Input: Data is presented for ethylammonium nitrate (EAN) and 1-ethyl-3-methylimidazolium bis (trifluoro-methylsulfonyl) imide (EMIm TFSI).

ethylammonium nitrate

EAN

1-ethyl-3-methylimidazolium bis (trifluoro-methylsulfonyl) imide

EMIm TFSI


Input: Whereas EAN is a protic IL that forms a nanostructured sponge phase in the bulk, EMIm TFSI is aprotic and has weak (or absent) bulk association structure.

EAN

EMIm TFSI


Input: Comparison of results obtained for the two liquids elucidates how the strength of bulk liquid morphology effects lateral organisation at the surface, and any effect of IL class, i. e. protic versus aprotic.


Input: Imaging reveals EAN self assembles at the solid surface in a worm-like morphology, whereas EMIm cations adsorb in a more isolated fashion, but still in rows templated by the mica surface.

EAN

EMIm


Input: To the authors' knowledge, the wormlike structures present at the EAN-mica interface are the smallest self-assembled aggregates ever imaged on a solid surface.

EAN


Input: Review of clinical trials for mitochondrial disorders: 1997-2012.


Input: Over the last 15 years, some 16 open and controlled clinical trials for potential treatments of mitochondrial diseases have been reported or are in progress, and are summarized and reviewed herein.


Input: These include trials of administering dichloroacetate (an activator of pyruvate dehydrogenase complex), arginine or citrulline (precursors of nitric oxide), coenzyme Q10 (CoQ10; part of the electron transport chain and an antioxidant), idebenone (a synthetic analogue of CoQ10), EPI-743 (a novel oral potent 2-electron redox cycling agent), creatine (a precursor of phosphocreatine), combined administration (of creatine, alpha-lipoate, and CoQ10), and exercise training (to increase muscle mitochondria).

dichloroacetate

pyruvate

arginine

citrulline

nitric oxide

coenzyme Q10

idebenone

creatine

phosphocreatine

creatine

alpha-lipoate


Input: These trials have included patients with various mitochondrial disorders, a selected subcategory of mitochondrial disorders, or specific mitochondrial disorders (Leber hereditary optic neuropathy or mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes).


Input: The trial designs have varied from open-label/uncontrolled, open-label/controlled, or double-blind/placebo-controlled/crossover.


Input: Primary outcomes have ranged from single, clinically-relevant scores to multiple measures.


Input: Eight of these trials have been well-controlled, completed trials.


Input: Of these only 1 (treatment with creatine) showed a significant change in primary outcomes, but this was not reproduced in 2 subsequent trials with creatine with different patients.

creatine


Input: One trial (idebenone treatment of Leber hereditary optic neuropathy) did not show significant improvement in the primary outcome, but there was significant improvement in a subgroup of patients.

idebenone


Input: Despite the paucity of benefits found so far, well-controlled clinical trials are essential building blocks in the continuing search for more effective treatment of mitochondrial disease, and current trials based on information gained from these prior experiences are in progress.


Input: Because of difficulties in recruiting sufficient mitochondrial disease patients and the relatively large expense of conducting such trials, advantageous strategies include crossover designs (where possible), multicenter collaboration, and the selection of very few, clinically relevant, primary outcomes.


Input: Antenatal manifestations of mitochondrial disorders.


Input: Mitochondrial respiratory chain diseases are a heterogeneous group of pathologies caused by genetic alterations affecting mitochondrial energy production.


Input: Theoretically, this deficiency may lead to any symptoms, in any organ or tissue, at any age even before birth.


Input: The aim of our study was to identify the frequency and characterize antenatal manifestations identifying possible associations between mitochondrial disease and more specific and earlier manifestation.


Input: We retrospectively review the files of 44 paediatric subjects with genetic and biochemical alterations of respiratory chain identified in the first decade of life and compare data with a control group (n = 88).


Input: Our results show that maternal age was similar in both groups.


Input: The female gender was predominant in patients group.


Input: Gestational age at delivery was similar in both groups.


Input: Concerning birth weight, it was significantly lower (p = 0. 001) in patients (2899. 9 +/- 538. 3 vs. 3246. 6 +/- 460. 2 g).


Input: Fifteen pregnancies of the patients group were considered abnormal.


Input: Our findings show that intrauterine growth restriction was the most frequent antenatal feature observed.


Input: Neonatal morbidity was significantly higher (fivefold) in patients (p < 0. 001).


Input: The clinical findings are independent of the molecular defect type.


Input: Our results are preliminary and more studies are needed, in order to learn more about mitochondrial physiology and activity in embryological development for the assessment of mitochondrial disease progress in fetal life.


Input: However, the present work is a significant contribution, given the scarcity of information in this field.


Input: Left ventricular noncompaction (LVNC) and low mitochondrial membrane potential are specific for Barth syndrome.


Input: Barth syndrome (BTHS) is an X-linked mitochondrial defect characterised by dilated cardiomyopathy, neutropaenia and 3-methylglutaconic aciduria (3-MGCA).


Input: We report on two affected brothers with c. 646G > A (p. G216R) TAZ gene mutations.


Input: The pathogenicity of the mutation, as indicated by the structure-based functional analyses, was further confirmed by abnormal monolysocardiolipin/cardiolipin ratio in dry blood spots of the patients as well as the occurrence of this mutation in another reported BTHS proband.

monolysocardiolipin

cardiolipin


Input: In both brothers, 2D-echocardiography revealed some features of left ventricular noncompaction (LVNC) despite marked differences in the course of the disease; the eldest child presented with isolated cardiomyopathy from late infancy, whereas the youngest showed severe lactic acidosis without 3-MGCA during the neonatal period.


Input: An examination of the patients' fibroblast cultures revealed that extremely low mitochondrial membrane potentials (mt Delta Psi about 50% of the control value) dominated other unspecific mitochondrial changes detected (respiratory chain dysfunction, abnormal ROS production and depressed antioxidant defense).


Input: 1) Our studies confirm generalised mitochondrial dysfunction in the skeletal muscle and the fibroblasts of BTHS patients, especially a severe impairment in the mt Delta Psi and the inhibition of complex V activity.


Input: It can be hypothesised that impaired mt Delta Psi and mitochondrial ATP synthase activity may contribute to episodes of cardiac arrhythmia that occurred unexpectedly in BTHS patients.

ATP


Input: 2) Severe lactic acidosis without 3-methylglutaconic aciduria in male neonates as well as an asymptomatic mild left ventricular noncompaction may characterise the ranges of natural history of Barth syndrome.


Input: Facile solution synthesis of Ag @Pt core-shell nanoparticles with dendritic Pt shells.

Ag

Pt

Pt


Input: Ag @Pt nanoparticles with various dendritic Pt shells were successfully synthesized by using nonionic surfactants at room temperature.

Ag

Pt

Pt


Input: Our recent study demonstrated that the addition of nonionic surfactant plays an important key role in the synthesis of dendritic Pt nanostructures (J. Am. Chem. Soc., 2010, 132, 13636).

Pt


Input: Here we extend this synthetic concept to prepare various Ag @Pt nanoarchitectures.

Ag

Pt


Input: The different nanostructured Pt shells on the Ag core were confirmed by ultraviolet-visible absorption spectroscopy and transmission electron microscopy.

Pt

Ag


Input: As a preliminary electrochemical application, the obtained Ag @Pt nanostructures were applied in the methanol oxidation reaction (MOR) in 0. 5 M H (2) SO (4) solution containing 0. 5 M methanol.

Ag

Pt

methanol

H (2) SO (4)

methanol


Input: The Ag @Pt nanoparticles with thin dendritic Pt shells show superior CO-tolerance performance with a I (f)/I (b) value reaching 3. 71.

Ag

Pt

Pt

CO


Input: Our Ag @Pt nanostructures with good CO tolerant activity will be prominent catalysts for MOR.

Ag

Pt

CO


Input: A mechanistic study of the electrochemical oxygen reduction on the model semiconductor n-Ge (100) by ATR-IR and DFT.

oxygen

Ge


Input: The electrochemical oxygen reduction reaction (ORR) on a n-Ge (100) surface in 0. 1 M HClO4 was investigated in situ and operando using a combination of attenuated total reflection infrared (ATR-IR) spectroscopy and density functional (DFT) calculations.

oxygen

Ge


Input: The vibrational modes of the detected intermediates were assigned based on DFT calculations of solvated model clusters such as Ge-bound superoxides and peroxides.

Ge

superoxides

peroxides


Input: ATR-IR shows the Ge-bound superoxide with a transition dipole moment oriented at (28 +/- 10) degrees with respect to the surface normal.

Ge

superoxide


Input: At slightly negative potentials, the surface-bound peroxide is identified by an OOH bending mode as a further intermediate, oriented at a similar angle.

peroxide

OOH


Input: At strongly negative potentials, a surface-bound perchlorate is found.


Input: The findings indicate a multistep mechanism of the ORR.


Input: The reaction is furthermore coupled with the hydrogen evolution reaction (HER).

hydrogen


Input: Microfluidic platforms for RNA interference screening of virus-host interactions.


Input: RNA interference (RNAi) is a powerful tool for functional genomics with the capacity to comprehensively analyze host-pathogen interactions.


Input: High-throughput RNAi screening is used to systematically perturb cellular pathways and discover therapeutic targets, but the method can be tedious and requires extensive capital equipment and expensive reagents.


Input: To aid in the development of an inexpensive miniaturized RNAi screening platform, we have developed a two part microfluidic system for patterning and screening gene targets on-chip to examine cellular pathways involved in virus entry and infection.


Input: First, a multilayer polydimethylsiloxane (PDMS)-based spotting device was used to array siRNA molecules into 96 microwells targeting markers of endocytosis, along with siRNA controls.

polydimethylsiloxane

PDMS


Input: By using a PDMS-based spotting device, we remove the need for a microarray printer necessary to perform previously described small scale (e. g. cellular microarrays) and microchip-based RNAi screening, while still minimizing reagent usage tenfold compared to conventional screening.

PDMS


Input: Second, the siRNA spotted array was transferred to a reversibly sealed PDMS-based screening platform containing microchannels designed to enable efficient cell loading and transfection of mammalian cells while preventing cross-contamination between experimental conditions.

PDMS


Input: Validation of the screening platform was examined using Vesicular stomatitis virus and emerging pathogen Rift Valley fever virus, which demonstrated virus entry pathways of clathrin-mediated endocytosis and caveolae-mediated endocytosis, respectively.


Input: The techniques here are adaptable to other well-characterized infection pathways with a potential for large scale screening in high containment biosafety laboratories.


Input: Mini-chromosome maintenance complexes form a filament to remodel DNA structure and topology.


Input: Deregulation of mini-chromosome maintenance (MCM) proteins is associated with genomic instability and cancer.


Input: MCM complexes are recruited to replication origins for genome duplication.


Input: Paradoxically, MCM proteins are in excess than the number of origins and are associated with chromatin regions away from the origins during G1 and S phases.


Input: Here, we report an unusually wide left-handed filament structure for an archaeal MCM, as determined by X-ray and electron microscopy.


Input: The crystal structure reveals that an alpha-helix bundle formed between two neighboring subunits plays a critical role in filament formation.


Input: The filament has a remarkably strong electro-positive surface spiraling along the inner filament channel for DNA binding.


Input: We show that this MCM filament binding to DNA causes dramatic DNA topology change.


Input: This newly identified function of MCM to change DNA topology may imply a wider functional role for MCM in DNA metabolisms beyond helicase function.


Input: Finally, using yeast genetics, we show that the inter-subunit interactions, important for MCM filament formation, play a role for cell growth and survival.


Input: Transcriptional regulators of hepatic gluconeogenesis.


Input: Glucose is a primary fuel for generating energy in basic daily activities.

Glucose


Input: Thus, glucose homeostasis is tightly regulated by counter-regulatory hormones such as glucagon, cortisol, and insulin, which affect key organs including liver, skeletal muscle, pancreas, and adipocytes.

glucose


Input: Among metabolic tissues, liver plays a critical role in controlling glucose production under various hormonal and metabolic cues.

glucose


Input: Under fasting, acute activation of both glycogenolysis and gluconeogenesis is achieved by post-translational modification or allosteric activation of key rate-limiting enzymes, thereby enabling enhanced glucose production from the liver to maintain glucose homeostasis.

glucose

glucose


Input: More prolonged fasting or starvation leads to the chronic activation of gluconeogenesis that requires increased expression of key enzymes in the pathway, which is turned off under feeding conditions by the molecular events that are initiated by insulin.


Input: This process is normally achieved by the regulation of gene expression at the level of transcription.


Input: Recently, the transcriptional regulators of hepatic gluconeogenesis are considered as potential therapeutic targets for the treatment of type 2 diabetes.


Input: In this review, we would like to discuss the current knowledge regarding the key transcriptional activators and inhibitors of hepatic gluconeogenic program to provide the better insight into the control of glycemia in the disease status.


Input: Role of cytochrome P4502B6 in methadone metabolism and clearance.

methadone


Input: Methadone N-demethylation in vitro is catalyzed by hepatic cytochrome P4502B6 (CYP2B6) and CYP3A4, but clinical disposition is often attributed to CYP3A4.

Methadone N


Input: This investigation tested the hypothesis that CYP2B6 is a prominent CYP isoform responsible for clinical methadone N-demethylation and clearance, using the in vivo mechanism-based CYP2B6 inhibitor ticlopidine, given orally for 4 days.

methadone N

ticlopidine


Input: A preliminary clinical investigation with the CYP3A4/5 substrate probe alfentanil established that ticlopidine did not inhibit intestinal or hepatic CYP3A4/5.

alfentanil

ticlopidine


Input: Subjects received intravenous plus oral (deuterium-labeled) racemic methadone before and after ticlopidine.

deuterium

racemic methadone

ticlopidine


Input: Ticlopidine significantly and stereoselectively (S > R) inhibited methadone N-demethylation, decreasing plasma metabolite/methadone area under the curve ratios and metabolite formation clearances.

Ticlopidine

methadone N

methadone


Input: Ticlopidine also significantly increased the dose-adjusted plasma area under the curve for R-and S-methadone by 20% and 60%, respectively, after both intravenous and oral dosing.

Ticlopidine

R-and S-methadone


Input: CYP2B6 inhibition reduces methadone N-demethylation and clearance, and alters methadone concentrations, demonstrating an important role for CYP2B6 in clinical methadone disposition.

methadone N

methadone

methadone


Input: Carboxylic acid (bio) isosteres in drug design.

Carboxylic acid


Input: The carboxylic acid functional group can be an important constituent of a pharmacophore, however, the presence of this moiety can also be responsible for significant drawbacks, including metabolic instability, toxicity, as well as limited passive diffusion across biological membranes.

carboxylic acid


Input: To avoid some of these shortcomings while retaining the desired attributes of the carboxylic acid moiety, medicinal chemists often investigate the use of carboxylic acid (bio) isosteres.

carboxylic acid

carboxylic acid


Input: The same type of strategy can also be effective for a variety other purposes, for example, to increase the selectivity of a biologically active compound or to create new intellectual property.


Input: Several carboxylic acid isosteres have been reported, however, the outcome of any isosteric replacement cannot be readily predicted as this strategy is generally found to be dependent upon the particular context (i. e., the characteristic properties of the drug and the drug-target).

carboxylic acid


Input: As a result, screening of a panel of isosteres is typically required.


Input: In this context, the discovery and development of novel carboxylic acid surrogates that could complement the existing palette of isosteres remains an important area of research.

carboxylic acid


Input: The goal of this Minireview is to provide an overview of the most commonly employed carboxylic acid (bio) isosteres and to present representative examples demonstrating the use and utility of each isostere in drug design.

carboxylic acid


Input: Tumor localization and biochemical response to cure in tumor-induced osteomalacia.


Input: Tumor-induced osteomalacia (TIO) is a rare disorder of phosphate wasting due to fibroblast growth factor-23 (FGF23)-secreting tumors that are often difficult to locate.

phosphate


Input: We present a systematic approach to tumor localization and post-operative biochemical changes in 31 subjects with TIO.


Input: All had failed either initial, or re-localization (in case of recurrence or metastases at outside institutions).


Input: Functional imaging with (111) Indium-octreotide with single photon emission computed tomography (octreo-SPECT or SPECT/CT), and (18) fluorodeoxyglucose positron emission tomography/CT (FDG-PET/CT) were performed, followed by anatomic imaging (CT, MRI).

(111) Indium

(18) fluorodeoxyglucose


Input: Selective venous sampling (VS) was performed when multiple suspicious lesions were identified or high surgical risk was a concern.


Input: Tumors were localized in 20/31 subjects (64. 5%).


Input: Nineteen of 20 subjects underwent octreo-SPECT imaging, and 16/20 FDG-PET/CT imaging.


Input: Eighteen of 19 (95%) were positive on octreo-SPECT, and 14/16 (88%) on FDG-PET/CT.


Input: Twelve of 20 subjects underwent VS; 10/12 (83%) were positive.


Input: Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were: sensitivity = 0. 95, specificity = 0. 64, PPV = 0. 82 and NPV = 0. 88 for octreo-SPECT; sensitivity = 0. 88, specificity = 0. 36, PPV = 0. 62 and NPV = 0. 50 for FDG-PET/CT.


Input: Fifteen subjects had their tumor resected at our institution, and were disease-free at last follow-up.


Input: Serum phosphorus returned to normal in all subjects within 1-5 days.

phosphorus


Input: In 10 subjects who were followed for at least 7 days postoperatively, intact FGF23 (iFGF23) decreased to near undetectable within hours and returned to the normal range within 5 days.


Input: C-terminal FGF23 (cFGF23) decreased immediately but remained elevated, yielding a markedly elevated cFGF23/iFGF23 ratio.

C


Input: Serum 1, 25-dihydroxyvitamin D (3) (1, 25D) rose and exceeded the normal range.

1, 25-dihydroxyvitamin D (3)

1, 25D


Input: In this systematic approach to TIO tumor localization Octreo-SPECT was more sensitive and specific, but in many cases FDG-PET/CT was complementary.


Input: VS can discriminate between multiple suspicious lesions and increase certainty prior to surgery.


Input: Sustained elevations in cFGF23 and 1, 25D were observed, suggesting novel regulation of FGF23 processing and 1, 25D generation.

1, 25D

1, 25D


Input: (c) 2013 American Society for Bone and Mineral Research.


Input: Graphene Oxide-Based Fluorescent Biosensor for Protein Detection via Terminal Protection of Small-Molecule-Linked DNA.

Graphene Oxide


Input: A fluorescence method for protein detection is developed based on terminal protection of small-molecule-linked DNA by target protein and a graphene oxide-assisted DNA assay strategy.

graphene oxide


Input: This design results in fluorescence-enhanced detection that is sensitive and selective for the target protein.


Input: Vemurafenib potently induces endoplasmic reticulum stress-mediated apoptosis in BRAFV600E melanoma cells.

Vemurafenib


Input: The V600E mutation in the kinase BRAF is frequently detected in melanomas and results in constitutive activation of BRAF, which then promotes cell proliferation by the mitogen-activated protein kinase signaling pathway.


Input: Although the BRAFV600E kinase inhibitor vemurafenib has remarkable antitumor activity in patients with BRAFV600E-mutated melanoma, its effects are limited by the onset of drug resistance.

vemurafenib


Input: We found that exposure of melanoma cell lines with the BRAFV600E mutation to vemurafenib decreased the abundance of antiapoptotic proteins and induced intrinsic mitochondrial apoptosis.

vemurafenib


Input: Vemurafenib-treated melanoma cells showed increased cytosolic concentration of calcium, a potential trigger for endoplasmic reticulum (ER) stress, which can lead to apoptosis.

Vemurafenib

calcium


Input: Consistent with an ER stress-induced response, vemurafenib decreased the abundance of the ER chaperone protein glucose-regulated protein 78, increased the abundance of the spliced isoform of the transcription factor X-box binding protein 1 (XBP1) (which transcriptionally activates genes involved in ER stress responses), increased the phosphorylation of the translation initiation factor eIF2 alpha (which would be expected to inhibit protein synthesis), and induced the expression of ER stress-related genes.

vemurafenib

glucose


Input: Knockdown of the ER stress response protein activating transcription factor 4 (ATF4) significantly reduced vemurafenib-induced apoptosis.

vemurafenib


Input: Moreover, the ER stress inducer thapsigargin prevented invasive growth of tumors formed from vemurafenib-sensitive melanoma cells in vivo.

thapsigargin

vemurafenib


Input: In melanoma cells with low sensitivity or resistance to vemurafenib, combination treatment with thapsigargin augmented or induced apoptosis.

vemurafenib

thapsigargin


Input: Thus, thapsigargin or other inducers of ER stress may be useful in combination therapies to overcome vemurafenib resistance.

thapsigargin

vemurafenib


Input: Transforming growth factor beta integrates Smad 3 to mechanistic target of rapamycin complexes to arrest deptor abundance for glomerular mesangial cell hypertrophy.

rapamycin


Input: In many renal diseases, transforming growth factor beta (TGF beta)-stimulated canonical Smad 3 and noncanonical mechanistic target of rapamycin (mTOR) promote increased protein synthesis and mesangial cell hypertrophy.

rapamycin


Input: The cellular underpinnings involving these signaling molecules to regulate mesangial cell hypertrophy are not fully understood.


Input: Deptor has recently been identified as an mTOR interacting protein and functions as an endogenous inhibitor of the kinase activity for both TORC1 and TORC2.


Input: Prolonged incubation of mesangial cells with TGF beta reduced the levels of deptor concomitant with an increase in TORC1 and TORC2 activity.


Input: Sustained TGF beta activation was required to inhibit association of deptor with mTOR, whereas rapid activation had no effect.


Input: Using the mTOR inhibitor PP242, we found that TGF beta-induced both early and sustained activation of TORC1 and TORC2 was necessary for deptor suppression.


Input: PP242-induced reversal of deptor suppression by TGF beta was associated with a significant inhibition of TGF beta-stimulated protein synthesis and hypertrophy.


Input: Interestingly, expression of siRNA against Smad 3 or Smad 7, which blocks TGF beta receptor-specific Smad 3 signaling, prevented TGF beta-induced suppression of deptor abundance and TORC1/2 activities.


Input: Furthermore, overexpression of Smad 3 decreased deptor expression similar to TGF beta stimulation concomitant with increased TORC1 and TORC2 activities.


Input: Finally, knockdown of deptor reversed Smad 7-mediated inhibition of protein synthesis and mesangial cell hypertrophy induced by TGF beta.


Input: These data reveal the requirement of both early and late activation of mTOR for TGF beta-induced protein synthesis.


Input: Our results support that TGF beta-stimulated Smad 3 acts as a key node to instill a feedback loop between deptor down-regulation and TORC1/2 activation in driving mesangial cell hypertrophy.


Input: Tuning the magnetic properties of metal oxide nanocrystal heterostructures by cation exchange.

metal oxide


Input: For three types of colloidal magnetic nanocrystals, we demonstrate that postsynthetic cation exchange enables tuning of the nanocrystal' s magnetic properties and achieving characteristics not obtainable by conventional synthetic routes.


Input: While the cation exchange procedure, performed in solution phase approach, was restricted so far to chalcogenide based semiconductor nanocrystals, here ferrite-based nanocrystals were subjected to a Fe (2 +) to Co (2 +) cation exchange procedure.

ferrite

Fe (2 +)

Co (2 +)


Input: This allows tracing of the compositional modifications by systematic and detailed magnetic characterization.


Input: In homogeneous magnetite nanocrystals and in gold/magnetite core shell nanocrystals the cation exchange increases the coercivity field, the remanence magnetization, as well as the superparamagnetic blocking temperature.


Input: For core/shell nanoheterostructures a selective doping of either the shell or predominantly of the core with Co (2 +) is demonstrated.

Co (2 +)


Input: By applying the cation exchange to FeO/CoFe (2) O (4) core/shell nanocrystals the Ne e l temperature of the core material is increased and exchange-bias effects are enhanced so that vertical shifts of the hysteresis loops are obtained which are superior to those in any other system.

FeO

CoFe (2) O (4)


Input: Attitude of German women towards hormone therapy: results of a lay survey.


Input: Abstract Objective: Hormone therapy (HT) use has experienced a substantial change since publication of Women' s Health Initiative (WHI) controlled trial.


Input: We aimed to investigate the attitude towards HT in German women aged 45-60 years.


Input: Study design: A questionnaire was sent to 9785 randomly selected women in Germany aged between 45 and 60 years.


Input: Results: Response rate was 19. 3% (n = 1, 893).


Input: Of those, 81% experienced climacteric symptoms.


Input: Vasomotor symptoms were most frequently reported (71. 2%; n = 1332).


Input: Of the respondents, 19. 7% (n = 369) used HT.


Input: The most frequently mentioned benefits of HT were the improvement of climacteric complaints (71. 2%; n = 1346), followed by the relief of osteoporosis (37. 2%; n = 697) and the " anti-aging " effect (16. 3%; n = 305).


Input: Breast cancer was stated as the main risk (64. 9%; n = 1215), closely followed by weight gain (53. 4%; n = 1000) and thromboembolism (48%; n = 898).


Input: About 44% of the women who has been advised by gynaecologists choose a HT, whereas this rate dropped down to 14. 3% and 11. 3% for women who have been advised by friends or media.


Input: Conclusion: German women were generally aware of the main risks and benefits of HT.


Input: " More informed " women appear to be more likely to use HT compared to " less informed " women.


Input: The media produces negative impression of HT.


Input: Development of Inhibitors of the PAS-B Domain of the HIF-2 alpha Transcription Factor.


Input: Hypoxia inducible factors (HIFs) are heterodimeric transcription factors induced in a variety of pathophysiological settings, including cancer.


Input: We describe the first detailed structure-activity relationship study of small molecules designed to inhibit HIF-2 alpha-ARNT heterodimerization by binding an internal cavity of the HIF-2 alpha PAS-B domain.


Input: Through a series of biophysical characterizations of inhibitor-protein interactions (NMR and X-ray crystallography), we have established the structural requirements for artificial inhibitors of the HIF-2 alpha-ARNT PAS-B interaction.


Input: These results may serve as a foundation for discovering therapeutic agents that function by a novel mode of action.


Input: Adverse effects of wood smoke PM (2. 5) exposure on macrophage functions.


Input: Epidemiological studies have shown a correlation between chronic biomass smoke exposure and increased respiratory infection.


Input: Pulmonary macrophages are instrumental in both the innate and the adaptive immune responses to respiratory infection.


Input: In the present study, in vitro systems were utilized where alveolar macrophages (AM) and bone marrow-derived macrophages (BMdM) were exposed to concentrated wood smoke-derived particulate matter (WS-PM) and mice were exposed in vivo to either concentrated WS-PM or inhaled WS.


Input: In vivo studies demonstrated that WS-exposed mice inoculated with Streptococcus pneumoniae had a higher bacterial load 24 h post-exposure, and corresponding AM were found to have decreased lymphocyte activation activity.


Input: Additionally, while classic markers of inflammation (cellular infiltration, total protein, neutrophils) were not affected, there were changes in pulmonary macrophages populations, including significant decreases in macrophages expressing markers of activation in WS-exposed mice.


Input: The lymphocyte activation activity of WS-PM-exposed AM was significantly suppressed, but the phagocytic activity appeared unchanged.


Input: In an effort to determine a pathway for WS-induced suppression, RelB activation, assessed by nuclear translocation, was observed in AM exposed to either inhaled WS or instilled WS-PM.


Input: Finally, an analysis of WS-PM fractions determined the presence of 4-5 polycyclic aromatic hydrocarbons (PAHs), and preliminary work suggests a potential role for these PAHs to alter macrophage functions.

polycyclic aromatic hydrocarbons

PAHs

PAHs


Input: These studies show a decreased ability of WS-exposed pulmonary macrophages to effectively mount a defense against infection, the effect lasts at least a week post-exposure, and appears to be mediated via RelB activation.


Input: Association of Inhalation Toxicologists' (AIT) review of regulatory aspects for inhalation toxicology studies.


Input: Regulatory guidelines are intended to provide recommendations on ways to achieve greater harmonization in the interpretation and application of technical procedures and requirements for product registration in order to reduce or obviate replication of the testing carried out during the research and development of new products.


Input: The objectives of such harmonization are more economical use of human, animal and material resources; the elimination of unnecessary delay in the global development and availability of new products while maintaining safeguards on quality, safety and efficacy; and the fulfillment of regulatory obligations to protect public health.


Input: Synthesis of superconducting nanocables of FeSe encapsulated in carbonaceous shell.

FeSe


Input: The recent discovery of superconductivity in iron selenide has attracted considerable attention due to the simplicity of composition, unconventional nature of superconductivity, and ease of synthesis.

iron selenide


Input: We have synthesized superconducting FeSe nanowires with a simple catalyst-aided vapor transport reaction at 800 degrees C in an inert atmosphere.

FeSe


Input: The precursors were chosen to be elemental Se and iron acetylacetonate [Fe (III) (C 5 H 8 O 2) 3].

Se

iron acetylacetonate

Fe (III) (C 5 H 8 O 2) 3


Input: These vaporized very easily, thereby facilitating transport, and also contributed to the formation of a carbonaceous shell encapsulating the FeSe nanowires.

FeSe


Input: The superconductivity of these nanocables was confirmed through magnetic measurements and a T (c) of =~ 8 K was obtained for an ensemble of nanocables.


Input: The length of FeSe filling inside the carbon nanofibers could be varied by controlling the reaction conditions while the diameter of nanowires was dependent on the thickness of Au-Pd coating used as a catalyst.

FeSe

carbon

Au-Pd


Input: Extensive analysis through high-resolution microscopy revealed that there was considerable lattice contraction of FeSe in the nanocable up to about 3. 6% along the c-direction leading to a reduced spacing between the (001) lattice planes.

FeSe


Input: Interestingly, this compression was more pronounced near the catalyst-FeSe interface and was reduced further along the length of the nanocable.

FeSe


Input: The presence of carbon nanofibers as a shell around the FeSe protected the FeSe nanowires from both atmospheric O 2 and moisture attack, as was evident from the very long ambient condition shelf life of these nanocables, and also makes them more stable under e-beam irradiation.

carbon

FeSe

FeSe

O 2


Input: Genistein, a natural product derived from soybeans, ameliorates polyglutamine-mediated motor neuron disease.

Genistein

polyglutamine


Input: Spinal and bulbar muscular atrophy (SBMA) is an inherited motor neuron disease caused by the expansion of a polyglutamine (polyQ) tract within the androgen receptor (AR) gene.

polyglutamine

polyQ

androgen


Input: The pathologic features of SBMA are motor neuron loss in the spinal cord and brainstem, and diffuse nuclear accumulation and nuclear inclusions of mutant AR in residual motor neurons and certain visceral organs.


Input: AR-associated coregulator 70 (ARA70) was the first coregulator of AR to be identified, and it has been shown to interact with AR and increase its protein stability.


Input: Here, we report that genistein, an isoflavone found in soy, disrupts the interaction between AR and ARA70 and promotes the degradation of mutant AR in neuronal cells and transgenic mouse models of SBMA.

genistein

isoflavone


Input: We also demonstrate that dietary genistein ameliorates behavioral abnormalities, improves spinal cord and muscle pathology, and decreases the amounts of monomeric AR and high-molecular-weight mutant AR protein aggregates in SBMA transgenic mice.

genistein


Input: Thus, genistein treatment may be a potential therapeutic approach for alleviating the symptoms of SBMA by disrupting the interactions between AR and ARA70.

genistein


Input: High T (g) bio-based aliphatic polyesters from bicyclic D-mannitol.

polyesters

bicyclic D-mannitol


Input: The carbohydrate-based diol 2, 4: 3, 5-di-O-methylene-d-mannitol (Manx) has been used to obtain aliphatic polyesters.

carbohydrate

diol 2, 4: 3, 5-di-O-methylene-d-mannitol

polyesters


Input: Manx is a symmetric bicyclic compound consisting of two fused 1, 3-dioxane rings and bearing two primary hydroxyl groups.

1, 3-dioxane

hydroxyl


Input: In terms of stiffness, it is comparable to the widely known isosorbide, but it affords the additional advantages of being much more reactive in polycondensation and capable of producing stereoregular polymers with fairly high molecular weights.

isosorbide


Input: A fully bio-based homopolyester (PManxS) has been synthesized by polycondensation in the melt from dimethyl succinate and Manx.

dimethyl succinate


Input: The high thermal stability of PManxS, its relatively high glass transition temperature (Tg = 68 degrees C) and elastic modulus, and its enhanced sensitivity to the action of lipases point to PManxS as a polyester of exceptional interest for those applications where biodegradability and molecular stiffness are priority requirements.

polyester


Input: In addition, random copolyesters (PBxManxyS) covering a broad range of compositions have been obtained using mixtures of Manx and 1, 4-butanediol in the reaction with dimethyl succinate.

1, 4-butanediol

dimethyl succinate


Input: All PBxManxyS were semicrystalline and displayed Tg values from-29 to + 51 degrees C steadily increasing with the content in Manx units.


Input: The stress-strain behavior of these copolyesters largely depended on their content in Manx and they were enzymatically degraded faster than PBS.


Input: TCDD and corticosterone on testicular steroidogenesis and antioxidant system of epididymal sperm in rats.

TCDD

corticosterone


Input: 2, 3, 7, 8-Tetrachloro dibenzo-p-dioxin (TCDD), an endocrine-disrupting environmental pollutant, has been found to cause male reproductive toxicity.

2, 3, 7, 8-Tetrachloro dibenzo-p-dioxin

TCDD


Input: Glucocorticoids have been found to influence the metabolic pathway of TCDD.

TCDD


Input: Stress, which affects the male reproductive function, is marked by an increase in the level and activity of glucocorticoids in the body.


Input: The present study was carried out to understand the effect of TCDD on testicular steroidogenesis and sperm antioxidant system under the influence of increased level of corticosterone in the body.

TCDD

corticosterone


Input: Adult male rats were treated with either TCDD (100 ng/kg bw/day) or corticosterone (3 mg/kg bw/day) or both for 15 days.

TCDD

corticosterone


Input: Treatment with either TCDD or corticosterone was found to suppress the levels of steroidogenic acute regulatory protein and androgen-binding protein and reduce the activities of steroidogenic enzymes in testis while increasing oxidative stress in ventral prostate, seminal vesicles and epididymal sperm.

TCDD


Input: In rats treated with both TCDD and corticosterone, the suppression of testicular steroidogenesis and increase in oxidative stress observed in ventral prostate, seminal vesicles and epididymal sperm were significant as compared to TCDD alone treated rats.

TCDD

corticosterone

TCDD


Input: The levels of Fas and FasL proteins were also increased in rats subjected to either TCDD or corticosterone treatment.

TCDD

corticosterone


Input: In rats treated with both compounds, the increase observed in testicular levels of Fas and FasL was significant as compared to TCDD alone treated rats.

TCDD


Input: Effect of TCDD on testicular steroidogenesis and antioxidant system of epididymal sperm may get enhanced under increased level of glucocorticoids in the body.

TCDD


Input: The genome-defence gene Tex19. 1 suppresses LINE-1 retrotransposons in the placenta and prevents intra-uterine growth retardation in mice.


Input: DNA methylation plays an important role in suppressing retrotransposon activity in mammalian genomes, yet there are stages of mammalian development where global hypomethylation puts the genome at risk of retrotransposition-mediated genetic instability.


Input: Hypomethylated primordial germ cells appear to limit this risk by expressing a cohort of retrotransposon-suppressing genome-defence genes whose silencing depends on promoter DNA methylation.


Input: Here, we investigate whether similar mechanisms operate in hypomethylated trophectoderm-derived components of the mammalian placenta to couple expression of genome-defence genes to the potential for retrotransposon activity.


Input: We show that the hypomethylated state of the mouse placenta results in activation of only one of the hypomethylation-sensitive germline genome-defence genes: Tex19. 1.


Input: Tex19. 1 appears to play an important role in placenta function as Tex19. 1 (-/-) mouse embryos exhibit intra-uterine growth retardation and have small placentas due to a reduction in the number of spongiotrophoblast, glycogen trophoblast and sinusoidal trophoblast giant cells.


Input: Furthermore, we show that retrotransposon mRNAs are derepressed in Tex19. 1 (-/-) placentas and that protein encoded by the LINE-1 retrotransposon is upregulated in hypomethylated trophectoderm-derived cells that normally express Tex19. 1.


Input: This study suggests that post-transcriptional genome-defence mechanisms are operating in the placenta to protect the hypomethylated cells in this tissue from retrotransposons and suggests that imbalances between retrotransposon activity and genome-defence mechanisms could contribute to placenta dysfunction and disease.


Input: Tetrabenzoporphyrins: synthetic developments and applications.

Tetrabenzoporphyrins


Input: Tetrabenzoporphyrins have attracted considerable worldwide attention over the last few decades.

Tetrabenzoporphyrins


Input: Since the discovery of these pigments, chemists, biologists, medical professionals and material scientists have devoted pronounced efforts in order to develop synthetic methods and discover useful applications for these compounds.


Input: Nowadays, tetrabenzoporphyrins occupy a prominent position in porphyrin chemistry, and this review is intended to cover the main synthetic methods and applications of these compounds.

tetrabenzoporphyrins

porphyrin


Input: Engineering a serum-resistant and thermostable vesicular stomatitis virus G glycoprotein for pseudotyping retroviral and lentiviral vectors.


Input: Vesicular stomatitis virus G glycoprotein (VSV-G) is the most widely used envelope protein for retroviral and lentiviral vector pseudotyping; however, serum inactivation of VSV-G pseudotyped vectors is a significant challenge for in vivo gene delivery.


Input: To address this problem, we conducted directed evolution of VSV-G to increase its resistance to human serum neutralization.


Input: After six selection cycles, numerous common mutations were present.


Input: On the basis of their location within VSV-G, we analyzed whether substitutions in several surface exposed residues could endow viral vectors with higher resistance to serum.


Input: S162T, T230N and T368A mutations enhanced serum resistance, and additionally K66T, T368A and E380K substitutions increased the thermostability of VSV-G pseudotyped retroviral vectors, an advantageous byproduct of the selection strategy.


Input: Analysis of a number of combined mutants revealed that VSV-G harboring T230N + T368A or K66T + S162T + T230N + T368A mutations exhibited both higher in vitro resistance to human serum and higher thermostability, as well as enhanced resistance to rabbit and mouse serum.


Input: Finally, lentiviral vectors pseudotyped with these variants were more resistant to human serum in a murine model.


Input: These serum-resistant and thermostable VSV-G variants may aid the application of retroviral and lentiviral vectors to gene therapy. Gene Therapy advance online publication, 31 January 2013; doi: 10. 1038/gt. 2013. 1.


Input: Predicting metabolic clearance for drugs that are actively transported into hepatocytes: incubational binding as a consequence of in vitro hepatocyte concentration is a key factor.


Input: Incubational binding or the fraction of drug unbound in an in vitro incubation, fuinc, is an important parameter to predict or measure in the pursuit of accurate clearance predictions from in vitro data.


Input: Here we describe a method for fuinc determination directly in the hepatocyte intrinsic clearance (CLint) assay with emphasis on compounds that are actively transported into hepatocytes, hypothesizing that for such compounds the typical protocol of 1 million hepatocytes/ml systematically underestimates the maximum attainable unbound intracellular drug concentration.


Input: Using the transporter substrate atorvastatin as a test compound, incubations were performed and a mathematical model applied to describe metabolism, distribution, and binding at different hepatocyte concentrations.

atorvastatin


Input: From these investigations it was evident that, since binding is more extensive intracellularly than in the medium, increased partitioning into the cellular volume, due to active uptake, increases the total amount of atorvastatin bound in the incubation.

atorvastatin


Input: Consequently, a significant lowering of the hepatocyte concentration impacts the free drug concentration in the incubation and increases the observed rate of metabolism and therefore observed CLint (that is, when viewed from the media drug concentration).


Input: The applicability of the findings was tested for a series of 11 actively transported zwitterions for which standard rat hepatocyte metabolic CLint data (1 million cells/ml incubation) poorly predicted in vivo clearance (average fold error of 5. 4).


Input: Using metabolic CLint determined at a lower hepatocyte concentration (0. 125 million cells/ml) considerably improved clearance predictions (average fold error of 2. 3).


Input: Investigation of the toxicokinetics of petroleum hydrocarbon distillates with the earthworm Eisenia andrei.

petroleum hydrocarbon


Input: The Canada-wide standards for petroleum hydrocarbons in soils regulate petroleum hydrocarbons based on four distillate ranges: F1 (C6-C10), F2 (> C10-C16), F3 (> C16-C34), and F4 (> C34).

petroleum hydrocarbons

petroleum hydrocarbons


Input: Previous toxicity tests with earthworms and F2, as well as two subfractions of F3, F3a (> C16-C23) and F3a (> C23-C34), indicate that test durations might not be sufficiently long to reach threshold effect concentrations, likely because of the differing toxicokinetics for each distillate.


Input: A study was conducted to determine the toxicokinetics of both aliphatic and aromatic fractions of F2, F3a, and F3b with the earthworm Eisenia andrei.


Input: Peak accumulation curves were observed for F2 aliphatics and aromatics and F3a aromatics, likely as a result of changes in exposure concentration over the test duration via loss or a decrease in the bioavailable fraction.


Input: Biota-soil accumulation factors were > 1 for total F2 aliphatics and aromatics and F3a aromatics as well as for several individual polyaromatic hydrocarbons for each distillate.

polyaromatic hydrocarbons


Input: Aromatics were disproportionately accumulated over aliphatics and were the main contributors to toxicity; therefore, aromatics and aliphatics should be regulated separately.


Input: The toxicokinetics were used to interpret previous toxicity data.


Input: Higher molecular weight distillates need longer-than-standard test durations to determine toxicity, so toxicity test results from fixed, standard-duration tests are not strictly comparable for these petroleum distillates.


Input: Environ.


Input: Toxicol.


Input: Chem.


Input: 2013; 32: 1006-1015.


Input: (c) 2013 SETAC.


Input: Cocoa polyphenols enhance positive mood states but not cognitive performance: a randomized, placebo-controlled trial.

polyphenols


Input: This study aimed to examine the acute and sub-chronic effects of cocoa polyphenols on cognition and mood.

polyphenols


Input: In a randomized, double-blind study, healthy middle-aged participants received a dark chocolate drink mix standardized to contain 500 mg, 250 mg or 0 mg of polyphenols (placebo) in a parallel-groups design.

polyphenols


Input: Participants consumed their assigned treatment once daily for 30 days.


Input: Cognition was measured with the Cognitive Drug Research system and self-rated mood with the Bond-Lader Visual Analogue Scale.


Input: Participants were tested at baseline, at 1, 2. 5 and 4 h after a single acute dose and again after receiving 30 days of treatment.


Input: In total, 72 participants completed the trial.


Input: After 30 days, the high dose of treatment significantly increased self-rated calmness and contentedness relative to placebo.


Input: Mood was unchanged by treatment acutely while cognition was unaffected by treatment at all time points.


Input: This randomized controlled trial is perhaps the first to demonstrate the positive effects of cocoa polyphenols on mood in healthy participants.

polyphenols


Input: This provides a rationale for exploring whether cocoa polyphenols can ameliorate the symptoms associated with clinical anxiety or depression.

polyphenols


Input: Opiate agonists and antagonists modulate taste perception in opiate-maintained and recently detoxified subjects.


Input: Heroin addicts consume large quantities of refined sugars.

Heroin

sugars


Input: This study investigated the effect of opiate use and antagonism on sweet taste in opiate-maintained drug users and detoxified former chronic opiate users, using a within-subject design.


Input: Seven opiate users received methadone and seven buprenorphine maintenance.

methadone

buprenorphine


Input: Six detoxified subjects received naltrexone.

naltrexone


Input: Sucrose recognition thresholds and measurements of pleasantness and intensity were determined before and four hours after 1) a single dose of methadone or buprenorphine or 2) naltrexone.

Sucrose

methadone

buprenorphine

naltrexone


Input: Control data were taken from a cohort of healthy volunteers including smokers.


Input: All measures of sweet and salt taste perception were significantly greater in opiate users and recently detoxified subjects compared to control subjects, with the exception of sweet pleasantness, which returned to control level after detoxification.


Input: Acute methadone administration reduced salt thresholds and unpleasantness to control levels.

methadone


Input: Increased sweet thresholds and salt unpleasantness in detoxified subjects were reversed by acute opioid antagonism, returning to control levels.


Input: These results suggest that opiate use and antagonism alters taste perception.


Input: Some of the alterations reverse on detoxification (sweet pleasantness), and others can be reversed by opioid antagonism (sweet threshold, salt unpleasantness).


Input: Changes in taste perception may underlie altered consumption of refined sugars in opiate users.

sugars


Input: Heracleifolinosides A-F, new triterpene glycosides from Cimicifuga heracleifolia, and their inhibitory activities against hypoxia and reoxygenation.

Heracleifolinosides A-F

triterpene glycosides


Input: Six new 9, 19-cycloartane triterpene glycosides, heracleifolinosides A-F (1-6), and one new chromone, norkhelloside (7), were isolated from the rhizome of Cimicifuga heracleifolia, together with 15 known compounds (8-22).

9, 19-cycloartane triterpene glycosides

heracleifolinosides A-F

norkhelloside


Input: The structures of the new compounds were elucidated by means of spectroscopic methods including 2D NMR and mass spectrometry.


Input: The extracts of C. heracleifolia and all the isolated compounds were tested for activities against hypoxia and reoxygenation injury in human umbilical vein endothelial cells.


Input: Heracleifolinoside B (2) is effectively resistant to hypoxia and reoxygenation-induced human umbilical vein endothelial cell injury, with cell viabilities of 61. 95 +/- 2. 04%, 77. 04 +/- 4. 44%, and 83. 65 +/- 3. 29% at concentrations of 1, 10, and 100 micro M, respectively.

Heracleifolinoside B


Input: Model for conformational relaxation of flexible conjugated polymers: application to p-phenylenevinylene trimers in nonpolar solvents.

p-phenylenevinylene trimers


Input: Photoexcitation of flexible conjugated polymers is invariably followed by a fast conformational/torsional relaxation towards a configuration favouring coplanarity of the conjugated segments.


Input: In general, the experimental relaxation rate constant (k (CR)) depends on the solvent viscosity (eta) and temperature (T), and is not proportional to T/eta.


Input: A theory capable of explaining the observed dependence of k (CR) on T and eta over a wide range of these variables is not available.


Input: This gap is filled here by presenting a stochastic model that includes the participation of the oligomer side chain in storing and dissipating the stresses induced by photoexcitation.


Input: The model is able to account for the softening of solute-solvent interactions and its predictions are found to be in excellent agreement with the observed relaxation rate constants of a series of substituted p-phenylenevinylene trimers [ChemPhysChem 2009, 10, 448-454] on T, eta and the size of the side-chains.

p-phenylenevinylene trimers


Input: A method to predict and understand fish survival under dynamic chemical stress using standard ecotoxicity data.


Input: The authors present a method to predict fish survival under exposure to fluctuating concentrations and repeated pulses of a chemical stressor.


Input: The method is based on toxicokinetic-toxicodynamic modeling using the general unified threshold model of survival (GUTS) and calibrated using raw data from standard fish acute toxicity tests.


Input: The model was validated by predicting fry survival in a fish early life stage test.


Input: Application of the model was demonstrated by using Forum for Co-ordination of Pesticide Fate Models and Their Use surface water (FOCUS-SW) exposure patterns as model input and predicting the survival of fish over 485 d.


Input: Exposure patterns were also multiplied by factors of five and 10 to achieve higher exposure concentrations for fish survival predictions.


Input: Furthermore, the authors quantified how far the exposure profiles were below the onset of mortality by finding the corresponding exposure multiplication factor for each scenario.


Input: The authors calculated organism recovery times as additional characteristic of toxicity as well as number of peaks, interval length between peaks, and mean duration as additional characteristics of the exposure pattern.


Input: The authors also calculated which of the exposure patterns had the smallest and largest inherent potential toxicity.


Input: Sensitivity of the model to parameter changes depends on the exposure pattern and differs between GUTS individual tolerance and GUTS stochastic death.


Input: Possible uses of the additional information gained from modeling to inform risk assessment are discussed.


Input: Inhibitors of JAK2 and JAK3: an update on the patent literature 2010-2012.


Input: INTRODUCTION: Janus kinases (JAKs) comprise a family of four enzymes, JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2), centrally implicated in cell signaling processes important in cancer and immune-inflammatory diseases.

tyrosine


Input: Progression in the field has taken a recent step forward with the approval of ruxolitinib (Jakafi), a selective inhibitor of JAK1/2 and very recently tofacitinib (Xeljanz), a pan-JAK inhibitor.

ruxolitinib

Jakafi

tofacitinib

Xeljanz


Input: There are many new JAK family enzyme inhibitors in the clinic now with a range of selectivity profiles.


Input: More selective JAK2 or JAK3 compounds are now coming through in considerable numbers and this review attempts to provide an update of the recent patent literature of those new compounds.


Input: An overview is given on the diversity of core structures employed for inhibitor design showing that the vast majority of compounds are based on classic ATP-competitive kinase inhibitor heterocycles.

ATP


Input: AREAS COVERED: This review updates new patents claiming JAK2 and/or JAK3 inhibitors published from 2010 to 2012.


Input: Pre-2010 patents have been extensively covered in previous reviews.


Input: Comments on the context of each chemical series are given where applicable to orientate the readers on the bewildering array of molecular designs now available.


Input: This review does not cover JAK1 or TYK2 inhibitors but mention is made of these where they occur within series of JAK2/3 inhibitors.


Input: Given the overlap between many pharmacophores, it was not possible to completely separate inhibitors of JAK2 from JAK3, hence the material is organized by JAK2, JAK3 and JAK2/3 and within each section by alphabetical order of the patent assignee, some companies having published five or more patents, such as Ambit (10), Incyte (9), Galapagos (7), Almirall (6) and Biocryst (5).


Input: A total of 98 patents are reviewed herein.


Input: EXPERT OPINION: JAK inhibitor therapy is entering a significant new era with the advent on the market of the JAK1/2 inhibitor ruxolitinib and the pan-JAK inhibitor tofacitinib, with unprecedented speed of development.

ruxolitinib

tofacitinib


Input: Selectivity against the four individual JAK family enzymes, JAK1, 2, 3 and TYK2, is now a key goal since they each play subtly different roles in cytokine-induced cell signaling.


Input: The future looks bright for patients as many new drugs are being developed and now combinations of JAK inhibitors with other targeted agents are being studied in the clinic.


Input: These advances are expected to lead to further significant progress improving patient outcomes and quality of life.


Input: Stereochemical control of polymorph transitions in nanoscale reactors.


Input: Crystallization of glycine in the cylindrical nanopores of anodic aluminum oxide (AAO) revealed the formation of metastable beta-glycine in pores having diameters less than 200 nm.

glycine

aluminum oxide

AAO

beta-glycine


Input: Two-dimensional X-ray microdiffraction indicated that the [010] axis of the embedded beta-glycine nanocrystals coincided with the pore direction, identical to behavior observed previously in the cylindrical nanopores of polymer monoliths.

beta-glycine


Input: Whereas the beta-glycine nanocrystals were stable indefinitely in ambient air and persisted upon heating, they transformed to the alpha polymorph upon standing at room temperature and 90% relative humidity (RH).

beta-glycine


Input: The alpha-glycine nanocrystals were oriented with the [010] axis nearly perpendicular to the pore direction, reflecting a nearly 90 degrees rotation of the glycine molecules during the transition.

alpha-glycine

glycine


Input: When the beta-glycine nanocrystals were formed in the AAO cylinders in the presence of small amounts of racemic hydrophobic amino acid auxiliaries, which are known to bind selectively to the (010) and (010) faces on the fast-growing end of beta-glycine enantiomorphs, the beta --> alpha phase transition at 90% RH was suppressed.

beta-glycine

AAO

amino acid

beta-glycine


Input: In contrast, beta-glycine nanocrystals grown in the presence of an enantiopure amino acid auxiliary, which binds to the fast-growing end of only one of the enantiomorphs, thus suppressing its formation and leaving the other enantiomorph unperturbed, transformed into the alpha polymorph under the same conditions.

beta-glycine

amino acid


Input: This observation confirms that binding of an amino acid to the {010} faces is stereoselective and that access of water to these faces is essential for the transition to the alpha polymorph.

amino acid


Input: The impact of functionalization on the stability, work function, and photoluminescence of reduced graphene oxide.

reduced graphene oxide


Input: Reduced graphene oxide (rGO) is a promising material for a variety of thin-film optoelectronic applications.

Reduced graphene oxide

rGO


Input: Two main barriers to its widespread use are the lack of (1) fabrication protocols leading to tailored functionalization of the graphene sheet with oxygen-containing chemical groups, and (2) understanding of the impact of such functional groups on the stability and on the optical and electronic properties of rGO.

graphene

oxygen

rGO


Input: We carry out classical molecular dynamics and density functional theory calculations on a large set of realistic rGO structures to decompose the effects of different functional groups on the stability, work function, and photoluminescence.

rGO


Input: Our calculations indicate the metastable nature of carbonyl-rich rGO and its favorable transformation to hydroxyl-rich rGO at room temperature via carbonyl-to-hydroxyl conversion reactions near carbon vacancies and holes.

carbonyl

rGO

hydroxyl

rGO

carbonyl

hydroxyl

carbon


Input: We demonstrate a significant tunability in the work function of rGO up to 2. 5 eV by altering the composition of oxygen-containing functional groups for a fixed oxygen concentration, and of the photoluminescence emission by modulating the fraction of epoxy and carbonyl groups.

rGO

oxygen

oxygen

epoxy

carbonyl


Input: Taken together, our results guide the application of tailored rGO structures in devices for optoelectronics and renewable energy.

rGO


Input: The contrasting activity of iodido versus chlorido ruthenium and osmium arene azo-and imino-pyridine anticancer complexes: control of cell selectivity, cross-resistance, p53 dependence, and apoptosis pathway.

iodido

chlorido ruthenium

osmium arene azo-and imino-pyridine


Input: Organometallic half-sandwich complexes [M (p-cymene) (azo/imino-pyridine) X] (+) where M = Ru (II) or Os (II) and X = Cl or I, exhibit potent antiproliferative activity toward a range of cancer cells.

[M (p-cymene) (azo/imino-pyridine) X] (+)

M = Ru (II) or Os (II)

X = Cl or I


Input: Not only are the iodido complexes more potent than the chlorido analogues, but they are not cross-resistant with the clinical platinum drugs cisplatin and oxaliplatin.

iodido

chlorido

platinum

cisplatin

oxaliplatin


Input: They are also more selective for cancer cells versus normal cells (fibroblasts) and show high accumulation in cell membranes.


Input: They arrest cell growth in G1 phase in contrast to cisplatin (S phase) with a high incidence of late-stage apoptosis.

cisplatin


Input: The iodido complexes retain potency in p53 mutant colon cells.

iodido


Input: All complexes activate caspase 3.


Input: In general, antiproliferative activity is greatly enhanced by low levels of the glutathione synthase inhibitor l-buthionine sulfoxime.

glutathione

l-buthionine sulfoxime


Input: The work illustrates how subtle changes to the design of low-spin d (6) metal complexes can lead to major changes in cellular metabolism and to potent complexes with novel mechanisms of anticancer activity.


Input: Metastable Cu (I)-niobate semiconductor with a low-temperature, nanoparticle-mediated synthesis.

Cu (I)


Input: A nanoparticle synthetic strategy for the preparation of a new metastable Cu (I)-niobate is described, and that involves multipored Li 3 NbO 4 nanoparticles as a precursor.

Cu (I)

niobate

Li 3 NbO 4


Input: A hydrothermal reaction of HNbO 3 and LiOH. H 2 O in PEG200 and water at ~ 180 degrees C yields ~ 15-40 nm Li 3 NbO 4 particles.

HNbO 3

LiOH. H 2 O

Li 3 NbO 4


Input: These particles are subsequently used in a solvothermal copper (I)-exchange reaction with excess CuCl at 150 degrees C.

copper (I)

CuCl


Input: Heating these products within the used CuCl flux (mp = 430 degrees C) to 450 degrees C for 30 min yields ~ 4-12 nm Cu 2 Nb 8 O 2 1 crystalline nanoparticles, and for a heating time of 24 h yields mu m-sized, rod-shaped crystals.

CuCl

Cu 2 Nb 8 O 2 1


Input: The new structure was characterized by single-crystal X-ray diffraction to have a condensed network consisting of NbO 7 polyhedra and chains of elongated CuO 4 tetrahedra.

NbO 7

CuO 4


Input: The compound thermally decomposes starting at ~ 250 degrees C and higher temperatures, depending on the particle sizes, owing to the loss of the weakly coordinated Cu (I) cations from the structure and a concurrent disproportionation reaction at its surfaces.

Cu (I)


Input: Thus, conventional solid-state reactions involving higher temperatures and bulk reagents have proven unsatisfactory for its synthesis.


Input: The measured bandgap size is ~ 1. 43-1. 65 eV (indirect) and shows a dependence on the particle sizes.


Input: Electronic structure calculations based on density functional theory show that the bandgap transition results from the excitation of electrons at the band edges between filled Cu (I) 3d (1) 0-orbitals and empty Nb (V) 4d 0-orbitals, respectively.

Cu (I)

Nb (V)


Input: The p-type nature of the Cu 2 Nb 8 O 2 1 particles was confirmed in photoelectrochemical measurements on polycrystalline films that show a strong photocathodic current under visible-light irradiation in aqueous solutions.

Cu 2 Nb 8 O 2 1


Input: These results demonstrate the general utility of reactive nanoscale precursors in the synthetic discovery of new Cu (I)-based semiconducting oxides and which also show promise for use in solar energy conversion applications.

Cu (I)

oxides


Input: Self-assembly of symmetric brush diblock copolymers.


Input: Self-assembled structures of brush block copolymers (BrBCPs) with polylactide (PLA) and polystyrene (PS) side chains were studied.

polylactide

PLA

polystyrene


Input: The polynorbornene-backbone-based BrBCPs containing approximately equal volume fractions of each block self-assembled into highly ordered lamellae with domain spacing ranging from 20 to 240 nm by varying molecular weight of the backbone in the bulk state, as revealed by small-angle X-ray scattering (SAXS).

polynorbornene


Input: The domain size increased approximately linearly with backbone length, which indicated an extended conformation of the backbone in the ordered state.


Input: In situ SAXS measurements suggested that the BrBCPs self-assemble with an extremely fast manner which could be attributed to a reduced number of entanglements between chains.


Input: The strong segregation theory and Monte Carlo simulation also confirmed this near-linear dependence of the domain spacing on backbone length, rationalizing experimental results.


Input: Structures and cytotoxic evaluation of new and known acyclic Ene-Ynes from an American Samoa Petrosia sp.


Input: Sponge.


Input: Four new compounds, (-)-petrosynoic acids A-D (1-4), and five known congeners, pellynols A (5), C (6), D (7), F (8), and I (9), were isolated from a Petrosia sp. marine sponge collected in American Samoa.

(-)-petrosynoic acids A-D

pellynols A (5), C (6), D (7), F (8), and I


Input: Isolation work was guided by cytotoxicity against human lung cancer cells (H460).


Input: The structures of the C31-C33 polyacetylenes (1-9) were determined on the basis of 1D-and 2D-NMR analysis, mass spectrometry, and comparison of specific rotation values.

C31-C33 polyacetylenes


Input: Compounds 1-9 were found to be broadly cytotoxic with limited selectivity for cancer cells, as they were all moderately active against the A2058 (melanoma), H522-T1 (lung), and H460 (lung) human cancer cell lines as well as IMR-90 quiescent human fibroblast cells.


Input: pH-dependent motion of self-propelled droplets due to Marangoni effect at neutral pH.


Input: Oil droplets loaded with surfactant propel themselves with a velocity up to 6 mm s (-1) when they are placed in an aqueous phase of NaOH solution or buffer solution.

NaOH


Input: The required driving force for such motion is generated on the interface of the droplets by the change in interfacial tension, due to deprotonation of the surfactant.


Input: This force induces Marangoni convection, which gives rise to a circulating flow inside the droplets.


Input: The droplets begin to move when the axis of this circulation deviates from the vertical line.


Input: This motion depends on the pH condition of the aqueous phase.


Input: When the initial value of pH is adjusted such that the pH exceeds the threshold at the equilibrium state, the droplets move spontaneously.


Input: It was seen that the droplets were independent of the material of the solid substrates because the droplets were not directly in contact with the surface of the substrate.


Input: The condition for the onset of this spontaneous motion was verified by comparing the prediction from the linear stability analysis with experiments.


Input: The stability analysis overestimates the value of the driving force, causing instability.


Input: Synthesis and characterization of a matrix-metalloproteinase responsive silk-elastinlike protein polymer.


Input: Silk-elastinlike protein polymers (SELPs) are recombinant polymers consisting of tandem repeats of silk (GAGAGS) and elastin (GVGVP) units.


Input: By modification of the length and composition of these repeats, the properties of SELP hydrogels can be controlled for specific applications including nucleic acid and virus delivery and tissue engineering.


Input: Here, the structure of SELPs is further modified to include a sequence that is sensitive to matrix-metalloproteinases (MMPs).


Input: MMPs are a ubiquitous family of extracellular matrix-modifying enzymes that are commonly associated with numerous vital processes.


Input: Increased levels of MMPs are found at high levels locally in many types of solid tumors.


Input: By modifying the SELP backbone with MMP-sensitive peptide sequences, a hydrogel that is degradable by MMPs was produced.


Input: The MMP-sensitivity of the polymer was examined by incubation with MMP-2 and MMP-9, which yielded complete cleavage of all full-length polymers by 36 hours and 48 hours, respectively, with no observable effect on unmodified SELP.


Input: Hydrogel sensitivity was tested by exposure to MMP-2 or MMP-9 for 2 weeks, during which samples were taken to analyze protein loss from the hydrogel and release of 100 nm fluorescent beads.


Input: Following the incubation period, hydrogels were tested in mechanical compression to examine the loss of hydrogel stiffness due to degradation.


Input: It was found that MMP-2 and MMP-9 caused 63% and 44% increased protein loss and 65% and 95% increased release from MMP-sensitive hydrogels, while the compressive modulus decreased by 41% and 29%.


Input: These results suggest the potential of MMP-responsive SELPs for localized delivery of bioactive agents where MMPs are overexpressed.


Input: Biobased polyesters with composition-dependent thermomechanical properties: synthesis and characterization of poly (butylene succinate-co-butylene azelate).

polyesters

poly (butylene succinate-co-butylene azelate)


Input: Environmentally friendly poly (butylenesuccinate-co-butyleneazelate) (P (BS-co-BAz) s) aliphatic copolyesters with composition-dependent thermomechanical properties were synthesized from succinic acid (SuA), 1, 4-butanediol (BDO), and dimethylazelate (DMAz) through a two-step polycondensation reaction.

poly (butylenesuccinate-co-butyleneazelate)

P (BS-co-BAz) s

aliphatic copolyesters

succinic acid

SuA

1, 4-butanediol

BDO

dimethylazelate

DMAz


Input: The molar SuA/AzA ratio was varied from 4: 1 to 1: 4, and the chemical structure and molecular characteristics of resulting (co) polyesters were characterized by NMR and SEC, whereas thermal properties and crystallinity were studied by differential scanning calorimetry (DSC), dynamic mechanical thermal analyses (DMTA), and X-ray diffraction (XRD).

SuA

AzA

(co) polyesters


Input: A good agreement between theoretical and experimental SuA/AzA molar ratios in the copolyesters was achieved, together with the recovery of semicrystalline random copolymers of uniform composition along the chains.

SuA

AzA

copolyesters


Input: NMR, DSC, DMTA, and XRD results show that depending on their composition the P (BS-co-BAz) copolyesters might find applications from elastomers to high-impact thermoplastics.

P (BS-co-BAz) copolyesters


Input: Formulation, in vitro evaluation and study of variables on tri-layered gastro-retentive delivery system of diltiazem HCl.

diltiazem HCl


Input: Abstract Context: Tri-layered floating tablets using only one grade of polyethylene oxide (PEO) would enable easy manufacturing, reproducibility and controlled release for highly soluble drugs.

polyethylene oxide

PEO


Input: Objective: To evaluate the potential of PEO as a sole polymer for the controlled release and to study the effect of formulation variables on release and gastric retention of highly soluble Diltiazem hydrochloride (DTZ).

PEO

Diltiazem hydrochloride

DTZ


Input: Methods: Tablets were compressed with middle layer consisting of drug and polymer while outer layers consisted of polymer with sodium bicarbonate.

sodium bicarbonate


Input: Design of formulation to obtain 12 h, zero-order release and rapid floatation was done by varying the grades, quantity of PEO and sodium bicarbonate.

PEO

sodium bicarbonate


Input: Dissolution data were fitted in drug release models and swelling/erosion studies were undertaken to verify the drug release mechanism.


Input: Effect of formulation variables and tablet surface morphology using scanning electron microscopy were studied.


Input: Results and discussion: The optimized formula passed the criteria of USP dissolution test I and exhibited floating lag-time of 3-4 min.


Input: Drug release was faster from low molecular weight (MW) PEO as compared to high MW.

PEO


Input: With an increase in the amount of sodium bicarbonate, faster buoyancy was achieved due to the increased CO (2) gas formation.

sodium bicarbonate

CO (2)


Input: Drug release followed zero-order and gave a good fit to the Korsmeyer-Peppas model, which suggested that drug release was due to diffusion through polymer swelling.


Input: Conclusion: Zero-order, controlled release profile with the desired buoyancy can be achieved by using optimum formula quantities of sodium bicarbonate and polymer.

sodium bicarbonate


Input: The tri-layered system shows promising delivery of DTZ, and possibly other water-soluble drugs.

DTZ


Input: Recent progress and challenges in the discovery of new neuraminidase inhibitors.


Input: INTRODUCTION: At present, the key public health concern is to define the way in which the next influenza pandemic should be controlled.


Input: While influenza vaccines are available, their effectiveness could be significantly reduced if new strains differ significantly from those of the vaccines.


Input: Therefore, antiviral drugs play an important role in the prevention and management of influenza.


Input: The influenza neuraminidase (NA), a surface-glycoprotein enzyme involved in releasing the virus from the host cell, has been considered as an essential therapeutic target for treatment and prophylaxis of influenza infection.


Input: It is a highly conserved feature of the active site across all influenza A and B viruses and is of particular interest because compounds NA inhibitors (NAIs) can be cross-reactive against multiple types and subtypes of influenza.


Input: Currently, there are two NAI drugs which are licensed worldwide: oseltamivir and zanamivir, and two more drugs which have received recent approval in Japan: peramivir and laninamivir.

oseltamivir

zanamivir

peramivir

laninamivir


Input: Sudden changes in NAI susceptibility have stressed the urgent need in searching for novel inhibitors.


Input: AREAS COVERED: In this review, a potential pitfall in NA-based assays and the progress in the chemical synthesis of all patented NAIs from February 2006 to July 2012 are discussed.


Input: EXPERT OPINION: Both NA enzyme inhibition and X-ray crystallography data have suggested that the strategy of designing NAIs binding to the highly conserved region of NA can lead to inhibitors that are effective against all influenza NA subtypes.


Input: A number of new synthetic entries having unique structural frameworks that were designed based on computational study of X-ray structures of NA.


Input: They strongly exhibited the activity of NA in the low nanomolar range such as phosphonate congeners of zanamivir and oseltarmivir.

phosphonate

zanamivir

oseltarmivir


Input: Screening strategies based on the chemical diversity of natural products have revealed that flavonoids are the most prominent scaffolds possessing NA inhibitory activity.

flavonoids


Input: However, these substituted phenyl-benzopyrane compounds have been reported to exert a considerable quenching effect, causing false-positive results in the commonly used method of enzyme-based NA inhibition assays, and thus, reliability of the flavonoid-based NAIs reported in the literature.

phenyl-benzopyrane

flavonoid


Input: Liver, plasma and erythrocyte levels of thiamine and its phosphate esters in rats with acute ethanol intoxication: a comparison of thiamine and benfotiamine administration.

thiamine

phosphate esters

ethanol

thiamine

benfotiamine


Input: Thiamine and benfotiamine are vitamin B1 and pro-vitamin B1 substances, respectively.

Thiamine

benfotiamine

vitamin B1

pro-vitamin B1


Input: Vitamin B1 plays an essential role in energy metabolism, and its deficiency leads to neurologic and cardiovascular pathologies, as seen in alcoholics.

Vitamin B1

alcoholics


Input: This study presents new data about the effects of thiamine hydrochloride or benfotiamine treatment given to rats with acute alcohol intoxication, on the distribution of thiamine and its phosphate esters in liver, plasma and erythrocytes.

thiamine hydrochloride

benfotiamine

alcohol

thiamine

phosphate esters


Input: The treatments were effective in increasing thiamine levels in plasma, erythrocytes and liver cells.

thiamine


Input: The benfotiamine-treated group had its total plasma thiamine increased by 100%.

benfotiamine

thiamine


Input: In erythrocytes, thiamine levels were 4-and 25-fold higher in the groups treated with thiamine and benfotiamine, respectively, compared with the untreated groups.

thiamine

thiamine

benfotiamine


Input: Liver thiamine was increased by 60% in the treated groups compared with the untreated groups.

thiamine


Input: Thus, we verified the high bioavailability especially of benfotiamine within 6h of ethanol administration.

benfotiamine

ethanol


Input: Short-term assessment of toxicological aspects, oxidative and inflammatory response to dietary melon superoxide dismutase in rats.

superoxide


Input: The protective effects of SODB, a gastro-resistant encapsulated melon superoxide dismutase, on haematological and biochemical parameters and inflammatory and oxidative status, were evaluated in the blood and liver tissue.

superoxide


Input: The study consisted in a 28-day experiment on rats supplemented with three doses (10, 40 and 160USOD/day) of SODB-M, SODB-D or SODB-S, different depending on the nature of the coating (palm oil, shellac or gum Arabic respectively).


Input: No mortality, abnormal clinical signs, behavioural changes or macroscopic findings were observed whatever the groups.


Input: Haematological parameters (total red blood cell count, haemoglobin content, haematocrit, red cell indices, white blood cell count and platelets count) were not modified in SODB treated-groups.


Input: No marked change was recorded in biochemical parameters (plasma urea, creatinine, lipids, electrolytes, bilirubin, transaminases and gamma-glutamyl transferase).

urea

creatinine

bilirubin

gamma-glutamyl


Input: The liver endogenous antioxidant enzymes (copper/zinc and manganese superoxide dismutase) expressions were significantly increased in the rats receiving the highest dose of SODB (160USOD/day) whatever the coating.

copper

zinc

manganese superoxide


Input: Moreover, interleukin-6, a marker of inflammation, was significantly decreased in these high dose-treated-groups.


Input: The present study indicates that dietary supplementation of SODB on rats has no harmful side effects and could be beneficial especially at high doses.


Input: Anti-oxidant and natural killer cell activity of Korean red ginseng (Panax ginseng) and urushiol (Rhus vernicifera Stokes) on non-alcoholic fatty liver disease of rat.

urushiol


Input: Anti-oxidative and immunologic effects of the Korea red ginseng (KRG; Panax ginseng) and urushiol (Rhus vernicifera Stokes) on non-alcoholic fatty liver disease (NAFLD) were evaluated.

urushiol


Input: Forty-five rats (five Long-Evans Tokushima Otsuka and 40 Otsuka Long-Evans Tokushima Fatty [OLETF] rats) received chew diets for 10months; after this period.


Input: The OLETF rats were divided into the following four groups according to diet for 2months: NAFLD (chew), KRG (chew + KRG [200mg/kg/day]), urushiol (chew + urushiol [0. 5mg/kg/day]), and ursodeoxycholic acid (UDCA) (chew + UDCA [15mg/kg/day]) groups.

urushiol

urushiol

ursodeoxycholic acid

UDCA

UDCA


Input: Liver function, lipid profiles and anti-oxidant activity of liver and serum, natural killer (NK) cell activity, and pathology were compared.


Input: In KRG and urushiol groups, the level of serum triglyceride ([302. 0 +/- 70. 4 and 275. 2 +/- 63. 8] vs. 527. 7 +/- 153. 3mg/dL) were lower compared with that of NAFLD group (p < 0. 05).

urushiol

triglyceride


Input: The levels of HDL-cholesterol (liver tissue: [4. 8 +/- 0. 2 and 4. 8 +/- 0. 5] vs. 4. 2 +/- 0. 2mg/g) and NK cell activity ([3485 +/- 910 and 3559 +/- 910] vs. 2486 +/- 619 counts) were significantly higher than those of the NAFLD group (p < 0. 001).

cholesterol


Input: Inflammation with neutrophil infiltration was observed in only two rats in the NAFLD group.


Input: These results suggest that 2months of oral KRG or urushiol administration improves lipid profiles and stimulates NK cell activity, while inhibiting steatohepatitis in OLEFT rats.

urushiol


Input: TNF alpha and Fas/FasL pathways are involved in 9-Methoxycamptothecin-induced apoptosis in cancer cells with oxidative stress and G2/M cell cycle arrest.


Input: 9-Methoxycamptothecin (MCPT) has been recently reported to have a strong anticancer activity.

MCPT


Input: However, its detailed mechanism of action in human cancer cells has not been well clarified.


Input: The results showed that MCPT induced cytotoxicity in seven human cancer cell lines in a dose dependent manner after 72h, with A2780 and Hela cell lines more sensitive, so the two cell lines were chosen to do further studies.

MCPT


Input: MCPT induced strong G2/M arrest in both A2780 cells and Hela cells after 24h, following by substantial sub-G1 arrest (indicating apoptosis).

MCPT


Input: The apoptosis was verified by staining with Annexin V-FITC and propidium iodide.

FITC

propidium iodide


Input: ROS generation increased significantly in MCPT-induced apoptosis.

MCPT


Input: Meanwhile, the apoptosis appeared to be dependent on caspase-3,-8 and-9 in A2780 cells, and caspase-3 in Hela cells.


Input: In addition, MCPT induced up-regulation expression of most of seventeen genes in both cell lines.

MCPT


Input: Western blot verified that changes of TNF alpha, Fas, P53 and P27 protein level were consistent with their gene expression changes.


Input: Taken together, MCPT plays an important role in tumor growth suppression by inducing apoptosis in both cell lines via extrinsic and intrinsic apoptotic pathways, and has the potential to be developed into an antitumor agent.

MCPT


Input: Hierarchical organization of osteoblasts reveals the significant role of CD166 in hematopoietic stem cell maintenance and function.


Input: The role of osteoblasts (OB) in maintaining hematopoietic stem cells (HSC) in their niche is well elucidated, but the exact definition, both phenotypically and hierarchically of OB responsible for these functions is not clearly known.


Input: We previously demonstrated that OB maturational status influences HSC function whereby immature OB with high Runx2 expression promote hematopoietic expansion.


Input: Here, we show that Activated Leukocyte Cell Adhesion Molecule (ALCAM) or CD166 expression on OB is directly correlated with Runx2 expression and high hematopoiesis enhancing activity (HEA).


Input: Fractionation of OB with lineage markers: Sca1, osteopontin (OPN), CD166, CD44, and CD90 revealed that Lin-Sca1-OPN + CD166 + cells (CD166 +) and their subpopulations fractionated with CD44 and CD90 expressed high levels of Runx2 and low levels of osteocalcin (OC) demonstrating the relatively immature status of these cells.


Input: Conversely, the majority of the Lin-Sca1-OPN + CD166-cells (CD166-) expressed high OC levels suggesting that CD166-OB are more mature.


Input: In vitro hematopoietic potential of LSK cells co-cultured for 7days with fresh OB or OB pre-cultured for 1, 2, or 3 weeks declined precipitously with increasing culture duration concomitant with loss of CD166 expression.


Input: Importantly, LSK cells co-cultured with CD166 + CD44 + CD90 + OB maintained their in vivo repopulating potential through primary and secondary transplantation, suggesting that robust HEA activity is best mediated by immature CD166 + OB with high Runx2 and low OC expression.


Input: These studies begin to define the hierarchical organization of osteoblastic cells and provide a more refined definition of OB that can mediate HEA.


Input: Alteration of proteoglycan sulfation affects bone growth and remodeling.


Input: Diastrophic dysplasia (DTD) is a chondrodysplasia caused by mutations in the SLC26A2 gene, leading to reduced intracellular sulfate pool in chondrocytes, osteoblasts and fibroblasts.

sulfate


Input: Hence, proteoglycans are undersulfated in the cartilage and bone of DTD patients.


Input: To characterize the bone phenotype of this skeletal dysplasia we used the Slc26a2 knock-in mouse (dtd mouse), that was previously validated as an animal model of DTD in humans.


Input: X-rays, bone densitometry, static and dynamic histomorphometry, and in vitro studies revealed a primary bone defect in the dtd mouse model.


Input: We showed in vivo that this primary bone defect in dtd mice is due to decreased bone accrual associated with a decreased trabecular and periosteal appositional rate at the cell level in one month-old mice.


Input: Although the osteoclast number evaluated by histomorphometry was not different in dtd compared to wild-type mice, urine analysis of deoxypyridinoline cross-links and serum levels of type I collagen C-terminal telopeptides showed a higher resorption rate in dtd mice compared to wild-type littermates.

deoxypyridinoline

C


Input: Electron microscopy studies showed that collagen fibrils in bone were thinner and less organized in dtd compared to wild-type mice.


Input: These data suggest that the low bone mass observed in mutant mice could possibly be linked to the different bone matrix compositions/organizations in dtd mice triggering changes in osteoblast and osteoclast activities.


Input: Overall, these results suggest that proteoglycan undersulfation not only affects the properties of hyaline cartilage, but can also lead to unbalanced bone modeling and remodeling activities, demonstrating the importance of proteoglycan sulfation in bone homeostasis.


Input: APE1/Ref-1 prevents oxidative inactivation of ERK for G1-to-S progression following lead acetate exposure.

lead acetate


Input: Apurinic/apyrimidinic endonuclease 1 (APE1)/redox effector factor-1 is a multifunctional enzyme involved in DNA base excision repair and protein redox regulation.


Input: Previously, we have showed that lead acetate (Pb) elicits EGFR activation to initiate the SFK/PKC alpha/Ras/Raf-1/MKK1/2/ERK signaling cascade functioning against genotoxicity.

lead acetate

Pb


Input: Here, we explore whether APE1 and reactive oxygen species (ROS) affect ERK signaling and cell cycle progression following Pb exposure.

oxygen

Pb


Input: We found that Pb induced APE1 expression and ROS generation in CL3 human lung cancer cells.

Pb


Input: The Pb-elicited ROS levels and cytotoxicity were further enhanced by introducing small interfering RNA specific for APE1 (siAPE1).

Pb


Input: E3330, an inhibitor of APE1 redox activity, also augmented the ROS levels and cytotoxicity in Pb-treated cells.

Pb


Input: Intriguingly, the capability of Pb to activate ERK was abolished under siAPE1 or E3330 co-treatments; conversely, forced expression of APE1 up-regulated the ERK activation by Pb or serum in both Cys65-redox activity dependent and independent manners.

Pb

Pb


Input: Moreover, APE1 formed complex with ERK2, and its redox activity could rescue ERK oxidative inactivation.


Input: APE1 redox activity also facilitated the Cyclin D1 expression and G1-to-S progression following Pb exposure.

Pb


Input: In summary, the results indicate that APE1 is a direct redox regulator of ERK for maintaining the kinase activity to promote cell proliferation.


Input: Synthesis, quantitative structure-activity relationship and biological evaluation of 1, 3, 4-oxadiazole derivatives possessing diphenylamine moiety as potential anticancer agents.

1, 3, 4-oxadiazole

diphenylamine


Input: Synthesis of 2, 5-disubstituted-1, 3, 4-oxadiazole (2a-c), 3-substituted aminomethyl-5-substituted-1, 3, 4-oxadiazole-2 (3H)-thione (4a-m) and 2-substituted thio-5-substituted-1, 3, 4-oxadiazole (5a, b) had been described.

2, 5-disubstituted-1, 3, 4-oxadiazole

3-substituted aminomethyl-5-substituted-1, 3, 4-oxadiazole-2 (3H)-thione

2-substituted thio-5-substituted-1, 3, 4-oxadiazole


Input: All the synthesized derivatives were screened for anticancer activity against HT29 and MCF7 cancer cell lines using Sulfo-Rodamine B (SRB) standard method.

Sulfo-Rodamine B

SRB


Input: Most of the tested compounds exploited potent antiproliferative activity against HT29 cancer cell line rather than MCF7 cancer cell line.


Input: Compounds 2a-c, 4f and 5a exhibited potent cytotoxicity (IC (50) 1. 3-2. 0 micro M) and selectivity against HT29 cancer cell line.


Input: Quantitative structure-activity relationship (QSAR) study was applied to find a correlation between the experimental antiproliferative activities of the newly synthesized oxadiazole derivatives with their physicochemical parameter and topological index.

oxadiazole


Input: Statistical modeling, optimization and characterization of spray-dried solid self-microemulsifying drug delivery system using design of experiments.


Input: The present study systematically and simultaneously investigates the influence of process variables of spray-drying on the properties of solid self-microemulsifying drug delivery system (SMEDDS) using design of experiment (DOE) and optimizes them in order to produce solid-SMEDDS satisfying pre-defined powder quality attributes.


Input: Flurbiprofen-loaded liquid-SMEDDS was dispersed in dextran and spray-dried.

Flurbiprofen


Input: After preliminary screening, the independent factors selected according to three-factor, three-level Box-Behnken design were inlet temperature (X (1)), feed rate (X (2)) and carrier concentration (X (3)).


Input: The responses used to compute the effects of independent factors were moisture content (Y (1)), yield (Y (2)), drug content (Y (3)) and droplet size (Y (4)) of the micro-emulsion.


Input: SMEDDS powder characteristics such as morphology, thermal behavior, crystallinity and flowability were also considered.


Input: Models were developed and model fitting analysis showed an adequate fit for all responses, indicating good predictability.


Input: Significant effects of processing parameters on powder characteristics were observed.


Input: The spray-drying process parameters were optimized as inlet temperature (134 degrees C), feed rate (5%) and carrier concentration (0. 6%) to produce solid-SMEDDS with acceptable moisture content (0. 72 +/- 0. 02%), yield (58. 5 +/- 2. 9%), drug content (70. 1 +/- 2. 7 mg/g) and droplet size (166. 8 +/- 13. 8 nm).


Input: Validation of the optimization process in five batches showed experimental value very close to the predicted one, ensuring the reproducibility of the developed models.


Input: Furthermore, optimized parameters resulted a highly crystalline flurbiprofen changed to an amorphous form.

flurbiprofen


Input: In conclusion, this study demonstrated the applicability of the DOE approach for optimizing the process parameters to manufacture solid-SMEDDS with desired quality attributes.


Input: Organosilicon compounds as adult T-cell leukemia cell proliferation inhibitors.

Organosilicon


Input: Aggressive forms of adult T-cell leukemia (ATL) respond poorly to conventional anticancer chemotherapy, and new lead compounds are required for the development of drugs to treat this fatal disease.


Input: Recently, we developed ATL cell-selective proliferation inhibitors based on a tetrahydrotetramethylnaphthalene (TMN) skeleton 1, and here we report the design and synthesis of silicon analogs of TMN derivatives.

tetrahydrotetramethylnaphthalene

TMN

silicon

TMN


Input: Among them, compound 13 showed the most potent growth-inhibitory activity towards the ATL cell line S1T, though its selectivity for S1T over the non-ATL cell line MOLT-4 was only moderate.


Input: This result, as well as computational studies, suggests that sila-substitution (C/Si exchange) is useful for structure optimization of these inhibitors.

C

Si


Input: Temporal stability of magic-number metal clusters: beyond the shell closing model.


Input: The anomalous stability of magic-number metal clusters has been associated with closed geometric and electronic shells and the opening of HOMO-LUMO gaps.


Input: Despite this enhanced stability, magic-number clusters are known to decay and react in the condensed phase to form other products.


Input: Improving our understanding of their decay mechanisms and developing strategies to control or eliminate cluster instability is a priority, to develop a more complete theory of their stability, to avoid studying mixtures of clusters produced by the decay of purified materials, and to enable technology development.


Input: Silver clusters are sufficiently reactive to facilitate the study of the ambient temporal stability of magic-number metal clusters and to begin to understand their decay mechanisms.

Silver


Input: Here, the solution phase stability of a series of silver: glutathione (Ag: SG) clusters was studied as a function of size, pH and chemical environment.

silver

glutathione

Ag


Input: Cluster stability was found to be a non-monotonic function of size.


Input: Electrophoretic separations showed that the dominant mechanism involved the redistribution of mass toward smaller sizes, where the products were almost exclusively previously known cluster sizes.


Input: Optical absorption spectra showed that the smaller clusters evolved toward the two most stable cluster sizes.


Input: The net surface charge was found to play an important role in cluster stabilization although charge screening had no effect on stability, contrary to DLVO theory.


Input: The decay mechanism was found to involve the loss of Ag (+) ions and silver glutathionates.

Ag (+)

silver glutathionates


Input: Clusters could be stabilized by the addition of Ag (+) ions and destabilized by either the addition of glutathione or the removal of Ag (+) ions.

Ag (+)

glutathione

Ag (+)


Input: Clusters were also found to be most stable in near neutral pH, where they had a net negative surface charge.


Input: These results provide new mechanistic insights into the control of post-synthesis stability and chemical decay of magic-number metal clusters, which could be used to develop design principles for synthesizing specific cluster species.


Input: Biomarkers for predicting future metastasis of human gastrointestinal tumors.


Input: The recent advances in surgery and radiation therapy have significantly improved the prognosis of patients with primary cancer, and the major challenge of cancer treatment now is metastatic disease development.


Input: The 5-year survival rate of cancer patients who have distant metastasis at diagnosis is extremely low, suggesting that prediction and early detection of metastasis would definitely improve their prognosis because suitable patient therapeutic management and treatment strategy can be provided.


Input: Cancer cells from a primary site give rise to a metastatic tumor via a number of steps which require the involvement and altered expression of many regulators.


Input: These regulators may serve as biomarkers for predicting metastasis.


Input: Over the past few years, numerous regulators have been found correlating with metastasis.


Input: In this review, we summarize the findings of a number of potential biomarkers that are involved in cadherin-catenin interaction, integrin signaling, PI3K/Akt/mTOR signaling and cancer stem cell identification in gastrointestinal cancers.


Input: We will also discuss how certain biomarkers are associated with the tumor microenvironment that favors cancer metastasis.


Input: The role of cortisol and psychopathy in the cycle of violence.

cortisol


Input: RATIONALE: Child abuse and neglect are universal risk factors for delinquency, violence, and aggression; this phenomenon is known as the cycle of violence.


Input: Additional factors-psychopathy, impulsiveness, and disruptions in the hypothalamic-pituitary-adrenal (HPA) axis-play a role in aggressive behavior but have rarely been examined in the same conceptual and experimental framework.


Input: OBJECTIVES: We sought to examine the above-mentioned risk factors for aggression in a prospective study employing psychopharmacologic and psychometric techniques.


Input: METHODS: Sixty-seven adult participants were given an acute dose of 20 mg cortisol in a placebo-controlled, within-subject, counter-balanced dosing design.

cortisol


Input: Salivary cortisol was measured at baseline and at regular intervals across a 5 h testing period.

cortisol


Input: Following dosing, state-aggressive behavior was measured by a laboratory task, the Point-Subtraction Aggression Paradigm.


Input: History of child abuse/neglect, psychopathy, impulsivity, and a trait measure of aggression were assessed through self-report questionnaires.


Input: RESULTS: Using multiple regression, a model including abuse/neglect, psychopathy, impulsivity, and baseline cortisol explained 58% of the variance in trait aggression and 26% of the variance in state aggression.

cortisol


Input: Abuse/neglect predicted diminished HPA-axis reactivity and HPA-axis reactivity showed a trend toward predicting state and trait aggression, although it was not a significant mediating variable between abuse/neglect and aggression.


Input: CONCLUSIONS: The results indicate that child maltreatment, psychopathy and HPA-axis reactivity interact to provide a confluence over aggressive behavior, and intervention efforts need to consider all these factors.


Input: One-Pot Facile Synthesis of Double-Shelled SnO2 Yolk-Shell-Structured Powders by Continuous Process as Anode Materials for Li-ion Batteries.

Li


Input: Double-shelled SnO2 yolk-shell-structured powders are prepared by applying a new facile one-pot process.


Input: Carbon-SnO2 composite powder particles are first formed as an intermediate product inside a tubular reactor.

Carbon


Input: Step-by-step combustion of carbon from outside the composite powder particles forms the double-shelled SnO2 yolk-shell-structured powder particles.

carbon


Input: The SnO2 yolk-shell-structured powders show excellent electrochemical properties.