Input: The most probable structures of (NaNO3, nH2O) 3 molecular system were investigated by using our global search algorithm we developed recently (GSAM code) both at the B3LYP/6-311 + G (d, p) and the B3LYP-D/6-311 + G (d, p) levels of theory.

(NaNO3, nH2O) 3


Input: The quality of the structural model is illustrated by comparing the B3LYP/6-311 + G (d, p) and B3LYP-D/6-311 + G (d, p) anharmonic vibrational signatures with those obtained from IR experiments.


Input: While an average deviation of 16 cm (-1) is observed in the case of the B3LYP computations, the deviation is reduced to 7 cm (-1) for the B3LYP-D computations.


Input: Abdominal adiposity through adipocyte secretion products, a risk factor for endometrial cancer.


Input: Abstract Background and aim: The adipose cell has been considered an inert cell from a secretory point of view.


Input: Studies over the past years have confirmed the capacity of the adipocyte to synthesize many substances including: adiponectin, leptin, which integrate multiple metabolic and endocrine signals.


Input: In the context of endometrial cancer, abdominal obesity as a risk factor is associated with a chronic inflammatory process, confirmed by the increase of inflammatory markers.


Input: The study aimed to identify a correlation between abdominal obesity, plasma adipokine levels and endometrial cancer.


Input: Material and method: Two groups of patients were included in the study: group I-44 patients diagnosed with endometrial cancer, group II-44 patients without gynecological pathology or inflammatory disorders.


Input: After the performance of clinical examination and anthropometric measurements, abdominal fat was determined by dual X-ray absorptiometry and plasma adiponectin and leptin levels were measured.


Input: Results: A significantly higher abdominal fat and leptin value was found in the group of patients in with endometrial cancer (p < 0. 0001), while the plasma adiponectin level was significantly lower, compared to the control group (p < 0. 0001).


Input: Abdominal fat was in a negative linear correlation with the plasma adiponectin level and in a positive linear correlation with the plasma leptin level.


Input: Conclusions: The measurement of adiponectin and leptin levels associated with the determination of abdominal adipose tissue can be a useful predictor factor for endometrial cancer.


Input: Symptomatic Amyloid Goiters: Report of 5 Cases.


Input: Background: Massive amyloid deposition in the thyroid to the point of goiter formation is rare.


Input: Here we describe the clinical presentation and outcomes of 5 patients with amyloid goiter (radiographically confirmed goiter in the context of tissue-proven thyroid amyloidosis) encountered in the past 23 years at our institution.


Input: Methods: Mayo Clinic archives were searched between 1987 and 2010 for diagnosis " thyroid amyloidosis, " " amyloid deposits, " " amyloid deposition, " or " liquid chromatography consistent with amyloid. " Inclusion criteria were symptomatic thyromegaly; tissue confirmation of thyroid enlarged by amyloid deposits; and radiologic confirmation of thyroid enlargement.


Input: Results: Five patients were identified who met all inclusion criteria.


Input: Amyloid goiter etiology included both primary and secondary amyloidosis, and the goiters ranged from 50 to 130 g each.


Input: Diagnosis was made by fine-needle aspiration biopsy with Congo red staining and, if needed, spectrophotometry.


Input: All 5 patients had histories of persistent hoarseness for several years prior to presentation with compressive symptoms referable to their enlarging thyroids, and all had some degree of thyroid dysfunction (both hypothyroidism and hyperthyroidism) by the end of our follow-up period, which ranged from 5 months to 13 years.


Input: Two patients underwent surgical intervention (s), 2 were managed conservatively, and in 1, the goiter shrank following systemic therapy for amyloidosis.


Input: Conclusions: Our clinical observations suggest slower goiter progression and a higher prevalence of thyroid dysfunction than previously thought.


Input: Ultralow friction induced by tribochemical reactions: a novel mechanism of lubrication on steel surfaces.

steel


Input: The tribological properties of two steel surfaces rubbing against each other are measured while they are in contact with 1, 3-diketones of varying structure.

steel

1, 3-diketones


Input: Such systems show after a short running-in period ultralow friction properties with a coefficient of friction of as low as mu = 0. 005.


Input: It is suggested that the extremely favorable friction properties are caused by a tribochemical reaction between the 1, 3-diketones and the steel surfaces, leading to formation of a chelated iron-diketo complex.

1, 3-diketones

iron

diketo


Input: The influence of temperature and the molecular structure of the 1, 3 diketo-lubricants onto the friction properties of the system is elucidated under both static and dynamic conditions.

1, 3 diketo


Input: With progression of the tribochemical reaction, the sliding surfaces become very conformal and smooth, so that the pressure is greatly reduced and further wear is strongly reduced.


Input: All iron particles potentially generated by wear during the initial running-in period are completely dissolved through complex formation.

iron


Input: It is proposed that the tribochemical polishing reaction causes a transition from boundary lubrication to fluid lubrication.


Input: Discovery of a novel series of non-nucleoside thumb pocket 2 HCV NS5B polymerase inhibitors.

nucleoside


Input: A novel series of non-nucleoside thumb pocket 2 HCV NS5B polymerase inhibitors were derived from a fragment-based approach using information from X-ray crystallographic analysis of NS5B-inhibitor complexes and iterative rounds of parallel synthesis.

nucleoside


Input: Structure-based drug design strategies led to the discovery of potent sub-micromolar inhibitors 11a-c and 12a-c from a weak-binding fragment-like structure 1 as a starting point.


Input: Acetaminophen reduces lipopolysaccharide-induced fever by inhibiting cyclooxygenase-2.

Acetaminophen


Input: Acetaminophen is one of the world' s most commonly used drugs to treat fever and pain, yet its mechanism of action has remained unclear.

Acetaminophen


Input: Here we tested the hypothesis that acetaminophen blocks fever through inhibition of cyclooxygenase-2 (Cox-2), by monitoring lipopolysaccharide induced fever in mice with genetic manipulations of enzymes in the prostaglandin cascade.

acetaminophen

prostaglandin


Input: We exploited the fact that lowered levels of a specific enzyme make the system more sensitive to any further inhibition of the same enzyme.


Input: Mice were immune challenged by an intraperitoneal injection of bacterial wall lipopolysaccharide and their body temperature recorded by telemetry.


Input: We found that mice heterozygous for Cox-2, but not for microsomal prostaglandin E synthase-1 (mPGES-1), displayed attenuated fever, indicating a rate limiting role of Cox-2.

prostaglandin E


Input: We then titrated a dose of acetaminophen that did not inhibit the lipopolysaccharide-induced fever in wild-type mice.

acetaminophen


Input: However, when the same dose of acetaminophen was given to Cox-2 heterozygous mice, the febrile response to lipopolysaccharide was strongly attenuated, resulting in an almost normalized temperature curve, whereas no difference was seen between wild-type and heterozygous mPGES-1 mice.

acetaminophen


Input: Furthermore, the fever to intracerebrally injected prostaglandin E2 was unaffected by acetaminophen treatment.

prostaglandin E2

acetaminophen


Input: These findings reveal that acetaminophen, similar to aspirin and other non-steroidal anti-inflammatory drugs, is antipyretic by inhibiting cyclooxygenase-2, and not by inhibiting mPGES-1 or signaling cascades downstream of prostaglandin E2.

acetaminophen

aspirin

prostaglandin E2


Input: Species differences in the neuromuscular activity of post-synaptic neurotoxins from two Australian black snakes (Pseudechis porphyriacus and Pseudechis colletti).


Input: Bites by Australian black snakes (Pseudechis spp.) do not cause neurotoxicity in human envenoming.


Input: This is unusual as in vitro neurotoxicity has been reported for all Pseudechis spp. venoms.


Input: The present study aimed to identify, isolate and characterise neurotoxins from the venoms of Pseudechis porphyriacus and Pseudechis colletti to elucidate the reason for the lack of neurotoxicity in humans.


Input: alpha-Elapitoxin-Ppr1 and alpha-elapitoxin-Pc1 were isolated from P. porphyriacus and P. colletti, respectively, using reverse-phase high performance liquid chromatography.


Input: Each toxin consisted of 62 amino acids with molecular weights of 6746. 5Da and 6759. 6Da, respectively.


Input: alpha-Elapitoxin-Ppr1 and alpha-elapitoxin-Pc1 caused concentration-dependent (0. 1-0. 3 mu M) inhibition of indirect twitches in the chick biventer cervicis nerve-muscle preparation.


Input: Both toxins inhibited contractile responses to exogenous ACh and CCh, but not KCl, suggesting a post-synaptic mode of action at the nicotinic acetylcholine receptor (nAChR).

ACh

KCl

acetylcholine


Input: CCh concentration-response curves obtained in the presence or absence of alpha-elapitoxin-Ppr1 or alpha-elapitoxin-Pc1 indicated pA2 values of 6. 97 +/- 0. 03 and 7. 04 +/- 0. 07, respectively.


Input: Neither alpha-elapitoxin-Ppr1 (0. 1 mu M) nor alpha-elapitoxin-Pc1 (0. 1 mu M) had a significant effect on the electrically-induced twitches of the rat isolated phrenic nerve-diaphragm preparation.


Input: When the venom with the toxin removed (10 mu g/ml) was added to both the rat and chick preparations, the inhibition was significantly less than that caused by the intact whole venoms (10 mu g/ml).


Input: The current study shows that alpha-elapitoxin-Ppr1 and alpha-elapitoxin-Pc1 act as pseudo-irreversible antagonists at the nAChR of the skeletal neuromuscular junction and that the avian preparation is more sensitive to the neurotoxic effects of these toxins than the mammalian preparation.


Input: Total saponins of Panax notoginseng enhance VEGF and relative receptors signals and promote angiogenesis derived from rat bone marrow mesenchymal stem cells.

saponins


Input: ETHNOPHARMACOLOGICAL RELEVANCE: Total saponins of Panax notoginseng (tPNS), main constituents extracted from Panax Notoginseng, a highly valued traditional Chinese medicine, has been shown to increase protein expression and the secretion of vascular endothelial growth factor (VEGF) in human umbilical vein endothelial cells.


Input: AIMS OF THE STUDY: The effects of tPNS on angiogenesis were studied in rat bone marrow mesenchymal stem cells (rBMSCs).


Input: MATERIALS AND METHODS: rBMSCs were stimulated by tPNS of 48h.


Input: The mRNA expression levels of VEGF-A, Flt-1 and Kdr in rBMSCs were determined by quantitative real time PCR (qRT-PCR).


Input: rBMSCs were induced to differentiate into endothelial-like cells and the effects of tPNS on the angiogenesis ability of rBMSCs and rBMSCs after endothelial differentiation were assayed by a Matrigel model in vivo and in vitro.


Input: RESULTS: tPNS (100 mu g/ml) significantly enhanced the mRNA expression level of VEGF-A and Kdr compared to the control group, while they had no obvious effect on the expression of Flt-1.


Input: tPNS (1 mu g/ml and 100 mu g/ml) significantly increased capillary network forming of rBMSCs after endothelial differentiation in Matrigel in vitro.


Input: tPNS (50 mu g/kg, 100 mu g/kg and 150 mu g/kg) also significantly increased angiogenesis induced by the combination with implantation of rBMSCs and Matrigel in vivo.


Input: CONCLUSION: tPNS up-regulate VEGF-A and Kdr expression, and promote angiogenesis in rat bone marrow mesenchymal stem cells.


Input: In Vitro Metabolism and Kinetics Studies on Methylone.

Methylone


Input: Abuse of the stimulant designer drug methylone (methylenedioxymethcathinone) has been documented in most parts of the world.

methylone

methylenedioxymethcathinone


Input: As with many of the new designer drugs that continuously appear in the illicit drug market, little is known about the pharmacokinetics of methylone.

methylone


Input: Using in vitro studies, CYP2D6 was determined to be the primary enzyme that metabolizes methylone, with minor contributions from CYP1A2, CYP2B6, and CYP2C19.

methylone


Input: The major metabolite was identified as dihydroxymethcathinone, and the minor metabolites were N-hydroxy-methylone, nor-methylone, and dihydro-methylone.

dihydroxymethcathinone

N-hydroxy-methylone

dihydro-methylone


Input: Measuring the formation of the major metabolite, biphasic Michaelis-Menten kinetic parameters were determined: Vmax, 1 = 0. 046 +/- 0. 005 (S. E.) nmol/min/mg protein, Km, 1 = 19. 0 +/- 4. 2 mu M, Vmax, 2 = 0. 22 +/- 0. 04 nmol/min/mg protein, and Km, 2 = 1953 +/- 761 mu M; the low-capacity and high-affinity contribution was assigned to the activity of CYP2D6.


Input: Additionally, a time-dependent loss of CYP2D6 activity was observed when the enzyme was preincubated with methylone, reaching a maximum rate of inactivation at high methylone concentrations, indicating that methylone is a mechanism-based inhibitor of CYP2D6.

methylone

methylone


Input: The inactivation parameters were determined to be KI = 15. 1 +/- 3. 4 (S. E) mu M and kinact = 0. 075 +/- 0. 005 min (-1).


Input: Determination of the mutagenic and genotoxic potential of simulated leachate from an automobile workshop soil on eukaryotic system.


Input: Contamination of soil and water bodies with spent engine oil and petroleum products is a serious ecological problem, primarily in the automobile workshops and garages.


Input: This has potential short and chronic adverse health risks.


Input: Information is currently scarce on the potential mutagenicity and genotoxicity of such wastes.


Input: In this study, the potential mutagenic and genotoxic effects of simulated leachate from automobile workshop soil in Sagamu, Ogun state, Nigeria, were investigated.


Input: The assays utilized were bone marrow micronucleus (MN) and chromosome aberration (CA), sperm morphology and sperm count in mice.


Input: The physicochemical analysis of the leachate was also carried out.


Input: Experiments were carried out at concentrations of 1, 5, 10, 25, 50, 75 and 100% (volume per volume; leachate: distilled water) of the leachate sample.


Input: MN analysis showed a concentration-dependent induction of micronucleated polychromatic erythrocytes across the treatment groups.


Input: In the CA test, there was concentration-dependent significant reduction in mitotic index and induction of different types of CAs.


Input: Assessment of sperm shape showed a significant increase in sperm abnormalities with significant decrease in mean sperm count in treated groups.


Input: Heavy metals analyzed in the tested sample are believed to contribute significantly to the observed genetic damage.


Input: This indicates that automobile workshop soil-simulated leachate contains potential genotoxic agents and constitutes a genetic risk in exposed human population.


Input: Isolation of Five New Flavonoids from Melicope triphylla.

Flavonoids


Input: Five new flavonoids, 5, 8-dihydroxy-3, 7-dimethoxy-3', 4'-methylenedioxyflavone (1), 7-hydroxy-3, 5-dimethoxy-3', 4'-methylenedioxyflavone (2), 7-(2, 3-dihydroxy-3-methylbutoxy)-3, 5-dimethoxy-3', 4'-methylenedioxyflavone (3), 7-(2, 3-dihydroxy-3-methylbutoxy)-3, 3', 4', 5-tetramethoxyflavone (4), and 7-(2, 3-dihydroxy-3-methylbutoxy)-3, 3', 4', 5, 8-pentamethoxyflavone (5), were isolated from the leaves of Melicope triphylla.

flavonoids

5, 8-dihydroxy-3, 7-dimethoxy-3', 4'-methylenedioxyflavone

7-hydroxy-3, 5-dimethoxy-3', 4'-methylenedioxyflavone

7-(2, 3-dihydroxy-3-methylbutoxy)-3, 5-dimethoxy-3', 4'-methylenedioxyflavone

7-(2, 3-dihydroxy-3-methylbutoxy)-3, 3', 4', 5-tetramethoxyflavone

7-(2, 3-dihydroxy-3-methylbutoxy)-3, 3', 4', 5, 8-pentamethoxyflavone


Input: In addition, six known flavonoids were detected: 3, 4', 5-trihydroxy-3', 7, 8-trimethoxyflavone (6), 5, 7-dihydroxy-3-methoxy-3', 4'-methylenedioxyflavone (7), 4', 5, 7-trihydroxy-3, 3'-dimethoxyflavone (8), 4', 7-dihydroxy-3, 3', 5, 8-tetramethoxyflavone (9), 4', 7-dihydroxy-3, 3', 5-trimethoxyflavone (10), and 4', 5, 7-trihydroxy-3, 3', 8-trimethoxyflavone (11).

flavonoids

3, 4', 5-trihydroxy-3', 7, 8-trimethoxyflavone

5, 7-dihydroxy-3-methoxy-3', 4'-methylenedioxyflavone

4', 5, 7-trihydroxy-3, 3'-dimethoxyflavone

4', 7-dihydroxy-3, 3', 5, 8-tetramethoxyflavone

4', 7-dihydroxy-3, 3', 5-trimethoxyflavone

4', 5, 7-trihydroxy-3, 3', 8-trimethoxyflavone


Input: The new compound structures were determined by spectroscopic methods.


Input: Compounds 1-5 did not exhibit any ichthyotoxic activity against Japanese killifish (medaka in Japanese) (Oryzias latipes var.) at 10 ppm.


Input: Synthesis of 2, 3-Bis (halomethyl) quinoxaline Derivatives and Evaluation of Their Antibacterial and Antifungal Activities.

2, 3-Bis (halomethyl) quinoxaline


Input: Quinoxaline derivatives having bis (fluoromethyl), bis (chloromethyl), or bis (iodomethyl) groups at the 2-and 3-positions, and various electron-donating/withdrawing substituents at the 6-and/or 7-positions, were synthesized.

Quinoxaline

bis (fluoromethyl)

bis (chloromethyl)

bis (iodomethyl)


Input: Their antibacterial and antifungal activities were evaluated by means of minimum inhibitory concentration assays.


Input: The relationships between the substituents and the antimicrobial activities of the quinoxaline derivatives indicate that the electrophilicity of the halomethyl units plays an important role in generating the antimicrobial activity.

quinoxaline

halomethyl


Input: Medicinal Flowers.


Input: XXXVIII.


Input: Structures of Acylated Sucroses and Inhibitory Effects of Constituents on Aldose Reducatase from the Flower Buds of Prunus mume.

Acylated Sucroses


Input: The methanolic extract from the flower buds of Prunus mume, cultivated in Zhejiang province, China, showed an inhibitory effect on aldose reductase.

aldose


Input: From the methanolic extract, five new acylated sucroses, mumeoses F-J, were isolated together with 29 known compounds.

acylated sucroses

mumeoses F-J


Input: The chemical structures of the new compounds were elucidated on the basis of chemical and physicochemical evidence.


Input: The inhibitory effects of the isolated compounds on aldose reductase were also investigated.

aldose


Input: Acylated quinic acid analogs, which are one of the major compounds of the flower buds of P. mume, were shown to substantially inhibit aldose reductase.

Acylated quinic acid

aldose


Input: In particular, mumeic acid-A was found to exhibit a potent inhibitory effect [IC50 = 0. 4 micro m].

mumeic acid-A


Input: Antimutagenic and genoprotective effects of Saraca asoca bark extract.


Input: < abstract > Aim of the study: Traditionally herbal formulations have been used effectively for the management of disorders that are now being accepted worldwide.


Input: Saraca asoca bark extract (SAE) finds use in traditional herbal medicine.


Input: In the present study, SAE were studied for their antioxidant, antimutagenic, and antigenotoxic properties.


Input: METHODS: SAE were evaluated for antimutagenic property in Salmonella strains (TA97a, TA98, TA100, and TA102), in the presence and absence of metabolic activation (S9).


Input: The SAE was also studied for antigenotoxic property against cyclophosphamide (CP) in Swiss albino male mice in vivo.

cyclophosphamide


Input: The extract was analyzed using high-performance liquid chromatography (HPLC).


Input: RESULTS: The study reveals antimutagenic property of the bark extract in Salmonella strains in the presence and absence of metabolic activation (S9).


Input: The study reports antigenotoxic property of the bark extract against CP in vivo.


Input: Thiobarbituric acid reactive species assay on the bark extract revealed antioxidant property.

Thiobarbituric acid


Input: HPLC revealed the presence of two peaks corresponding to gallic acid and (-)-epicatechin, respectively.

gallic acid

(-)-epicatechin


Input: CONCLUSION: The study clearly reveals the antimutagenic and antigenotoxic properties of SAE.


Input: </abstract >


Input: Azidoacetylene-interpretation of gas phase infrared spectra based on high-level vibrational configuration interaction calculations.

Azidoacetylene


Input: Azidoacetylene is a highly explosive substance, which has been synthesized and characterized for the first time quite recently [Banert et al., Angew. Chem., Int. Ed., 2012, 51, 7515].

Azidoacetylene


Input: As outlined in this work, the vibrational spectrum of azidoacetylene is dominated by strong couplings.

azidoacetylene


Input: For that reason, we have studied the vibrational spectrum of the title compound by gas phase measurements and high-level vibrational structure calculations beyond the harmonic approximation.


Input: Based on the interplay of theory and experiment, we were able to identify all fundamentals, strong Fermi resonances and intense overtones, which contribute to the spectrum.


Input: A 5' flanking region of Gonadotropin Regulated Testicular RNA Helicase (GRTH/DDX25) gene directs its cell specific androgen regulated gene expression in testicular germ cells.

androgen


Input: Gonadotropin Regulated Testicular RNA Helicase (GRTH/Ddx25) is a post-transcriptional regulator of genes that are essential for spermatid elongation and completion of spermatogenesis.


Input: It also prevents Leydig cells (LC) from gonadotropin overstimulation of androgen production.

androgen


Input: In transgenic (Tg) mice carrying deletions of the GRTH 5' flanking regions we previously demonstrated that the-1085 bp to ATG contains the elements for basal and androgen-induced LC specific expression.

androgen


Input: No expression in germ cells (GC) was found with sequences extended up to-3. 6 Kb.


Input: To define regulatory regions of GRTH required for expression in GC, Tg mice were generated with 5' flanking sequence 6. 4 Kb (6. 4 Kb-Tg) and/or deletion using GFP as reporter gene in the present study.


Input: GFP was expressed in all lines.


Input: Immuno-histochemistry analysis showed that 6. 4Kb-Tg directed GFP expression in both GC and LC.


Input: Deletion of the sequence-205 bp to-3. 6 Kb (6. 4Kb/del-Tg) directs GFP expression only in meiotic and haploid GCs.


Input: This indicated that the distal region-6. 4 Kb/-3. 6 Kb is required for GRTH cell specific expression in GC.


Input: Also, it inhibits the expression of GRTH in LC directed by the 205 bp promoter, an effect that is neutralized by the-3. 6Kb/-205bp sequence.


Input: Flutamide treatment prevents GFP/GRTH expression in Tg lines demonstrating in vivo direct and indirect effects of endogenous androgen on GC and LC, respectively.

androgen


Input: Our studies have generated and characterized transgenic lines that can be utilized to define requirements for cell specific expression of the GRTH gene and to further advance our knowledge on the regulation of GRTH by androgen in germ cells.

androgen


Input: Estrogen Receptor-alpha Variant, ER-alpha 36, is Involved in Tamoxifen Resistance and Estrogen Hypersensitivity.

Estrogen

Tamoxifen

Estrogen


Input: Antiestrogens such as tamoxifen provided a successful treatment for ER-positive breast cancer for the past two decades.

tamoxifen


Input: However, most breast tumors are eventually resistant to tamoxifen therapy.

tamoxifen


Input: The molecular mechanisms underlying tamoxifen resistance have not been well established.

tamoxifen


Input: Recently, we reported that breast cancer patients with tumors expressing high concentrations of ER-alpha 36, a variant of ER-alpha, benefited less from tamoxifen therapy than those with low concentrations of ER-alpha 36, suggesting that increased ER-alpha 36 concentration is one of the underlying mechanisms of tamoxifen resistance.

tamoxifen

tamoxifen


Input: Here, we investigated the function and underlying mechanism of ER-alpha 36 in tamoxifen resistance.

tamoxifen


Input: We found that tamoxifen increased ER-alpha 36 concentrations and tamoxifen-resistant MCF7 cells expressed high concentrations of ER-alpha 36.

tamoxifen

tamoxifen


Input: In addition, MCF7 cells with forced expression of recombinant ER-alpha 36 and H3396 cells expressing high concentrations of endogenous ER-alpha 36 were resistant to tamoxifen.

tamoxifen


Input: ER-alpha 36 downregulation in tamoxifen-resistant cells with the shRNA method restored tamoxifen sensitivity.

tamoxifen

tamoxifen


Input: We also found tamoxifen acted as a potent agonist by activating phosphorylation of the AKT kinase in ER-alpha 36 expressing cells.

tamoxifen


Input: Finally, we found that cells with high concentration of ER-alpha 36 protein were hypersensitive to estrogen; activating ERK phosphorylation at pM range.

estrogen


Input: Our results thus demonstrated that elevated ER-alpha 36 concentration is one of the mechanisms by which ER-positive breast cancer cells escape tamoxifen therapy and provided a rational to develop novel therapeutic approaches for tamoxifen resistant patients by targeting ER-alpha 36.

tamoxifen

tamoxifen


Input: Ovarian Expression of Insulin-Like Peptide 3 (INSL3) and Its Receptor (RXFP2) During Development of Bovine Antral Follicles and Corpora Lutea and Measurement of Circulating INSL3 Levels During Synchronized Estrous Cycles.


Input: Insulin-like peptide 3 (INSL3), a major product of testicular Leydig cells, is also expressed by the ovary, but its functional role remains poorly understood.


Input: Here, we quantified expression of INSL3 and its receptor RXFP2 in theca interna cell (TIC) and granulosa cell compartments of developing bovine antral follicles and in corpora lutea (CL).


Input: INSL3 and RXFP2 mRNA levels were much higher in TIC than granulosa cell and increased progressively during follicle maturation with INSL3 peaking in large (11-18 mm) estrogen-active follicles and RXFP2 peaking in 9-to 10-mm follicles before declining in larger (11-18 mm) follicles.

estrogen


Input: Expression of both INSL3 and RXFP2 in CL was much lower than in TIC.


Input: In situ hybridization and immunohistochemistry confirmed abundant expression of INSL3 mRNA and protein in TIC.


Input: These observations indicate follicular TIC rather than CL as the primary site of both INSL3 production and action, implying a predominantly autocrine/paracrine role in TIC.


Input: To corroborate the above findings, we showed that in vitro exposure of TIC to a luteinizing concentration of LH greatly attenuated expression of both INSL3 and its receptor while increasing progesterone secretion and expression of STAR and CYP11A1.

progesterone


Input: Moreover, in vivo, a significant cyclic variation in plasma INSL3 was observed during synchronized estrous cycles.


Input: INSL3 and estradiol-17 beta followed a similar pattern, both increasing after luteolysis, before falling sharply after the LH surge.

estradiol-17 beta


Input: Thus, theca-derived INSL3, likely from the dominant preovulatory follicle, is detectable in peripheral blood of cattle, and expression is down-regulated during luteinization induced by the preovulatory LH surge.


Input: Collectively, these findings underscore the likely role of INSL3 as an important intrafollicular modulator of TIC function/steroidogenesis, while raising doubts about its potential contribution to CL function.


Input: Ionizing radiation-inducible microRNA miR-193a-3p induces apoptosis by directly targeting Mcl-1.


Input: The functions of microRNAs (miRNAs) as either oncogenes or tumor suppressors in regulating cancer-related events have been established.


Input: We analyzed the alterations in the miRNA expression profile of the glioma cell line U-251 caused by ionizing radiation (IR) by using an miRNA array and identified several miRNAs whose expression was significantly affected by IR.


Input: Among the IR-responsive miRNAs, we further examined the function of miR-193a-3p, which exhibited the most significant growth-inhibiting effect.


Input: miR-193a-3p was observed to induce apoptosis in both U-251 and HeLa cells.


Input: We also demonstrated that miR-193a-3p induces the accumulation of intracellular reactive oxygen species (ROS) and DNA damage as determined by the level of gamma H2AX and by performing the comet assay.

oxygen


Input: The induction of both apoptosis and DNA damage by miR-193a-3p was blocked by antioxidant treatment, indicating the crucial role of ROS in the action of miR-193a-3p.


Input: Among the putative target proteins, the expression of Mcl-1, an anti-apoptotic Bcl-2 family member, decreased because of miR-193a-3p transfection.


Input: A reporter assay using a luciferase construct containing the 3'-untranslated region of Mcl-1 confirmed that Mcl-1 is a direct target of miR-193a-3p.


Input: Down-regulation of Mcl-1 by siRNA transfection closely mimicked the outcome of miR-193a-3p transfection showing increased ROS, DNA damage, cytochrome c release, and apoptosis.


Input: Ectopic expression of Mcl-1 suppressed the pro-apoptotic action of miR-193a-3p, suggesting that Mcl-1 depletion is critical for miR-193a-3p induced apoptosis.


Input: Collectively, our results suggest a novel function for miR-193a-3p and its potential application in cancer therapy.


Input: Site-specific O-glycosylation on the MUC2 mucin inhibits cleavage by the Porphyromonas gingivalis secreted cysteine protease (RgpB).

O

cysteine


Input: The colonic epithelial surface is protected by an inner mucus layer which the commensal microflora cannot penetrate.


Input: We previously demonstrated that Entamoeba histolytica (E. h.) secretes a protease capable of dissolving this layer that is required for parasite penetration.


Input: Here, we asked if there are bacteria that can secrete similar proteases.


Input: We screened bacterial culture supernatants for such activity using recombinant fragments of the MUC2 mucin, the major structural component and the only gel-forming mucin in the colonic mucus.


Input: MUC2 has two central heavily O-glycosylated mucin domains that are protease-resistant and has cysteine rich N-and C-termini responsible for polymerization.

O

cysteine

N

C


Input: Culture supernatants of Porphyromonas gingivalis (P. g.), a bacterium that secretes proteases responsible for periodontitis, cleaved the MUC2-C terminal region, whereas the N-terminal region was unaffected.

N


Input: The active enzyme was isolated and identified as Arg-gingipain B (RgpB).


Input: Two cleavage sites were localized to IR v TT and NR v QA.


Input: IR v TT cleavage will disrupt the MUC2 polymers.


Input: As this site has two potential O-glycosylation sites we tested whether recombinant GalNAc-transferases (GalNAc-Ts) could glycosylate a synthetic peptide covering the IRTT sequence.

O

GalNAc

GalNAc


Input: Only GalNAc-T3 was able to glycosylate the second Thr in IRTT, rendering the sequence resistant to cleavage by RgpB.

GalNAc


Input: Furthermore, when GalNAc-T3 was expressed in CHO-cells expressing the MUC2 C-terminal, the second threonine was glycosylated and the protein became resistant to RgpB cleavage.

GalNAc

CHO

threonine


Input: These findings suggest that bacteria can produce proteases capable of dissolving the inner protective mucus layer by specific cleavages in the MUC2 mucin and that this cleavage can be modulated by site-specific O-glycosylation.

O


Input: Biological Active Analogues of the Opioid Peptide Biphalin: Mixed alpha/beta (3)-Peptides.

Biphalin


Input: Natural residues of the dimeric opioid peptide Biphalin were replaced by the corresponding homo-beta (3) amino acids.

Biphalin

homo-beta (3) amino acids


Input: The derivative 1 containing h beta (3) Phe in place of Phe showed good mu-and delta-receptor affinities (Ki (delta) = 0. 72 nM; Ki (mu) = 1. 1 nM) and antinociceptive activity in vivo together with an increased enzymatic stability in human plasma.

h beta (3) Phe

Phe


Input: 3-Hydroxypyridin-2-thione as Novel Zinc Binding Group for Selective Histone Deacetylase Inhibition.

Zinc


Input: Small molecules bearing hydroxamic acid as the zinc binding group (ZBG) have been the most effective histone deacetylase inhibitors (HDACi) to date.

zinc


Input: However, concerns about the pharmacokinetic liabilities of the hydroxamic acid moiety have stimulated research efforts aimed at finding alternative nonhydroxamate ZBGs.

hydroxamic acid


Input: We have identified 3-hydroxypyridin-2-thione (3-HPT) as a novel ZBG that is compatible with HDAC inhibition.


Input: 3-HPT inhibits HDAC 6 and HDAC 8 with an IC50 of 681 and 3675 nM, respectively.


Input: Remarkably, 3-HPT gives no inhibition of HDAC 1.


Input: Subsequent optimization led to several novel 3HPT-based HDACi that are selective for HDAC 6 and HDAC 8.


Input: Furthermore, a subset of these inhibitors induces apoptosis in various cancer cell lines.


Input: Oxadiazole-isopropylamides as potent and non-covalent proteasome inhibitors.

Oxadiazole-isopropylamides


Input: Abstract Screening of the 50, 000 ChemBridge compound library led to the identification of the oxadiazole-isopropylamide 1 (PI-1833) which inhibited CT-L activity (IC50 0. 60 mu M) with little effects on the other 2 major proteasome proteolytic activities, T-L and PGPH-L.

oxadiazole-isopropylamide


Input: LC/MS-MS and dialysis show that 1 is a non-covalent and rapidly reversible CT-L inhibitor.


Input: Focused library synthesis provided 11ad (PI-1840) with CT-L activity (IC50 27 nM).


Input: Detailed SAR studies indicate that the amide moiety and the 2 phenyl rings are sensitive toward modifications.

amide

phenyl


Input: Hydrophobic residues, such as propyl or butyl, in the para-position (not ortho or meta) of the A-ring and a meta-pyridyl group as B-ring significantly improve activity.

propyl

butyl

meta-pyridyl


Input: Compound 11ad (IC50 0. 37 micro M) is more potent than 1 (IC50 3. 5 micro M) at inhibiting CT-L activity in intact MDA-MB-468 human breast cancer cells and inhibiting their survival.


Input: The activity of 11ad warrants further pre-clinical investigation of this class as non-covalent proteasome inhibitors.


Input: Potent Proteasome Inhibitors Derived from the Unnatural Cis-Cyclopropane Isomer of Belactosin A: Synthesis, Biological Activity, and Mode of Action.

Cis-Cyclopropane

Belactosin A


Input: The natural product belactosin A (1) with a trans-cyclopropane structure is a useful prototype compound for developing potent proteasome (core particle, CP) inhibitors.

belactosin A

trans-cyclopropane


Input: To date, 1 and its analogs are the only CP ligands bind to both the non-primed S1 pocket as well as the primed substrate binding channel, however, these molecules harbor a high IC50 value of more than 1 micro M.


Input: We have performed structure activity relationship studies, hereby elucidating unnatural cis-cyclopropane derivatives of 1 that exhibit high potency to primarily block the chymotrypsin-like active site of the human constitutive (cCP) and immunoproteasome (iCP).

cis-cyclopropane


Input: The most active compound 3e reversibly inhibits cCP and iCP similarly with an IC50 of 5. 7 nM.


Input: X-ray crystallographic analysis of the yeast proteasome in complex with 3e revealed that the ligand accommodates predominantly to the primed substrate binding channel and covalently binds to the active site threonine residue via its beta-lactone ring-opening.

threonine

beta-lactone


Input: Development of an ALK2-Biased BMP Type I Receptor Kinase Inhibitor.


Input: The bone morphogenetic protein (BMP) signaling pathway has essential functions in development, homeostasis, and the normal and pathophysiologic remodeling of tissues.


Input: Small molecule inhibitors of the BMP receptor kinase family have been useful for probing physiologic functions of BMP signaling in vitro and in vivo and may have roles in the treatment of BMP-mediated diseases.


Input: Here we describe the development of a selective and potent inhibitor of the BMP type I receptor kinases, LDN-212854, which in contrast to previously described BMP receptor kinase inhibitors exhibits nearly 4 orders of selectivity for BMP versus the closely related TGF-beta and Activin type I receptors.


Input: In vitro, LDN-212854 exhibits some selectivity for ALK2 in preference to other BMP type I receptors, ALK1 and ALK3, which may permit the interrogation of ALK2-mediated signaling, transcriptional activity, and function.


Input: LDN-212854 potently inhibits heterotopic ossification in an inducible transgenic mutant ALK2 mouse model of fibrodysplasia ossificans progressiva.


Input: These findings represent a significant step toward developing selective inhibitors targeting individual members of the highly homologous BMP type I receptor family.


Input: Such inhibitors would provide greater resolution as probes of physiologic function and improved selectivity against therapeutic targets.


Input: Bacteria-adsorbed palygorskite stabilizes the quaternary phosphonium salt with specific-targeting capability, long-term antibacterial activity, and lower cytotoxicity.

palygorskite

quaternary phosphonium salt


Input: In order to extend the antibacterial time of quaternary phosphonium salt in bacteria, palygorskite (PGS) is used as the carrier of dodecyl triphenyl phosphonium bromide (DTP), and a DTP-PGS hybrid is prepared.

quaternary phosphonium salt

palygorskite

PGS

dodecyl triphenyl phosphonium bromide

DTP

DTP

PGS


Input: Antibacterial performance of this novel hybrid is investigated for both Gram-positive and Gram-negative bacteria.


Input: The results show that the DTP could be absorbed on the surface of PGS which had bacteria-adsorbed capability.

DTP

PGS


Input: The DTP-PGS hybrid, combining the advantages of PGS and DTP, display specific-targeting capability, long-term antibacterial activity, and lower cytotoxicity, suggesting the great potential application as PGS-based antibacterial powder.

DTP

PGS

PGS

DTP

PGS


Input: Artificial Neural Networks for Efficient Clustering of Conformational Ensembles and their Potential for Medicinal Chemistry.


Input: The biological function of proteins is strictly related to their molecular flexibility and dynamics: enzymatic activity, protein-protein interactions, ligand binding and allosteric regulation are important mechanisms involving protein motions.


Input: Computational approaches, such as Molecular Dynamics (MD) simulations, are now routinely used to study the intrinsic dynamics of target proteins as well as to complement molecular docking approaches.


Input: These methods have also successfully supported the process of rational design and discovery of new drugs.


Input: Identification of functionally relevant conformations is a key step in these studies.


Input: This is generally done by cluster analysis of the ensemble of structures in the MD trajectory.


Input: Recently Artificial Neural Network (ANN) approaches, in particular methods based on Self-Organising Maps (SOMs), have been reported performing more accurately and providing more consistent results than traditional clustering algorithms in various data-mining problems.


Input: In the specific case of conformational analysis, SOMs have been successfully used to compare multiple ensembles of protein conformations demonstrating a potential in efficiently detecting the dynamic signatures central to biological function.


Input: Moreover, examples of the use of SOMs to address problems relevant to other stages of the drug-design process, including clustering of docking poses, have been reported.


Input: In this contribution we review recent applications of ANN algorithms in analysing conformational and structural ensembles and we discuss their potential in computer-based approaches for medicinal chemistry.


Input: PFKFB3 activation in cancer cells by the p38/MK2 pathway in response to stress stimuli.


Input: PFK-2/FBPase-2 (6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase) catalyses the synthesis and degradation of Fru-2, 6-P2 (fructose-2, 6-bisphosphate), a key modulator of glycolysis and gluconeogenesis.

Fru-2, 6-P2

fructose-2, 6-bisphosphate


Input: The PFKFB3 gene is involved in cell proliferation owing to its role in carbohydrate metabolism.

carbohydrate


Input: Here we analyze its mechanism of regulation as an immediately early gene controlled by stress stimuli that activate p38/MK2 pathway.


Input: We report that exposure of HeLa and T98G cells to different stress stimuli (NaCl, H2O2, UV radiation and anisomycin) leads to a rapid increase (15-30 minutes) in PFKFB3 mRNA levels.

NaCl

anisomycin


Input: The use of specific inhibitors in combination with MK2-deficient cells implicate control by MK2 protein kinase.


Input: Transient transfection of HeLa cells with deleted gene promoter constructs allowed us to identify a Serum Response Element (SRE) to which Serum Response Factor (SRF) binds and thus transactivates PFKFB3 gene transcription.


Input: Direct Binding of phospho-SRF to the SRE sequence (-918 nt) was confirmed by ChIP (chromatin immunoprecipiation) assays.


Input: Moreover, PFKFB3 isoenzyme phosphorylation at Ser461 by MK2 increases PFK-2 activity.


Input: Together, the results suggest a multimodal mechanism of stress stimuli affecting PFKFB3 transcriptional regulation and kinase activation by protein phosphorylation, resulting in an increase in Fru-2, 6-P2 concentration and stimulation of glycolysis in cancer cells.

Fru-2, 6-P2


Input: Identification of a new interaction mode between the Src homology 2 (SH2) domain of C-terminal Src kinase (Csk) and Csk-binding protein (Cbp)/phosphoprotein associated with glycosphingolipid microdomains (PAG).

C


Input: Proteins with Src homology 2 (SH2) domains play major roles in tyrosine kinase signaling.

tyrosine


Input: Structures of many SH2 domains have been studied, and the regions involved in their interactions with ligands have been elucidated.


Input: However, these analyses have been performed using short peptides comprising phosphotyrosine followed by a few amino acids, which are described as the canonical recognition sites.

phosphotyrosine

amino acids


Input: Here we report the solution structure of the SH2 domain of C-terminal Src kinase (Csk) in complex with a longer phosphopeptide from Csk-binding protein (Cbp).

C


Input: This structure, together with biochemical experiments, revealed the existence of a novel binding region in addition to the canonical phosphotyrosine-314 binding site of Cbp.

phosphotyrosine


Input: Mutational analysis of this second region in cells showed that both canonical and novel binding sites are required for tumor suppression through the Cbp-Csk interaction.


Input: Furthermore, the data indicate an allosteric connection between Cbp binding and Csk activation that arises from residues in the beta B/beta C loop of the SH2 domain.


Input: G-protein coupled receptor agonist BV8/prokineticin-2 and STAT3 form a feed-forward loop in both normal and malignant myeloid cells.


Input: An important role of Bv8 in mobilization of myeloid cells and myeloid cell-dependent angiogenesis has been established.


Input: Recently, it has also been shown that granulocyte colony stimulating factor (G-CSF)-induced Bv8 expression is Stat3 dependent in CD11b + Gr1 + myeloid cells.


Input: However, Bv8 downstream signaling pathway (s) intrinsic to myeloid cells crucial for angiogenesis, and potentially also for development of cancers of myeloid origin, remains largely unknown.


Input: Here we show that BV8 activates STAT3, which is critical for regulating genes important for both tumor cell proliferation/survival and tumor angiogenesis, in both normal and malignant myeloid cells.


Input: Further, BV8-induced STAT3 activation requires Janus activated kinase 2 (JAK2) activity as shown by both genetic and pharmacologic inhibition.


Input: Knocking down BV8 in human myeloid leukemia cells inhibits STAT3 activity and expression of STAT3-downstream angiogenic and pro-proliferation/survival genes, leading to a decrease in tumor cell viability.


Input: BV8 shRNA expressing leukemia cells exhibit reduced STAT3 activity and tumor growth in vivo.


Input: Taken together, we have delineated a signaling pathway downstream of BV8 that plays critical roles in both the tumor microenvironment and malignant myeloid cells for angiogenesis and tumor cell proliferation/survival.


Input: Visual evoked potentials in children prenatally exposed to methylmercury.

methylmercury


Input: Prenatal exposure to methylmercury can cause both neurobehavioral deficits and neurophysiological changes.

methylmercury


Input: However, evidence of neurotoxic effects within the visual nervous system is inconsistent, possibly due to incomplete statistical adjustment for beneficial nutritional factors.


Input: We evaluated the effect of prenatal methylmercury exposure on visual evoked potential (VEP) latencies in Faroese children with elevated prenatal methylmercury exposure.

methylmercury

methylmercury


Input: A cohort of 182 singleton term births was assembled in the Faroe Islands during 1994-1995.


Input: At age 7 years, VEP tracings were obtained from 139 cohort subjects after exclusion of subjects with abnormal vision conditions.


Input: We used multiple regression analysis to evaluate the association of mercury concentrations in cord blood and maternal hair at parturition with VEP latencies after adjustment for potential confounders that included the cord-serum phospholipid concentration of n-3 polyunsaturated fatty acids (PUFAs) and the duration of breastfeeding.

mercury

polyunsaturated fatty acids

PUFAs


Input: Unadjusted correlations between mercury exposure and VEP latencies were equivocal.

mercury


Input: Multiple regression models showed that increased mercury concentrations, especially in maternal hair, were associated with delayed latencies for VEP peak N145.

mercury


Input: After covariate adjustment, a delay of 2. 22ms (p = 0. 02) was seen for each doubling of the mercury concentration in maternal hair.

mercury


Input: In agreement with neuropsychological findings, the present study suggests that prenatal methylmercury exposure may have an adverse effect on VEP findings despite the absence of clinical toxicity to the visual system.

methylmercury


Input: However, this association was apparent only after adjustment for n-3 PUFA status.

PUFA


Input: Spongiatriol inhibits nuclear factor kappa B activation and induces apoptosis in pancreatic cancer cells.

Spongiatriol


Input: Pancreatic cancer, the fourth leading cause of cancer death in the US, is highly resistant to all current chemotherapies, and its growth is facilitated by chronic inflammation.


Input: The majority of pro-inflammatory cytokines initiate signaling cascades that converge at the activation of the Nuclear Factor Kappa B (NF kappa B), a signal transduction molecule that promotes cell survival, proliferation and angiogenesis.


Input: In an effort to identify novel inhibitors of NF kappa B, the HBOI library of pure compounds was screened using a reporter cell line that produces luciferin under the transcriptional control of NF kappa B.


Input: Seven compounds were identified through this screen, but in the case of five of them, their reported mechanism of action made them unlikely to be specific NF kappa B inhibitors.


Input: Spongiatriol, a marine furanoditerpenoid that was first isolated in the 1970s, is shown here to inhibit NF kappa B transcriptional activity in a reporter cell line, to reduce levels of phosphorylated (active) NF kappa B in the AsPC-1 cell line, to have an IC50 for cytotoxicity in the low micromolar range against the AsPC-1, BxPC-3, MiaPaCa-2 and Panc-1 pancreatic cancer cell lines, and to induce moderate but significant apoptosis in both the AsPC-1 and the Panc-1 cell lines.

Spongiatriol

furanoditerpenoid


Input: Is There Visceral Adipose Tissue (VAT) Intracellular Hypercortisolism in Human Obesity?


Input: The fact that obesity is a prominent feature of Cushing' s syndrome (systemic hypercortisolism of adrenocortical origin) stimulated a 40-year search for evidence of systemic hypercortisolism in human obesity.


Input: That search has failed to find such evidence.


Input: For the past 15 years, however, studies have been done to evaluate a possible alternative type of hypercortisolism in obesity, namely visceral adipose tissue (VAT) intracellular hypercortisolism.


Input: The current review summarizes the evidence published so far about this possibility.


Input: There have been three types of evidence studied: direct measurement of the VAT levels of 11 beta-hydroxysteroid dehydrogenase type I (11-HSD-1), which converts biologically inactive cortisone to biologically active cortisol; direct measurement of splanchnic cortisol production; and evaluation of the effect of a specific inhibitor of 11-HSD-1 on metabolic abnormalities associated with obesity, particularly diabetes mellitus.

11 beta-hydroxysteroid

cortisone

cortisol

cortisol


Input: The results are complex and difficult to interpret.


Input: Our conclusion is that the presence of VAT intracellular hypercortisolism in human obesity is possible but unlikely.


Input: Long-term Effects of Perinatal Androgenization on Reproductive Parameters of Male Rat Offspring Androgenization and Male Rat Reproduction.


Input: It is known that during sex differentiation, fetal androgens are critical determinants of the male phenotype.

androgens


Input: Although testosterone is necessary for normal development of male sexual behavior, perinatal androgen treatment can result in disruption of normal male sexual reproduction.

testosterone

androgen


Input: Pregnant Wistar rats were administered either corn oil (vehicle) or testosterone propionate at 0. 2 mg/kg from gestational day 12 until the end of lactation and the reproductive function of male offspring was evaluated at 90 (adulthood) and 270 (middle age) days of age.

testosterone propionate


Input: Perinatal androgenization in the rat provoked a reduction in sperm production and reserves in adulthood that did not affect fertility and did not persist at more advanced ages, as shown by the results at post-natal day 270.


Input: If perinatal androgenization promotes similar effects in humans of reproductive age, the results of the present work can impact male reproduction health, given the less efficient spermatogenesis and lower sperm reserves in the human epididymis, compared to rodents.


Input: The CYP2B6 * 6 Allele Significantly Alters the N-demethylation of Ketamine Enantiomers In Vitro.

Ketamine


Input: Ketamine is primarily metabolized to norketamine by hepatic cytochrome P450 (CYP) 2B6 and CYP3A4-mediated N-demethylation.

Ketamine

norketamine


Input: However, the relative contribution from each enzyme remains controversial.


Input: The CYP2B6 * 6 allele is associated with reduced enzyme expression and activity that may lead to interindividual variability in ketamine metabolism.

ketamine


Input: We examined the N-demethylation of individual ketamine enantiomers using human liver microsomes (HLMs) genotyped for the CYP2B6 * 6 allele, insect cell expressed recombinant CYP2B6 and CYP3A4 enzymes and COS-1 cell expressed recombinant CYP2B6. 1 and CYP2B6. 6 protein variant.

ketamine


Input: Effects of CYP-selective inhibitors on norketamine formation were also determined in HLMs.

norketamine


Input: The two-enzyme Michaelis-Menten model best fitted the HLM kinetic data.


Input: The Km value for the high affinity enzyme and the low affinity enzyme were similar to those for the expressed CYP2B6 and CYP3A4, respectively.


Input: The intrinsic clearance for both ketamine enantiomers by the high affinity enzyme in HLMs with CYP2B6 * 1/* 1 genotype were at least 2-fold and 6-fold higher, respectively, than those for CYP2B6 * 1/* 6 genotype and CYP2B6 * 6/* 6 genotype.

ketamine


Input: The Vmax and Km values for CYP2B6. 1 were approximately 160% and 70% of those for CYP2B6. 6, respectively.


Input: ThioTEPA (CYP2B6 inhibitor, 25 mu M) and the monoclonal antibody against CYP2B6 but not troleandomycin (CYP3A4 inhibitor, 25 mu M) or the monoclonal antibody against CYP3A4 inhibited ketamine N-demethylation at clinically relevant concentrations.

ThioTEPA

troleandomycin

ketamine


Input: The degree of inhibition was significantly reduced in HLMs with the CYP2B6 * 6 allele (gene-dose P < 0. 05).


Input: These results indicate a major role of CYP2B6 in ketamine N-demethylation in vitro and a significant impact of the CYP2B6 * 6 allele on enzyme-ketamine binding and catalytic activity.

ketamine

ketamine


Input: Molecular Dynamics Simulations of CO2 Formation in Interstellar Ices.


Input: CO2 ice is one of the most abundant components in ice-coated interstellar ices besides H2O and CO, but the most favorable path to CO2 ice is still unclear.

CO


Input: Molecular dynamics calculations on the ultraviolet photodissociation of different kinds of CO-H2O ice systems have been performed at 10 K in order to demonstrate that the reaction between CO and an OH molecule resulting from H2O photodissociation through the first excited state is a possible route to form CO2 ice.

CO

CO

OH


Input: However, our calculations, which take into account different ice surface models, suggest that there is another product with a higher formation probability ((3. 00 +/- 0. 07) x 10 (-2)), which is the HOCO complex, whereas the formation of CO2 has a probability of only (3. 6 +/- 0. 7) x 10 (-4).

HOCO


Input: The initial location of the CO is key to obtain reaction and form CO2: the CO needs to be located deep into the ice.

CO

CO


Input: The HOCO complex becomes trapped in the cold ice surface in the trans-HOCO minimum because it quickly loses its internal energy to the surrounding ice, preventing further reaction to H + CO2.

HOCO

trans-HOCO

H


Input: Several laboratory experiments have been carried out recently, and they confirm that CO2 can also be formed through other, different routes.


Input: Here we compare our theoretical results with the data available from experiments studying the formation of CO2 through a similar pathway as ours, even though the initial conditions were not exactly the same.


Input: Our results also show that the HCO van der Waals complex can be formed through the interaction of CO with the H atom that is formed as a product of H2O photodissociation.

HCO

CO

H


Input: Thus, the reaction of the H atom photofragment following H2O photodissociation with CO can be a possible route to form HCO ice.

H

CO

HCO


Input: Thermal Stability of Peroxy Acyl Nitrates Formed in the Oxidation of CxF2x + 1CH2C (O) H (x = 1, 6) in the Presence of NO2.

Peroxy Acyl Nitrates

CxF2x + 1CH2C (O) H


Input: The formation of CxF2x + 1CH2C (O) OONO2 (x = 1, 6) from the photooxidation of CxF2x + 1CH2C (O) H (x = 1, 6) in the presence of NO2 was investigated.

CxF2x + 1CH2C (O) OONO2

CxF2x + 1CH2C (O) H


Input: The infrared spectrum of C6F13CH2C (O) OONO2 is reported for the first time, and thermal stability for both peroxynitrates at 295 K and 9. 0 mbar is informed.

C6F13CH2C (O) OONO2


Input: Kinetic parameters (activation energy and pre-exponential factor) for CF3CH2C (O) OONO2 at 9. 0 and 1000 mbar are: 108 +/- 2 kJ/mol, 1. 5 x 10 (15) and 114 +/- 2 kJ/mol, 2. 4 x 10 (16), respectively.

CF3CH2C (O) OONO2


Input: A comparison is made between fluoro and hydrogenated peroxy acyl nitrates.

peroxy acyl nitrates


Input: Effect of pioglitazone on body composition and bone density in subjects with prediabetes in the ACT NOW trial.

pioglitazone


Input: AIMS: This study examined the effects of pioglitazone on body weight and bone mineral density (BMD) prospectively in patients with impaired glucose tolerance as pioglitazone (TZD) increases body weight and body fat in diabetic patients and increases the risk of bone fractures.

pioglitazone

glucose

pioglitazone

TZD


Input: METHODS: A total of 71 men and 163 women aged 49. 3 (10. 7) years [mean (s. d.)]; body mass index (BMI), 34. 5 (5. 9) kg/m (2) were recruited at five sites for measurements of body composition by dual energy X-ray absorptiometry at baseline and at conversion to diabetes or study end, if they had not converted.


Input: RESULTS: Mean follow-up was 33. 6 months in the pioglitazone group and 32. 1 months in the placebo group.

pioglitazone


Input: Body weight increased 4. 63 +/- 0. 60 (m +/- s. e.) kg in the pioglitazone group compared to 0. 98 +/- 0. 62 kg in the PIO group (p < 0. 0001).

pioglitazone


Input: Body fat rose 4. 89 +/- 0. 42 kg in the pioglitazone group compared to 1. 41 +/- 0. 44 kg, (p < 0. 0001) in placebo-treated subjects.

pioglitazone


Input: The increase in fat was greater in legs and trunk than in the arms.


Input: BMD was higher in all regions in men and significantly so in most.


Input: PIO decreased BMD significantly in the pelvis in men and women, decreased BMD in the thoracic spine and ribs of women and the lumbar spine and legs of men.


Input: Bone mineral content also decreased significantly in arms, legs, trunk and in the total body.


Input: CONCLUSIONS: Pioglitazone increased peripheral fat more than truncal fat and decreased BMD in several regions of the body.

Pioglitazone


Input: Cis-silencing of PIP5K1B evidenced in Friedreich' s ataxia patient cells results in cytoskeleton anomalies.


Input: Friedreich' s ataxia (FRDA) is a progressive neurodegenerative disease characterized by ataxia, variously associating heart disease, diabetes mellitus and/or glucose intolerance.

glucose


Input: It results from intronic expansion of GAA triplet repeats at the FXN locus.


Input: Homozygous expansions cause silencing of the FXN gene and subsequent decreased expression of the encoded mitochondrial frataxin.


Input: Detailed analyses in fibroblasts and neuronal tissues from FRDA patients have revealed profound cytoskeleton anomalies.


Input: So far, however, the molecular mechanism underlying these cytoskeleton defects remains unknown.


Input: We show here that gene silencing spreads in cis over the PIP5K1B gene in cells from FRDA patients (circulating lymphocytes and primary fibroblasts), correlating with expanded GAA repeat size.


Input: PIP5K1B encodes phosphatidylinositol 4-phosphate 5-kinase beta type I (pip5k1 beta), an enzyme functionally linked to actin cytoskeleton dynamics that phosphorylates phosphatidylinositol 4-phosphate [PI (4) P] to generate phosphatidylinositol-4, 5-bisphosphate [PI (4, 5) P2].

phosphatidylinositol 4-phosphate

phosphatidylinositol 4-phosphate

PI (4) P

phosphatidylinositol-4, 5-bisphosphate

PI (4, 5) P2


Input: Accordingly, loss of pip5k1 beta function in FRDA cells was accompanied by decreased PI (4, 5) P2 levels and was shown instrumental for destabilization of the actin network and delayed cell spreading.

PI (4, 5) P2


Input: Knockdown of PIP5K1B in control fibroblasts using shRNA reproduced abnormal actin cytoskeleton remodeling, whereas over-expression of PIP5K1B, but not FXN, suppressed this phenotype in FRDA cells.


Input: In addition to provide new insights into the consequences of the FXN gene expansion, these findings raise the question whether PIP5K1B silencing may contribute to the variable manifestation of this complex disease.


Input: Evaluation of in vitro and in vivo genotoxicity of single-walled carbon nanotubes.

carbon


Input: Single-walled carbon nanotubes (SWCNTs) have extensive potential industrial applications due to their unique physical and chemical properties; yet this also increases the chance of human and environment exposure to SWCNTs.

carbon


Input: Due to the current lack of hazardous effect information on SWNCTs, a standardized genotoxicity battery test was conducted to clarify the genetic toxicity potential of SWCNTs (diameter: 1-1. 2 nm, length: ~ 20 mu m) according to Organization for Economic Cooperation and Development test guidelines 471 (bacterial reverse mutation test), 473 (in vitro chromosome aberration test), and 474 (in vivo micronuclei test) with a good laboratory practice system.


Input: The test results showed that the SWCNTs did not induce significant bacterial reverse mutations at 31. 3-500 mu g/plate in Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537 or in Escherichia coli strain WP2uvrA, with and without a metabolic activation system.


Input: Furthermore, the in vitro chromosome aberration test showed no significant increase in structural or numerical chromosome aberration frequencies at SWCNT dose levels of 12. 5-50 mu g/ml in the presence and absence of metabolic activation.


Input: However, dose-dependent cell growth inhibition was found at all the SWCNT dose levels and statistically significant cytotoxic effects observed at certain concentrations in the presence and absence of metabolic activation.


Input: Finally, the SWCNTs did not evoke significant in vivo micronuclei frequencies in the polychromatic erythrocytes of an imprinting control region mice at 25-100 mg/kg.


Input: Thus, according to the results of the present study, the SWCNTs were not found to have a genotoxic effect on the in vitro and in vivo test systems.


Input: Potential anticancer activity of carvone in N2a neuroblastoma cell line.

carvone


Input: Carvone (CVN) is a monocyclic monoterpene found in the essential oils of Mentha spicata var. crispa (Lamiaceae) and Carum carvi L.

Carvone

CVN

monocyclic monoterpene


Input: (Apiaceae) plants and has been reported to have antioxidant, antimicrobial, anticonvulsant, and antitumor activities.


Input: The beneficial health properties of CVN have encouraged us to look into its anticancer activity.

CVN


Input: To the best of our knowledge, reports are not available on the anticancer activity of CVN in cultured primary rat neuron and N2a neuroblastoma (NB) cells.

CVN


Input: Therefore, the present study is an attempt toward exploring the potential anticancer activity of CVN, if any, in cultured primary rat neuron and N2a NB cells.

CVN


Input: Our results indicated that CVN (only at 25 mg/L) treatment led to an increase in the total antioxidant capacity levels in cultured primary rat neuron cells compared with control cells.

CVN


Input: Also, CVN (at concentrations higher than 100 mg/L) treatment led to an increase in the total oxidative stress levels in both cell types.

CVN


Input: The mean values of the total scores of cells showing DNA damage (for comet assay) were not found to be significantly different from the control values in both cells (p > 0. 05).


Input: On the other hand, after 24 h treatment with CVN, 3-(4, 5-dimethylthiazol-2-yl)-2, 5 diphenyltetrazolium bromide assay showed that CVN application significantly reduced the cell viability rates in both cell types at concentrations higher than 100 mg/L.

CVN

3-(4, 5-dimethylthiazol-2-yl)-2, 5 diphenyltetrazolium bromide

CVN


Input: Summarizing, our data suggest that CVN represents little potential for promising anticancer agent to improve brain tumors therapy.

CVN


Input: Modeling CO2 reduction on Pt (111).

Pt (111)


Input: Density functional theory was used to model the electrochemical reduction of CO2 on Pt (111) with an explicit solvation layer and the presence of extra hydrogen atoms to represent a negatively charged electrode.

Pt (111)

hydrogen


Input: We focused on the electronic energy barriers for the first four lowest energy proton-electron transfer steps for reducing CO2 on Pt (111) beginning with adsorbed * CO2 and continuing with * COOH, * CO + H2O, * COH, and ending with * C + H2O.

Pt (111)

COOH

CO

COH

C


Input: We find that simple elementary steps in which a proton is transferred to an adsorbate (such as the protonation of * CO to * COH) have small barriers on the order of 0. 1 eV.

CO

COH


Input: Elementary steps in which a proton is transferred and a C-O bond is simultaneously cleaved show barriers on the order of 0. 5 eV.

C-O


Input: All barriers calculated for these steps show no sign of being insurmountable at room temperature.


Input: To explain why these barriers are so small, we analyze the charge density and the density of states plots to see that first, the electron transfer is decoupled from the proton transfer so that in the initial state, the surface and adsorbate are already charged up and can easily accept the proton from solution.


Input: Also, we see that in the cases where barriers are on the order of 0. 1 eV, electron density in the initial state localizes on the oxygen end of the adsorbate, while electron density is more spread out on the surface for initial states of the C-O bond cleaving elementary steps.

oxygen

C-O


Input: Comparing molecular photofragmentation dynamics in the gas and liquid phases.


Input: This article explores the extent to which insights gleaned from detailed studies of molecular photodissociations in the gas phase (i. e. under isolated molecule conditions) can inform our understanding of the corresponding photofragmentation processes in solution.


Input: Systems selected for comparison include a thiophenol (p-methylthiophenol), a thioanisole (p-methylthioanisole) and phenol, in vacuum and in cyclohexane solution.

thiophenol

p-methylthiophenol

thioanisole

p-methylthioanisole

phenol

cyclohexane


Input: UV excitation in the gas phase results in RX-Y (X = O, S; Y = H, CH3) bond fission in all cases, but over timescales that vary by ~ 4 orders of magnitude-all of which behaviours can be rationalised on the basis of the relevant bound and dissociative excited state potential energy surfaces (PESs) accessed by UV photoexcitation, and of the conical intersections that facilitate radiationless transfer between these PESs.

RX-Y

O

S

H


Input: Time-resolved UV pump-broadband UV/visible probe and/or UV pump-broadband IR probe studies of the corresponding systems in cyclohexane solution reveal additional processes that are unique to the condensed phase.

cyclohexane


Input: Thus, for example, the data clearly reveal evidence of (i) vibrational relaxation of the photoexcited molecules prior to their dissociation and of the radical fragments formed upon X-Y bond fission, and (ii) geminate recombination of the RX and Y products (leading to reformation of the ground state parent and/or isomeric adducts).

RX


Input: Nonetheless, the data also show that, in each case, the characteristics (and the timescale) of the initial bond fission process that occurs under isolated molecule conditions are barely changed by the presence of a weakly interacting solvent like cyclohexane.

cyclohexane


Input: These condensed phase studies are then extended to an ether analogue of phenol (allyl phenyl ether), wherein UV photo-induced RO-allyl bond fission constitutes the first step of a photo-Claisen rearrangement.

ether

phenol

allyl phenyl ether

RO

allyl


Input: Characterization and Expression of the Gene Encoding En-MAPK1, an Intestinal Cell Kinase (ICK)-like Kinase Activated by the Autocrine Pheromone-Signaling Loop in the Polar Ciliate, Euplotes nobilii.


Input: In the protozoan ciliate Euplotes, a transduction pathway resulting in a mitogenic cell growth response is activated by autocrine receptor binding of cell type-specific, water-borne signaling protein pheromones.


Input: In Euplotes raikovi, a marine species of temperate waters, this transduction pathway was previously shown to involve the phosphorylation of a nuclear protein kinase structurally similar to the intestinal-cell and male germ cell-associated kinases described in mammals.


Input: In E. nobilii, which is phylogenetically closely related to E. raikovi but inhabits Antarctic and Arctic waters, we have now characterized a gene encoding a structurally homologous kinase.


Input: The expression of this gene requires + 1 translational frameshifting and a process of intron splicing for the production of the active protein, designated En-MAPK1, which contains amino acid substitutions of potential significance for cold-adaptation.

amino acid


Input: Intracellular cleavable poly (2-dimethylaminoethyl methacrylate) functionalized mesoporous silica nanoparticles for efficient siRNA delivery in vitro and in vivo.

poly (2-dimethylaminoethyl methacrylate)

silica


Input: A low cytotoxicity and high efficiency delivery system with the advantages of low cost and facile fabrication is needed for the application of small interfering RNA (siRNA) delivery both in vitro and in vivo.


Input: For these prerequisites, cationic polymer-mesoporous silica nanoparticles (ssCP-MSNs) were prepared by surface functionalized mesoporous silica nanoparticles with disulfide bond cross-linked poly (2-dimethylaminoethyl methacrylate) (PDMAEMA).

silica

silica

disulfide

poly (2-dimethylaminoethyl methacrylate)

PDMAEMA


Input: In vitro and in vivo evaluations were performed.


Input: The synthesized ssCP-MSNs are 100-150 nm in diameter with a pore size of 10 nm and a positively charged surface with a high zeta potential of 27 mV.


Input: Consequently, the ssCP-MSNs showed an excellent binding capacity for siRNA, and an enhancement in the cell uptake and cytosolic availability of siRNA.


Input: Furthermore, the intracellular reducing cleavage of the disulfide bonds cross-linking the PDMAEMA segments led to intracellular cleavage of PDMAEMA from ssCP-MSNs, which facilitated the intracellular triggered release of siRNA.

disulfide

PDMAEMA

PDMAEMA


Input: Therefore, promoted RNA interference was observed in HeLa-Luc cells, which was equal to that of Lipofectamine 2000.


Input: Significantly, compared to Lipofectamine 2000, the ssCP-MSNs were more biocompatible, with low cytotoxicity (even non-cytotoxicity) and promotion of cell proliferation to HeLa-Luc cells.


Input: The in vivo systemic distribution studies certified that ssCP-MSNs/siRNA could prolong the duration of siRNA in vivo, and that they accumulated in the adrenal gland, liver, lung, spleen, kidney, heart and thymus after intravenous injection.


Input: Encouragingly, with the ability to deliver siRNA to a tumor, ssCP-MSNs/siRNA showed a tumor suppression effect in the HeLa-Luc xenograft murine model after intravenous injection.


Input: Therefore, the ssCP-MSNs cationic polymer-mesoporous silica nanoparticles with low cytotoxicity are promising for siRNA delivery.


Input: Effects of mixtures of azole fungicides in postimplantation rat whole-embryo cultures.

azole


Input: The effect of mixtures of azole fungicides on development of postimplantation rat whole-embryos cultured in vitro has been tested.

azole


Input: On the basis of bench mark dose (BMD) modeling of the in vitro effect in rat embryo, the potency of 7 azoles was determined and compared.

azoles


Input: Then, relative potency factors have been derived based on either the NOAEL or on the BMD curve.


Input: Alternatively, each compound was used as index compound (IC), and IC-equivalent concentrations have been calculated for each mixture.


Input: Expected effects of such IC-equivalent concentrations of the mixture were derived from the appropriate BMD curve.


Input: Test mixture includes the agrochemicals triadimefon and imazalil (MIX2) or triadimefon, imazalil, and the clinically used fluconazole (MIX3) at their previously determined no-effect concentration, corresponding to approximately a benchmark response of 5-10%.

triadimefon

imazalil

triadimefon

imazalil

fluconazole


Input: Subsequently, we tested the effect of a mixture of the agrochemicals triadimefon, imazalil, triadimenol, cyproconazole, tebuconazole, and flusilazole (MIX6) at concentration levels derived from their established human acceptable daily intake.

triadimefon

imazalil

triadimenol

cyproconazole

tebuconazole

flusilazole


Input: MIX6 was also added with fluconazole at concentration levels indicated as the minimum therapeutically effective plasmatic concentration (MIX7A) or ten times this level (MIX7B).

fluconazole


Input: Generally, the experimental response was higher than the estimated one, by a factor of 2-6.


Input: Our data suggest that it is in principle correct to assume that azoles act as teratogens via a common mode of action and therefore should be grouped together for risk assessment.


Input: The synergistic effect needs to be confirmed with more combinations of concentrations/compounds in vitro and with specific in vivo experiments.


Input: High responsivity, fast ultraviolet photodetector fabricated from ZnO nanoparticle-graphene core-shell structures.

ZnO

graphene


Input: We report a simple, efficient and versatile method for assembling metal oxide nanomaterial-graphene core-shell structures.

metal oxide

graphene


Input: An ultraviolet photodetector fabricated from the ZnO nanoparticle-graphene core-shell structures showed high responsivity and fast transient response, which are attributed to the improved carrier transport efficiency arising from graphene encapsulation.

ZnO

graphene

graphene


Input: Adsorption of diferrocenylacetylene on Au (111) studied by scanning tunneling microscopy.

diferrocenylacetylene

Au (111)


Input: Scanning tunneling microscopy images of diferrocenylacetylene (DFA) coadsorbed with benzene on Au (111) show individual and close-packed DFA molecules, either adsorbed alongside benzene or on top of a benzene monolayer.

diferrocenylacetylene

DFA

benzene

Au (111)

DFA

benzene

benzene


Input: Images acquired over a range of positive and negative tip-sample bias voltages show a shift in contrast, with the acetylene linker appearing brighter than the ferrocenes at positive sample bias (where unoccupied states primarily contribute) and the reverse contrast at negative bias.

acetylene

ferrocenes


Input: Density functional theory was used to calculate the electronic structure of the gas-phase DFA molecule, and simulated images produced through two-dimensional projections of these calculations approximate the experimental images.

DFA


Input: The symmetry of both experimental and calculated molecular features for DFA rules out a cis adsorption geometry, and comparison of experiment to simulation indicates torsion around the inter-ferrocene axis between 90 degrees and 180 degrees (trans); the cyclopentadienyl rings are thus angled with respect to the surface.

DFA

ferrocene

cyclopentadienyl


Input: Axitinib in metastatic renal cell carcinoma: results of a pharmacokinetic and pharmacodynamic analysis.

Axitinib


Input: Axitinib is a potent and selective inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, approved for second-line therapy for advanced renal cell carcinoma (RCC).

Axitinib


Input: Axitinib population pharmacokinetic and pharmacokinetic/pharmacodynamic relationships were evaluated.

Axitinib


Input: Using nonlinear mixed effects modeling with pooled data from 383 healthy volunteers, 181 patients with metastatic RCC, and 26 patients with other solid tumors in 17 trials, the disposition of axitinib was best described by a 2-compartment model with first-order absorption and a lag time, with estimated mean systemic clearance (CL) of 14. 6 L/h and central volume of distribution (Vc) of 47. 3 L.

axitinib


Input: Of 12 covariates tested, age over 60 years and Japanese ethnicity were associated with decreased CL, whereas Vc increased with body weight.


Input: However, the magnitude of predicted changes in exposure based on these covariates does not warrant dose adjustments.


Input: Multivariate Cox proportional hazard regression and logistic regression analyses showed that higher exposure and diastolic blood pressure were independently associated with longer progression-free and overall survivals and higher probability of partial response in metastatic RCC patients.


Input: These findings support axitinib dose titration to increase plasma exposure in patients who tolerate axitinib, and also demonstrate diastolic blood pressure as a potential marker of efficacy.

axitinib

axitinib


Input: Aerosol particle size does not predict pharmacokinetic determined lung dose in children.


Input: In vitro measures of aerosol particles size, such as the fine particle mass, play a pivotal role for approval of inhaled anti-asthmatic drugs.


Input: However, the validity as a measure of dose to the lungs in children lacks evidence.


Input: In this study we investigated for the first time the association between an in vivo estimate of lung dose of inhaled drug in children and the corresponding particle size segments assessed ex vivo.


Input: Lung dose of fluticasone propionate after inhalation from a dry powder inhaler (Diskus (R)) was studied in 23 children aged 4-7 and 12-15 years with mild asthma.

fluticasone propionate

Diskus


Input: Six-hour pharmacokinetics was assessed after single inhalation.


Input: The corresponding emitted mass of drug in segments of aerosol particle size was assessed ex vivo by replicating the inhalation flows recorded by transducers built into the Diskus (R) inhaler and re-playing them in a breathing simulator.

Diskus


Input: There was no correlation between any inhaled particle size segment and lung dose assessed by pharmacokinetics and adjusted for age and body size.


Input: Measures of particles size segments were not related to lung dose in children.


Input: Until further evidence is provided it may be warranted to emphasize pharmacokinetic or pharmacodynamic assessments of drug delivery to the lung.


Input: The N-and C-termini of ZO-1 are surrounded by distinct proteins and functional protein networks.


Input: The proteins and functional protein networks of the tight junction remain incompletely defined.


Input: Among the currently known proteins are barrier forming proteins like occludin and the claudin family, scaffolding proteins like ZO-1, and some cytoskeletal, signaling and cell polarity proteins.


Input: To define a more complete list of proteins and infer their functional implications, we identified the proteins which are within molecular dimensions of ZO-1 by fusing biotin ligase to either its N-or C-terminus, expressing these fusion proteins in MDCK epithelial cells and purifying and identifying the resulting biotinylated proteins by mass spectrometry.

biotin


Input: Out of a predicted proteome of =~ 9000 we identified more than 400 proteins tagged by biotin ligase fused to ZO-1, with both identical and distinct proteins near the N-and C-terminal ends.

biotin

N

C


Input: Those proximal to the N-terminus were enriched in transmembrane tight junction proteins and those proximal to the C-terminus were enriched in cytoskeletal proteins.


Input: We also identified many unexpected, but easily rationalized proteins.


Input: In addition, functional networks of interacting proteins were tagged, such as the basolateral but not apical polarity network.


Input: These results provide a rich inventory of proteins and potential novel insights into functions and protein networks that should catalyze further understanding of tight junction biology.


Input: Unexpectedly, the technique demonstrates high spatial resolution which could be generally applied to defining subcellular protein compartmentalization.


Input: Treatment-, Patient-, and Disease-Related Factors and the Emergence of Adverse Events with Tyrosine Kinase Inhibitors for the Treatment of Chronic Myeloid Leukemia.

Tyrosine


Input: Four breakpoint cluster region (BCR)-ABL1 tyrosine kinase inhibitors (TKIs) are currently available for the treatment of chronic myeloid leukemia (CML): imatinib, nilotinib, dasatinib, and bosutinib.

tyrosine

imatinib

nilotinib

dasatinib

bosutinib


Input: Choosing the most appropriate TKI requires clinicians to consider a host of patient-, disease-, and treatment-related factors, not the least of which include the safety profiles of the agents.


Input: This review discusses the potential impact of treatment-, patient-, and disease-related characteristics on the emergence of adverse events during TKI therapy, with a focus on the underlying mechanisms believed to be responsible for a number of important adverse events associated with these agents and what implications they may have for treatment choice, particularly in the setting of first-line treatment.


Input: A literature search of the PubMed database was conducted to identify articles that described the molecular mechanisms of BCR-ABL1-mediated leukemic transformation, the efficacy and safety of imatinib, nilotinib, dasatinib, and bosutinib in patients with CML, the kinase-binding spectrum of each TKI, and evidence suggesting a link between the TKI-binding profile and adverse events.

imatinib

nilotinib

dasatinib

bosutinib


Input: The pattern of adverse events associated with each agent is important when selecting treatment with a TKI.


Input: Clinical studies suggest that imatinib, nilotinib, dasatinib, and bosutinib have differing safety profiles, which are in part attributable to the specificity and selectivity of each agent.

imatinib

nilotinib

dasatinib

bosutinib


Input: Although much basic research must be conducted to further illuminate the mechanisms responsible for TKI-related adverse events, on-and off-target effects are believed to be at least partly responsible for cardiovascular toxicity, myelosuppression, fluid retention, gastrointestinal toxicity, and dermatologic toxicity.


Input: Increased understanding of the factors that affect TKI-associated adverse events and long-term safety data will enable a more informed approach to the selection of therapy best suited to the individual needs of patients with CML.


Input: A Localized Surface Plasmon Resonance-Based Multicolor Electrochromic Device with Electrochemically Size-Controlled Silver Nanoparticles.

Silver


Input: The first localized surface plasmon resonance (LSPR)-based multicolor electrochromic device with reversible five optical states is demonstrated.


Input: In this device, the size of deposited silver nanoparticles is electrochemically controlled using a voltage-step method in which two different voltages are applied successively.

silver


Input: The electrochemically size-controlled silver nanoparticles enable a reversible multiple-color change by a shift of the LSPR band.

silver


Input: Validation of a Novel Approach for Dose Individualization in Pharmacotherapy Using Gabapentin in a Proof of Principles Study.

Gabapentin


Input: STUDY OBJECTIVE: To demonstrate the premise of individualized dosing charts (IDCs) as a clinical-bedside decision-support tool to individualize dosage regimens for drugs in which the interpatient variability is controlled by the pharmacokinetic (PK) behavior of the patient, to calculate the optimal sampling schedule (OSS), which minimizes the number of blood samples per patient.


Input: The approach is illustrated with available PK data for gabapentin.

gabapentin


Input: DESIGN: Retrospective proof of principles study using gabapentin PK data from a published clinical trial.

gabapentin


Input: PATIENTS: Nineteen subjects in a trial designed to uncover the importance of the genetic contributions to variability in gabapentin absorption, renal elimination, and transport; subjects were monitored for 36 hours after administration of a single dose of gabapentin 400 mg, and plasma concentrations were determined at 14 time points.

gabapentin

gabapentin


Input: MEASUREMENTS AND MAIN RESULTS: When the PK profiles were different between subjects, the IDCs are dramatically different from each other and from the IDC for an " average " patient representing the patient population.


Input: The dose amount and dosing interval must be adjusted to maximize the probability of staying within the target concentration range.


Input: An optimal sampling methodology based on the assumption-free Bayesian approach is used to distinguish the PK profile of an individual patient from the patient population.


Input: In the case of gabapentin, only two optimally selected test blood samples, at 1. 5 and 6 hours after administration of a single doses, were necessary.

gabapentin


Input: The average sensitivity and the average specificity of the OSS was 99% and 96%, respectively.


Input: CONCLUSION: IDCs display the risk of a patient violating the target concentration range for any dosage regimen.


Input: They can be used as a clinical-bedside decision-support tool in a patient-physician partnership to decide on a dose amount and dosing interval that are medically acceptable while practical and convenient to ensure compliance.


Input: By using the assumption-free Bayesian approach and the OSS, the number of samples required from a new patient to individualize the dosage regimen can be reduced significantly while preserving high levels of sensitivity and specificity.


Input: Prospective studies are being planned to validate the encouraging results.


Input: This approach can be extended to any drug if PK data and a target concentration range are available for either therapeutic drug monitoring or target concentration intervention.


Input: Impact of Sildenafil on Survival of Patients With Eisenmenger Syndrome.

Sildenafil


Input: The favorable effects of short-term use of sildenafil on patients with Eisenmenger syndrome have been reported.

sildenafil


Input: We further studied the impact of long-term use of sildenafil on survival of these patients.

sildenafil


Input: In this study, the baseline data of patients newly diagnosed as Eisenmenger syndrome in our hospital between January 2005 and December 2009 were retrospectively collected.


Input: Patients were followed-up either by telephone contacts or during visits in our out-patient clinic.


Input: A total of 121 patients (68 patients in conventional group and 53 patients in sildenafil group) were finally included and 29 patients were re-evaluated after sildenafil therapy for 3-4 months.

sildenafil

sildenafil


Input: Compared with the baseline, a 6-minute walk distance, functional classes, plasma hemoglobin level, and hemodynamics were significantly improved after sildenafil treatment.

sildenafil


Input: During a median follow-up period of 35. 8 months, 15 patients died (11 patients in conventional group).


Input: The 1-and 3-year survival rates in sildenafil group were 97. 0% and 95. 2%, significantly higher than 90. 6% and 82. 9% in conventional group P =. 025).

sildenafil


Input: Multivariate analysis showed that sildenafil therapy, functional class and mean pulmonary arterial pressure were independently associated with survival.

sildenafil


Input: Therefore, long-term sildenafil therapy improved survival in patients with Eisenmenger syndrome.

sildenafil


Input: Clinical update on the management of atrial fibrillation.


Input: Atrial fibrillation (AF) is a cardiac arrhythmia associated with significant morbidity and mortality, affecting more than 3 million people in the United States and 1-2% of the population worldwide.


Input: Its estimated prevalence is expected to double within the next 50 years.


Input: During the past decade, there have been significant advances in the treatment of AF.


Input: Studies have demonstrated that a rate control strategy, with a target resting heart rate between 80 and 100 beats/minute, is recommended over rhythm control in the vast majority of patients.


Input: The CHA2 DS2 >= (congestive heart failure, hypertension, age >= 65 yrs, diabetes mellitus, stroke or transient ischemic attack, vascular disease, female gender) scoring system is a potentially useful stroke risk stratification tool that incorporates additional risk factors to the commonly used CHADS2 (congestive heart failure, hypertension, age >= 75 years, diabetes mellitus, stroke transient ischemic attack) scoring tool.


Input: Similarly, a convenient scheme, termed HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly), to assess bleeding risk has emerged that may be useful in select patients.

alcohol


Input: Furthermore, new antithrombotic strategies have been developed as potential alternatives to warfarin, including dual-antiplatelet therapy with clopidogrel plus aspirin and the development of new oral anticoagulants such as dabigatran, rivaroxaban, and apixaban.

warfarin

clopidogrel

aspirin

dabigatran

rivaroxaban

apixaban


Input: Vernakalant has emerged as another potential option for pharmacologic conversion of AF, whereas recent trials have better defined the role of dronedarone in the maintenance of sinus rhythm.

Vernakalant

dronedarone


Input: Finally, catheter ablation represents another alternative to manage AF, whereas upstream therapy with inhibitors of the renin-angiotensin-aldosterone system, statins, and polyunsaturated fatty acids could potentially prevent the occurrence of AF.

aldosterone

statins

polyunsaturated fatty acids


Input: Despite substantial progress in the management of AF, significant uncertainty surrounds the optimal treatment of this condition.


Input: An analysis of skeletal development in osteoblast-and chondrocyte-specific Runx2 knockout mice.


Input: Global gene deletion studies in mice and humans have established the pivotal role of runt related transcription factor-2 (Runx2) in both intramembranous and endochondral ossification processes during skeletogenesis.


Input: In this study, we for the first time generated mice carrying a conditional Runx2 allele with exon 4, which encodes the Runt domain, flanked by loxP sites.


Input: These mice were crossed with alpha 1 (I)-collagen-Cre or alpha 1 (II)-collagen-Cre transgenic mice to obtain osteoblast-or chondrocyte-specific Runx2 deficient mice, respectively.


Input: As seen in Runx2 (-/-) mice, perinatal lethality was observed in alpha 1 (II)-Cre; Runx2 (flox/flox) mice, but this was not the case in animals in which alpha 1 (I)-collagen-Cre was used to delete Runx2.


Input: When using double staining with Alizarin red for mineralized matrix and Alcian blue for cartilaginous matrix, we observed previously that mineralization was totally absent at embryonic day 15. 5 throughout the body in Runx2 (-/-) mice, but was found in areas undergoing intramembranous ossification such as skull and clavicles in alpha 1 (II)-Cre; Runx2 (flox/flox) mice.

Alizarin red

Alcian blue


Input: In newborn alpha 1 (II)-Cre; Runx2 (flox/flox) mice, mineralization impairment was restricted to skeletal areas undergoing endochondral ossification including long bones and vertebrae.


Input: In contrast, no apparent skeletal abnormalities were seen in mutant embryo, newborn, and 3-to 6-week old-mice in which Runx2 had been deleted with the alpha 1 (I)-collagen-Cre driver.


Input: These results suggest that Runx2 is absolutely required for endochondral ossification during embryonic and postnatal skeletogenesis, but that disrupting its expression in already committed osteoblasts as achieved here with the alpha 1 (I)-collagen-Cre driver does not affect overtly intramembranous and endochondral ossification.


Input: The Runx2 floxed allele established here is undoubtedly useful for investigating the role of Runx2 in particular cells.


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


Input: Bone stiffness and failure load are related with clinical parameters in men with chronic obstructive pulmonary disease.


Input: Osteoporosis is frequently seen in patients with chronic obstructive pulmonary disease (COPD).


Input: Since research on bone structure and bone strength in COPD patients is limited, the objectives of this pilot study were: 1.


Input: To compare bone structure, stiffness and failure load, measured at the peripheral skeleton, between men with and without COPD after stratification for areal bone mineral density (aBMD), and 2.


Input: To relate clinical parameters with bone stiffness and failure load in men with COPD.


Input: We included 30 men with COPD (normal aBMD n = 18, osteoporosis n = 12) and 17 men without COPD (normal aBMD n = 9, osteoporosis n = 8).


Input: We assessed pack-years of smoking, body mass index (BMI), fat free mass index (FFMI), pulmonary function (FEV1, FEV1/FVC, DLCO and KCO) and extent of emphysema.


Input: Bone structure of the distal radius and tibia was assessed by high resolution peripheral quantitative computed tomography (HR-pQCT), and bone stiffness and failure load of the distal radius and tibia were estimated from micro finite element analysis (micro FEA).


Input: After stratification for aBMD and COPD, men with osteoporosis showed abnormal bone structure (p < 0. 01), lower bone stiffness (p < 0. 01) and lower failure load (p < 0. 01) compared with men with normal aBMD, and men with COPD had comparable bone structure, stiffness and failure load compared with men without COPD.


Input: In men with COPD, lower FFMI was related with lower bone stiffness and failure load of the radius and tibia and lower DLCO and KCO were related with lower bone stiffness and failure load of the tibia after normalization with respect to femoral neck aBMD.


Input: Thus, this pilot study could not detect differences in bone structure, stiffness and failure load between men with and without COPD after stratification for aBMD.


Input: FFMI and gas transfer capacity of the lung were significantly related with bone stiffness and failure load in men with COPD after normalization with respect to femoral neck aBMD.


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


Input: In Situ Study of CO Oxidation on HOPG-Supported Pt Nanoparticles.

CO

Pt


Input: Catalyzed CO oxidation: A newly designed high-pressure flow cell is utilized to study CO oxidation on Pt nanoparticles in situ by simultaneous quadrupole mass spectrometry and high-pressure X-ray photoelectron spectroscopy.

CO

CO

Pt


Input: The spectroscopy data show that the active catalyst consists of metallic Pt with both chemisorbed O and patches/shell of surface oxides.

Pt

O

oxides


Input: Clinical Study to Assess the Efficacy and Safety of a Citrus Polyphenolic Extract of Red Orange, Grapefruit, and Orange (Sinetrol-XPur) on Weight Management and Metabolic Parameters in Healthy Overweight Individuals.


Input: The present study investigated the efficacy and safety effects of Sinetrol-XPur (polyphenolic citrus dry extract) in weight management; metabolic parameters; and inflammatory, glycemic and oxidative status.


Input: In a 12-week, randomized, double-blind, placebo-controlled trial, Sinetrol-XPur was given to overweight subjects twice daily with meals in the tested group (N = 47) versus a placebo group (N = 48).


Input: Waist and hip circumference and abdominal fat were decreased in the Sinetrol-XPur group as compared with the placebo group (p < 0. 0001) (-5. 71% vs-1. 56% for waist,-4. 71% vs-1. 35% for hip and-9. 73% vs-3. 18% for fat).


Input: Inflammatory markers were reduced (C-reactive protein:-22. 87% vs + 61%; fibrinogen:-19. 93% vs-1. 61%, p < 0. 01).


Input: Oxidative stress was lowered as seen by the reduction of malondialdehyde (-14. 03% vs 2. 76%) and the increase in superoxide dismutase and glutathione (17. 38% vs 2. 19% and 4. 63% vs-2. 36%, respectively, p < 0. 01).

malondialdehyde

superoxide

glutathione


Input: No adverse effects were observed.


Input: Kidney, liver, and lipid panels remained unchanged.


Input: These results indicated that Sinetrol-XPur supplementation is a viable option for reducing abdominal fat, waist and hip circumference, and body weight and for improving inflammatory, glycemic, and oxidative status in healthy overweight individuals.


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


Input: The electronic origin of unusually large (n) JFN coupling constants in some fluoroximes.

fluoroximes


Input: SOPPA (CCSD) calculations show that the FC term is the most important contribution to the through-space transmission of JFN coupling constants for the fluoroximes studied in this work.

fluoroximes


Input: Because of the well-known behavior of FC term, a new rationalization for the experimental (TS) JFN SSCC is presented.


Input: It is mainly based on the overlap matrix (Sij) between fluorine and nitrogen lone pairs obtained from NBO analyses.

fluorine

nitrogen


Input: An expression is proposed to take into account the influence of the electronic density (Dij) between coupled nuclei as well as the s% character at the site of the coupling nuclei of bonds and non-bonding electron pairs involved in Dij.


Input: In using this approach, a linear correlation between (TS) JFN versus Dij is obtained.


Input: The most important aspect of this rationalization is related to the facility for understanding the behavior of some unusual experimental coupling constants.


Input: It is shown that, at least in this case, the electronic origin of the so-called through-space coupling is transmitted through to the overlap of orbitals on the coupled atoms, suggesting that, at least for these compounds, instead of through-space coupling, it should better be dubbed as' through overlapping orbital coupling'.


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


Input: Vibrational sum-frequency generation activity of a 2, 4-dinitrophenyl phospholipid hybrid bilayer: retrieving orientational parameters from a DFT analysis of experimental data.

2, 4-dinitrophenyl


Input: The vibrational nonlinear activity of films of 2, 4-dinitrophenyl phospholipid (DNP) at the solid interface is measured by sum-frequency generation spectroscopy (SFG).

2, 4-dinitrophenyl


Input: Hybrid bilayers are formed by a Langmuir-Schaefer approach in which the lipid layer is physisorbed on top of a self-assembled monolayer of dodecanethiol on Pt with the polar heads pointing out from the surface.

dodecanethiol

Pt


Input: The SFG response is investigated in two vibrational frequency domains, namely, 3050-2750 and 1375-1240 cm (-1).


Input: The first region probes the CH stretching modes of DNP films, and the latter explores the vibrational nonlinear activity of the 2, 4-dinitroaniline moiety of the polar head of the lipid.

CH

2, 4-dinitroaniline


Input: Analysis of the CH stretching vibrations suggests substantial conformational order of the aliphatic chains with only a few gauche defects.

CH


Input: To reliably assign the detected SFG signals to specific molecular vibrations, DFT calculations of the IR and Raman activities of molecular models are performed and compared to experimental solid-state spectra.


Input: This allows unambiguous assignment of the observed SFG vibrations to molecular modes localized on the 2, 4-dinitroaniline moiety of the polar head of DNP.

2, 4-dinitroaniline


Input: Then, SFG spectra of DNP in the 1375-1240 cm (-1) frequency range are simulated and compared with experimental ones, and thus the 1, 4-axis of the 2, 4-dinitrophenyl head is estimated to have tilt and rotation angles of 45 +/- 5 degrees and 0 +/- 30 degrees, respectively.

2, 4-dinitrophenyl