterning on the myogenesis of MSCs isolated from three different sources (bone marrow, fetal tissue, and adipose) is reported.


Input: All the well-aligned cells, regardless of source, predominantly commit to myogenic lineage, as shown by the significant upregulation of myogenic gene markers and positive myosin heavy chain staining.


Input: It is demonstrated that our novel micropattern can be used as a generic platform for inducing myogenesis of MSCs from different sources and may also have the potential to be extended to induce other lineage commitment.


Input: 3D Graphene Foams Cross-linked with Pre-encapsulated Fe3 O4 Nanospheres for Enhanced Lithium Storage.

Graphene

Fe3 O4

Lithium


Input: Electrostatic assembly between Fe3 O4 nanospheres and graphene oxide, and subsequent hydrothermal assembly with additional graphene sheets, leads to Fe3 O4 nanospheres encapsulated in the graphene shells and interconnected by the graphene networks.

Fe3 O4

graphene oxide

graphene

Fe3 O4

graphene

graphene


Input: Such 3D Fe3 O4/graphene foams exhibit enhanced lithium storage with excellent cycling performance and rate capability.

Fe3 O4

graphene

lithium


Input: Morphometric and Functional Changes of Salivary Gland Dysfunction after Radioiodine Ablation in a Murine Model.

Radioiodine


Input: Background: Ablation of the thyroid tissue using radioiodine (RI) after the surgical removal of well-differentiated thyroid cancer (WDTC) can induce radiation-related salivary gland (SG) dysfunction.

radioiodine


Input: However, in vivo changes of SGs following RI administration in appropriate animal models are not well described in the literature.


Input: This study was undertaken to document morphometric and functional changes during the 12 months following RI administration in a murine model of RI-induced SG dysfunction.


Input: Methods: Female C57BL/6, 4-week-old mice (n = 60) were divided into a RI-treated group (n = 30) that received RI orally (0. 01 mCi/g body weight) or an unexposed control group (n = 30).


Input: Mice in both groups were divided into five subgroups (n = 6 per subgroup) and sacrificed at 1, 2, 3, 6, and 12 months post-RI administration.


Input: Salivary flow rates (SFR) and salivary lag times were measured at 1, 2, 3, 6, and 12 months after RI administration.


Input: Morphological and histological examinations and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays were performed.

deoxynucleotidyl

dUTP


Input: In addition, changes in salivary 99m Tc pertechnetate uptake and excretion were observed by single-photon emission computed tomography (SPECT).

99m Tc pertechnetate


Input: Results: In RI-treated mice, the SGs were significantly lighter compared to unexposed controls at all study time points.


Input: Lag times to salivation in the RI-treated group were greater than in the unexposed controls, but mean SFR were lower.


Input: Histologic examinations of SGs in the RI-group showed pale cytoplasm, atypical ductal configuration, septal widening, cytoplasmic vacuolization with pleomorphism, lymphocyte infiltration, and increased fibrosis.


Input: Furthermore, more apoptotic cells were observed in acini and ducts in the RI group.


Input: In addition, patterns of 99m Tc pertechnetate uptake and excretion in the RI-group were quite different from those observed in controls at 1 and 12 months post-RI.

99m Tc pertechnetate


Input: Conclusion: Various histological alterations were observed in mice exposed to radioiodine, that is, an increase in apoptotic acini and ductal cells and functional SG deterioration.

radioiodine


Input: The murine model of RI-induced SG dysfunction used in the present study appears to be applicable to preclinical research on RI-induced sialadenitis in patients with WDTC.


Input: Recommendations for the Use of Prolonged-Release Fampridine in Patients with Multiple Sclerosis (MS).

Fampridine


Input: Prolonged-release fampridine (fampridine PR) is a potassium channel blocker that improves conductivity of signal on demyelinated axons in central nervous system.

fampridine

fampridine PR

potassium


Input: Fampridine PR has been approved to improve speed of walking in patients with multiple sclerosis.

Fampridine PR


Input: This statement provides a brief summary of data on fampridine PR and recommendations on practical use of the medication in clinical practice, prediction, and evaluation of response to treatment and patient management.

fampridine PR


Input: Synaptotagmin 1 is required for vesicular Ca (2 +)/H (+)-antiport activity.

Ca (2 +)

H (+)


Input: A low-affinity Ca (2 +)/H (+)-antiport was described in the membrane of mammalian brain synaptic vesicles.

Ca (2 +)

H (+)


Input: Electrophysiological studies showed that this antiport contributes to the extreme brevity of excitation-release coupling in rapid synapses.


Input: Synaptotagmin-1, a vesicular protein interacting with membranes upon low-affinity Ca (2 +)-binding, plays a major role in excitation-release coupling, by synchronizing calcium entry with fast neurotransmitter release.

Ca (2 +)

calcium


Input: Here, we report that synaptotagmin-1 is necessary for expression of the vesicular Ca (2 +)/H (+)-antiport.

Ca (2 +)

H (+)


Input: We measured Ca (2 +)/H (+)-antiport activity in vesicles and granules of pheochromocytoma PC12 cells by three methods: (1) Ca (2 +)-induced dissipation of the vesicular H (+)-gradient; (2) bafilomycin-sensitive calcium accumulation and (3) pH-jump-induced calcium accumulation.

Ca (2 +)

H (+)

Ca (2 +)

H (+)

bafilomycin

calcium

calcium


Input: The results were congruent and highly significant: Ca (2 +)/H (+)-antiport activity is detectable only in acidic organelles expressing functional synaptotagmin-1.

Ca (2 +)

H (+)


Input: In contrast, synaptotagmin-1-deficient cells-and cells where transgenically encoded synaptotagmin-1 was acutely photo-inactivated-were devoid of any Ca (2 +)/H (+)-antiport activity.

Ca (2 +)

H (+)


Input: Therefore, in addition to its previously described functions, synaptotagmin-1 is involved in a rapid vesicular Ca (2 +) sequestration through a Ca (2 +)/H (+) antiport.

Ca (2 +)

Ca (2 +)

H (+)


Input: This article is protected by copyright.


Input: All rights reserved.


Input: Cell-Cycle Changes and Oxidative Stress Response to Magnetite in A549 Human Lung Cells.

Magnetite


Input: In a recent study, magnetite was investigated for its potential to induce toxic effects and influence signaling pathways.

magnetite


Input: It was clearly demonstrated that ROS formation leads to mitochondrial damage and genotoxic effects in A549 cells.


Input: On the basis of these findings, we wanted to elucidate the origin of magnetite-mediated ROS formation and its influence on the cell cycle of A549 and H1299 human lung epithelial cells.

magnetite


Input: Concentration-and size-dependent superoxide formation, measured by electron paramagnetic resonance (EPR), was observed.

superoxide


Input: Furthermore, we could show that the GSH level decreased significantly after exposure to magnetite particles, while catalase (CAT) activity was increased.

GSH

magnetite


Input: These effects were also dependent on particle size, albeit less pronounced than those observed with EPR.


Input: We were able to show that incubation of A549 cells prior to particle treatment with diphenyleneiodonium (DPI), a NADPH-oxidase (NOX) inhibitor, leads to decreased ROS formation, but this effect was not observed for the NOX inhibitor apocynin.

diphenyleneiodonium

DPI

NADPH

apocynin


Input: Soluble iron does not contribute considerably to ROS production.

iron


Input: Analysis of cell-cycle distribution revealed a pronounced sub-G1 peak, which cannot be linked to increased cell death.


Input: Western blot analysis did not show activation of p53 but upregulation of p21 in A549.


Input: Here, we were unexpectedly able to demonstrate that exposure to magnetite leads to p21-mediated G1-like arrest.

magnetite


Input: This has been reported previously only for low concentrations of microtubule stabilization drugs.


Input: Importantly, the arrested sub-G1 cells were viable and showed no caspase 3/7 activation.


Input: Antimicrobial and demelanizing activity of Ganoderma lucidum extract, p-hydroxybenzoic and cinnamic acids and their synthetic acetylated glucuronide methyl esters.

p-hydroxybenzoic and cinnamic acids

acetylated glucuronide methyl esters


Input: Mushroom extracts or isolated compounds may be useful in the search of new potent antimicrobial agents.


Input: Herein, it is described the synthesis of protected (acetylated) glucuronide derivatives of p-hydroxybenzoic and cinnamic acids, two compounds identified in the medicinal mushroom Ganoderma lucidum.

p-hydroxybenzoic and cinnamic acids


Input: Their antimicrobial and demelanizing activities were evaluated and compared to the parent acids and G. lucidum extract.


Input: p-Hydroxybenzoic and cinnamic acids, as also their protected glucuronide derivatives revealed high antimicrobial (antibacterial and antifungal) activity, even better than the one showed by commercial standards.

p-Hydroxybenzoic and cinnamic acids


Input: Despite the variation in the order of parent acids and the protected glucuronide derivatives, their antimicrobial activity was always higher than the one revealed by the extract.


Input: Nevertheless, the extract was the only one with demelanizing activity against Aspergillus niger.


Input: The acetylated glucuronide derivatives could be deprotected to obtain glucuronide metabolites, which circulate in the human organism as products of the metabolism of the parent compounds.


Input: Synthesis and antiprogestational properties of novel 17-fluorinated steroids.

17-fluorinated steroids


Input: Progesterone receptor (PR) plays a key role in reproductive functions, and compounds that inhibit progesterone action (antiprogestins) have potential use in the treatment of estrogen-and progesterone-dependent diseases, including uterine leiomyomas and breast cancer.

Progesterone

progesterone

antiprogestins

estrogen

progesterone


Input: In the present study, we chemically synthesized novel 17-fluorinated steroids and evaluated the cytotoxicity profiles of these compounds in T47D breast cancer cells compared to the activity of known antiprogestins, including ZK230 211, RU-486, CDB2914, CDB4124 and ORG33628.

17-fluorinated steroids

antiprogestins

ZK230 211


Input: We analyzed in vitro receptor-binding assays and PR-transactivation assays to establish the antiprogestational activity of these molecules.


Input: The representative antiprogestin EC304 was found to inhibit in vitro tumorigenicity in a dose-dependent fashion in T47D cells by a colony formation assay at 1 and 10nM concentrations.


Input: The potent in vivo antiprogestational activity of EC304 was also demonstrated in an antinidation assay for the interruption of early pregnancy in rats.


Input: The strong antiprogestational activity and absence of antiglucocorticoid activity in EC compounds may demonstrate their utility in the treatment of leiomyoma, endometriosis and breast cancer.


Input: Renal accumulation and effects of intraperitoneal injection of extracted microcystins in omnivorous crucian carp (Carassius auratus).


Input: An acute toxicological experiment was designed to characterize the sequence of renal ultrastructural changes with accumulated MCs in crucian carp injected intraperitoneally (i. p.) with extracted microcystins (mainly MC-RR and-LR) at two doses, 50 and 200 mu g MC-LReq. kg (-1) body weight.


Input: Quantitative and qualitative determinations of MCs in the kidney were conducted by HPLC and LC-MS, respectively.


Input: MC-RR content in kidney of crucian carp showed a time dose-dependent increase within 48 h post-injection, followed by a sharp decline afterward, while no MC-LR in kidney was detectable throughout the experiment.


Input: Ultrastructural changes in the kidney of crucian carp progressed with increasing accumulated MCs and exposure times within 48 h post-injection, whereas renal ultrastructural recovery of crucian carp in the 50 mu g MC-LReq. kg (-1) dose group was evident at 168 h post-injection.


Input: Our ultrastructural observation suggests that the membranous structure is the main action site of MCs in the kidney, among which mitochondria damage in the tubules is clearly an early, and presumably a critically important effect of MCs.


Input: The increases in blood urea nitrogen (BUN) and creatinine (CR) in both dose groups further revealed severe impairment occurred in the kidney of crucian carp.

urea nitrogen

creatinine


Input: Cephalic phase insulin secretion is KATP channel-independent.


Input: Glucose-induced insulin secretion from pancreatic beta-cells depends critically on activity of ATP-sensitive K + channels (KATP channel).

Glucose

ATP

K +


Input: We previously generated mice lacking Kir6. 2, the pore subunit of the beta-cell KATP channel (Kir6. 2-/-), that show almost no insulin secretion in response to glucose in vitro.

glucose


Input: In the present study, we compared insulin secretion by voluntary feeding (self-motivated, oral nutrient ingestion) and by forced feeding (intra-gastric nutrient injection via gavage) in wild-type (Kir6. 2 +/+) and Kir6. 2-/-mice.


Input: Under ad libitum feeding or during voluntary feeding of standard chow, blood glucose levels and plasma insulin levels were similar in Kir6. 2 +/+ and Kir6. 2-/-mice.

glucose


Input: By voluntary feeding of carbohydrate alone, insulin secretion was induced significantly in Kir6. 2-/-mice, but was markedly attenuated compared to that in Kir6. 2 +/+ mice.

carbohydrate


Input: On forced feeding of standard chow or carbohydrate alone, the insulin secretory response was markedly impaired or completely absent in Kir6. 2-/-mice.

carbohydrate


Input: Pre-treatment of a muscarine receptor antagonist, atropine methyl nitrate, which does not cross the blood-brain barrier, almost completely blocked insulin secretion induced by voluntary feeding of standard chow or carbohydrate in Kir6. 2-/-mice.

atropine methyl nitrate

carbohydrate


Input: Substantial glucose-induced insulin secretion was induced in pancreas perfusion study of Kir6. 2-/-mice only in the presence of carbamylcholine.

glucose

carbamylcholine


Input: These results suggest that a KATP channel-independent mechanism mediated by the vagal nerve plays a critical role in insulin secretion in response to nutrients in vivo.


Input: MAPKAPK2/3 Regulate SERCA2a Expression and Fiber Type Composition to Modulate Skeletal Muscle and Cardiomyocyte Function.


Input: The MAPK-activated protein kinases 2 and 3 (MAPKAPK2/3, MK2/3) represent protein kinases downstream of the p38 mitogen-activated protein kinase (MAPK).


Input: Using MK2/3 double knockout mice (MK2/3 (-/-)), we analyzed the role of MK2/3 in cross-striated muscle by transcriptome and proteome analyses, and by histology.


Input: We demonstrated enhanced expression of the slow oxidative skeletal muscle myofiber gene program, including the PPAR gamma coactivator 1 alpha (PGC-1 alpha).


Input: Using reporter gene and electrophoretic gel mobility shift assays we demonstrated that MK2 catalytic activity directly regulated the promoters of the fast fiber-specific myosin heavy chain IId/x and the slow fiber-specific sarco/endoplasmic reticulum Ca (2 +)-ATPase (SERCA) 2 gene.

Ca (2 +)


Input: Elevated SERCA2a gene expression caused by a decreased transcription factor Egr-1 to Sp1 ratio was associated with accelerated relaxation and enhanced contractility in MK2/3 (-/-) cardiomyocytes, concomitant with improved force parameters in MK2/3 (-/-) soleus muscle.


Input: These results link MK2/3 to the regulation of calcium dynamics and identify enzymatic activity of MK2/3 as a critical factor for modulating cross-striated muscle function by generating a unique muscle phenotype exhibiting both, reduced fatigability and enhanced force in MK2/3 (-/-) mice.

calcium


Input: Hence, the p38-MK2/3 axis may represent a novel target for the design of therapeutic strategies for diseases related to fiber type changes or impaired SERCA2 function.


Input: N-alkylation of highly quaternized chitosan derivatives affects the paracellular permeation enhancement in bronchial epithelia in vitro.

N


Input: This study describes the structure-activity relationship for carefully characterized N-alkyl-N-quaternary chitosan derivatives as permeation enhancers for drugs that are mainly absorbed through the paracellular pathway, such as macromolecular drugs and hydrophilic drugs, in a well defined bronchial epithelial cell line.

N-alkyl

N


Input: The O-methyl free derivatives used in the study were fully trimethylated (100%) N, N, N-trimethyl chitosan (TMC) and N-propyl-(QuatPropyl), N-butyl-(QuatButyl) and N-hexyl (QuatHexyl)-N, N-dimethyl chitosan, with 85-91% degree of quaternization.

O-methyl

N, N, N-trimethyl

N-propyl-(QuatPropyl)

N-butyl-(QuatButyl)

N-hexyl (QuatHexyl)-N, N-dimethyl


Input: The fully trimethylated TMC, from 0. 25mg/ml, decreased transepithelial electrical resistance (TER) in a reversible manner and enhanced the permeation of the macromolecule FITC-dextran 4kDa (FD4) 2-5 fold.


Input: TMC did not cause any alterations in the tight junction (TJ) protein claudin-4 or in F-actin architecture.


Input: QuatHexyl was the most effective polymer to produce enhanced permeation and decreased TER from 0. 016mg/ml.

QuatHexyl


Input: Nevertheless, this enhanced permeation was accompanied by reduced viability and dissociation of F-actin and claudin-4 proteins.


Input: The structure-activity relationship suggests that more lipophilic derivatives show more permeation enhancement, TJ disassembly, and less viability in the order of hexyl =~ butyl > propyl > methyl and demonstrates that the permeation effect is not only mediated by permanent positive charge but also through by the extent of N-alkylation.

hexyl

butyl

propyl

methyl

N


Input: These results are relevant to elucidate the structural factors contributing to the permeation enhancement of chitosan derivatives and for potential use in pulmonary applications.


Input: Association of PON1 genotype and haplotype with susceptibility to coronary artery disease and clinical outcomes in dual antiplatelet-treated Han Chinese patients.


Input: PURPOSE: The aim of this study was to evaluate the association of PON1 genetic variants with the susceptibility to coronary artery disease (CAD) and with the clinical endpoints in aspirin and clopidogrel (dual antiplatelet therapy)-treated Han Chinese patients with CAD after percutaneous coronary intervention (PCI).

aspirin

clopidogrel


Input: METHODS: A total of 538 Han Chinese patients undergoing PCI and receiving dual-antiplatelet therapy were sequentially recruited to the study and followed for up to 1 year.


Input: Healthy controls (n = 539) were enrolled during the same period.


Input: All study participants were genotyped for five genetic variants in PON1 and the cytochrome P450 2C19 * 2 mutation (CYP2C19 * 2).


Input: The effect of genetic variants on disease risk and clinical outcome of major adverse cardiac events (MACE) within 1 year or bleeding within 6 months was assessed.


Input: RESULTS: CYP2C19 * 2 was associated with a higher risk of MACE (adjusted P = 0. 0098), but a lower risk of bleeding events (adjusted P = 0. 0016).


Input: The PON1 Q192R polymorphism was significantly associated with a lower risk of bleeding events [odds ratio (OR) 0. 61, 95% confidence interval (CI) 0. 43-0. 87, adjusted P = 0. 0066).


Input: The haplotype bearing the PON1-126C allele was associated with a higher risk to CAD (OR 1. 48, 95% CI 1. 04-2. 09, P = 0. 029) and a higher risk of bleeding events (OR 1. 68, 95% CI 1. 10-2. 56, P = 0. 017) compared to the most frequent haplotype.


Input: The transcription activity of haplotype p-162A-126C-108C in the PON1 promoter was 2. 6-fold higher than that of the most frequent haplotype (p-162G-126G-108T).


Input: CONCLUSIONS: Based on these results, we suggest that the haplotype-bearing PON1-126C allele contributes to the disease risk and the risk of bleeding events in dual antiplatelet-treated CAD patients after PCI.


Input: Structural transitions in mixed ternary noble gas clusters.

noble


Input: The properties of noble gas systems can be greatly extended by heterogeneous mixtures of elements.

noble


Input: The geometrical structures and energies of mixed Ar-Kr-Xe clusters were investigated using ternary Lennard-Jones (TLJ) potential.

Ar

Kr

Xe


Input: For the Ar19Kr n Xe19, Ar19Kr19Xe n, and Ar n Kr19Xe19 (n = 0-17) clusters investigated, the results show that only two minimum energy configurations exist, i. e., polytetrahedron and six-fold pancake.

Ar19Kr n Xe19

Ar19Kr19Xe n

Ar n Kr19Xe19


Input: The inner core of all these clusters is composed mainly of Ar atoms, and Kr and Xe atoms are distributed on the surface with well mixed pattern for polytetrahedral and segregate pattern for six-fold pancake configurations.

Ar

Kr

Xe


Input: The relative stability property of Ar-Kr-Xe clusters with a certain composition is discussed.

Ar

Kr

Xe


Input: Moreover, the role of heterogeneity on the strain was investigated, and reduced strain energies in Ar-Kr-Xe clusters were studied to find possible ways of reducing strain.

Ar

Kr

Xe


Input: The results showed that the strain energies were affected mainly by Ar-Ar, Ar-Kr, and Xe-Xe bonds.

Ar

Ar

Ar

Kr

Xe

Xe


Input: Blood-brain barrier structure and function and the challenges for CNS drug delivery.


Input: The neurons of the central nervous system (CNS) require precise control of their bathing microenvironment for optimal function, and an important element in this control is the blood-brain barrier (BBB).


Input: The BBB is formed by the endothelial cells lining the brain microvessels, under the inductive influence of neighbouring cell types within the' neurovascular unit' (NVU) including astrocytes and pericytes.


Input: The endothelium forms the major interface between the blood and the CNS, and by a combination of low passive permeability and presence of specific transport systems, enzymes and receptors regulates molecular and cellular traffic across the barrier layer.


Input: A number of methods and models are available for examining BBB permeation in vivo and in vitro, and can give valuable information on the mechanisms by which therapeutic agents and constructs permeate, ways to optimize permeation, and implications for drug discovery, delivery and toxicity.


Input: For treating lysosomal storage diseases (LSDs), models can be included that mimic aspects of the disease, including genetically-modified animals, and in vitro models can be used to examine the effects of cells of the NVU on the BBB under pathological conditions.


Input: For testing CNS drug delivery, several in vitro models now provide reliable prediction of penetration of drugs including large molecules and artificial constructs with promising potential in treating LSDs.


Input: For many of these diseases it is still not clear how best to deliver appropriate drugs to the CNS, and a concerted approach using a variety of models and methods can give critical insights and indicate practical solutions.


Input: Region-specific regulation of 5-HT1B receptors in the rat brain by chronic venlafaxine treatment.

venlafaxine


Input: RATIONALE: Venlafaxine is a non-selective serotonin and noradrenaline reuptake inhibitor antidepressant drug for which clinical studies have suggested a high level efficacy and a possible early action onset compared to the classical antidepressants.

Venlafaxine

serotonin

noradrenaline


Input: Its therapeutic effects might be due, at least in part, to adaptive changes in serotonergic neurotransmission, through the activation of the different 5-HT receptor subtypes.


Input: 5-HT1B receptors are located in the axon terminals of both serotonergic and non-serotonergic neurons, where they act as inhibitory autoreceptors or heteroreceptors, respectively.


Input: However, the information about the involvement of this subtype in the mechanism of action of antidepressants is limited and quite controversial.


Input: OBJECTIVES: The aim of this study was to evaluate the effect of venlafaxine (10 mg kg (-1) day (-1), p. o.) after 21 days of treatment on the density of 5-HT1B receptors and their functionality in rat brain.

venlafaxine


Input: METHODS: Effects of chronic venlafaxine were evaluated at different levels of 5-HT1B receptor by using receptor autoradiography, [(35) S] GTP gamma S binding, and the regulation of body temperature induced by selective 5-HT1B agonist.

venlafaxine

[(35) S] GTP gamma S


Input: RESULTS: Our results show that venlafaxine induced an increase in sensitivity of 5-HT1B receptors in hypothalamus both at G-protein level and the control of core temperature without affecting the receptor density.

venlafaxine


Input: CONCLUSIONS: These results demonstrate that adaptive changes on 5-HT1B receptors induced by chronic administration of venlafaxine exhibit regional differences suggesting that the hypothalamus might be an important site of drug action.

venlafaxine


Input: Design, synthesis and spectroscopic characterisation of a focused library based on the polyandrocarpamine natural product scaffold.

polyandrocarpamine


Input: A focused library based on the marine natural products polyandrocarpamines A (1) and B (2) has been designed and synthesised using parallel solution-phase chemistry.

polyandrocarpamines A


Input: In silico physicochemical property calculations were performed on synthetic candidates in order to optimise the library for drug discovery and chemical biology.


Input: A library of ten 2-aminoimidazolone products (3-12) was prepared by coupling glycocyamidine and a variety of aldehydes using a one-step stereoselective aldol condensation reaction under microwave conditions.

glycocyamidine

aldehydes


Input: All analogues were characterised by NMR, UV, IR and MS.


Input: The library was evaluated for cytotoxicity towards the prostate cancer cell lines, LNCaP, PC-3 and 22Rv1.


Input: Copyright (c) 2013 John Wiley & Sons, Ltd.


Input: Suppression of Epithelial to Mesenchymal Transitioning (EMT) Enhances Ex Vivo Reprogramming of Human Exocrine Pancreatic Tissue towards Functional Insulin Producing beta-Like Cells.


Input: Due to the lack of tissue available for islet transplantation, new sources of beta-cells have been sought for the treatment of type 1 diabetes.


Input: The aim of this study was to determine whether the human exocrid fraction from the islet isolation procedure could be reprogrammed to provide additional islet tissue for transplantation.


Input: The exocrine enriched cells rapidly dedifferentiated in culture and grew as a mesenchymal monolayer.


Input: Genetic lineage tracing confirmed that these mesenchymal cells arose in part through a process of epithelial to mesenchymal transitioning (EMT).


Input: A protocol was developed whereby transduction of these mesenchymal cells with adenoviruses containing Pdx1, Ngn3, MafA and Pax4 generated a population of cells that were enriched in glucagon-secreting alpha-like cells.


Input: Transdifferentiation or reprogramming towards insulin secreting beta-cells was enhanced, however, when using unpassaged cells in combination with inhibition of EMT by inclusion of ROCK and TGF-beta 1 inhibitors.


Input: Resultant cells were able to secrete insulin in response to glucose and on transplantation, to normalise blood glucose levels in streptozotocin diabetic NOD/Scid mice.

glucose

glucose

streptozotocin


Input: In conclusion, reprogramming of human exocrine enriched tissue can best be achieved using fresh material under conditions whereby EMT is inhibited.


Input: . rather than allowing the culture to expand as a mesenchymal monolayer.


Input: Factors Associated With Microalbuminuria in 7, 549 Children and Adolescents With Type 1 Diabetes in the T1D Exchange Clinic Registry.


Input: OBJECTIVETo examine factors associated with clinical microalbuminuria (MA) diagnosis in children and adolescents in the T1D Exchange clinic registry. RESEARCH DESIGN AND METHODST1D Exchange participants < 20 years of age with type 1 diabetes >= 1 year and urinary albumin-to-creatinine ratio (ACR) measured within the prior 2 years were included in the analysis.

creatinine


Input: MA diagnosis required all of the following: 1) a clinical diagnosis of sustained MA or macroalbuminuria, 2) confirmation of MA diagnosis by either the most recent ACR being >= 30 mg/g or current treatment with an ACE inhibitor (ACEI) or angiotensin receptor blocker (ARB), and 3) no known cause for nephropathy other than diabetes.


Input: Logistic regression was used to assess factors associated with MA. RESULTSMA was present in 329 of 7, 549 (4. 4%) participants, with a higher frequency associated with longer diabetes duration, higher mean glycosylated hemoglobin (HbA1c) level, older age, female sex, higher diastolic blood pressure (BP), and lower BMI (P <= 0. 01 for each in multivariate analysis).


Input: Older age was most strongly associated with MA among participants with HbA1c >= 9. 5% (>= 80 mmol/mol).


Input: MA was uncommon (< 2%) among participants with HbA1c < 7. 5% (< 58 mmol/mol).


Input: Of those with MA, only 36% were receiving ACEI/ARB treatment. CONCLUSIONSOur results emphasize the importance of good glycemic and BP control, particularly as diabetes duration increases, in order to reduce the risk of nephropathy.


Input: Since age and diabetes duration are important nonmodifiable factors associated with MA, the importance of routine screening is underscored to ensure early diagnosis and timely treatment of MA.


Input: Patent indicators: a window to pharmaceutical market success.


Input: Pharmaceutical success in the market is the best reward for pharmaceutical investors undergoing the lengthy, costly and risky process of pharmaceutical Research and Development (R & D).


Input: Drugs with high market revenues trigger fierce competition between pharmaceutical enterprises, as is demonstrated by the increasing Mergers & Acquisitions (M & A) cases focusing on seizing the best-selling products.


Input: On the other hand, patents, as the best shield for innovative drugs against generic drugs, become a powerful weapon for pharmaceutical enterprises to win the substantial returns generated by market exclusivity.


Input: Patents seem to be directly responsible for the commercial success of new medicines.


Input: In this context, it is of great significance to find out the empirical associations between pharmaceutical commercial success and patents.


Input: By comprehensively analysing 127 drugs marketed in the USA and their 621 American patents, this article identifies the evidence to link various patent indicators with pharmaceutical sales in actual market.


Input: Diversity in Structural Consequences of MexZ Mutations in Pseudomonas aeruginosa.


Input: Pseudomonas aeruginosa is the major cause of morbidity and mortality in patients with cystic fibrosis.


Input: The high level of intrinsic and acquired antibiotic resistance of P. aeruginosa is attributable to the low permeability of its outer membrane in combination with the expression of several multidrug resistance efflux systems.


Input: MexZ, the negative regulator of the MexXY efflux pump, is found to be the most frequently mutated gene in P. aeruginosa isolated from cystic fibrosis patient lungs, confirming its importance in multidrug resistance.


Input: Structural consequences of four MexZ mutations, including L25P, G46V, P151L, and S202F, have been explored based on the known structure of MexZ using both molecular modeling and molecular dynamics methods.


Input: According to obtained results, G46V mutation, which completely abolishes the ability of MexZ binding to DNA, occurs in a specific evolutionary conserved region of MexZ.


Input: In addition, the most fluctuation values occur in DNA-binding domain and Helix4.


Input: The obtained results explore details of diversity in structural consequences of MexZ mutations in P. aeruginosa.


Input: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays.


Input: Understanding potential health risks is a significant challenge due to large numbers of diverse chemicals with poorly characterized exposures and mechanisms of toxicities.


Input: The present study analyzes 976 chemicals (including failed pharmaceuticals, alternative plasticizers, food additives, and pesticides) in Phase I and II of the U. S.


Input: EPA' s ToxCast (TM) project across 331 cell-free enzymatic and ligand-binding high-throughput screening (HTS) assays.


Input: Half-maximal activity concentrations (AC50) were identified for 729 chemicals in 256 assays (7, 135 chemical-assay pairs).


Input: Some of the most commonly affected assays were CYPs (CYP2C9, CYP2C19), transporters (mitochondrial TSPO, norepinephrine, dopaminergic), and GPCRs (aminergic).

norepinephrine


Input: Heavy metals, surfactants, and dithiocarbamate fungicides showed promiscuous, but distinctly different patterns of activity whereas many of the pharma compounds showed promiscuous activity across GPCRs.

dithiocarbamate


Input: Literature analysis confirmed > 50% of the activities for the most potent chemical-assay pairs (56), but also revealed 10 missed interactions.


Input: Twenty-two chemicals with known estrogenic activity were correctly identified for the majority (77%), missing only the weaker interactions.


Input: In many cases, novel findings for previously unreported chemical-target combinations clustered with known chemical-target interactions.


Input: Results from this large inventory of chemical-biological interactions can inform read-across methods as well as to link potential targets to molecular initiating events in adverse outcome pathways for diverse toxicities.


Input: This abstract does not necessarily reflect U. S.


Input: EPA policy.


Input: Ultrasensitive Polarized Up-Conversion of Tm (3 +)-Yb (3 +) Doped beta-NaYF4 Single Nanorod.

Tm (3 +)-Yb (3 +) Doped beta-NaYF4


Input: Up-conversion luminescence in rare earth ions (REs) doped nanoparticles has attracted considerable research attention for the promising applications in solid-state lasers, three-dimensional displays, solar cells, biological imaging, and so forth.


Input: However, there have been no reports on REs doped nanoparticles to investigate their polarized energy transfer up-conversion, especially for single particle.


Input: Herein, the polarized energy transfer up-conversion from REs doped fluoride nanorods is demonstrated in a single particle spectroscopy mode for the first time.

fluoride


Input: Unique luminescent phenomena, for example, sharp energy level split and singlet-to-triplet transitions at room temperature, multiple discrete luminescence intensity periodic variation with polarization direction, are observed upon excitation with 980 nm linearly polarized laser.


Input: Furthermore, nanorods with the controllable aspect ratio and symmetry are fabricated for analysis of the mechanism of polarization anisotropy.


Input: The comparative experiments suggest that intraions transition properties and crystal local symmetry dominate the polarization anisotropy, which is also confirmed by density functional theory calculations.


Input: Taking advantage of the REs based up-conversion, potential application in polarized microscopic multi-information transportation is suggested for the polarization anisotropy from REs doped fluoride single nanorod or nanorod array.

fluoride


Input: Stability of sulforaphane for topical formulation.

sulforaphane


Input: Abstract Context: Sulforaphane (SFN) is a natural compound that has been investigated as a chemopreventive agent.

Sulforaphane

SFN


Input: SFN has been shown to inhibit the activator-protein-1 (AP-1) transcription factor and may be effective for inhibition of ultraviolet (UV) induced skin carcinogenesis.

SFN


Input: This study was designed to investigate the stability of SFN as a function of pH, temperature and in various solvents and formulations.

SFN


Input: Materials and methods: Stability was analyzed using high-performance liquid chromatography.


Input: A potential lead formulation was identified and evaluated in vivo.


Input: Results: SFN was determined to undergo apparent first-order degradation kinetics for the conditions explored.

SFN


Input: It was observed that SFN undergoes base catalyzed degradation.

SFN


Input: Buffer species and solvent type impacts stability as well.


Input: SFN was found to be very sensitive to temperature with degradation rate changing by a factor of nearly 3. 1 for every 10 degrees C change in temperature (at pH 4. 0).

SFN


Input: SFN completely degraded after 30 days in a conventional pharmaceutical cream formulation.

SFN


Input: Improved stability was observed in organic formulation components.


Input: Stability studies were conducted on two nonaqueous topical formulations: a polyethylene glycol (PEG) ointment base and an organic oleaginous base.

polyethylene glycol

PEG


Input: Conclusion: Topically applied SFN in the PEG base formulation significantly reduced AP-1 activation after UV stimulation in the skin of a transgenic mouse model, indicating that SFN in this formulation retains efficacy in vivo.

SFN

PEG

SFN


Input: DNA Interactions in Crowded Nanopores.


Input: The motion of DNA in crowded environments is a common theme in physics and biology.


Input: Examples include gel electrophoresis and the self-interaction of DNA within cells and viral capsids.


Input: Here we study the interaction of multiple DNA molecules within a nanopore by tethering the DNA to a bead held in a laser optical trap to produce a " molecular tug-of-war ".


Input: We measure this tether force as a function of the number of DNA molecules in the pore and show that the force per molecule decreases with the number of molecules.


Input: A simple scaling argument based on a mean field theory of the hydrodynamic interactions between multiple DNA strands explains our observations.


Input: At high salt concentrations, when the Debye length approaches the size of the counterions, the force per molecule becomes essentially independent of the number of molecules.


Input: We attribute this to a sharp decrease in electroosmotic flow which makes the hydrodynamic interactions ineffective.


Input: Spontaneous partition of carbon nanotubes in polymer-modified aqueous phases.

carbon


Input: The distribution of nanoparticles in different aqueous environments is a fundamental problem underlying a number of processes, ranging from biomedical applications of nanoparticles to their effects on the environment, health, and safety.


Input: Here, we study distribution of carbon nanotubes (CNTs) in two immiscible aqueous phases formed by the addition of polyethylene glycol (PEG) and dextran.

carbon

polyethylene glycol

PEG


Input: This well-defined model system exhibits a strikingly robust phenomenon: CNTs spontaneously partition between the PEG-and the dextran-rich phases according to nanotube' s diameter and metallicity.

PEG


Input: Thermodynamic analysis suggests that this chirality-dependent partition is determined by nanotube' s intrinsic hydrophobicity and reveals two distinct regimes in hydrophobicity-chirality relation: a small diameter (< 1 nm) regime, where curvature effect makes larger diameter tubes more hydrophobic than small diameter ones, and a large diameter (> 1. 2 nm) regime, where nanotube' s polarizability renders semiconducting tubes more hydrophobic than metallic ones.


Input: These findings reveal a general rule governing CNT behaviors in aqueous phase and provide an extremely simple way to achieve spatial separation of CNTs by their electronic structures.


Input: Protein kinase inhibitor design by targeting the Asp-Phe-Gly (DFG) motif: the role of the DFG motif in the design of epidermal growth factor receptor inhibitors.

Asp-Phe-Gly


Input: The Asp-Phe-Gly (DFG) motif plays an important role in the regulation of kinase activity.

Asp-Phe-Gly


Input: Structure-based drug design was performed to design compounds able to interact with the DFG motif; epidermal growth factor receptor (EGFR) was selected as an example.


Input: Structural insights obtained from the EGFR/2a complex suggested that an extension from the meta-position on the phenyl group (ring-5) would improve interactions with the DFG motif.

phenyl


Input: Indeed, introduction of an N, N-dimethylamino tail resulted in 4b, which showed almost 50-fold improvement in inhibition compared to 2a.

N, N-dimethylamino


Input: Structural studies confirmed this N, N-dimethylamino tail moved towards the DFG motif to form a salt bridge with the side chain of Asp831.

N, N-dimethylamino


Input: That the interactions with the DFG motif greatly contribute to the potency of 4b is strongly evidenced by synthesizing and testing compounds 2a, 3g and 4f: when the charge interactions are absent, the inhibitory activity decreased significantly.


Input: Quantitative analysis of global phosphorylation changes with high-resolution tandem mass spectrometry and stable isotopic labeling.


Input: Quantitative measurement of specific protein phosphorylation sites is a primary interest of biologists, as site-specific phosphorylation information provides insights into cell signaling networks and cellular dynamics at a system level.


Input: Over the last decade, selective phosphopeptide enrichment methods including IMAC and metal oxides (TiO2 and ZrO2) have been developed and greatly facilitate large scale phosphoproteome analysis of various cells, tissues and living organisms, in combination with modern mass spectrometers featuring high mass accuracy and high mass resolution.

metal oxides


Input: Various quantification strategies have been applied to detecting relative changes in expression of proteins, peptides, and specific modifications between samples.


Input: The combination of mass spectrometry-based phosphoproteome analysis with quantification strategies provides a straightforward and unbiased method to identify and quantify site-specific phosphorylation.


Input: We describe common strategies for mass spectrometric analysis of stable isotope labeled samples, as well as two widely applied phosphopeptide enrichment methods based on IMAC (NTA-Fe (3 +)) and metal oxide (ZrO2).

NTA-Fe (3 +)

metal oxide


Input: Instrumental configurations for on-line LC-tandem mass spectrometric analysis and parameters of conventional bioinformatic analysis of large data sets are also considered for confident identification, localization, and reliable quantification of site-specific phosphorylation.


Input: Molecular Mechanisms of the antitumor activity of SB225002: A novel microtubule inhibitor.


Input: SB225002 (SB) is an IL-8 receptor B (IL-8RB) antagonist that has previously been shown to inhibit IL-8-based cancer cell invasion, and to possess in vivo anti-inflammatory and anti-nociceptive effects.


Input: The present study presented an evidence for the cell cycle-targeting activity of SB in a panel of p53-mutant human cancer cell lines of different origin, and investigated the underlying molecular mechanisms.


Input: A combination of cell cycle analysis, immunocytometry, immunoblotting, and RNA interference revealed that SB induced a BubR1-dependent mitotic arrest.


Input: Mechanistically, SB was shown to possess a microtubule destabilizing activity evidenced by hyperphosphorylation of Bcl2 and BclxL, suppression of microtubule polymerization and induction of a prometaphase arrest.


Input: Molecular docking studies suggested that SB has a good affinity towards vinblastine-binding site on beta-tubulin subunit.

vinblastine


Input: Of note, SB265610 which is a close structural analogue of SB225002 with a potent IL-8RB antagonistic activity did not exhibit a similar antimitotic activity.


Input: Importantly, in P-glycoprotein overexpressing NCI/Adr-Res cells the antitumor activity of SB was unaffected by multidrug resistance.


Input: Interestingly, the mechanisms of SB-induced cell death were cell-line dependent, where in invasive hepatocellular carcinoma HLE cells the significant contribution of BAK-dependent mitochondrial apoptosis was demonstrated.


Input: Conversely, SB activated p38 MAPK signaling in colorectal adenocarcinoma cells SW480, and pharmacologic inhibition of p38 MAPK activity revealed its key role in mediating SB-induced caspase-independent cell death.


Input: In summary, the present study introduced SB as a promising antitumor agent which has the potential to exert its activity through dual mechanisms involving microtubules targeting and interference with IL-8-drivin cancer progression.


Input: Wogonoside displays anti-inflammatory effects through modulating inflammatory mediator expression using RAW264. 7 cells.

Wogonoside


Input: ETHNOPHARMACOLOGICAL RELEVANCE: The root of Scutellaria baicalensis Georgi, also called Huangqin in China, is an herbal-based nutraceutical which is usually used in Chinese medicated diet (CMD).


Input: As an abundant ingredient in Huangqin, wogonoside is a flavonoid glycoside.

wogonoside

flavonoid glycoside


Input: The present work investigated the anti-inflammatory activities of wogonoside in lipopolysaccharides (LPS)-induced RAW264. 7 cells.

wogonoside


Input: MATERIALS AND METHODS: RAW264. 7 cells were used.


Input: The inhibition of wogonoside against nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in LPS-induced RAW264. 7 cells were measured.

wogonoside

nitric oxide

NO

prostaglandin E2


Input: Additionally, the effects of wogonoside on mRNA expression of inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX2), TNF-alpha and IL-6 were also investigated.

wogonoside

nitric oxide


Input: RESULTS AND DISCUSSION: Wogonoside not only dose-dependently decreased the production of inflammatory mediators including NO and PGE2 but also inhibited the release of pro-inflammatory cytokines including TNF-alpha and IL-6 in LPS-induced RAW264. 7 cells.

Wogonoside

NO


Input: Furthermore, wogonoside possessed significantly in vitro inhibitory effects on the gene expression of iNOS, COX2, TNF-alpha and IL-6.

wogonoside


Input: CONCLUSION: These results suggest that wogonoside may be used as a functional food component for prevention and treatment of inflammation.

wogonoside


Input: Assuring Safety Without Animal Testing: The Case for the Human Testis In Vitro.


Input: From 15-17 June 2011, a dedicated workhop was held on the subject of in vitro models for mammalian spermatogenesis and their applications in toxicological hazard and risk assessment.


Input: The workshop was sponsored by the Dutch ASAT initiative (Assuring Safety without Animal Testing), which aims at promoting innovative approaches towards toxicological hazard and risk assessment on the basis of human and in vitro data, and replacement of animal studies.


Input: Participants addressed the state of the art regarding human and animal evidence for compound mediated testicular toxicity, reviewed existing alternative assay models, and brainstormed about future approaches, specifically considering tissue engineering.


Input: The workshop recognized the specific complexity of testicular function exemplified by dedicated cell types with distinct functionalities, as well as different cell compartments in terms of microenvironment and extracellular matrix components.


Input: This complexity hampers quick results in the realm of alternative models.


Input: Nevertheless, progress has been achieved in recent years, and innovative approaches in tissue engineering may open new avenues for mimicking testicular function in vitro.


Input: Although feasible, significant investment is deemed essential to be able to bring new ideas into practice in the laboratory.


Input: For the advancement of in vitro testicular toxicity testing, one of the most sensitive end points in regulatory reproductive toxicity testing, such an investment is highly desirable.


Input: Relations between stimulation of mesolimbic dopamine and place conditioning in rats produced by cocaine or drugs that are tolerant to dopamine transporter conformational change.

dopamine

cocaine

dopamine


Input: RATIONALE: Dopamine transporter (DAT) conformation plays a role in the effectiveness of cocaine-like and other DAT inhibitors.

Dopamine

cocaine


Input: Cocaine-like stimulants are intolerant to DAT conformation changes having decreased potency in cells transfected with DAT constructs that face the cytosol compared to wild-type DAT.

Cocaine


Input: In contrast, analogs of benztropine (BZT) are among compounds that are less affected by DAT conformational change.

benztropine

BZT


Input: METHODS: We compared the displacement of radioligand binding to various mammalian CNS sites, acute stimulation of accumbens shell dopamine levels, and place conditioning in rats among cocaine and four BZT analogs with Cl substitutions on the diphenyl-ether system including two with carboalkoxy substitutions at the 2-position of the tropane ring.

dopamine

cocaine

BZT

Cl

diphenyl-ether

carboalkoxy

tropane


Input: RESULTS: Binding assays confirmed high-affinity and selectivity for the DAT with the BZT analogs which also produced significant stimulation of mesolimbic dopamine efflux.

BZT

dopamine


Input: Because BZT analogs produced temporal patterns of extracellular dopamine levels different from those by cocaine (3-10 mg/kg, i. p.), the place conditioning produced by BZT analogs and cocaine was compared at doses and times at which both the increase in dopamine levels and rates of increase were similar to those produced by an effective dose of cocaine.

BZT

dopamine

cocaine

BZT

cocaine

dopamine

cocaine


Input: Despite this equilibration, none of the BZT analogs tested produced significant place conditioning.

BZT


Input: CONCLUSIONS: The present results extend previous findings suggesting that cocaine-like actions are dependent on a binding equilibrium that favors the outward conformational state of the DAT.

cocaine


Input: In contrast, BZT analogs with reduced dependence on DAT conformation have reduced cocaine-like behavioral effects and may prove useful in development of medications for stimulant abuse.

BZT

cocaine


Input: The von Hippel-Lindau Protein pVHL Inhibits Ribosome Biogenesis and Protein Synthesis.


Input: pVHL, product of von Hippel-Lindau (VHL) tumor suppressor gene, functions as the substrate recognition component of an E3-ubiquitin ligase complex that targets hypoxia inducible factor alpha (HIFalpha) for ubiquitination and degradation.


Input: Besides HIFalpha, pVHL also interacts with other proteins and has multiple functions.


Input: Here, we report that pVHL inhibits ribosome biogenesis and protein synthesis.


Input: We find that pVHL associates with the 40S ribosomal protein S3 (RPS3) but does not target it for destruction.


Input: Rather, the pVHL-RPS3 association interferes with the interaction between RPS3 and RPS2.


Input: Expression of pVHL also leads to nuclear retention of pre-40S ribosomal subunits, diminishing polysomes and 18S rRNA levels.


Input: We also demonstrate that pVHL suppresses both cap-dependent and cap-independent protein synthesis.


Input: Our findings unravel a novel function of pVHL and provide insight into the regulation of ribosome biogenesis by the tumor suppressor pVHL.


Input: Decreased Permeability Surface Area for Glucose in Obese Women with Postprandial Hyperglycemia: No Effect of Phosphodiesterase-5 (PDE-5) Inhibition.

Glucose


Input: Insulin-mediated microvascular recruitment is recognized as a potential mechanism contributing to insulin resistance.


Input: In this study, we compared a marker of microvascular function, the permeability surface area for glucose (PSglu), and forearm glucose uptake after an OGTT in obese women with impaired glucose metabolism and healthy lean nondiabetic women, with the aim to characterize whether decreased permeability surface area for glucose or decreased glucose uptake may contribute to postprandial hyperglycemia in the obese group.

glucose

glucose

glucose

glucose

glucose


Input: In addition, we evaluated whether the phosphodiesterase-5 (PDE-5) inhibitor tadalafil, in a randomized double blind placebo controlled design, might attenuate postprandial glucose levels in obese women.

tadalafil

glucose


Input: For these purposes, intramuscular microdialysis, blood sampling from arterial and venous blood of the forearm, and measurements of forearm blood flow were performed.


Input: The results showed an impaired permeability surface area for glucose (IAUC PSglu 31 +/- 13 vs. 124 +/- 31; p < 0. 05) in obese when compared with lean participants, but no differences in forearm glucose uptake appeared between the groups.

glucose

glucose


Input: Furthermore, a single dose of tadalafil 10 mg showed no improvement of the permeability surface area for glucose, glucose uptake, or circulating glucose levels in obese participants.

tadalafil

glucose

glucose

glucose


Input: In conclusion, the postprandial PSglu response was impaired in obese women showing postprandial hyperglycemia, indicating a compromised microcirculation.


Input: However, we were unable to demonstrate any acute effect on either vascular function or glucose uptake of the phosphodiesterase-5 (PDE-5) inhibitor tadalafil.

glucose

tadalafil


Input: Dietary Flaxseed Oil Supplementation Mitigates the Effect of Lead on the Enzymes of Carbohydrate Metabolism, Brush Border Membrane, and Oxidative Stress in Rat Kidney Tissues.

Carbohydrate


Input: Lead is a heavy metal widely distributed in the environment.


Input: Lead is a ubiquitous environmental toxin that is capable of causing numerous acute and chronic illnesses.


Input: Human and animal exposure demonstrates that lead is nephrotoxic.


Input: However, attempts to reduce lead-induced nephrotoxicity were not found suitable for clinical use.


Input: Recently, flaxseed oil (FXO), a rich source of omega-3 fatty acids and lignans, has been shown to prevent/reduce the progression of certain types of cardiovascular and renal disorders.

omega-3 fatty acids

lignans


Input: In view of this, the present study investigates the protective effect of FXO on lead acetate (PbAc)-induced renal damage.

lead acetate

PbAc


Input: Rats were pre-fed normal diet and the diet rich in FXO for 14 days, and then, four doses of lead acetate (25 mg/kg body weight) were administered intraperitoneally while still on diet.

lead acetate


Input: Various serum parameters, enzymes of carbohydrate metabolism, brush border membrane (BBM), and oxidative stress were analyzed in rat kidney.

carbohydrate


Input: PbAc nephrotoxicity was characterized by increased serum creatinine and blood urea nitrogen.

PbAc

creatinine

urea nitrogen


Input: PbAc increased the activities of lactate dehydrogenase and NADP-malic enzyme, whereas it decreased malate and glucose-6-phosphate dehydrogenase, glucose-6-phosphatase, fructose-1, 6-bisphosphatase, and BBM enzyme activities.

PbAc

lactate

NADP

malate

glucose

fructose


Input: PbAc caused oxidant/antioxidant imbalances as reflected by increased lipid peroxidation and decreased activities of superoxide dismutase, glutathione peroxidase, and catalase.

PbAc

superoxide

glutathione


Input: In contrast, FXO alone enhanced the enzyme activities of carbohydrate metabolism, BBM, and antioxidant defense system.

carbohydrate


Input: FXO feeding to PbAc-treated rats markedly enhanced resistance to PbAc-elicited deleterious effects.

PbAc

PbAc


Input: In conclusion, dietary FXO supplementation ameliorated PbAc-induced specific metabolic alterations and oxidative damage by empowering antioxidant defense mechanism and improving BBM integrity and energy metabolism.

PbAc


Input: Topological Dangling Bonds with Large Spin Splitting and Enhanced Spin Polarization on the Surfaces of Bi2Se3.


Input: We investigate the topological surface state properties at various surface cleaves in the topological insulator Bi2Se3, via first principles calculations and scanning tunneling microscopy/spectroscopy (STM/STS).


Input: While the typical surface termination occurs between two quintuple layers, we report the existence of a surface termination within a single quintuple layer where dangling bonds form with giant spin splitting owing to strong spin-orbit coupling.


Input: Unlike Rashba split states in a 2D electron gas, these states are constrained by the band topology of the host insulator with topological properties similar to the typical topological surface state, and thereby offer an alternative candidate for spintronics usage.


Input: We name these new states " topological dangling-bond states ".


Input: The degree of the spin polarization of these states is greatly enhanced.


Input: Since dangling bonds are more chemically reactive, the observed topological dangling-bond states provide a new avenue for manipulating band dispersions and spin-textures by adsorbed atoms or molecules.


Input: Efficient cell and cell-sheet harvesting based on smart surfaces coated with a multifunctional and self-organizing Elastin-Like Recombinamer.


Input: A wide range of smart surfaces with novel properties relevant for biomedical applications have been developed recently.


Input: Herein we focus on thermoresponsive surfaces that switch between cell-adherent and non-adherent states, and their applications for cell harvesting.


Input: These smart surfaces are obtained by covalently coupling a tailored Elastin-Like Recombinamer onto glass surfaces by means of the well-known and widely applied Click Chemistry methodology.


Input: The resulting recombinamer-functionalized surfaces have been characterized by means of water contact angle measurements, XPS and TOF-SIMS.


Input: A cell-based analysis of these surfaces with human fibroblasts showed a high degree of adhesion to the surface in its adherent state (37 (o) C), thus promoting cell viability and proliferation.


Input: A temperature decrease triggers reorganization of the recombinamer, thus markedly increasing the number of non-adherent domains and masking the adherent ones.


Input: This process allows a specific and efficient temporal control of cell adhesion and cell detachment.


Input: After determination of the properties required for a suitable cell-harvesting system, optimization of the process allows single cells or cell sheets from at least two types of cells (HFF-1 and ADSCs) to be rapidly harvested.


Input: Aromatic glycosides from the flower buds of Lonicera japonica.

Aromatic glycosides


Input: Six new glycosides (1-6) have been isolated from the flower buds of Lonicera japonica.


Input: Their structures including the absolute configurations were determined by spectroscopic and chemical methods as (-)-2-hydroxy-5-methoxybenzoic acid 2-O-beta-d-(6-O-benzoyl)-glucopyranoside (1), (-)-4-hydroxy-3, 5-dimethoxybenzoic acid 4-O-beta-d-(6-O-benzoyl)-glucopyranoside (2), (-)-(E)-3, 5-dimethoxyphenylpropenoic acid 4-O-beta-d-(6-O-benzoyl)-glucopyranoside (3), (-)-(7S, 8R)-(4-hydroxyphenylglycerol 9-O-beta-d-[6-O-(E)-4-hydroxy-3, 5-dimethoxyphenylpropenoyl]-glucopyranoside (4), (-)-(7S, 8R)-(4-hydroxy-3-methoxyphenylglycerol 9-O-beta-d-[6-O-(E)-4-hydroxy-3, 5-dimethoxyphenylpropenoyl]-glucopyranoside (5), and (-)-4-hydroxy-3-methoxyphenol beta-d-{6-O-[4-O-(7S, 8R)-(4-hydroxy-3-methoxyphenylglycerol-8-yl)-3-methoxybenzoyl]}-glucopyranoside (6), respectively.

(-)-2-hydroxy-5-methoxybenzoic acid 2-O-beta-d-(6-O-benzoyl)-glucopyranoside

(-)-4-hydroxy-3, 5-dimethoxybenzoic acid 4-O-beta-d-(6-O-benzoyl)-glucopyranoside

(-)-(E)-3, 5-dimethoxyphenylpropenoic acid 4-O-beta-d-(6-O-benzoyl)-glucopyranoside

(-)-(7S, 8R)-(4-hydroxyphenylglycerol 9-O-beta-d-[6-O-(E)-4-hydroxy-3, 5-dimethoxyphenylpropenoyl]-glucopyranoside

(-)-(7S, 8R)-(4-hydroxy-3-methoxyphenylglycerol 9-O-beta-d-[6-O-(E)-4-hydroxy-3, 5-dimethoxyphenylpropenoyl]-glucopyranoside

(-)-4-hydroxy-3-methoxyphenol beta-d-{6-O-[4-O-(7S, 8R)-(4-hydroxy-3-methoxyphenylglycerol-8-yl)-3-methoxybenzoyl]}-glucopyranoside


Input: Sub-nanomolar Detection of Prostate Specific Membrane Antigen in Synthetic Urine by Synergistic, Dual Ligand Phage.


Input: The sensitive detection of cancer biomarkers in urine could revolutionize cancer diagnosis and treatment.


Input: Such detectors must be inexpensive, easy to interpret, and sensitive.


Input: This report describes a bioaffinity matrix of viruses integrated into PEDOT films for electrochemical sensing of prostate specific membrane antigen (PSMA), a prostate cancer biomarker.

PEDOT


Input: High sensitivity to PSMA resulted from synergistic action by two different ligands to PSMA on the same phage particle.


Input: One ligand was chemically synthesized and wrapped around the phage, and the second was genetically encoded.


Input: The dual ligands result in a bidentate binder with high copy, dense ligand display for enhanced PSMA detection through a chelate-based, avidity effect.


Input: Biosensing with virus-PEDOT films provides a 100 pM limit of detection for PSMA in synthetic urine without requiring enzymatic or other amplification.

PEDOT


Input: Oxidative damage and genotoxic effect in mice caused by sub-chronic exposure to low-dose volatile organic compounds.


Input: Abstract Volatile organic compounds (VOCs) are widely used as constituents of household chemicals.


Input: Although adverse health effects have been reported, long-term exposure to low-level VOCs mixture has not been studied.


Input: Especially, there is a lack of substantial information on the sensitive biomarkers and carcinogenic markers.


Input: In the present study, we examined oxidative stress and genotoxic effects of sub-chronic low-dose VOCs mixture (formaldehyde, benzene, toluene and xylene).

formaldehyde

benzene

toluene

xylene


Input: Male Kunming mice were exposed to 0 (control) and three different doses of VOCs mixture (group 1S, 5S and 10S) for 90 d (2 h/d).


Input: Group 1S is 0. 10, 0. 11, 0. 20 and 0. 20 mg/m (3), group 5S is 0. 50, 0. 55, 1. 00 and 1. 00 mg/m (3), group 10S is 1. 00, 1. 10, 2. 00 and 2. 00 mg/m (3), which, respectively, corresponded to 1, 5 and 10 times of indoor air quality standard (IAQS) in China.


Input: One day following VOCs exposure, oxidative stress markers in lung, 8-hydroxy-2'-deoxyguanosine in bronchoalveolar lavage fluid and genotoxicity (DNA damage) in liver were examined.


Input: Results showed that exposure to VOCs (IAQS dose) resulted in oxidative damages of lung, which were supported by the significant changes on reactive oxygen species, reduced glutathione (GSH), GSH S-transferase, total antioxidative capacity, malondialdehyde, protein carbonyl and nitric oxide (NO).

oxygen

reduced glutathione

GSH

GSH S

malondialdehyde

carbonyl

nitric oxide

NO


Input: Moreover, oxidative stress markers in group 5S and 10S (except NO) in lung were affected significantly.

NO


Input: In addition, VOCs exposure also induced significantly DNA damage in liver.


Input: Our study suggested long-term VOCs inhalation at low levels caused oxidative stress and genotoxicity response in mice.


Input: Since effects were seen at the current IAQS level, further studies below this level are necessary.


Input: Surgical resection of brain metastases-impact on neurological outcome.


Input: Brain metastases (BM) develop in about 30% of all cancer patients.


Input: Surgery plays an important role in confirming neuropathological diagnosis, relieving mass effects and improving the neurological status.


Input: To select patients with the highest benefit from surgical resection, prognostic indices (RPA, GPA) have been formulated which are solely focused on survival without considering neurological improvement.


Input: In this study we analyzed the impact of surgical resection on the neurological status in addition to overall survival in 206 BM patients.


Input: Surgical mortality and morbidity was 0. 0% and 10. 3% respectively.


Input: New neurologic deficits occurred in 6. 3% of all patients.


Input: The median overall survival was 6. 3 months.


Input: Poor RPA class and short time interval between diagnosis of cancer and the occurrence of BM were independent factors predictive for poor survival.