Input: Adjustment for vocabulary (estimated premorbid ability) was used to estimate lifetime cognitive change. RESULTSMeasures of cognitive decline were significantly associated with stroke, NT-proBNP, ABI, and cIMT, but not with nonstroke vascular events.


Input: The association of stroke with increased estimated lifetime cognitive decline (standardized beta,-0. 12) and of subclinical markers with actual 4-year decline (standardized beta,-0. 12, 0. 12, and-0. 15 for NT-proBNP, ABI, and cIMT, respectively) reached the Bonferroni-adjusted level of statistical significance (P < 0. 006).


Input: Results altered only slightly on adjustment for vascular risk factors. CONCLUSIONSStroke and subclinical markers of cardiac stress and generalized atherosclerosis are associated with cognitive decline in older patients with type 2 diabetes.


Input: Further investigation into the potential use of subclinical vascular disease markers in predicting cognitive decline is warranted.


Input: Co-Ni layered double hydroxides for water oxidation in neutral electrolyte.

Co

Ni

hydroxides


Input: The electrochemical properties of Co-Ni layered double hydroxides (LDHs) as efficient electrocatalysts for water oxidation were investigated in potassium phosphate electrolyte under neutral pH condition.

Co

Ni

hydroxides

potassium phosphate


Input: The Co-Ni LDHs with a core-shell structure were fabricated using a facile route from a Co-Ni hydroxide precursor with iodine as a topotactic oxidizer.

Co

Ni

Co

Ni hydroxide

iodine


Input: The unique core-shell morphology is likely due to the enrichment of Co (iii) hydroxide in the inner core indicated by selected area electron diffraction and energy-dispersive spectroscopy.

Co (iii) hydroxide


Input: Through a self-assembling process at the organic/inorganic interface and dip-coating, the Co-Ni LDHs were deposited onto FTO glass substrates to prepare composite electrodes.

Co

Ni


Input: Low over-potential and high current density was achieved in the oxygen evolution reaction.

oxygen


Input: The excellent electrocatalytic activity of Co-Ni LDHs may be attributed to more accessible Co active sites and rapid movement of interlayer ions within their layered structure.

Co

Ni

Co


Input: Acute alcohol effects on subtypes of impulsivity and the role of alcohol-outcome expectancies.

alcohol

alcohol


Input: RATIONALE: It is well established that alcohol acutely impairs the ability to inhibit a pre-potent response (motor impulsivity), but its effects on cognitive impulsivity, including temporal (delayed gratification) and reflection (decision making) impulsivity, are not clear.

alcohol


Input: An important factor contributing to the effects of alcohol is cognitive expectancies of alcohol-related outcomes.

alcohol

alcohol


Input: OBJECTIVES: The current study investigated the effect of alcohol, and alcohol outcome expectancies, on subtypes of impulsivity.

alcohol

alcohol


Input: METHODS: Impulsivity was tested using the Stop Signal, the Single Key Impulsivity and the Information Sampling Task for motor, temporal and reflection impulsivity, respectively.


Input: Participants (n = 48) received placebo, a low (0. 4 g/kg) or high dose (0. 8 g/kg) of alcohol, before completing the impulsivity measures.

alcohol


Input: RESULTS: Motor impulsivity was affected by alcohol dose; participants receiving a high dose displayed reduced inhibitory control.

alcohol


Input: Reflection impulsivity was affected by cognitive alcohol expectancies, but not by alcohol condition; participants expecting greater cognitive and behavioural impairment by alcohol exhibited low impulsivity.

alcohol

alcohol

alcohol


Input: Temporal impulsivity was not affected by either alcohol dose or outcome expectancies.

alcohol


Input: CONCLUSIONS: These data suggest that the effects of alcohol on the subtypes of impulsivity are dissociable.

alcohol


Input: Motor impulsivity is sensitive to the pharmacological effects of alcohol, whereas the reflection subtype is affected by cognitive alcohol expectancies.

alcohol

alcohol


Input: The findings have implications for the understanding of impulsive behaviour under the influence of alcohol.

alcohol


Input: A New Strategy for Selective Targeting of Progesterone Receptor with Passive Antagonists.

Progesterone


Input: Currently available progesterone receptor (PR) antagonists, such as mifepristone (RU486), lack specificity and display partial agonist properties, leading to potential drawbacks in their clinical use.

progesterone

mifepristone


Input: Recent X-ray crystallographic studies have identified key contacts involved in the binding of agonists and antagonists with PR opening the way for a new rational strategy for inactivating PR.


Input: We report here the synthesis and characterization of a novel class of PR antagonists designed from such studies.


Input: The lead molecule, the homosteroid APR19, displays in vivo endometrial antiprogesterone activity.

homosteroid APR19


Input: APR19 inhibits progesterone-induced PR recruitment and transactivation from synthetic and endogenous gene promoters.

progesterone


Input: Importantly, it exhibits high PR selectivity with respect to other steroid hormone receptors, and is devoid of any partial agonist activity on PR target gene transcription.

steroid


Input: Two-hybrid and immunostaining experiments reveal that APR19-bound PR is unable to interact with either transcriptional coactivators (SRC1, SCR2) or corepressors (NCoR, SMRT), in contrast to RU486-PR complexes.


Input: APR19 also inhibits agonist-induced phosphorylation of serine 294 regulating PR transcriptional activity and turnover kinetics.

serine


Input: In-silico docking studies based on the crystal structure of the PR ligand-binding domain show that, in contrast to progesterone, APR19 does not establish stabilizing hydrogen bonds with the ligand binding cavity, resulting in an unstable ligand-receptor complex.

progesterone

hydrogen


Input: Altogether, these properties highly distinguish APR19 from RU486 and likely its derivatives, suggesting that it belongs to a new class of pure antiprogestins which inactivate PR by a passive mechanism.


Input: These specific PR antagonists open new perspectives for long term hormonal therapy.


Input: Cellular insulin resistance disrupts leptin-mediated control of neuronal signaling and transcription.


Input: Central resistance to the actions of insulin and leptin is associated with the onset of obesity and type 2 diabetes mellitus (T2DM), whereas leptin and insulin signaling is essential for both glucose and energy homeostasis.

glucose


Input: Although it is known that leptin resistance can lead to attenuated insulin signaling, whether insulin resistance can lead to or exacerbate leptin resistance is unknown.


Input: To investigate the molecular events underlying crosstalk between these signaling pathways, immortalized hypothalamic neuronal models, rHypoE-19 and mHypoA-2/10, were utilized.


Input: Prolonged insulin exposure was used to induce cellular insulin resistance, and thereafter leptin-mediated regulation of signal transduction and gene expression was assessed.


Input: Leptin directly repressed agouti-related peptide (AgRP) mRNA levels, but induced urocortin-2 (UCN2), insulin receptor substrate-1 (IRS1), IRS2, and IR transcription, through leptin-mediated phosphatidylinositol-3-kinase (PI3K)/Akt activation.

phosphatidylinositol


Input: Neuronal insulin resistance, as assessed by attenuated Akt phosphorylation, blocked leptin-mediated signal transduction, and AgRP, UCN2, IRS1, IRS2 and IR synthesis.


Input: Insulin resistance caused a substantial decrease in IR protein levels, forkhead box protein 1 (FoxO1) phosphorylation, and an increase in suppressor of cytokine signaling 3 (SOCS3) protein levels.


Input: Cellular insulin resistance may cause or exacerbate neuronal leptin resistance, and by extension, obesity.


Input: It is essential to unravel the effects of neuronal insulin resistance given that both peripheral, as well as the less widely studied central insulin resistance, may contribute to the development of metabolic, reproductive and cardiovascular disorders.


Input: This study provides an improved understanding of the complex cellular crosstalk between insulin-leptin signal transduction that is disrupted during neuronal insulin resistance.


Input: VERY HIGH PREVALENCE OF ULTRASOUND THYROID SCAN ABNORMALITIES IN HEALTHY VOLUNTEERS IN MODENA, ITALY.


Input: Background: Italy is characterized by high prevalence of goiter.


Input: To date, only limited data about the prevalence of goiter in the Italian adult population are available.


Input: Aim.


Input: To investigate the prevalence of thyroid ultrasound abnormalities in adults unaware of any thyroid disease and evaluate the rate of differentiated thyroid cancer (DTC) obtained by this intervention.


Input: Methods.


Input: US thyroid scan was performed in adult volunteers recruited by advertisement in Modena, Italy.


Input: 135 women and 66 men (n = 201), unaware of any thyroid disease (mean age of 46 +/- 10. 7 years) underwent their first thyroid US scan.


Input: Results.


Input: US thyroid abnormalities were found in 101 subjects (50. 3%): 91 nodular goiters (45. 2%) and 13 US-thyroiditis (6. 5%) associated with positive auto-antibodies in 11 of them.


Input: 17 subjects (18%) with nodules underwent US-FNAB with the following cytological class (C) outcome: 14 patients C2 (82%), 1 patient C3 (6%), 2 patients had C4 (12%), the latter received histological confirmation.


Input: Conclusions.


Input: The prevalence of thyroid abnormalities, is very high in subjects unaware of any thyroid disease.


Input: DTC was found in 1% of subjects and in 2% of those affected by nodular goiter.


Input: Compared to the detection rate of the well-established screening programs for breast (0. 45%) and colorectal (0. 27%) cancer, the prevalence of DTC seems to be much higher.


Input: Thyroid US screening could allow the detection of DTC in asymptomatic subjects and this diagnosis often includes DTC at an advanced stage.


Input: Thus, US screening not necessarily results in the over-diagnosis of clinically not relevant thyroid diseases.


Input: Female sexual dysfunction in women with thyroid disorders.


Input: Background.


Input: Few data exist on the prevalence of FSD in thyroid disorders.


Input: Aim.


Input: We evaluated FSD in women with thyroid diseases and in control age matched healthy women to investigate the relationship between sexual function, and thyroid hormones.


Input: Methods.


Input: One hundred and four women with thyroid diseases and 53 controls participated in the study.


Input: Eighteen with hyperthyroidism (Group1), 22 hypothyroidism (Group2), 45 Hashimoto' s thyroiditis (Group3), 19 nodular goiter (Group4) underwent thyroid function evaluation and sonography.


Input: The Female Sexual Function Index (FSFI) assessed sexual function.


Input: Results.


Input: The prevalence of FSD was 46. 1% in thyroid diseases and 20. 7% in controls.


Input: Only in Group4, the prevalence (68. 4%) was significantly higher than in controls (P < 0. 005).


Input: The mean total FSFI score were 20. 1 +/- 7. 1 in women with thyroid diseases and 25. 6 +/- 4. 7 in the controls (P < 0. 001).


Input: Compared with controls, there was a significant decrease of desire in Group2; desire, arousal and lubrication in Group3; desire, arousal, lubrication, orgasm and satisfaction in Group4.


Input: In thyroid diseases the prevalence of FSD was 53% and 42%, while in the controls was 55% and 20%, in menopausal and pre-menopausal groups, respectively.


Input: We found a significant inverse correlation between TSH and FSFI (r =-0. 7, P = 0. 01) in Group 4, which showed the lowest FSFI score (17. 8 +/- 5. 7) and the highest BMI (28. 4 +/- 7. 1 Kg/m2). Conclusions: Women with thyroid diseases present a higher prevalence of FSD than controls.


Input: Although our findings suggest a higher impairment of sexual function in Group4 and a role for TSH in FSD, further researches are needed.


Input: A XAS study of the luminescent Eu centers in thiosilicate phosphors.

Eu

thiosilicate


Input: Due to its bright yellow-to-red emission, europium doped Ca2SiS4 is a very interesting material for phosphor converted light emitting diodes.

europium


Input: The emission spectrum is highly dependent on the Eu concentration and can consist of more than one emission band.

Eu


Input: We combined X-ray absorption fine structure and photoluminescence measurements to analyze the structure of europium centers in (Ca, Eu) 2SiS4 luminescent powders.

europium

(Ca, Eu) 2SiS4


Input: This paper provides an explanation for the concentration dependency of the emission spectra.


Input: We find that at low dopant concentrations a large fraction of trivalent europium ions is unexpectedly present in the powders.

europium


Input: These trivalent europium ions tend to form defect clusters in the luminescent powders.

europium


Input: Furthermore we observe a preferential substitution of the europium ions over the two different substitutional Ca sites, which changes upon increasing the dopant concentration.

europium

Ca


Input: At high dopant concentration, the powder crystallizes in the monoclinic Eu2SiS4 structure.

monoclinic Eu2SiS4


Input: Once more a preferential substitution of the europium ions is observed.

europium


Input: Summarizing, the influence of the concentration on the emission spectrum is explained by a difference in preferential occupation of the Eu ions in the lattice.

Eu


Input: Anti-asthmatic Effects of Baicalin in a Mouse Model of Allergic Asthma.

Baicalin


Input: The aim of the study was to investigate the anti-asthmatic effects of baicalin (BA) and the possible mechanisms.

baicalin


Input: Asthma model was established by ovalbumin (OVA) intraperitoneal injection.


Input: A total of 60 mice were randomly assigned to six experimental groups: control, model, dexamethasone (2 mg/kg), and BA (10 mg/kg, 20 mg/kg, 40 mg/kg).

dexamethasone


Input: Airway resistance (RI) and lung compliance (Cdyn) were measured, histological studies were evaluated by the hematoxylin and eosin staining, Th1/Th2, OVA-specific serum, and BALF IgE levels and Th17 cytokines were evaluated by enzyme-linked immunosorbent assay, and Th17 cells was evaluated by flow cytometry (FCM).

hematoxylin

eosin


Input: Our study demonstrated that BA inhibited OVA-induced increases in RI and eosinophil count; interleukin (IL)-4, IL-17A levels, and Cdyn were recovered and increased IFN-gamma level in bronchoalveolar lavage fluid.


Input: Histological studies demonstrated that BA substantially inhibited OVA-induced eosinophilia in lung tissue and airway tissue.


Input: FCM studies demonstrated that BA substantially inhibited Th17 cells.


Input: These findings suggest that BA may effectively ameliorate the progression of asthma and could be used as a therapy for patients with allergic asthma.


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


Input: Solvent-induced delamination of a multifunctional two dimensional coordination polymer (adv. Mater. 15/2013).


Input: Unprecedented full delamination of a multifunctional 2D metal-organic framework (MOF) assisted only by solvent interaction is carried out on page 2141 by F e lix Zamora, Salome Delgado, and co-workers.


Input: This observation is a direct consequence of the structure of the starting material, characterized by interlayer cavities that can be filled by the solvent molecules, producing delamination in a simple and reproducible way.


Input: Age-Related Macular Degeneration.


Input: Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, and the prevalence of the disease increases exponentially with every decade after age 50 years.


Input: It is a multifactorial disease involving a complex interplay of genetic, environmental, metabolic, and functional factors.


Input: Besides smoking, hypertension, obesity, and certain dietary habits, a growing body of evidence indicates that inflammation and the immune system may play a key role in the development of the disease.


Input: AMD may progress from the early form to the intermediate form and then to the advanced form, where two subtypes exist: the nonneovascular (dry) type and the neovascular (wet) type.


Input: The results from the Age-Related Eye Disease Study have shown that for the nonneovascular type of AMD, supplementation with high-dose antioxidants (vitamin C, vitamin E, and beta-carotene) and zinc is recommended for those with the intermediate form of AMD in one or both eyes or with advanced AMD or vision loss due to AMD in one eye.

vitamin C

vitamin E

beta-carotene

zinc


Input: As for the neovascular type of the advanced AMD, the current standard of therapy is intravitreal injections of vascular endothelial growth factor inhibitors.


Input: In addition, lifestyle and dietary modifications including improved physical activity, reduced daily sodium intake, and reduced intake of solid fats, added sugars, cholesterol, and refined grain foods are recommended.

sodium

sugars

cholesterol


Input: To date, no study has demonstrated that AMD can be cured or effectively prevented.


Input: Clearly, more research is needed to fully understand the pathophysiology as well as to develop prevention and treatment strategies for this devastating disease.


Input: Low Driving Voltage and High Mobility Ambipolar Field-Effect Transistors with PbS Colloidal Nanocrystals.

PbS


Input: PbS colloidal nanocrystals (NCs) are promising materials for optoelectronic devices, due to their size-tunable properties.

PbS


Input: However, there is still minimal understanding of their charge transport mechanism.


Input: Through a combination of ligand selections, ambipolar transistor structure optimization, and electrochemical gating usage, high carrier mobility is achieved.


Input: The outstanding device characteristics open possibility to investigate the intrinsic transport properties of PbS NCs.

PbS


Input: Large Areal Mass, Flexible and Free-Standing Reduced Graphene Oxide/Manganese Dioxide Paper for Asymmetric Supercapacitor Device.

Graphene Oxide

Manganese Dioxide


Input: Well-separated RGO sheets decorated with MnO2 nanoparticles facilitate easy access of the electrolyte ions to the high surface area of the paper electrode, enabling fabrication of thicker electrode with heavier areal mass and higher areal capacitance (up to 897 mF cm (-2)).


Input: Electrochemical performance of the bent asymmetric device with total active mass of 15 mg remains similar to the one in the flat configuration, demonstrating good mechanical robustness of the device.


Input: A lipoprotein receptor cluster IV mutant preferentially binds amyloid-beta and regulates its clearance from the mouse brain.


Input: Soluble low-density lipoprotein receptor-related protein-1 (sLRP1) binds ~ 70% of amyloid beta-peptide (A beta) in human plasma.


Input: In Alzheimer' s disease (AD) and individuals with mild cognitive impairment converting to AD, plasma sLRP1 levels are reduced and sLRP1 is oxidized which results in diminished A beta peripheral binding and higher levels of free A beta in plasma.


Input: Experimental studies have shown that free circulating A beta re-enters the brain and that sLRP1 and/or its recombinant wild-type cluster IV (WT-LRPIV) prevent A beta from entering the brain.


Input: Treatment of Alzheimer' s APPsw +/0 mice with WT-LRPIV has been shown to reduce brain A beta pathology.


Input: In addition to A beta, LRPIV binds multiple ligands.


Input: To enhance LRPIV binding for A beta relative to other LRP1 ligands, we generated a library of LRPIV-derived fragments and full-length LRPIV variants with glycine (G) replacing aspartic acid (D) residues 3394, 3556 and 3674 in the calcium binding sites.

glycine

aspartic acid

calcium


Input: Compared to WT-LRPIV, a lead LRPIV-D3674G mutant had 1. 6-fold and 2. 7-fold higher binding affinity for A beta 40 and A beta 42 in vitro, respectively, and a lower binding affinity for other LRP1 ligands, e. g., apoliporotein E2, E3 and E4 (1. 3-1. 8-fold), tissue plasminogen activator (2. 7-fold), matrix metalloproteinase-9 (4. 1-fold) and Factor Xa (3. 8-fold).


Input: LRPIV-D3674G cleared mouse endogenous brain A beta 40 and A beta 42 25-27% better than WT-LRPIV.


Input: A 3-month subcutaneous treatment of APPsw +/0 mice with LRPIV-D3674G (40 mu g/kg/day) reduced A beta 40 and A beta 42 levels in the hippocampus, cortex and cerebrospinal fluid by 60-80%, and improved cerebral blood flow responses and hippocampal function at 9 months of age.


Input: Thus, LRPIV-D3674G is an efficient new A beta clearance therapy.


Input: Synthesis of diazenido-ligated vanadium nanoparticles.

diazenido

vanadium


Input: Metallic vanadium nanoparticles stabilized with 4-octylphenyldiazenido groups (particle size: 1. 7 +/- 0. 2 nm) were synthesized via the reduction of VCl4 with superhydride (LiBHEt3) in the presence of 4-octylphenyldiazonium salt in an Ar-filled glovebox.

vanadium

superhydride


Input: The resulting particles were characterized using TEM, elemental analysis, and XPS measurements.


Input: The unusual reaction on the surface resulted in the passivation of V-N = N-Ar covalent bonds.

V-N = N-Ar


Input: The stabilization effect of dielectric constant and acidic amino acids on arginine-arginine (arg-arg) pairings: database survey and computational studies.

acidic amino acids

arginine

arginine


Input: Database survey in this study revealed that about one-third of the protein structures deposited in the Protein Data Bank (PDB) contain arginine-arginine (Arg-Arg) pairing with a carbon... carbon (CZ... CZ) interaction distance less than 5 A.

arginine

arginine

Arg-Arg

carbon

carbon


Input: All the Arg-Arg pairings were found to bury in a polar environment composed of acidic residues, water molecules, and strong polarizable or negatively charged moieties from binding site or bound ligand.

Arg-Arg


Input: Most of the Arg-Arg pairings are solvent exposed and 68. 3% Arg-Arg pairings are stabilized by acidic residues, forming Arg-Arg-Asp/Glu clusters.

Arg-Arg

Arg-Arg

Arg-Arg-Asp

Glu


Input: Density functional theory (DFT) was then employed to study the effect of environment on the pairing structures.


Input: It was revealed that Arg-Arg pairings become thermodynamically stable (about-1 kcal/mol) as the dielectric constant increases to 46. 8 (DMSO), in good agreement with the results of the PDB survey.

Arg-Arg


Input: DFT calculations also demonstrated that perpendicular Arg-Arg pairing structures are favorable in low dielectric constant environment, while in high dielectric constant environment parallel structures are favorable.

Arg-Arg


Input: Additionally, the acidic residues can stabilize the Arg-Arg pairing structures to a large degree.

Arg-Arg


Input: Energy decomposition analysis of Arg-Arg pairings and Arg-Arg-Asp/Glu clusters showed that both solvation and electrostatic energies contribute significantly to their stability.

Arg-Arg

Arg-Arg-Asp

Glu


Input: The results reported herein should be very helpful for understanding Arg-Arg pairing and its application in drug design.

Arg-Arg


Input: Enhanced Hematite Water Electrolysis Using a 3D Antimony-Doped Tin Oxide Electrode.

Hematite

Antimony-Doped Tin Oxide


Input: We present herein an example of nanocrystalline antimony-doped tin oxide (nc-ATO) disordered macroporous " inverse opal " 3D electrodes as efficient charge-collecting support structures for the electrolysis of water using a hematite surface catalyst.

antimony-doped tin oxide

ATO

hematite


Input: The 3D macroporous structures were created via templating of polystyrene spheres, followed by infiltration of the desired precursor solution and annealing at high temperature.

polystyrene


Input: Using cyclic voltammetry and electrochemical impedance spectroscopy, it was determined that the use of this 3D transparent conducting oxide with a hematite surface catalyst allowed for a seven-fold increase in active surface area for water splitting with respect to its 2D planar counterpart.

oxide

hematite


Input: This ratio of surface areas was evaluated based on the presence of oxidized trap states on the hematite surface, as determined from the equivalent circuit analysis of the Nyquist plots.

hematite


Input: Furthermore, the presence of nc-ATO 2D and 3D " underlayer " structures with hematite deposited on top resulted in decreased charge transfer resistances and an increase in the number of available active surface sites at the semiconductor-liquid junction when compared to hematite films lacking any nc-ATO substructures.

ATO

hematite

hematite

ATO


Input: Finally, absorption, transmission and reflectance spectra of all of the tested films were measured, suggesting the feasibility of using 3D disordered structures in photoelectrochemical reactions, due to the high absorption of photons by the surface catalyst material and trapping of light within the structure.


Input: Engineering bacterial efflux pumps for solar-powered bioremediation of surface waters.


Input: Antibiotics are difficult to selectively remove from surface waters by present treatment methods.


Input: Bacterial efflux pumps have evolved the ability to discriminately expel antibiotics and other noxious agents via proton and ATP driven pathways.

ATP


Input: Here, we describe light-dependent removal of antibiotics by engineering the bacterial efflux pump AcrB into a proteovesicle system.


Input: We have created a chimeric protein with the requisite proton motive force by coupling AcrB to the light-driven proton pump Delta-rhodopsin (dR) via a glycophorin A transmembrane domain.


Input: This creates a solar powered protein material capable of selectively capturing antibiotics from bulk solutions.


Input: Using environmental water and direct sunlight, our AcrB-dR vesicles removed almost twice as much antibiotic as the treatment standard, activated carbon.

carbon


Input: Altogether, the AcrB-dR system provides an effective means of extracting antibiotics from surface waters as well as potential antibiotic recovery through vesicle solubilization.


Input: Zinc Promotes the Death of Hypoxic Astrocytes by Upregulating Hypoxia-Induced Hypoxia-Inducible Factor-1alpha Expression via Poly (ADP-ribose) Polymerase-1.

Zinc

Poly (ADP-ribose)


Input: AIM: Pathological release of excess zinc ions has been implicated in ischemic brain cell death.

zinc


Input: However, the underlying mechanisms remain to be elucidated.


Input: In stroke, ischemia-induced zinc release and hypoxia-inducible factor-1 (HIF-1) accumulation concurrently occur in the ischemic tissue.

zinc


Input: The present study tests the hypothesis that the presence of high intracellular zinc concentration is a major cause of modifications to PARP-1 and HIF-1 alpha during hypoxia, which significantly contributes to cell death during ischemia.

zinc


Input: METHODS: Primary cortical astrocytes and C8-D1A cells were exposed to different concentrations of zinc chloride.

zinc chloride


Input: Cell death rate and protein expression of HIF-1 and Poly (ADP-ribose) polymerase (PARP)-1 were examined after 3-h hypoxic treatment.

Poly (ADP-ribose)


Input: RESULTS: Although 3-h hypoxia or 100 mu M of zinc alone did not induce noticeable cytotoxicity, their combination led to a dramatic increase in astrocytic cell death in a zinc-concentration-dependent manner.

zinc

zinc


Input: Exposure of astrocytes to hypoxia for 3 h remarkably increased the levels of intracellular zinc and HIF-1 alpha protein, which was further augmented by added exogenous zinc.

zinc

zinc


Input: Notably, HIF-1 alpha knockdown blocked zinc-induced astrocyte death.

zinc


Input: Moreover, knockdown of PARP-1, another important protein in the response of hypoxia, attenuated the overexpression of HIF-1 alpha and reduced the cell death rate.


Input: CONCLUSIONS: Our studies show that zinc promotes hypoxic cell death through overexpression of the hypoxia response factor HIF-1 alpha via the cell fate determine factor PARP-1 modification, which provides a novel mechanism for zinc-mediated ischemic brain injury.

zinc

zinc


Input: Type 2 innate signals stimulate fibro/adipogenic progenitors to facilitate muscle regeneration.


Input: In vertebrates, activation of innate immunity is an early response to injury, implicating it in the regenerative process.


Input: However, the mechanisms by which innate signals might regulate stem cell functionality are unknown.


Input: Here, we demonstrate that type 2 innate immunity is required for regeneration of skeletal muscle after injury.


Input: Muscle damage results in rapid recruitment of eosinophils, which secrete IL-4 to activate the regenerative actions of muscle resident fibro/adipocyte progenitors (FAPs).


Input: In FAPs, IL-4/IL-13 signaling serves as a key switch to control their fate and functions.


Input: Activation of IL-4/IL-13 signaling promotes proliferation of FAPs to support myogenesis while inhibiting their differentiation into adipocytes.


Input: Surprisingly, type 2 cytokine signaling is also required in FAPs, but not in myeloid cells, for rapid clearance of necrotic debris, a process that is necessary for timely and complete regeneration of tissues.


Input: Small RNA-Mediated Activation of Sugar Phosphatase mRNA Regulates Glucose Homeostasis.

Sugar

Glucose


Input: Glucose homeostasis is strictly controlled in all domains of life.

Glucose


Input: Bacteria that are unable to balance intracellular sugar levels and deal with potentially toxic phosphosugars cease growth and risk being outcompeted.

sugar

phosphosugars


Input: Here, we identify the conserved haloacid dehalogenase (HAD)-like enzyme YigL as the previously hypothesized phosphatase for detoxification of phosphosugars and reveal that its synthesis is activated by an Hfq-dependent small RNA in Salmonella typhimurium.

haloacid

phosphosugars


Input: We show that the glucose-6-P-responsive small RNA SgrS activates YigL synthesis in a translation-independent fashion by the selective stabilization of a decay intermediate of the dicistronic pldB-yigL messenger RNA (mRNA).

glucose


Input: Intriguingly, the major endoribonuclease RNase E, previously known to function together with small RNAs to degrade mRNA targets, is also essential for this process of mRNA activation.


Input: The exploitation of and targeted interference with regular RNA turnover described here may constitute a general route for small RNAs to rapidly activate both coding and noncoding genes.


Input: Discovery of novel orally bioavailable GPR40 agonists.


Input: The GPR40 (FFA1) has emerged as an attractive target for a novel insulin secretagogue with glucose dependency.

glucose


Input: A series of novel orally bioavailable GPR40 agonists was discovered.


Input: SAR study and structural optimization led to identification of compounds 28a and 30a as potent GPR40 agonists with superior physiochemical properties and robust in vivo efficacy in rhesus monkeys.


Input: Structure and T Cell Inhibition Properties of B7 Family Member, B7-H3.


Input: T cell activity is controlled by a combination of antigen-dependent signaling through the T cell receptor and a set of auxiliary signals delivered through antigen-independent interactions, including the recognition of the B7 family of ligands.


Input: B7-H3 is a recently identified B7 family member that is strongly overexpressed in a range of cancers and correlates with poor prognosis.


Input: We report the crystal structure of murine B7-H3 at a 3 A resolution, which provides a model for the organization of the IgV and IgC domains within the ectodomain.


Input: We demonstrate that B7-H3 inhibits T cell proliferation and show that the FG loop of the IgV domain plays a critical role in this function.


Input: B7-H3 crystallized as an unusual dimer arising from the exchange of the G strands in the IgV domains of partner molecules.


Input: This arrangement, in combination with previous reports, highlights the dynamic nature and plasticity of the immunoglobulin fold.


Input: Mechanisms and Metabolic Implications of Regional Differences among Fat Depots.


Input: Fat distribution is closely linked to metabolic disease risk.


Input: Distribution varies with sex, genetic background, disease state, certain drugs and hormones, development, and aging.


Input: Preadipocyte replication and differentiation, developmental gene expression, susceptibility to apoptosis and cellular senescence, vascularity, inflammatory cell infiltration, and adipokine secretion vary among depots, as do fatty-acid handling and mechanisms of enlargement with positive-energy and loss with negative-energy balance.

fatty-acid


Input: How interdepot differences in these molecular, cellular, and pathophysiological properties are related is incompletely understood.


Input: Whether fat redistribution causes metabolic disease or whether it is a marker of underlying processes that are primarily responsible is an open question.


Input: Beyond the Sympathetic Tone: The New Brown Fat Activators.


Input: If we could avoid the side effects associated with global sympathetic activation, activating brown adipose tissue to increase thermogenesis would be a safe way to lose weight.


Input: The discovery of adrenergic-independent brown fat activators opens the prospect of developing this alternative way to efficiently and safely induce negative energy balance.


Input: Hsp70 silencing with siRNA in nanocarriers enhances cancer cell death induced by the inhibitor of Hsp90.


Input: Inducers of heat shock protein 70 (Hsp70) commonly promote cancer cell viability whereas inhibitors of Hsp90 reduce it.


Input: The anticancer agent celastrol, interferes with signal transduction pathways involving these heat shock proteins.

celastrol


Input: The objective of this in vitro study was to silence inducible Hsp70 and to promote celastrol-induced tumor cell death.

celastrol


Input: Hsp70 siRNA loaded chitosan-TPP carriers were prepared by ionic gelation and characterized by photon correlation spectroscopy and asymmetric flow field-flow fractionation combined with dynamic light scattering.

TPP


Input: Viability of human leukemia and glioblastoma cells and Hsp70 silencing was determined following treatment with chitosan-TPP-Hsp70 siRNA particles.

TPP


Input: The results showed that silencing of Hsp70 by chitosan-TPP-Hsp70 siRNA treatment significantly reduced cell viability, and enhanced antiproliferative effects of celastrol in leukemia and glioblastoma cells.

TPP

celastrol


Input: In glioblastoma spheroids, higher concentrations of celastrol and Hsp70 siRNA in chitosan-TPP nanocarriers were necessary to induce cell death.

celastrol

TPP


Input: Two new steroidal saponins from Selaginella uncinata (Desv.) Spring and their protective effect against anoxia.

steroidal saponins


Input: Four steroidal saponins were isolated from the anti-anoxic fraction of the 60% EtOH extract of Selaginella uncinata, including two new compounds, (3 beta, 7 beta, 12 beta, 25R)-spirost-5-ene-3, 7, 12-triol-3-O-alpha-L-rhamnopyranosyl-(1 --> 2)-O-[alpha-L-rhamnopyranosyl-(1 --> 4)]-O-beta-d-glucopyranoside (1), (2 alpha, 3 beta, 12 beta, 25R)-spirost-5-ene-2, 3, 12-triol-3-O-alpha-L-rhamnopyranosyl-(1 --> 2)-O-[alpha-L-rhamnopyranosyl-(1 --> 4)]-O-beta-d-glucopyranoside (2) and two known compounds, (3 beta, 12 beta, 25R)-spirost-5-ene-3, 12-diol-3-O-alpha-L-rhamnopyranosyl-(1 --> 2)-O-[alpha-L-rhamnopyranosyl-(1 --> 4)]-O-beta-d-glucopyranoside, (3), (1 alpha, 3 beta, 25R)-spirost-5-ene-2-diol-3-O-alpha-L-rhamnopyranosyl-(1 --> 2)-O-[alpha-L-rhamnopyranosyl (1 --> 4)]-O-beta-d-glucopyranoside (4).

steroidal saponins

EtOH

(3 beta, 7 beta, 12 beta, 25R)-spirost-5-ene-3, 7, 12-triol-3-O-alpha-L-rhamnopyranosyl-(1 --> 2)-O-[alpha-L-rhamnopyranosyl-(1 --> 4)]-O-beta-d-glucopyranoside

(2 alpha, 3 beta, 12 beta, 25R)-spirost-5-ene-2, 3, 12-triol-3-O-alpha-L-rhamnopyranosyl-(1 --> 2)-O-[alpha-L-rhamnopyranosyl-(1 --> 4)]-O-beta-d-glucopyranoside

(3 beta, 12 beta, 25R)-spirost-5-ene-3, 12-diol-3-O-alpha-L-rhamnopyranosyl-(1 --> 2)-O-[alpha-L-rhamnopyranosyl-(1 --> 4)]-O-beta-d-glucopyranoside

(1 alpha, 3 beta, 25R)-spirost-5-ene-2-diol-3-O-alpha-L-rhamnopyranosyl-(1 --> 2)-O-[alpha-L-rhamnopyranosyl (1 --> 4)]-O-beta-d-glucopyranoside


Input: The four compounds showed potent protective effect against anoxia in the anoxic PC12 cells assay, among which compounds 1 and 2 were the most active.


Input: To our knowledge, this is the first study to report the steroidal saponins in the plant S. uncinata and demonstrate their protective effect against anoxia in PC12 cell assay.

steroidal saponins


Input: Substituted methcathinones differ in transporter and receptor interactions.

methcathinones


Input: The use of synthetic methcathinones, components of " bath salts, " is a world-wide health concern.

methcathinones


Input: These compounds, structurally similar to methamphetamine (METH) and 3, 4-methylendioxymethamphetamine (MDMA), cause tachycardia, hallucinations and psychosis.

methamphetamine

METH

3, 4-methylendioxymethamphetamine

MDMA


Input: We hypothesized that these potentially neurotoxic and abused compounds display differences in their transporter and receptor interactions as compared to amphetamine counterparts.

amphetamine


Input: 3, 4-Methylenedioxypyrovalerone and naphyrone had high affinity for radioligand binding sites on recombinant human dopamine (hDAT), serotonin (hSERT) and norepinephrine (hNET) transporters, potently inhibited [(3) H] neurotransmitter uptake, and, like cocaine, did not induce transporter-mediated release.

3, 4-Methylenedioxypyrovalerone

naphyrone

dopamine

serotonin

norepinephrine

[(3) H]

cocaine


Input: Butylone was a lower affinity uptake inhibitor.

Butylone


Input: In contrast, 4-fluoromethcathinone, mephedrone and methylone had higher inhibitory potency at uptake compared to binding and generally induced release of preloaded [(3) H] neurotransmitter from hDAT, hSERT and hNET (highest potency at hNET), and thus are transporter substrates, similar to METH and MDMA.

mephedrone

methylone

[(3) H]

METH

MDMA


Input: At hNET, 4-fluoromethcathinone was a more efficacious releaser than METH.

METH


Input: These substituted methcathinones had low uptake inhibitory potency and low efficacy at inducing release via human vesicular monoamine transporters (hVMAT2).

methcathinones

monoamine


Input: These compounds were low potency (1) h5-HT1A receptor partial agonists, (2) h5-HT2A receptor antagonists, (3) weak h5-HT2C receptor antagonists.


Input: This is the first report on aspects of substituted methcathinone efficacies at serotonin (5-HT) receptors and in superfusion release assays.

methcathinone

serotonin


Input: Additionally, the drugs had no affinity for dopamine receptors, and high-nanomolar to mid-micromolar affinity for hSigma1 receptors.

dopamine


Input: Thus, direct interactions with hVMAT2 and serotonin, dopamine, and hSigma1 receptors may not explain psychoactive effects.

serotonin

dopamine


Input: The primary mechanisms of action may be as inhibitors or substrates of DAT, SERT and NET.


Input: Optimization of a 1, 5-dihydrobenzo [b] [1, 4] diazepine-2, 4-dione series of HIV capsid assembly inhibitors 1: Addressing configurational instability through scaffold modification.

1, 5-dihydrobenzo [b] [1, 4] diazepine-2, 4-dione


Input: The optimization of a 1, 5-dihydrobenzo [b] [1, 4] diazepine-2, 4-dione series of inhibitors of HIV-1 capsid assembly that possess a labile stereocenter at C3 is described.

1, 5-dihydrobenzo [b] [1, 4] diazepine-2, 4-dione


Input: Quaternization of the C3 position of compound 1 in order to prevent racemization gave compound 2, which was inactive in our capsid disassembly assay.


Input: A likely explanation for this finding was revealed by in silico analysis predicting a dramatic increase in energy of the bioactive conformation upon quaternization of the C3 position.


Input: Replacement of the C3 of the diazepine ring with a nitrogen atom to give the 1, 5-dihydro-benzo [f] [1, 3, 5] triazepine-2, 4-dione analog 4 was well tolerated.

diazepine

1, 5-dihydro-benzo [f] [1, 3, 5] triazepine-2, 4-dione


Input: Introduction of a rigid spirocyclic system at the C3 position gave configurationally stable 1, 5-dihydrobenzo [b] [1, 4] diazepine-2, 4-dione analog 5, which was able to access the bioactive conformation without a severe energetic penalty and inhibit capsid assembly.

1, 5-dihydrobenzo [b] [1, 4] diazepine-2, 4-dione


Input: Preliminary structure-activity relationships (SAR) and X-ray crystallographic data show that knowledge from the 1, 5-dihydrobenzo [b] [1, 4] diazepine-2, 4-dione series of inhibitors of HIV-1 capsid assembly can be transferred to these new scaffolds.

1, 5-dihydrobenzo [b] [1, 4] diazepine-2, 4-dione


Input: Variation in the dorsal gradient distribution is a source for modified scaling of germ layers in Drosophila.


Input: Specification of germ layers along the dorsoventral axis by morphogenetic gradients is an ideal model to study scaling properties of gradients and cell fate changes during evolution.


Input: Classical anatomical studies in divergent insects (e. g., flies and grasshoppers) revealed that the neuroectodermal size is conserved and originates similar numbers of neuroblasts of homologous identity [1-3].


Input: In contrast, mesodermal domains vary significantly in closely related Drosophila species [4].


Input: To further investigate the underlying mechanisms of scaling of germ layers across Drosophila species, we quantified the Dorsal (Dl)/NF-kappa B gradient, the main morphogenetic gradient that initiates separation of the mesoderm, neuroectoderm, and ectoderm [5-7].


Input: We discovered a variable range of Toll activation across species and found that Dl activates mesodermal genes at the same threshold levels in melanogaster sibling species.


Input: We also show that the Dl gradient distribution can be modulated by nuclear size and packing densities.


Input: We propose that variation in mesodermal size occurs at a fast evolutionary rate and is an important mechanism to define the ventral boundary of the neuroectoderm.


Input: Seasonal variation in the toxicological properties of size-segregated indoor and outdoor air particulate matter.


Input: Ambient air particulate matter (PM) as well as microbial contaminants in the indoor air are known to cause severe adverse health effects.


Input: It has been shown that there is a clear seasonal variation in the potency of outdoor air particles to evoke inflammation and cytotoxicity.


Input: However, the role of outdoor sources in the indoor air quality, especially on its toxicological properties, remains largely unknown.


Input: In this study, we collected size segregated (PM10-2. 5, PM2. 5-0. 2 and PM0. 2) particulate samples with a high volume cascade impactor (HVCI) on polyurethane foam and fluoropore membrane filters.

polyurethane


Input: The samples were collected during four different seasons simultaneously from indoor and outdoor air.


Input: Thereafter, the samples were weighed and extracted with methanol from the filters before undergoing toxicological analyses.

methanol


Input: Mouse macrophages (RAW264. 7) were exposed to particulate sample doses of 50, 150 and 300 mu g/ml for 24h.


Input: Thereafter, the levels of the proinflammatory cytokine (TNF-alpha), NO-production, cytotoxicity (MTT-test) and changes in the cell cycle (SubG1, G1, S and G2/M phases) were investigated.

NO

MTT


Input: PM10-2. 5 particles evoked the highest inflammatory and cytotoxic responses.


Input: Instead, PM2. 5-0. 2 samples exerted the greatest effect on apoptotic activity in the macrophages.


Input: With respect to the outdoor air samples, particles collected during warm seasons had a stronger potency to induce inflammatory and cytotoxic responses, whereas no such clear effect was seen with the corresponding indoor air samples.


Input: Outdoor air samples were associated with higher inflammatory potential, whereas indoor air samples had overall higher cytotoxic properties.


Input: This indicates that the outdoor air has a limited influence on the indoor air quality in a modern house.


Input: Thus, the indoor sources dominate the toxicological responses obtained from samples collected inside house.


Input: (1) H NMR-based metabonomics study on the toxicity alleviation effect of other traditional Chinese medicines in Niuhuang Jiedu tablet to realgar (As2S2).

(1) H


Input: ETHNOPHARMACOLOGICAL RELEVANCE: Niuhuang Jiedu Tablet (NJT) is an effective prescription of traditional Chinese medicine (TCM) used in treating acute tonsillitis, pharyngitis, periodontitis and mouth ulcer.


Input: NJT is prepared from Xionghuang (Realgar, As2S2), Rengong Niuhuang (Bovis Calculus Artificialis), Bingpian (Borneolum Synthcticum), Shigao (Gypsum Fibrosum), Dahuang (Rhei Radix et Rhizoma), Huangqin (Scutellariae Radix), Jiegeng (Platycodonis Radix) and Gancao (Glycyrrhizae Radix et Rhizoma).


Input: In the prescription, significant level of realgar (As2S2) as a potentially toxic element is contained.

realgar


Input: AIM OF THE STUDY: In this study, (1) H NMR-based metabonomics approach has been used to investigate the toxicity of realgar (As2S2) after being counterbalanced by other TCMs in NJT.

(1) H

realgar


Input: MATERIALS AND METHODS: Male Wistar rats were divided into five groups: control, group I (treated with Realgar), group II (treated with Realgar, Bovis Calculus Artificialis, Borneolum Synthcticum, Gypsum Fibrosum, Rhei Radix et Rhizoma, Scutellariae Radix, Platycodonis Radix and Glycyrrhizae Radix et Rhizoma), group III (treated with Realgar, Bovis Calculus Artificialis, Borneolum Synthcticum and Gypsum Fibrosum) and group IV (treated with Realgar, Rhei Radix et Rhizoma, Scutellariae Radix, Platycodonis Radix and Glycyrrhizae Radix et Rhizoma).

Realgar

Realgar

Realgar

Realgar


Input: Based on (1) H-NMR spectra of urine and serum from rats, PCA and PLS-DA were performed to identify different metabolic profiles.

(1) H


Input: Liver and kidney histopathology examinations and serum clinical chemistry analysis were also performed.


Input: RESULTS: PLS-DA scores plots demonstrated that the cluster of group I was separated from that of control rats, while group II was located close to control rats, indicating that metabolic profiles of group II were restored toward those of control rats.


Input: The metabolic profiles of group III were similar to those of group I, while the metabolic profiles of group II were almost in line with those of group II.


Input: Statistics results were confirmed by the histopathological examination and biochemical assay.


Input: CONCLUSION: Our results indicated that it was more secure and much less toxic for counterbalanced realgar (As2S2) in NJT.

realgar


Input: The effective material bases of toxicity alleviation to realgar (As2S2) were Dahuang (Rhei Radix et Rhizoma), Huangqin (Scutellariae Radix), Jiegeng (Platycodonis Radix) and Gancao (Glycyrrhizae Radix et Rhizoma), which regulated energy metabolism, choline metabolism, amino acid metabolism and gut flora disorder affected by realgar (As2S2) exposure.

realgar

choline

amino acid

realgar


Input: Systematic characterization of structure-activity relationships and ADMET compliance: a case study.


Input: Traditionally, activity landscape modeling has been focused on analyzing SAR, despite the fact that lead optimization in drug discovery involves concurrent enhancements of activity and ADMET properties of leads.


Input: As a case study, we discuss the systematic analysis of activity landscapes, incorporating ADMET considerations, using a dataset of 166 compounds screened for kappa-opioid receptor activity.


Input: Pairwise MACCS/Tanimoto structure similarities, property similarities utilizing 33 ADMET descriptors and a 35-dimensional' violation bit vector' representing drug-likeness are analyzed.


Input: We address the question about the range of ADMET property violations that arise from structural changes, subtle and significant.


Input: Pairs of compounds are identified bearing identical, comparable and significantly different drug-likeness in the three informative regions of structure-activity landscapes.


Input: Unraveling Hidden Regulatory Sites in Structurally Homologous Metalloproteases.


Input: Monitoring enzymatic activity in vivo of individual homologous enzymes such as the matrix metalloproteinases (MMPs) by antagonist molecules is highly desired for defining physiological and pathophysiological pathways.


Input: However, the rational design of antagonists targeting enzyme catalytic moieties specific to one of the homologous enzymes often appears to be an extremely difficult task.


Input: This is mainly due to the high structural homology at the enzyme active sites shared by members of the protein family.


Input: Accordingly, controlling enzymatic activity via alternative allosteric sites has become an attractive proposition for drug design targeting individual homologous enzymes.


Input: Yet, the challenge remains to identify such regulatory alternative sites that are often hidden and scattered over different locations on the protein' s surface.


Input: We have designed branched amphiphilic molecules exhibiting specific inhibitory activity towards individual members of the MMP family.


Input: These amphiphilic isomers share the same chemical nature, providing versatile nonspecific binding reactivity that allows to probe hidden regulatory residues on a given protein surface.


Input: Using the advantage provided by amphiphilic ligands, here we explore a new approach for determining hidden regulatory sites.


Input: This approach includes diverse experimental analysis, such as structural spectroscopic analyses, NMR, and protein crystallography combined with computational prediction of effector binding sites.


Input: We demonstrate how our approach works by analyzing members of the MMP family that possess a unique set of such sites.


Input: Our work provides a proof of principle for using ligand effectors to unravel hidden regulatory sites specific to members of the structurally homologous MMP family.


Input: This approach may be exploited for the design of novel molecular effectors and therapeutic agents affecting protein catalytic function via interactions with structure-specific regulatory sites.


Input: Prior oral exposure to environmental immunosuppressive chemicals methoxychlor, parathion, or piperonyl butoxide aggravates allergic airway inflammation in NC/Nga mice.

methoxychlor

parathion

piperonyl butoxide


Input: BACKGROUND: Immunosuppressive environmental chemicals may increase the potency of allergens and thereby play a role in the development of respiratory tract allergies, such as allergic rhinitis and asthma.


Input: OBJECTIVES: We investigated the association between environmental immunosuppressive chemicals and the allergic airway inflammation development.


Input: METHODS: We used a mouse model of ovalbumin (OVA)-induced allergic airway inflammation.


Input: NC/Nga mice were exposed orally to pesticides parathion (an organophosphate compound) or methoxychlor (an organochlorine compound), or to an insecticide synergist piperonyl butoxide, prior to OVA intraperitoneal sensitization and inhalation challenge.

parathion

organophosphate

methoxychlor

organochlorine

piperonyl butoxide


Input: We assessed serum IgE levels, B-cell counts, cytokine production, IgE production in hilar lymph nodes, eosinophil counts, chemokine levels in bronchoalveolar lavage fluid, and cytokine gene expression in the lung.


Input: RESULTS: Exposure to environmental immunosuppressive chemicals markedly increased serum IgE-IgE-positive B-cells, IgE and cytokines in lymph nodes-eosinophils and chemokines in BALF-IL-10a and IL-17 in the lung.


Input: CONCLUSIONS: Allergic airway inflammation can be aggravated by prior exposure to immunosuppressive environmental chemicals.


Input: Aminopropylindenes derived from Grundmann' s ketone as a novel chemotype of oxidosqualene cyclase inhibitors.

Aminopropylindenes

Grundmann' s ketone


Input: A series of aminopropylindenes, designed as mimics of a cationic high energy intermediate in the oxidosqualene cyclase (1) (OSC)-mediated cyclization of 2, 3-oxidosqualen to lanosterol was prepared from Grundmann' s ketone.

aminopropylindenes

oxidosqualene

2, 3-oxidosqualen

lanosterol

Grundmann' s ketone


Input: Screening on OSCs from five different organisms revealed interesting activities and selectivities of some of the compounds.


Input: A N, N-dimethylaminopropyl derivative showed promising inhibition of Trypanosoma cruzi OSC in combination with low cytotoxicity, and showed significant reduction of cholesterol biosynthesis in a human cell line.

N, N-dimethylaminopropyl

cholesterol


Input: Pleiotropic effect of histamine H4 receptor modulation in the central nervous system.

histamine


Input: The histamine H4 receptor (H4R) is expressed primarily on cells involved in inflammation and immune responses.

histamine


Input: Recently, it has been reported the functional expression of H4R within neurons of the central nervous system, but their role has been poorly understood.


Input: The present study aimed to elucidate the physiopathological role of cerebral H4R in animal models by the intracerebroventricular administration of the H4R agonist VUF 8430 (20-40 mu g per mouse).

VUF 8430


Input: Selectivity of results was confirmed by the prevention of the effects produced by the H4R antagonist JNJ 10191584 (3-9 mg/kg p. o.).

JNJ 10191584


Input: Neuronal H4R activation induced acute thermal antinociception, indicating that neuronal histamine H4R might be involved in the production of antinociception in the absence of an inflammatory process.

histamine


Input: An anxiolytic-like effect of intensity comparable to that exerted by diazepam, used as reference drug, was produced in the light-dark box test.

diazepam


Input: VUF 8430 reversed the scopolamine-induced amnesia in the passive avoidance test and showed anorexant activity in food deprived mice.

VUF 8430

scopolamine


Input: Conversely, the H4R activation did not modify the immobility time in the tail suspension test.


Input: Rotarod performance test was employed to demonstrate that the effects observed following the administration of VUF 8430 and JNJ 10191584 were not due to impaired motor function of animals.

VUF 8430

JNJ 10191584


Input: Furthermore, both compounds did not alter spontaneous mobility and exploratory activity in the hole board test.


Input: These results show the antinociceptive, antiamnesic, anxiolytic and anorexant effects induced by neuronal H4R agonism, suggesting that H4 modulators may have broader utility further the control of inflammatory and immune processes.


Input: Lesions of the dorsomedial striatum impair formation of attentional set in rats.


Input: Behavioural flexibility refers to the ability to rapidly adapt to novel situations and it has been suggested that the frontal lobe and basal ganglia are implicated in various components of adjusting to changes in environmental contingencies.


Input: Behavioural flexibility can be assessed using attentional set-shifting tasks, in which performance is impaired after damage to the prefrontal cortex.


Input: The present study explores the downstream contribution of the prefrontal projection zone in the dorsomedial striatum (DMS) to attentional set shifting.


Input: Rats were tested in two set-shifting tasks following quinolinic acid injections bilaterally into the DMS.

quinolinic acid


Input: When tested in a rodent version of the set-shifting task, rats with a DMS lesion displayed a greater number of errors during the reversal stages of the task than sham lesion controls but the nature of the errors did not differ between the two groups.


Input: Interestingly, when the rats were tested in a modified version of the set-shifting task, directly designed for measuring the formation of an attentional set, sham lesion controls displayed a pronounced shift-cost, evident of successful set-formation.


Input: In contrast, rats with DMS lesions failed to form an attentional set, showing no performance cost when a shift of attention was required.


Input: These results support previous reports of the importance of the DMS in behavioural flexibility but also suggest that this region is vital for the formation of set, possibly by extrapolating different perceptions into a unified representation of a dimension.


Input: Poor-prognosis colon cancer is defined by a molecularly distinct subtype and develops from serrated precursor lesions.


Input: Colon cancer is a clinically diverse disease.


Input: This heterogeneity makes it difficult to determine which patients will benefit most from adjuvant therapy and impedes the development of new targeted agents.


Input: More insight into the biological diversity of colon cancers, especially in relation to clinical features, is therefore needed.


Input: We demonstrate, using an unsupervised classification strategy involving over 1, 100 individuals with colon cancer, that three main molecularly distinct subtypes can be recognized.


Input: Two subtypes have been previously identified and are well characterized (chromosomal-instable and microsatellite-instable cancers).


Input: The third subtype is largely microsatellite stable and contains relatively more CpG island methylator phenotype-positive carcinomas but cannot be identified on the basis of characteristic mutations.

CpG


Input: We provide evidence that this subtype relates to sessile-serrated adenomas, which show highly similar gene expression profiles, including upregulation of genes involved in matrix remodeling and epithelial-mesenchymal transition.


Input: The identification of this subtype is crucial, as it has a very unfavorable prognosis and, moreover, is refractory to epidermal growth factor receptor-targeted therapy.


Input: Kinetics and mechanism of oxygen reduction in a protic ionic liquid.

oxygen


Input: The oxygen reduction reaction (ORR) has been studied at Pt surfaces in the protic ionic liquid diethylmethylammonium trifluoromethanesulfonate.

oxygen

diethylmethylammonium trifluoromethanesulfonate


Input: Water content measurements suggested that the ORR proceeded in the ionic liquid predominantly via a 4-electron reduction to water.


Input: A mechanistic analysis using rotating ring-disk electrode (RRDE) voltammetry confirmed that negligible amounts of hydrogen peroxide were formed during the ORR.

hydrogen peroxide


Input: A kinetic analysis of the ORR was performed using rotating disk electrode (RDE) voltammetry and the importance of correcting for ohmic (iR) drop prior to performing kinetic measurements in the ionic liquid is demonstrated.


Input: A Tafel analysis of the RDE voltammetry data revealed a change in the ORR Tafel slope from 70 mV per decade at low ORR overpotentials to 117 mV per decade at high overpotentials, and the reason for this change is discussed.


Input: The change in the Tafel slope for the ORR with increasing overpotential meant that the exchange current density for the ORR varied from 0. 007 nA cm (-2) to 10 nA cm (-2), depending on the applied potential.


Input: Finally, the implications of these results for the development of protic ionic liquid fuel cells are discussed.


Input: Agomelatine: An antidepressant with new potent hepatoprotective effects on paracetamol-induced liver damage in rats.

Agomelatine

paracetamol


Input: Paracetamol was shown to induce hepatotoxicity or more severe fatal acute hepatic damage.

Paracetamol


Input: Agomelatine, commonly known as melatonin receptor agonist, is a new antidepressant, which resynchronizes circadian rhythms with subjective and objective improvements in sleep quality and architecture, as melatonin does.

Agomelatine

melatonin

melatonin


Input: In the present study, it was aimed to evaluate the hepatoprotective activity of agomelatine on paracetamol-induced hepatotoxicity and to understand the relationship between the hepatoprotective mechanism of agomelatine and antioxidant system and proinflammatory cytokines.

agomelatine

paracetamol

agomelatine


Input: A total of 42 rats were divided into 7 groups as each composed of 6 rats: (1) intact, (2) 40 mg/kg agomelatine, (3) 140 mg/kg N-acetylcysteine (NAC), (4) 2 g/kg paracetamol, (5) 2 g/kg paracetamol + 140 mg/kg NAC, (6) 2 g/kg paracetamol + 20 mg/kg agomelatine, and (7) 2 g/kg paracetamol + 40 mg/kg agomelatine groups.

agomelatine

N-acetylcysteine

NAC

paracetamol

paracetamol

NAC

paracetamol

agomelatine

paracetamol

agomelatine


Input: Paracetamol-induced hepatotoxicity was applied and liver and blood samples were analyzed histopathologically and biochemically.

Paracetamol


Input: There were statistically significant increases in the activities of aspartate aminotransferase, alanine aminotransferase, levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) and 8-iso-prostane, and decreases in the activity of superoxide dismutase and level of glutathione in the group treated with paracetamol.

aspartate

alanine

superoxide

glutathione

paracetamol


Input: Administration of agomelatine and NAC separately reversed these changes significantly.

agomelatine

NAC


Input: In conclusion, agomelatine administration protects liver cells from paracetamol-induced hepatotoxicity via antioxidant activity and reduced proinflammatory cytokines, such as TNF-alpha and IL-6.

agomelatine

paracetamol


Input: The influence of thermal degradation on the electrodeposition of aluminium from an air-and water-stable ionic liquid.

aluminium


Input: Aluminium electrodeposition is demonstrated from a thermally degraded ionic liquid solution.

Aluminium


Input: NMR and voltammetric analyses established that Al (3 +) reduction was remarkably similar to that in non-degraded IL solutions suggesting that the electroactive metal-containing species was unaffected by heat treatment.

Al (3 +)


Input: Electron microscopy revealed a significant grain refinement of the deposited metal.


Input: Combined toxicity of ferroferric oxide nanoparticles and arsenic to the ciliated protozoa Tetrahymena Pyriformis.

ferroferric oxide

arsenic


Input: Fe3O4 nanoparticles (NPs) have a high affinity for arsenic.

arsenic


Input: As a result of this association, Fe3O4 NPs loaded with high concentration of arsenic can enter into organisms and produce locally high concentrations of arsenic, which may lead to some unexpected toxicity to aquatic organisms.

arsenic

arsenic


Input: The objectives of this research were to investigate the toxic effect of Fe3O4 NPs in combination with As (V).

As (V)


Input: Cultured Tetrahymena pyriformis was chosen as a research model organism to evaluate the toxic effects of the combined agents.


Input: The results showed that after 24h of As (V) exposure, the median effective concentration of As (V) to T. pyriformis was 1. 29mg/L.

As (V)

As (V)


Input: Fe3O4 NPs alone were not only non-toxic, but actually promoted the growth of T. pyriformis at the experimental doses.


Input: After 24h exposure, the cell number increased by 32. 2% at an exposure level of 3mg/L Fe3O4 NPs.


Input: After 24h exposure to 1. 0mg/L As (V), the survival rate increased from 60. 5% in the absence of Fe3O4 NPs to 73. 8% and 83. 8% in the presence of 13mg/L and 19mg/L Fe3O4 NPs, respectively.

As (V)


Input: However, after 30h, the combined toxic effect of As (V) and Fe3O4 NPs on T. pyriformis was significantly enhanced and the survival rates for co-exposure to 1. 5mg/L As (V) and 13mg/L Fe3O4 NPs decreased from 92. 3% after 18h to 45. 3% after 30h.

As (V)

As (V)


Input: After 18h of exposure to Fe3O4 NPs alone, the intracellular ROS levels were markedly increased and achieved steady state.


Input: Compared with the control group, the intracellular ROS levels were significantly increased (2. 56-fold) by the combination of 19mg/L Fe3O4 NPs and 1. 0mg/L As (V).

As (V)


Input: Accumulation of As (V) in T. pyriformis led to an increase in trivalent arsenics as a result of the saturation of the cellular arsenic methylation capability or/and redox reactions.

As (V)

arsenics

arsenic


Input: These exposures also resulted in an imbalance between oxidants and antioxidants, resulting in oxidative damage and cell death.


Input: Transcriptomic analysis of cultured whale skin cells exposed to hexavalent chromium [Cr (VI)].

hexavalent chromium

Cr (VI)


Input: Hexavalent chromium Cr (VI) is known to produce cytotoxic effects in humans and is a highly toxic environmental contaminant.

Hexavalent chromium Cr (VI)


Input: Interestingly, it has been shown that free ranging sperm whales (Phyester macrocephalus) may have exceedingly high levels of Cr in their skin.

Cr


Input: Also, it has been demonstrated that skin cells from whales appear more resistant to both cytotoxicity and clastogenicity upon Cr exposure compared to human cells.

Cr


Input: However, the molecular genetic mechanisms employed in whale skin cells that might lead to Cr tolerance are unknown.

Cr


Input: In an effort to understand the underlying mechanisms of Cr (VI) tolerance and to illuminate global gene expression patterns modulated by Cr, we exposed whale skin cells in culture to varying levels of Cr (VI) (i. e., 0. 0, 0. 5, 1. 0 and 5. 0 mu g/cm (2)) followed by short read (100bp) next generation RNA sequencing (RNA-seq).

Cr (VI)

Cr

Cr (VI)


Input: RNA-seq reads from all exposures (=~ 280 million reads) were pooled to generate a de novo reference transcriptome assembly.


Input: The resulting whale reference assembly had 11K contigs and an N50 of 2954bp.


Input: Using the reads from each dose (0. 0, 0. 5, 1. 0 and 5. 0 mu g/cm (2)) we performed RNA-seq based gene expression analysis that identified 35 up-regulated genes and 19 down-regulated genes.


Input: The experimental results suggest that low dose exposure to Cr (1. 0 mu g/cm (2)) serves to induce up-regulation of oxidative stress response genes, DNA repair genes and cell cycle regulator genes.

Cr


Input: However, at higher doses (5. 0 mu g/cm (2)) the DNA repair genes appeared down-regulated while other genes that were induced suggest the initiation of cytotoxicity.


Input: The set of genes identified that show regulatory modulation at different Cr doses provide specific candidates for further studies aimed at determination of how whales exhibit resistance to Cr toxicity and what role (s) reactive oxygen species (ROS) may play in this process.

Cr

Cr

oxygen


Input: miR-194 suppresses metastasis of non-small cell lung cancer through regulating expression of BMP1 and p27 (kip1.)


Input: MicroRNAs (miRNAs) are increasingly implicated in regulating tumor malignance through their capacity to coordinately repress expression of tumor-related genes.


Input: Here, we show that overexpression of miR-194 in lung cancer cell lines, results in suppressing metastasis of lung cancer cells, while inhibiting its expression through' miRNA sponge' promotes the cancer cells to metastasize.


Input: miR-194 expression is also found to be in strongly negative association with metastasis in clinical specimens of non-small cell lung cancer.


Input: We demonstrate that miR-194 directly targets both BMP1 and p27 (kip1).


Input: The resulting downregulation of BMP1 leads to suppression of TGF beta activity and, thus, to downregulation of the expression of key oncogenic genes (matrix metalloproteinases MMP2 and MMP9).


Input: This leads, in turn, to decreased tumor invasion.


Input: In addition, the miRNA-194-induced suppression of p27 (kip1) activates the RhoA pathway, producing enhanced development of actin stress fibers and impaired migration of cancer cells.


Input: These findings reveal two structurally independent but functionally linked branches of the regulatory and signaling pathway that together provide a bridge between the metastasis-depressing miRNA and the key genes that govern the malignancy of lung cancers. Oncogene advance online publication, 15 April 2013; doi: 10. 1038/onc. 2013. 108.


Input: The histone demethylase Jmjd3 sequentially associates with the transcription factors Tbx3 and Eomes to drive endoderm differentiation.


Input: Stem cell differentiation depends on transcriptional activation driven by lineage-specific regulators as well as changes in chromatin organization.


Input: However, the coordination of these events is poorly understood.


Input: Here, we show that T-box proteins team up with chromatin modifying enzymes to drive the expression of the key lineage regulator, Eomes during endodermal differentiation of embryonic stem (ES) cells.


Input: The Eomes locus is maintained in a transcriptionally poised configuration in ES cells.


Input: During early differentiation steps, the ES cell factor Tbx3 associates with the histone demethylase Jmjd3 at the enhancer element of the Eomes locus to allow enhancer-promoter interactions.


Input: This spatial reorganization of the chromatin primes the cells to respond to Activin signalling, which promotes the binding of Jmjd3 and Eomes to its own bivalent promoter region to further stimulate Eomes expression in a positive feedback loop.


Input: In addition, Eomes activates a transcriptional network of core regulators of endodermal differentiation.


Input: Our results demonstrate that Jmjd3 sequentially associates with two T-box factors, Tbx3 and Eomes to drive stem cell differentiation towards the definitive endoderm lineage.


Input: Synthesis of 3-O-propargylated betulinic acid and its 1, 2, 3-triazoles as potential apoptotic agents.

3-O-propargylated betulinic acid and its 1, 2, 3-triazoles


Input: Cytotoxic agents from nature are presently the mainstay of anticancer chemotherapy, and the need to reinforce the arsenal of anticancer agents is highly desired.


Input: Chemical transformation studies carried out on betulinic acid, through concise 1, 2, 3-triazole synthesis via click chemistry approach at C-3position in ring A have been evaluated for their cytotoxic potentiation against nine human cancer cell lines.

betulinic acid

1, 2, 3-triazole

C


Input: Most of the derivatives have shown higher cytotoxic profiles than the parent molecule.


Input: Two compounds i. e. 3 {1N (2-cyanophenyl)-1H-1, 2, 3-triazol-4yl} methyloxy betulinic acid (7) and 3 {1N (5-hydroxy-naphth-1yl)-1H-1, 2, 3-triazol-4yl} methyloxy betulinic acid (13) displayed impressive IC50 values (2. 5 and 3. 5 mu M respectively) against leukemia cell line HL-60 (5-7-fold higher potency than betulinic acid).

3 {1N (2-cyanophenyl)-1H-1, 2, 3-triazol-4yl} methyloxy betulinic acid

3 {1N (5-hydroxy-naphth-1yl)-1H-1, 2, 3-triazol-4yl} methyloxy betulinic acid


Input: As evident from various biological end points, inhibition of cell migration and colony formation, mitochondrial membrane disruption followed by DNA fragmentation and apoptosis, is demonstrated.


Input: Synthesis and in vitro antiproliferative effect of novel quinoline-based potential anticancer agents.

quinoline


Input: Several derivatives with a quinoline scaffold and a flexible, semi-flexible or rigid side chains at position 8 of the quinoline ring were synthesized and assessed for their in vitro activity versus the human colon cancer cell line HT29 and the human breast cancer cell line MDA-MB231.

quinoline

quinoline


Input: The HT29 cell line was more refractory to the cytotoxic activity of some compounds, meanwhile all the quinoline derivatives except one displayed high to moderate activity against MDA-MB231 with IC50 values ranging between 4. 6 and 48. 2 mu M.

quinoline


Input: The most active derivative in this study against both tested cell lines was the Schiff' s base 4e with IC50 of 4. 7 and 4. 6 mu M against HT29 and MDA-MB231, respectively.

Schiff' s base


Input: Gene identification and comparative molecular modeling of a Trypanosoma rangeli major surface protease.


Input: Trypanosoma rangeli is a hemoflagellate parasite which is able to infect humans.


Input: Distinct from Trypanosoma cruzi, the causative agent of Chagas disease, T. rangeli is non-pathogenic to the vertebrate host.


Input: The manner by which the T. rangeli interacts with the host is still unknown, but it certainly depends on the surface molecules.


Input: Major surface proteins (MSP) are GPI-anchored, zinc-dependent metalloproteases present in the surface of all trypanosomatids studied so far, which are implicated as virulence factors in pathogenic trypanosomatids, such as Leishmania spp and T. cruzi.


Input: The aims of this work were to generate the complete sequence of a T. rangeli MSP (TrMSP) gene and to determine the 3D-structure of the predicted protein by homology modeling.


Input: The plasmid bearing a complete copy of a TrMSP gene was completely sequenced and the predicted protein was modeled using Modeller software.


Input: Results indicate that TrMSP open reading frame (ORF) codes for a predicted 588 amino acid protein and shows all elements required for its posttranslational processing.

amino acid


Input: Multiple sequence alignment of TrMSP with other trypanosomatids' MSPs showed an extensive conservation of the N-terminal and central regions and a more divergent C-terminal region.

N

C


Input: Leishmania major MSP (LmMSP), which had its crystal structure previously determined, has an overall 35% identity with TrMSP.


Input: This identity allowed the comparative molecular modeling of TrMSP, which demonstrated a high degree of structural conservation between MSPs from other trypanosomatids (TrypMSPs).


Input: All modeled MSPs have a conserved folding pattern, apart from structural divergences in the C-domain and discrete differences of charge and topology in the catalytic cleft, and present the same geometry of the canonical HEXXH zinc-binding motif.

zinc


Input: The determination of surface charges of the molecules revealed that TrMSP is a predominantly positive protein, whereas LmMSP and Trypanosoma cruzi MSP (TcMSP) are negative proteins, suggesting that substrates recognized by TcMSP and LmMSP could not interact with TrMSP.


Input: Moreover, the comparison between TrMSP and TcMSP protein sequences has revealed 45 non-neutral amino acid substitutions, which can be further assessed through protein engineering.

amino acid


Input: The characteristics of TrMSP could explain, at least in part, the lack of pathogenicity of T. rangeli to humans and point to the necessity of identifying the biological targets of this enzyme.


Input: Long single ZnO nanowire for logic and memory circuits: NOT, NAND, NOR gate, and SRAM.

ZnO


Input: We demonstrate logic and static random access memory (SRAM) circuits using a 100 mu m long and 100 nm thin single ZnO nanowire (NW), which acts as a channel of field-effect transistors (FETs) with Al2O3 dielectrics.

ZnO


Input: NW FETs are thus arrayed in one dimension to consist of NOT, NAND, and NOR gate logic, and SRAM circuits.


Input: Two respective top-gate NW FETs with Au and indium-tin-oxide (ITO) were connected to form an inverter, the basic NOT gate component, since the former gate leads to an enhanced mode FET while the latter to depletion mode due to their work function difference.

Au

indium-tin-oxide

ITO


Input: Our inverters showed a high voltage gain of 22 under a 5 V operational voltage, resulting in successful operation of all other devices.


Input: We thus conclude that our long single NW approach is quite promising to extend the field of nano-electronics.


Input: Induction of the metabolic regulator Txnip in fasting-induced and natural torpor.


Input: Torpor is a physiological state characterised by controlled lowering of metabolic rate and core body temperature, allowing substantial energy savings during periods of reduced food availability or harsh environmental conditions.


Input: The hypothalamus coordinates energy homeostasis and thermoregulation, and plays a key role in directing torpor.


Input: We recently showed that mice lacking the orphan G protein coupled receptor Gpr50 readily enter torpor in response to fasting, and have now used these mice to conduct a microarray analysis of hypothalamic gene expression changes related to the torpor state.


Input: This revealed a strong induction of thioredoxin interacting protein (Txnip) in the hypothalamus of torpid mice, which was confirmed by quantitative RT-PCR and Western blot analyses.


Input: In situ hybridisation identified the ependyma lining the third ventricle as the principal site of torpor-related expression of Txnip.


Input: To characterise further the relationship between Txnip and torpor, we profiled Txnip expression in mice during prolonged fasting, cold exposure, and 2-deoxyglucose-induced hypometabolism, as well as in naturally occurring torpor bouts in the Siberian hamster.


Input: Strikingly, pronounced upregulation of Txnip expression was only observed in WT mice when driven into torpor, and during torpor in the Siberian hamster.


Input: Increase of Txnip was not limited to the hypothalamus, with exaggerated expression in white adipose tissue, brown adipose tissue, and liver also demonstrated in torpid mice.


Input: Given the recent identification of Txnip as a molecular nutrient sensor important in the regulation of energy metabolism, our data suggest that elevated Txnip expression is critical to regulating energy expenditure and fuel utilisation during the extreme hypometabolic state of torpor.


Input: Optimization of DDI Study Design: Comparison of Minimal PBPK Models on Prediction of CYP3A Inhibition by Ketoconazole.


Input: Ketoconazole is a potent CYP3A inhibitor used to assess the contribution of CYP3A to drug clearance and quantify the increase in drug exposure due to a strong inhibitor.

Ketoconazole


Input: Physiologically based pharmacokinetic (PBPK) models have been employed to evaluate dosing regimens resulting in maximal CYP3A inhibition by ketoconazole but have reached different conclusions.

ketoconazole


Input: We compare two PBPK models of the ketoconazole-midazolam interaction, Model 1 (Chien et al., 2006) and Model 2 implemented in Simcyp (version 11) to predict 16 published dosing regimens.

ketoconazole

midazolam


Input: Using Model 2, 41% of the study point estimates of AUC ratio and 71% of the 90% confidence intervals were predicted within 1. 5-fold of the observed but these increased to 82% and 100% respectively with Model 1.


Input: For midazolam, Model 2 predicted a maximal midazolam AUC ratio of 8 and a hepatic fraction metabolized by CYP3A of 0. 97 whereas Model 1 predicted 17 and 0. 90 respectively, which are more consistent with observed data.

midazolam

midazolam


Input: Based on Model 1, ketoconazole 400mg QD for at least 3 days and substrate administration within 2 hours is required for maximal CYP3A inhibition.

ketoconazole


Input: Ketoconazole dosing regimens that employ 200 mg BID underestimate the systemic fraction metabolized by CYP3A (0. 86 vs. 0. 90) for midazolam.

Ketoconazole

midazolam


Input: The systematic underprediction also applies to CYP3A substrates with high bioavailability and long half-lives.


Input: The superior predictive performance of Model 1 reflects the need for accumulation of ketoconazole at enzyme site and protracted inhibition.

ketoconazole


Input: Model 2 is not recommended for inferring optimal study design and estimation of fraction metabolized by CYP3A.


Input: Vandetanib: opening a new treatment practice in advanced medullary thyroid carcinoma.

Vandetanib


Input: Medullary thyroid cancer (MTC) is frequently diagnosed in a locally advanced or metastatic stage, and 10-year survival rates in these cases are below 20%.


Input: Cytotoxic chemotherapy has no significant impact on overall or progression-free survival.


Input: Vandetanib (Caprelsa ((R)), AstraZeneca) is a once-daily oral tyrosine kinase inhibitor that selectively inhibits signalling mediated by growth-factor receptor tyrosine kinase RET (constitutively activated in roughly 60% of all MTCs), vascular endothelial growth-factor receptors 2 and 3, and epidermal growth-factor receptors.

Vandetanib

Caprelsa

tyrosine

tyrosine


Input: It is the first systemic drug with demonstrated anti-tumor benefits in advanced MTC, and it has recently been approved for locally advanced or metastatic MTC by the United States Food and Drug Administration (April 2011) and the European Medicines Agency (February 2012).


Input: This review, starting from the phases II and III efficacy and safety data that led to these approvals, explores important issues related to dosing, patient selection, and strategies for managing the substantial risk of toxicity associated with the drug (including life-threatening cardiac events that are the subject of a black-box warning in the United States).


Input: All these issues still remain to be defined.


Input: Vandetanib is becoming a standard of care for symptomatic, progressive, metastatic MTCs, to be used selectively in those patients who are likely to benefit from it.

Vandetanib


Input: Structural Transformation between Supramolecular Nanofibers with Drastic Change of Conductivity by Heat and Ultrasound.


Input: Transformation with every fiber of its being: Dehydrobenzoannulene derivatives with a boomerang shape, dipole moment, and substituents that make diverse interactions enable the contruction of stimuli-responsive nanofibers despite the lack of stimuli-responsive groups in these compounds.


Input: Interestingly, the supramolecular nanofibers obtained after ultrasonic treatment displayed an 80% decrease in conductivity as compared to untreated nanofibers.


Input: This is the first example of an electronic wire for which the conductivity can be controlled by ultrasound.


Input: NMDA Receptor Activation Down-Regulates Expression of delta Subunit-Containing GABA-A Receptors in Cultured Hippocampal Neurons.

NMDA

GABA


Input: Neurosteroids are endogenous allosteric modulators of gamma amino-butyric acid type A receptors (GABARs), and enhance GABAR-mediated inhibition.

gamma amino-butyric acid


Input: However, GABARs expressed on hippocampal dentate granule neurons of epileptic animals are modified such that their neurosteroid sensitivity is reduced and delta subunit expression is diminished.


Input: The molecular mechanisms triggering this GABAR plasticity were explored.


Input: In the cultured hippocampal neurons treatment with NMDA (10 mu M) for 48 hrs reduced surface expression of delta and alpha 4 subunits, but did not increase expression of gamma 2 subunits.

NMDA


Input: The tonic current recorded from neurons in NMDA-treated cultures was reduced, and its neurosteroid modulation was also diminished.

NMDA


Input: In contrast, synaptic inhibition and its modulation by neurosteroids were preserved in these neurons.


Input: The time course of NMDA effects on surface and total delta subunit expression were distinct; shorter (6 hrs) treatment decreased surface expression, whereas longer treatment reduced both surface and total expression.

NMDA


Input: APV blocked NMDA effects on delta subunit expression.

APV

NMDA


Input: Chelation of calcium ions by BAPTA-AM or blockade of ERK1/2 activation by UO126 also prevented the NMDA effects.

calcium

BAPTA-AM

NMDA


Input: Thus prolonged activation of NMDA receptors in hippocampal neurons reduced GABAR delta subunit expression through Ca2 + entry and at least in part by ERK1/2 activation.

NMDA

Ca2 +


Input: Kinetic Evidence for a Non-Langmuir-Hinshelwood Surface Reaction: H/D Exchange over Pd Nanoparticles and Pd (111).

Hinshelwood

D

Pd

Pd (111)


Input: The mechanism of hydrogen recombination on a Pd (111) single crystal and well-defined Pd nanoparticles is studied using pulsed multi-molecular beam techniques and the H2/D2 isotope exchange reaction.

hydrogen

Pd (111)

Pd


Input: The focus of this study is to obtain a microscopic understanding of the role of subsurface hydrogen in enhancing the associative desorption of molecular hydrogen.

hydrogen

hydrogen


Input: HD production from H2 and D2 over Pd is investigated using pulsed molecular beams, and the temperature dependence and reaction orders are obtained for the rate of HD production under various reaction conditions designed to modulate the amount of subsurface hydrogen present.

HD

Pd

HD

hydrogen


Input: The experimental data are compared to the results of kinetic modeling based on different mechanisms for hydrogen recombination.

hydrogen


Input: We found that under conditions where virtually no subsurface hydrogen species are present, the HD formation rate can be described exceptionally well by a classic Langmuir-Hinshelwood model.

hydrogen

HD


Input: However, this model completely fails to reproduce the experimentally observed high HD formation rates and the reaction orders under reaction conditions where subsurface hydrogen is present.

HD

hydrogen


Input: To analyze this phenomenon, we develop two kinetic models that account for the role of subsurface hydrogen.

hydrogen


Input: First, we investigate the possibility of a change in the reaction mechanism, where recombination of one subsurface and one surface hydrogen species (known as a breakthrough mechanism) becomes dominant when subsurface hydrogen is present.

hydrogen

hydrogen


Input: Second, we investigate the possibility of the modified Langmuir-Hinshelwood mechanism with subsurface hydrogen lowering the activation energy for recombination of two hydrogen species adsorbed on the surface.

hydrogen

hydrogen


Input: We show that the experimental reaction kinetics can be well described by both kinetic models based on non-Langmuir-Hinshelwood-type mechanisms.


Input: Accurate detection of differential RNA processing.


Input: Deep transcriptome sequencing (RNA-Seq) has become a vital tool for studying the state of cells in the context of varying environments, genotypes and other factors.


Input: RNA-Seq profiling data enable identification of novel isoforms, quantification of known isoforms and detection of changes in transcriptional or RNA-processing activity.


Input: Existing approaches to detect differential isoform abundance between samples either require a complete isoform annotation or fall short in providing statistically robust and calibrated significance estimates.


Input: Here, we propose a suite of statistical tests to address these open needs: a parametric test that uses known isoform annotations to detect changes in relative isoform abundance and a non-parametric test that detects differential read coverages and can be applied when isoform annotations are not available.


Input: Both methods account for the discrete nature of read counts and the inherent biological variability.


Input: We demonstrate that these tests compare favorably to previous methods, both in terms of accuracy and statistical calibrations.


Input: We use these techniques to analyze RNA-Seq libraries from Arabidopsis thaliana and Drosophila melanogaster.


Input: The identified differential RNA processing events were consistent with RT-qPCR measurements and previous studies.


Input: The proposed toolkit is available from http://bioweb. me/rdiff and enables in-depth analyses of transcriptomes, with or without available isoform annotation.


Input: The effect of PTH (1-34) on fracture healing during different loading conditions.


Input: Parathyroid hormone (PTH) and PTH (1-34) have been shown to promote bone healing in several animal studies.


Input: It is known that the mechanical environment is important in fracture healing.


Input: Furthermore, PTH and mechanical loading has been suggested to have synergistic effects on intact bone.


Input: The aim of the present study was to investigate whether the effect of PTH (1-34) on fracture healing in rats was influenced by reduced mechanical loading.


Input: For this purpose we used female, 25-week-old ovariectomized rats.


Input: Animals were subjected to closed midshaft fracture of the right tibia ten weeks after ovariectomy.


Input: Five days before fracture, half of the animals received Botulinum Toxin A-injections in the muscles of the fractured leg to induce muscle paralysis (unloaded group), while the other half received saline injections (control group).


Input: For the following eight weeks, half of the animals in each group received injections of hPTH (1-34) (20 micro g/kg/day) and the other half received vehicle treatment.


Input: Fracture healing was assessed by radiology, DXA, histology and bone strength analysis.


Input: We found that unloading reduced callus area significantly, while no effects of PTH (1-34) on callus area were seen in neither normally nor unloaded animals.


Input: PTH (1-34) increased callus bone mineral density (BMD) and bone mineral content (BMC) significantly, while unloading decreased callus BMD and BMC significantly.


Input: PTH (1-34)-treatment increased bone volume of the callus in both unloaded and control animals.


Input: PTH (1-34)-treatment increased ultimate force of the fracture by 63% in both control and unloaded animals and no interaction of the two interventions could be detected.


Input: PTH (1-34) was able to stimulate bone formation in normally loaded as well as unloaded intact bone.


Input: In conclusion, the study confirms the stimulatory effect of PTH (1-34) on fracture healing and our data suggest that PTH (1-34) is able to promote fracture healing, as well as intact bone formation during conditions of reduced mechanical loading.


Input: Bottom-up Synthesis of Nanoscale Conjugation-Interrupted Frameworks and Their Electrical Properties.


Input: Soluble covalent organic nanoframeworks up to generation 2. 5 (G2. 5) are synthesized with self-similar H-shaped conformations by using a bottom-up approach including iterative C-H bond functionalization.

C-H


Input: The electrical characteristics of nanoscale thin-film semiconductors of the conjugation-interrupted frameworks can be tuned by post-modification with diazonium salt.

diazonium


Input: Dual Growth Factor Delivery Using Biocompatible Core-Shell Microcapsules for Angiogenesis.


Input: An optimized electrodropping system produces homogeneous core-shell microcapsules (C-S MCs) by using poly (L-lactic-co-glycolic acid) (PLGA) and alginate.

poly (L-lactic-co-glycolic acid)

PLGA


Input: Fluorescence imaging clearly shows the C-S domain in the MC.


Input: For release control, the use of high-molecular-weight PLGA (HMW 270 000) restrains the initial burst release of protein compared to that of low-MW PLGA (LMW 40 000).

PLGA

PLGA


Input: Layer-by-layer (LBL) assembly of chitosan and alginate on MCs is also useful in controlling the release profile of biomolecules.


Input: LBL (7-layer) treatment is effective in suppressing the initial burst release of protein compared to no LBL (0-layer).


Input: The difference of cumulative albumin release between HMW (7-layer LBL) and LMW (0-layer LBL) PLGA is determined to be more than 40% on day 5.

PLGA


Input: When dual angiogenic growth factors (GFs), such as platelet-derived GF (PDGF) and vascular endothelial GF (VEGF), are encapsulated separately in the core and shell domains, respectively, the VEGF release rate is much greater than that of PDGF, and the difference of the cumulative release percentage between the two GFs is about 30% on day 7 with LMW core PLGA and more than 45% with HMW core PLGA.

PLGA

PLGA


Input: As for the angiogenic potential of MC GFs with human umbilical vein endothelial cells (HUVECs), the fluorescence signal of CD31 + suggests that the angiogenic sprout of ECs is more active in MC-mediated GF delivery than conventional GF delivery, and this difference is significant, based on the number of capillary branches in the unit area.


Input: This study demonstrates that the fabrication of biocompatible C-S MCs is possible, and that the release control of biomolecules is adjustable.


Input: Furthermore, MC-mediated GFs remain in an active form and can upregulate the angiogenic activity of ECs.


Input: Surface Matters: Enhanced Bactericidal Property of Core-Shell Ag-Fe2 O3 Nanostructures to Their Heteromer Counterparts from One-Pot Synthesis.

Ag

Fe2 O3


Input: A facile one-pot synthesis of Ag @Fe2 O3 core-shell and Ag-Fe2 O3 heteromer nanoparticles is developed, and the core-shell nanoparticles have shown superior antibacterial properties compared to their heteromer counterparts and plain Ag nanoparticles.

Ag

Fe2 O3

Ag

Fe2 O3

Ag


Input: The mechanism for the increased efficiency is proposed to be due to the enhanced Ag ion release from the iron oxide shell-protected pristine Ag surface.

Ag

iron oxide

Ag


Input: Glassy Interfacial Dynamics of Ni Nanoparticles: Part II Discrete Breathers as an Explanation of Two-Level Energy Fluctuations.

Ni


Input: Recent studies of the dynamics of diverse condensed amorphous materials have indicated significant heterogeneity in the local mobility and a progressive increase in collective particle motion upon cooling that takes the form of string-like particle rearrangements.


Input: In a previous paper (Part I), we examined the possibility that fluctuations in potential energy E and particle mobility mu associated with this' dynamic heterogeneity' might offer information about the scale of collective motion in glassy materials based on molecular dynamics simulations of the glassy interfacial region of Ni nanoparticles (NPs) at elevated temperatures.

Ni


Input: We found that the noise exponent associated with fluctuations in the Debye-Waller factor, a mobility related quantity, was directly proportional to the scale of collective motion L under a broad range of conditions, but the noise exponent associated with E (t) fluctuations was seemingly unrelated to L.


Input: In the present work, we focus on this unanticipated difference between potential energy and mobility fluctuations by examining these quantities at an atomic scale.


Input: We find that the string atoms exhibit a jump-like motion between two well-separated bands of energy states and the rate at which these jumps occur seems to be consistent with the phenomenology of the' slow-beta' relaxation process of glass-forming liquids.


Input: Concurrently with these local E (t) jumps, we also find' quake-like' particle displacements having a power-law distribution in magnitude so that particle displacement fluctuations within the strings are strikingly different from local E (t) fluctuations.


Input: An analysis of these E (t) fluctuations suggests that we are dealing with' discrete breather' excitations in which large energy fluctuations develop in arrays of non-linear oscillators by virtue of large anharmonicity in the interparticle interactions and discreteness effects associated with particle packing.


Input: We quantify string collective motions on a fast caging times scale (picoseconds) and explore the significance of these collective motions for understanding the Boson peak of glass-forming materials.


Input: Tuning the Emission Properties of Fluorescent Ligands by Changing pH: The Unusual Case of an Acridine-Containing Polyamine Macrocycle.

Acridine


Input: Synthesis and characterization of a new macrocyclic compound, composed by a triethylentetraamine chain linking the 4 and 5 positions of an acridine moiety, are reported.

triethylentetraamine

acridine


Input: The molecule, devised as a fluorescent chemosensor for anions, has revealed an intriguing pH-dependent spectroscopic behavior, whose features are the specific object of this article.


Input: Ligand protonation in aqueous solution has been analyzed by means of potentiometric, (1) H NMR, UV-vis, and fluorescence emission measurements.

(1) H


Input: The molecule binds up to four protons in the pH range 2-11.


Input: Protonation takes place on the aliphatic tetraamine chain, while the acridine nitrogen does not participate to proton binding even at very low pH.

tetraamine

acridine nitrogen


Input: Differently from acridine, the UV-vis spectra are almost unaffected by the pH.

acridine


Input: On the opposite, the emission spectra are strongly pH-dependent.


Input: In fact, at low pH values, the spectra show a blue-shifted emission, resembling that of unprotonated acridine, while at slightly acidic and alkaline pH the fluorescence features a red-shifted band similar to that of acridinium cation.

acridinium


Input: This unusual behavior occurs in the mono-, bi-, and triprotonated forms of the compound and is interpreted as due to an excited state proton transfer from an aliphatic ammonium group adjacent to the acridine moiety to the acridine nitrogen.

aliphatic ammonium

acridine

acridine nitrogen


Input: In the fully protonated state, this process is prevented owing to unfavorable molecular arrangements mainly determined by electrostatic repulsions.


Input: This interpretation is supported by quantum mechanical calculations as well as molecular dynamics simulations.


Input: Self-Seeding in One Dimension: A Route to Uniform Fiber-like Nanostructures from Block Copolymers with a Crystallizable Core-Forming Block.


Input: One-dimensional micelles formed by the self-assembly of crystalline-coil poly (ferrocenyldimethylsilane) (PFS) block copolymers exhibit self-seeding behavior when solutions of short micelle fragments are heated above a certain temperature and then cooled back to room temperature.

poly (ferrocenyldimethylsilane)

PFS


Input: In this process, a fraction of the fragments (the least crystalline fragments) dissolves at elevated temperature, but the dissolved polymer crystallizes onto the ends of the remaining seed fragments upon cooling.


Input: This process yields longer nanostructures (up to 1 mu m) with uniform width (ca. 15 nm) and a narrow length distribution.


Input: In this paper, we describe a systematic investigation of factors that affect the self-seeding behavior of PFS block copolymer micelle fragments.

PFS


Input: For PI1000-PFS50 (the subscripts refer to the number average degree of polymerization) in decane, these factors include the presence of a good solvent (THF) for PFS and the effect of annealing the fragments prior to the self-seeding experiments.

decane

THF

PFS


Input: THF promoted the dissolution of the micelle fragments, while preannealing improved their stability.

THF


Input: We also extended our experiments to other PFS block copolymers with different corona-forming blocks.

PFS


Input: These included PI637-PFS53 in decane, PFS60-PDMS660 in decane (PDMS = polydimethylsiloxane), and PFS30-P2VP300 in 2-propanol (P2VP = poly (2-vinylpyridine)).

polydimethylsiloxane

poly (2-vinylpyridine