Input: Remarkably, when misregulated, it leads to tumorigenesis.


Input: Hedgehog signaling is triggered by binding of ligands with transmembrane receptor Ptch and is subsequently mediated by transcriptional effectors belonging to the Gli family, whose functions is tuned by a number of molecular interactions and post-synthetic modifications.


Input: The complex of these regulatory circuitries provides a tight control of developmental processes, mainly involving the modulation of genes determining the fate of stem cells.


Input: Similarly, Hedgehog regulates cancer stem cells fostering tumorigenesis.


Input: To this regard, these processes represent promising targets for novel therapeutic strategies aiming at the control of stemness reactivation and maintenance in cancer.


Input: Hydrogen sulfide increases nitric oxide production with calcium-dependent activation of endothelial nitric oxide synthase in endothelial cells.

Hydrogen sulfide

nitric oxide

calcium

nitric oxide


Input: Hydrogen sulfide (H (2) S) was recently discovered to be synthesized in mammalian tissues by several different enzymes.

Hydrogen sulfide

H (2) S


Input: Numerous studies have shown that H (2) S has vasodilator and antihypertensive effects in the cardiovascular system.

H (2) S


Input: However, intracellular mechanisms of the H (2) S-induced vasodilation and its interactions with other endothelium-derived relaxing factors, such as nitric oxide (NO), remain unclear.

H (2) S

nitric oxide

NO


Input: We investigated whether H (2) S directly regulates endothelial NO synthase (eNOS) activity and NO production in endothelial cells.

H (2) S

NO


Input: NaHS, a H (2) S donor, dose-dependently increased NO production in cultured endothelial cells.

NaHS

H (2) S

NO


Input: This effect was abolished by a calcium chelator (BAPTA-AM), but not by the absence of extracellular calcium.

calcium

BAPTA-AM

calcium


Input: The NaHS-induced NO production was partially blocked by inhibitors of ryanodine receptor (dantrolene) or inositol 1, 4, 5-triphosphate receptor (xestospongin C).

NaHS

NO

ryanodine

dantrolene

inositol 1, 4, 5-triphosphate

xestospongin C


Input: NaHS significantly increased intracellular calcium concentrations, and this effect was attenuated by dantrolene or xestospongin C.

NaHS

calcium

dantrolene

xestospongin C


Input: NaHS induced phosphorylation of eNOS at the activating phosphoserine residue 1179.

NaHS

phosphoserine


Input: The NaHS-induced eNOS phosphorylation and NO production were not affected by a PI3K/Akt inhibitor (wortmannin).

NaHS

wortmannin


Input: The data of this study suggest that H (2) S directly acts on endothelial cells to induce eNOS activation and NO production by releasing calcium from the intracellular store in endoplasmic reticulum, which may explain one of mechanisms of its vasodilator function.

H (2) S

calcium


Input: Efficient serum-resistant lipopolyplexes targeted to the folate receptor.

folate


Input: In this work, we have developed and evaluated a new targeted lipopolyplex (LPP), by combining polyethylenimine (PEI), 1, 2-dioleoyl-3-(trimethylammonium) propane (DOTAP)/Chol liposomes, the plasmids pCMVLuc/pCMVIL-12, and the ligand folic acid (FA), able to transfect HeLa and B16-F10 cells in the presence of very high concentration of serum (60% FBS).

polyethylenimine

PEI

1, 2-dioleoyl-3-(trimethylammonium) propane

DOTAP

folic acid


Input: These complexes (Fol-LPP) have a net positive surface charge.


Input: The combination of folic acid with lipopolyplexes also enhanced significantly the transfection activity of the therapeutic gene interleukin-12 (IL-12), without any significant cytotoxicity.

folic acid


Input: The specificity of the folate receptor (FR)-mediated gene transfer was corroborated by employing a folate receptor deficient cell line (HepG2).

folate

folate


Input: This formulation improved gene delivery showed by conventional lipoplexes or polyplexes resulting an efficient, simple, and nontoxic method for gene delivery of therapeutic genes in vitro and very probably in vivo.


Input: Ferulic acid modulates fluoride-induced oxidative hepatotoxicity in male Wistar rats.

Ferulic acid

fluoride


Input: The present study is aimed to evaluate the protective effect of ferulic acid (FA) on fluoride-induced oxidative hepatotoxicity in male Wistar rats.

ferulic acid

fluoride


Input: Fluoride (25 mg/L) was given orally to induce hepatotoxicity for 12 weeks.

Fluoride


Input: Hepatic damage were assessed using status of pathophysiological markers like serum marker enzymes like aspartate transaminase, alanine transaminase, alkaline phosphatase, acid phosphatase, gamma glutamyl transferase, lactate dehydrogenase, bilirubin, lipid profile, total protein content levels, and histopathological studies.

aspartate

alanine

gamma glutamyl

lactate

bilirubin


Input: Treatment with FA significantly reduced the degree of histological aberrations and rescued lipid peroxidation, as observed from reduced levels of lipid hydroperoxides, nitric oxide, restored levels of enzymic and non-enzymic antioxidants, and total protein content, with a concomitant decline in the levels of marker enzymes and lipid profile in fluoride-induced rats.

hydroperoxides

nitric oxide

fluoride


Input: These results suggest that ferulic acid has the ability to protect fluoride-induced hepatic damage.

ferulic acid

fluoride


Input: The clinical relevance of plasma protein binding changes.


Input: Controversy reigns as to how protein binding changes alter the time course of unbound drug concentrations in patients.


Input: Given that the unbound concentration is responsible for drug efficacy and potential drug toxicity, this area is of significant interest to clinicians and academics worldwide.


Input: The present uncertainty means that many questions relating to this area exist, including " How important is protein binding? ", " Is protein binding always constant? ", " Do pH and temperature changes alter binding? " and " How do protein binding changes affect dosing requirements? ".


Input: In this paper, we seek to address these questions and consider the data associated with altered pharmacokinetics in the presence of changes in protein binding and the clinical consequences that these may have on therapy, using examples from the critical care area.


Input: The published literature consistently indicates that a change in the protein binding and unbound concentrations of some drugs are common in certain specific patient groups such as the critically ill.


Input: Changes in pharmacokinetic parameters, including clearance and apparent volume of distribution (V (d)), may be dramatic.


Input: Drugs with high protein binding, high intrinsic clearance (e. g. clearance by glomerular filtration) and where dosing is not titrated to effect are most likely to be affected in a clinical context.


Input: Drugs such as highly protein bound antibacterials with multiple half-lives within a dosing interval and that have some level of renal clearance, such as ertapenem, teicoplanin, ceftriaxone and flucloxacillin, are commonly affected.

ertapenem

teicoplanin

ceftriaxone

flucloxacillin


Input: In response to these challenges, clinicians need to adapt dosing regimens rationally based on the pharmacokinetic/pharmacodynamic characteristics of the drug.


Input: We propose that further pharmacokinetic modelling-based research is required to enable the design of robust dosing regimens for drugs affected by altered protein binding.


Input: In vitro cytochrome p450 activity decreases in children with high pediatric end-stage liver disease scores.


Input: To improve the modeling and simulation of pharmacokinetics in pediatric patients, research into developmental and disease-specific determinants is needed.


Input: This article describes the evaluation of the activity of in vitro cytochrome P450 (P450), an important enzyme family in drug metabolism, in children with hepatic dysfunction.


Input: The activity of six P450 isoforms (CYP1A2, 2C9, 2C19, 2D6, 2E1, and 3A4) was evaluated in 31 patients with different pathologies, predominantly biliary atresia (n = 23).


Input: Hypervariable activity was observed for all the isoforms.


Input: Compared with average adult activity, low activity levels were seen for CYP1A2, 2C19, 2E1, and 3A4.


Input: For CYP2E1 and 3A4, a positive correlation between activity and abundance was observed.


Input: Age, comedication, and genotype could not be used as predictors for P450 activity in this patient population.


Input: In contrast, the pediatric end-stage liver disease score was negatively correlated with the ln (activity).


Input: This finding suggests a decrease in P450 activity with deteriorating hepatic function.


Input: Moreover, the activity of all isoforms was correlated, demonstrating a concomitant decrease of all isoforms in young patients with liver disease.


Input: To our knowledge, this is the first study to evaluate P450 activity in children with hepatic impairment.


Input: The presented data may provide support in the further optimization of a disease-specific model in this patient population.


Input: Induction of multidrug resistance transporter ABCG2 by prolactin in human breast cancer cells.


Input: The multidrug transporter, breast cancer resistance protein, ABCG2, is up-regulated in certain chemoresistant cancer cells and in the mammary gland during lactation.


Input: We investigated the role of the lactogenic hormone prolactin (PRL) in the regulation of ABCG2.


Input: PRL dose-dependently induced ABCG2 expression in T-47D human breast cancer cells.


Input: This induction was significantly reduced by short-interfering RNA-mediated knockdown of Janus kinase 2 (JAK2).


Input: Knockdown or pharmacologic inhibition of the down-stream signal transducer and activator of transcription-5 (STAT5) also blunted the induction of ABCG2 by PRL, suggesting a role for the JAK2/STAT5 pathway in PRL-induced ABCG2 expression.


Input: Corroborating these findings, we observed PRL-stimulated STAT5 recruitment to a region containing a putative gamma-interferon activation sequence (GAS) element at-434 base pairs upstream of the ABCG2 transcription start site.


Input: Introduction of a single mutation to the-434 GAS element significantly attenuated PRL-stimulated activity of a luciferase reporter driven by the ABCG2 gene promoter and 5'-flanking region containing the-434 GAS motif.


Input: In addition, this GAS element showed strong copy number dependency in its response to PRL treatment.


Input: Interestingly, inhibitors against the mitogen-activated protein kinase and phosphoinositide-3-kinase signaling pathways significantly decreased the induction of ABCG2 by PRL without altering STAT5 recruitment to the GAS element.

phosphoinositide


Input: We conclude that the JAK2/STAT5 pathway is required but not sufficient for the induction of ABCG2 by PRL.


Input: Obtusilactone B from Machilus Thunbergii targets barrier-to-autointegration factor to treat cancer.

Obtusilactone B


Input: Targeting specific molecules is a promising cancer treatment because certain types of cancer cells are dependent on specific oncogenes.


Input: This strategy led to the development of therapeutics that use monoclonal antibodies or small-molecule inhibitors.


Input: However, the continued development of novel molecular targeting inhibitors is required to target the various oncogenes associated with the diverse types and stages of cancer.


Input: Obtusilactone B is a butanolide derivative purified from Machilus thunbergii.

Obtusilactone B

butanolide


Input: In this study, we show that obtusilactone B functions as a small-molecule inhibitor that causes abnormal nuclear envelope dynamics and inhibits growth by suppressing vaccinia-related kinase 1 (VRK1)-mediated phosphorylation of barrier-to-autointegration factor (BAF).

obtusilactone B


Input: BAF is important in maintaining lamin integrity, which is closely associated with diseases that include cancer.


Input: Specific binding of obtusilactone B to BAF suppressed VRK1-mediated BAF phosphorylation and the subsequent dissociation of the nuclear envelope from DNA that allows cells to progress through the cell cycle.

obtusilactone B


Input: Obtusilactone B potently induced tumor cell death in vitro, indicating that specific targeting of BAF to block cell cycle progression can be an effective anticancer strategy.

Obtusilactone B


Input: Our results demonstrate that targeting a major constituent of the nuclear envelope may be a novel and promising alternative approach to cancer treatment.


Input: Synthesis and antitubercular activity of 2-(substituted phenyl/benzyl-amino)-6-(4-chlorophenyl)-5-(methoxycarbonyl)-4-methyl-3, 6-dihydropyrimidin-1-ium chlorides.

2-(substituted phenyl/benzyl-amino)-6-(4-chlorophenyl)-5-(methoxycarbonyl)-4-methyl-3, 6-dihydropyrimidin-1-ium chlorides


Input: A series of 2-(substituted phenyl/benzyl-amino)-6-(4-chlorophenyl)-5-(methoxycarbonyl)-4-methyl-3, 6-dihydropyrimidin-1-ium chlorides 7-13 and 15 was synthesized in their hydrochloride salt form.

2-(substituted phenyl/benzyl-amino)-6-(4-chlorophenyl)-5-(methoxycarbonyl)-4-methyl-3, 6-dihydropyrimidin-1-ium chlorides

hydrochloride


Input: The title compounds were characterized by FT-IR, NMR ((1) H and (13) C) and elemental analysis.

(1) H

(13) C


Input: They were evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv, multidrug resistance tuberculosis and extensively drug resistance tuberculosis by agar diffusion method and tested for the cytotoxic action on peripheral blood mononuclear cells by MTT assay.

MTT


Input: Among all the tested compounds in the series, compounds 7 and 11 emerged as promising antitubercular agents at 16 mu g/mL against multidrug resistance tuberculosis and over 64 mu g/mL against extensively drug resistance tuberculosis.


Input: The conformational features and supramolecular assembly of the promising compounds 7 and 11 were determined by single crystal X-ray study.


Input: A dual role of Se on Cd toxicity: evidences from the uptake of Cd and some essential elements and the growth responses in paddy rice.

Se

Cd

Cd


Input: This study was carried out to investigate the effects of selenium (Se) on the uptake and translocation of cadmium (Cd) and essential elements in paddy rice (Oryza sativa L., Shuangyou 998).

selenium

Se

cadmium

Cd


Input: Selenium could alleviate/aggravate Cd toxicity in paddy rice, which depended on the dosages of Se and/or Cd.

Selenium

Cd

Se

Cd


Input: When Cd treatment level was as low as 35. 6 mu M, <= 12. 7 mu M Se could inhibit the uptake of Cd in paddy rice and increase the biomass of paddy rice; however, with Cd levels reaching 89-178 mu M, the addition of Se resulted in increases in Cd uptake and exacerbated the growth of paddy rice.

Cd

Se

Cd

Cd

Se

Cd


Input: Cd always inhibited the uptake of Se.

Cd

Se


Input: Cd alone suppressed the uptake of Ca, Mg, Mn, Cu, and Zn; however, Se reversed the decreases in the concentrations of the said elements, suggesting an element regulation mechanism to relieve Cd toxicity.

Cd

Ca

Mg

Mn

Cu

Zn

Se

Cd


Input: Without Cd in the solution, low doses of Se increased the biomasses of shoots and roots at the expense of the more or less decreases in the concentrations of Ca, Mg, K, Fe, Mn, Cu, and shoot Zn, indicating an antagonistic effect of Se on these cations.

Cd

Se

Ca

Mg

K

Fe

Mn

Cu

Zn

Se


Input: The presence of Cd could also reverse these decreases especially at the highest treatment levels for both Se and Cd, also suggesting an element regulation mechanism responsible for the detoxification of high dosages of Se.

Cd

Se

Cd

Se


Input: Consequently, when Se is used to alleviate Cd toxicity, attention must be paid to the Cd pollution extent and doses of Se supplement.

Se

Cd

Cd

Se


Input: Diatom frustules as light traps enhance DSSC efficiency.


Input: Diatoms are one of the most successful photosynthetic organisms and given the important role that their shells (frustules) play in light trapping we explored their use in multilayered materials for application as photoanodes in dye sensitised solar cells (DSSCs).


Input: We find a substantial improvement in energy conversion efficiency of 30%, increasing from 3. 5% to 4. 6% with diatom incorporation.


Input: Involvement of lysosomal exocytosis in the excretion of mesoporous silica nanoparticles and enhancement of the drug delivery effect by exocytosis inhibition.

silica


Input: The exocytosis of phosphonate modified mesoporous silica nanoparticles (P-MSNs) is demonstrated and lysosomal exocytosis is identified as the mechanism responsible for this event.

phosphonate

silica


Input: Regulation of P-MSN exocytosis can be achieved by inhibiting or accelerating lysosomal exocytosis.


Input: Slowing down P-MSN exocytosis enhances the drug delivery effect of CPT-loaded P-MSNs by improving cell killing.

CPT


Input: Overexpression of ATP-binding cassette transporter ABCG2 as a potential mechanism of acquired resistance to vemurafenib in BRAF (V600E) mutant cancer cells.

ATP

vemurafenib


Input: Melanoma is the most serious type of skin cancer with a high potential for metastasis and very low survival rates.


Input: The discovery of constitutive activation of the BRAF kinase caused by activating BRAF (V600E) kinase mutation in most melanoma patients led to the discovery of the first potent BRAF (V600E) signaling inhibitor, vemurafenib.

vemurafenib


Input: Vemurafenib was effective in treating advanced melanoma patients and was proposed for the treatment of other BRAF (V600E) mutant cancers as well.

Vemurafenib


Input: Unfortunately, the success of vemurafenib was hampered by the rapid development of acquired resistance in different types of BRAF (V600E) mutant cancer cells.

vemurafenib


Input: It becomes important to identify and evaluate all of the potential mechanisms of cellular resistance to vemurafenib.

vemurafenib


Input: In this study, we characterized the interactions of vemurafenib with three major ATP-binding cassette (ABC) transporters, ABCB1, ABCC1 and ABCG2.

vemurafenib

ATP


Input: We found that vemurafenib stimulated the ATPase activity and potently inhibited drug efflux mediated by ABCB1 and ABCG2.

vemurafenib


Input: Vemurafenib also restored drug sensitivity in ABCG2-overexpressing cells.

Vemurafenib


Input: Moreover, we revealed that in the presence of functional ABCG2, BRAF kinase inhibition by vemurafenib is reduced in BRAF (V600E) mutant A375 cells.

vemurafenib


Input: Taken together, our findings indicate that ABCG2 confers resistance to vemurafenib in A375 cells, suggesting involvement of this transporter in acquired resistance to vemurafenib.

vemurafenib

vemurafenib


Input: Thus, combination chemotherapy targeting multiple pathways could be an effective therapeutic strategy to overcome acquired resistance to vemurafenib for cancers harboring the BRAF (V600E) mutation.

vemurafenib


Input: New developments in the pharmacological modulation of wound healing after glaucoma filtration surgery.


Input: Despite the advent of many new devices for glaucoma surgery, scarring is the main cause of suboptimal pressure control and surgical failure in all forms of surgery.


Input: The cytotoxic antimetabolites, 5-flurouracil and mitomycin C both prolong success but with the increased risk of blinding complications.

mitomycin C


Input: A greater understanding of the cellular mechanisms of the wound healing response has led to the identification and modulation of potential therapeutic targets.


Input: These include transforming factor beta, inflammatory mediators, the acute phase protein serum amyloid P, vascular endothelial growth factor and the matrix metallaproteinases.


Input: While optimal drug delivery is still a major challenge, modulating these effects either directly or through downstream signalling promises to yield anti-scarring efficacy, while minimising side effects.


Input: An antioxidant regenerating system for continuous quenching of free radicals in chronic wounds.


Input: A novel antioxidant regenerating system consisting of cellobiose dehydrogenase (CDH), cellobiose, and phenolic antioxidants with potential application for continuous quenching of free radical species in chronic wounds was developed.

cellobiose

cellobiose

phenolic


Input: This antioxidant regenerating system, continuously quenched in situ produced. NO, O (2) (.-) and OH. radicals and the produced oxidized phenolic antioxidants were regenerated back to their original parent compounds by CDH using cellobiose as electron donor.

. NO

O (2) (.-)

OH.

phenolic

cellobiose


Input: This system therefore prevented the accumulation of oxidized phenolic antioxidants.

phenolic


Input: Interestingly, this study also challenges the relevance of using total antioxidant capacities values of plant crude extracts obtained using biologically none relevant radical species like (2, 2-diphenyl-1-picrylhydrazyl (DPPH)), Trolox Equivalent Antioxidant Capacity (TEAC), etc. when applied as medicinal remedies.

2, 2-diphenyl-1-picrylhydrazyl

DPPH

Trolox


Input: This is because methoxylated phenolic antioxidants like sinapic acid, ferulic acid; 2, 6-dimethoxyphenol readily donate their electrons to these radicals (DPPH, TEAC, etc.), thereby greatly influencing the total antioxidant values although this study showed that they are not at all effective in quenching O (2) (.-) radicals and again are not the most effective quenchers of NO and OH radicals as demonstrated during this study.

methoxylated phenolic

sinapic acid

ferulic acid

2, 6-dimethoxyphenol

DPPH

O (2) (.-)

NO

OH


Input: Combination treatment with progesterone and vitamin D hormone is more effective than monotherapy in ischemic stroke: The role of BDNF/TrkB/Erk1/2 signaling in neuroprotection.

progesterone

vitamin D


Input: We investigated whether combinatorial post-injury treatment with progesterone (P4) and vitamin D hormone (VDH) would reduce ischemic injury more effectively than P4 alone in an oxygen glucose deprivation (OGD) model in primary cortical neurons and in a transient middle cerebral artery occlusion (tMCAO) model in rats.

progesterone

vitamin D

oxygen glucose


Input: In the OGD model, P4 and VDH each showed neuroprotection individually, but combination of the " best " doses did not show substantial efficacy; instead, the lower dose of VDH in combination with P4 was the most effective.


Input: In the tMCAO model, P4 and VDH were given alone or in combination at different times post-occlusion for 7 days.


Input: In vivo data confirmed the in vitro findings and showed better infarct reduction at day 7 and functional outcomes (at 3, 5 and 7 days post-occlusion) after combinatorial treatment than when either agent was given alone.


Input: VDH, but not P4, upregulated heme oxygenase-1, suggesting a pathway for the neuroprotective effects of VDH differing from that of P4.

heme


Input: The combination of P4 and VDH activated brain-derived neurotrophic factor and its specific receptor, tyrosine kinase receptor-B.

tyrosine


Input: Under specific conditions VDH potentiates P4' s neuroprotective efficacy and should be considered as a potential partner of P4 in a low-cost, safe and effective combinatorial treatment for stroke.


Input: The nonfermentable dietary fiber hydroxypropyl methylcellulose modulates intestinal microbiota.

hydroxypropyl


Input: Diet influences host metabolism and intestinal microbiota; however, detailed understanding of this tripartite interaction is limited.


Input: To determine whether the nonfermentable fiber hydroxypropyl methylcellulose (HPMC) could alter the intestinal microbiota and whether such changes correlated with metabolic improvements, C57B/L6 mice were normalized to a high-fat diet (HFD), then either maintained on HFD (control), or switched to HFD supplemented with 10% HPMC, or a low-fat diet (LFD).

hydroxypropyl


Input: Compared to control treatment, both LFD and HPMC reduced weight gain (11. 8 and 5. 7 g, respectively), plasma cholesterol (23. 1 and 19. 6%), and liver triglycerides (73. 1 and 44. 6%), and, as revealed by 454-pyrosequencing of the microbial 16S rRNA gene, decreased microbial alpha-diversity and differentially altered intestinal microbiota.

cholesterol

triglycerides


Input: Both LFD and HPMC increased intestinal Erysipelotrichaceae (7. 3-and 12. 4-fold) and decreased Lachnospiraceae (2. 0-and 2. 7-fold), while only HPMC increased Peptostreptococcaceae (3. 4-fold) and decreased Ruminococcaceae (2. 7-fold).


Input: Specific microorganisms were directly linked with weight change and metabolic parameters in HPMC and HFD mice, but not in LFD mice, indicating that the intestinal microbiota may play differing roles during the two dietary modulations.


Input: This work indicates that HPMC is a potential prebiotic fiber that influences intestinal microbiota and improves host metabolism.


Input: Inhibition of glycogen synthase kinase-3 ameliorates beta-amyloid pathology and restores lysosomal acidification and mammalian target of rapamycin activity in the Alzheimer disease mouse model: in vivo and in vitro studies.

rapamycin


Input: Accumulation of beta-amyloid (A beta) deposits is a primary pathological feature of Alzheimer disease that is correlated with neurotoxicity and cognitive decline.


Input: The role of glycogen synthase kinase-3 (GSK-3) in Alzheimer disease pathogenesis has been debated.


Input: To study the role of GSK-3 in A beta pathology, we used 5XFAD mice co-expressing mutated amyloid precursor protein and presenilin-1 that develop massive cerebral A beta loads.


Input: Both GSK-3 isozymes (alpha/beta) were hyperactive in this model.


Input: Nasal treatment of 5XFAD mice with a novel substrate competitive GSK-3 inhibitor, L803-mts, reduced A beta deposits and ameliorated cognitive deficits.


Input: Analyses of 5XFAD hemi-brain samples indicated that L803-mts restored the activity of mammalian target of rapamycin (mTOR) and inhibited autophagy.

rapamycin


Input: Lysosomal acidification was impaired in the 5XFAD brains as indicated by reduced cathepsin D activity and decreased N-glycoyslation of the vacuolar ATPase subunit V0a1, a modification required for lysosomal acidification.

N


Input: Treatment with L803-mts restored lysosomal acidification in 5XFAD brains.


Input: Studies in SH-SY5Y cells confirmed that GSK-3 alpha and GSK-3 beta impair lysosomal acidification and that treatment with L803-mts enhanced the acidic lysosomal pool as demonstrated in LysoTracker Red-stained cells.


Input: Furthermore, L803-mts restored impaired lysosomal acidification caused by dysfunctional presenilin-1.


Input: We provide evidence that mTOR is a target activated by GSK-3 but inhibited by impaired lysosomal acidification and elevation in amyloid precursor protein/A beta loads.


Input: Taken together, our data indicate that GSK-3 is a player in A beta pathology.


Input: Inhibition of GSK-3 restores lysosomal acidification that in turn enables clearance of A beta burdens and reactivation of mTOR.


Input: These changes facilitate amelioration in cognitive function.


Input: MetalPDB: a database of metal sites in biological macromolecular structures.


Input: We present here MetalPDB (freely accessible at http://metalweb. cerm. unifi. it), a novel resource aimed at conveying the information available on the three-dimensional (3D) structures of metal-binding biological macromolecules in a consistent and effective manner.


Input: This is achieved through the systematic and automated representation of metal-binding sites in proteins and nucleic acids by way of Minimal Functional Sites (MFSs).


Input: MFSs are 3D templates that describe the local environment around the metal (s) independently of the larger context of the macromolecular structure embedding the site (s), and are the central objects of MetalPDB design.


Input: MFSs are grouped into equistructural (broadly defined as sites found in corresponding positions in similar structures) and equivalent sites (equistructural sites that contain the same metals), allowing users to easily analyse similarities and variations in metal-macromolecule interactions, and to link them to functional information.


Input: The web interface of MetalPDB allows access to a comprehensive overview of metal-containing biological structures, providing a basis to investigate the basic principles governing the properties of these systems.


Input: MetalPDB is updated monthly in an automated manner.


Input: Influence of coadministration of artemether and lumefantrine on selected plasma biochemical and erythrocyte oxidative stress indices in female Wistar rats.

artemether

lumefantrine


Input: Among the artemisinin-based combination therapy (ACT) regimens, artemisinin derivative, artemether in combination with lumefantrine (artemether-lumefantrine, AL) has achieved excellent results in the fight against malarial scourge.

artemisinin

artemisinin

artemether

lumefantrine

artemether

lumefantrine


Input: In this study, we evaluated the toxic potential of these drugs at the therapeutic doses in female Wistar rats.


Input: Animals were randomly divided into four groups: those administered 1% Tween 80 (control), those administered artemether (4 mg/kg body weight), those administered lumefantrine (24 mg/kg body weight), and those coadministered artemether (4 mg/kg body weight) and lumefantrine (24 mg/kg body weight).

Tween 80

artemether

lumefantrine

artemether

lumefantrine


Input: The drugs were orally administered twice daily for 3 days by gastric intubation after which selected plasma biochemical indices, and erythrocytes antioxidant defence and lipid peroxidation markers were evaluated.


Input: Coadministration of artemether and lumefantrine raised liver and renal function markers and increased atherogenic index.

artemether

lumefantrine


Input: While reduced glutathione, glucose-6-phosphate dehydrogenase (G6PD) and catalase activities were reduced, glutathione peroxidase and glutathione-s-transferase activities increased in all the treated groups compared to the control group.

glutathione

glutathione

glutathione


Input: The drugs caused significant (p < 0. 05) elevation of malondialdehyde (MDA) levels compared to the control group.

malondialdehyde

MDA


Input: These results imply that coadministration of artemether and lumefantrine may increase the risks of atherosclerosis as well as liver and renal function impairments in the users.

artemether

lumefantrine


Input: In addition, the drugs may also promote oxidative stress in the erythrocytes.


Input: Different fates of Alzheimer' s disease amyloid-beta fibrils remodeled by biocompatible small molecules.


Input: Amyloid fibrils implicated in numerous human diseases are thermodynamically very stable.


Input: Stringent conditions that would not be possible in a physiological environment are often required to disrupt the stable fibrils.


Input: Recently, there is increasing evidence that small molecules can remodel amyloid fibrils in a physiologically relevant manner.


Input: In order to investigate possible fibril remodeling mechanisms using this approach, we performed comparative studies on the structural features of the different amyloid-beta (A beta) aggregates remodeled from A beta fibrils by three biocompatible small molecules: methylene blue; brilliant blue G; and erythrosine B.

methylene blue

brilliant blue G

erythrosine B


Input: Combined with circular dichroism (CD), immuno-blotting, transmission electron microscopy (TEM), and atomic force microscopy (AFM) results, it was found that brilliant blue G-and erythrosine B-treatment generate fragmented A beta fibrils and protofibrils, respectively.

brilliant blue G

erythrosine B


Input: In contrast, incubation of the A beta fibrils with methylene blue perturbs fibrillar structure, leading to amorphous A beta aggregates.

methylene blue


Input: Our findings provide insights on the molecular mechanism of amyloid fibril formation and remodeling and also illustrate the possibility of controlled changes in biomolecule nanostructures.


Input: Neurotransmitters, psychotropic drugs and microglia: clinical implications for psychiatry.


Input: Psychiatric disorders have long and dominantly been regarded to be induced by disturbances of neuronal networks including synapses and neurotransmitters.


Input: Thus, the effects of psychotropic drugs such as antipsychotics and antidepressants have been understood to modulate synaptic regulation via receptors and transporters of neurotransmitters such as dopamine and serotonin.

dopamine

serotonin


Input: Recently, microglia, immunological/inflammatory cells in the brain, have been indicated to have positive links to psychiatric disorders.


Input: Positron emission tomography (PET) imaging and postmortem studies have revealed microglial activation in the brain of neuropsychiatric disorders such as schizophrenia, depression and autism.


Input: Animal models of neuropsychiatric disorders have revealed the underlying microglial pathologies.


Input: In addition, various psychotropic drugs have been suggested to have direct effects on microglia.


Input: Until now, the relationship between microglia, neurotransmitters and psychiatric disorders has not been well understood.


Input: Therefore, in this review, at first, we summarize recent findings of interaction between microglia and neurotransmitters such as dopamine, serotonin, norepinephrine, acetylcholine and glutamate.

dopamine

serotonin

norepinephrine

acetylcholine

glutamate


Input: Next, we introduce up-to-date knowledge of the effects of psychotropic drugs such as antipsychotics, antidepressants and antiepileptics on microglial modulation.


Input: Finally, we propose the possibility that modulating microglia may be a key target in the treatment of various psychiatric disorders.


Input: Further investigations and clinical trials should be conducted to clarify this perspective, using animal in vivo studies and imaging studies with human subjects.


Input: Recent developments in neurochemical imaging in schizophrenia: an update.


Input: The advent of neurochemical brain imaging methods has provided an opportunity to study the neurochemistry of the human brain in normal and abnormal development.


Input: The aim of this article is to provide an update on recent major developments in neurochemical imaging in schizophrenia research.


Input: In this concise review, we discuss the major findings on three neurotransmitters, namely dopamine, serotonin and glutamate.

dopamine

serotonin

glutamate


Input: The most promising radioligand for D (2)/D (3) neuroreceptor imaging is the agonist [(11) C] PHNO, with higher in vivo affinity for D (3) than D (2) receptors, which can be used to measure amphetamine-induced release of dopamine, and therefore a potential model of dopaminergic alterations in schizophrenia.

[(11) C] PHNO

amphetamine

dopamine


Input: Recent development of selective radiotracers allow imaging of the serotonin transporter (SERT) using positron emission tomography (PET) with selective tracers such as [(11) C] DASB.

serotonin

[(11) C] DASB


Input: Additionally, the glutamatergic hypothesis has evolved from theory to phase III clinical trials of newer agents with novel mechanisms.


Input: With the development of newer radioligands and the in vivo application of magnetic resonance spectroscopy (MRS) at relatively high magnetic field strengths, there is ample scope for further neuroimaging advances.


Input: Serotonin receptors of type 6 (5-HT6): from neuroscience to clinical pharmacology.

Serotonin


Input: The serotonin (5-HT) receptors of type 6 (5-HT6) are quite different from all other 5-HT receptors, as they include a short third cytoplasmatic loop and a long C-terminal tail, and one intron located in the middle of the third cytoplasmatic loop.

serotonin

C


Input: A lot of controversies still exist regarding their binding affinity, effects of 5-HT6 ligands on brain catecholamines, behavioral syndromes regulated by them, and brain distribution.

catecholamines


Input: In spite of the lack of information on metabolic pattern of the various compounds, some of 5-HT6 receptor ligands entered the clinical development as potential anti-dementia, antipsychotic, antidepressant and anti-obese drugs.


Input: The present paper is a comprehensive review on the state of art of the 5-HT6 receptors, while highlighting the potential clinical applications of 5-HT6 receptor agonists/antagonists.


Input: Transcranial brain stimulation in schizophrenia: targeting cortical excitability, connectivity and plasticity.


Input: Transcranial magnetic stimulation (TMS) is a very popular tool used within neuroscience.


Input: This and other associated techniques allow the in vivo investigation of cortical excitability, cortical connectivity and cortical plasticity.


Input: Schizophrenia is a brain disorder and various theories other than the dopamine hypothesis have been developed to describe its underlying neurobiology.

dopamine


Input: Supported by animal and post mortem studies, findings from TMS studies indicate that schizophrenia is a disease of reduced cortical inhibition and impaired intra-and intercortical connectivity.


Input: Further studies using repetitive TMS and other plasticity-inducing techniques have shown that cortical plasticity is altered in schizophrenia patients, supporting the recently discussed plasticity deficiency theory of schizophrenia.


Input: This review gives an introduction to the most frequently applied techniques, describes findings in schizophrenia patients and discusses these findings with regard to the neurotransmitters and associated receptors involved.


Input: In summary, there is emerging evidence of an important pathophysiological interplay between reduced inhibition, impaired connectivity and reduced plasticity in schizophrenia patients.


Input: Gamma-aminobutyric-acid-receptors and glutamtergic N-Methyl-D-aspartic-acid-receptors are most likely to be involved in this complex interplay, which may reflect a disturbed signal-to-noise ratio in schizophrenia patients.

Gamma-aminobutyric-acid

N-Methyl-D-aspartic-acid


Input: This review will discuss this issue with regard to the available treatment options and will give implications for future research and therapeutic strategies regarding disinhibition and neuroplasticity in schizophrenia.


Input: A general approach for combining voxel-based meta-analyses conducted in different neuroimaging modalities.


Input: Meta-analyses are useful to summarize the exponential amount of inconsistent and conflicting neuroimaging data.


Input: However, they are usually separately conducted for each different neuroimaging modality, preventing the multimodal integration of different imaging findings in a given neuropsychiatric disorder.


Input: Here, we describe an innovative method to meta-analytically combine the results of different imaging modalities, such as structural and functional paradigms.


Input: The method accounts for the presence of noise in the estimation of the p-values, and can be easily applied to any meta-analytical software.


Input: We hope that with this advanced imaging tool, researchers will be able to provide more complete multimodal pictures of the brain regions affected in different neuropsychiatric disorders.


Input: Distinct roles of methamphetamine in modulating spatial memory consolidation, retrieval, reconsolidation and the accompanying changes of ERK and CREB activation in hippocampus and prefrontal cortex.

methamphetamine


Input: Drugs of abuse modulated learning and memory in humans yet the underlying mechanism remained unclear.


Input: The extracellular signal-regulated kinase (ERK) and the transcription factor cAMP response element-binding protein (CREB) were involved in neuroplastic changes associated with learning and memory.

cAMP


Input: In the current study, we used a Morris water maze to examine the effect of methamphetamine (METH) on different processes of spatial memory in mice.

methamphetamine

METH


Input: We then investigated the status of ERK and CREB in the hippocampus and prefrontal cortex (PFC).


Input: We found that 1. 0 mg/kg dose of METH facilitated spatial memory consolidation when it was injected immediately after the last learning trial.

METH


Input: In contrast, the same dose of METH had no effect on spatial memory retrieval when it was injected 30 min before the test.

METH


Input: Furthermore, 1. 0 mg/kg dose of METH injected immediately after retrieval had no effect on spatial memory reconsolidation.

METH


Input: Activation of both ERK and CREB in the hippocampus was found following memory consolidation but not after retrieval or reconsolidation in METH-treated mouse groups.

METH


Input: In contrast, activation of both ERK and CREB in the PFC was found following memory retrieval but not other processes in METH-treated mouse groups.

METH


Input: These results suggested that METH facilitated spatial memory consolidation but not retrieval or reconsolidation.

METH


Input: Moreover, activation of the ERK and CREB signaling pathway in the hippocampus might be involved in METH-induced spatial memory changes.

METH


Input: Development of a repeated exposure protocol of human bronchial epithelium in vitro to study the long-term effects of atmospheric particles.


Input: Chronic exposure to atmospheric particles is suspected of exacerbating chronic inflammatory respiratory diseases but the underlying mechanisms remain poorly understood.


Input: An experimental strategy using human bronchial epithelial cells (NHBE) known to be one of the main target cells of particles in the lung was developed to investigate the long term effects of repeated exposure to particles.


Input: Primary cultures of NHBE cells were grown at an air-liquid interface and subjected to repeated treatments to particles.


Input: Fate of particles, pro inflammatory response and epithelial differentiation were studied during the 5 weeks following the final treatment.


Input: Ultrastructural observations revealed the biopersistence of particles in the bronchial epithelium.


Input: The expression of cytochrome P450 1A1, was transiently induced, suggesting that organic compounds could have been metabolized.


Input: The release of GM-CSF and IL-6 (biomarkers of pro-inflammatory response), was induced by particle treatments and was maintained up to 5weeks after treatments.


Input: The release of amphiregulin and TGF alpha (Growth Factor) was induced after each treatment.


Input: The number of cells expressing the mucin MUC5AC, a differentiation marker, was increased in particle-exposed epithelium.


Input: The experimental strategy we developed is suitable for investigating in greater depth the long term effects of particles on bronchial epithelial cells repeatedly exposed to atmospheric particles in vitro.


Input: Nano and microparticulate chitosan-based systems for antiviral topical delivery.


Input: Acyclovir (ACV) is one of the drugs of choice for the treatment of epidermal, ocular or systemic herpetic infections.

Acyclovir

ACV


Input: Nevertheless, its trans-mucosal limited absorption and the scarce contact time of the formulation with the mucosal surface-especially in the ocular mucosa-constitute a big limitation of the antiviral efficiency.


Input: The most effective way to solve these problems is to increase the quantity and the residence time of the drug over the ocular surface.


Input: In order to cope with all these requirements, micro-particles (MPs) and nano-particles (NPs) containing ACV have been developed using cross-linked chitosan with tripolyphosphate (TPP) due to the biocompatibility, bio-adhesion ability and the potential power as penetration enhancer of this polymer.

ACV

tripolyphosphate

TPP


Input: Particles were characterized by Fourier-transformed infrared (FTIR) spectroscopy, X-ray diffraction, SEM, Zeta potential and particle size.


Input: Encapsulation efficiency and release profiles in flow through diffusion cells were also determined.


Input: Besides the Slug Mucosal Irritation (SMI) assay has been applied as an alternative to the Draize test to predict the mucosal irritation of the selected formulation.


Input: FTIR and X-ray results suggested an electrostatic interaction ACV-Chitosan that made ACV be molecularly dispersed within the polymer matrix.

ACV

ACV


Input: Encapsulation efficiency was 75% for MP and 16% for NP.


Input: Release profiles in flow through diffusion cells were also determined.


Input: From the diffusion profiles, it was found that the amounts of ACV effectively diffused in 24h were 30, 430 and 80 mu g for the ACV solution, MP and NP respectively.

ACV

ACV


Input: SMI results showed that chitosan-based particles induced moderate irritation and mild tissue damage, what supposes that ACV-MP constitute a promising alternative for further development of an antiviral formulation.

ACV


Input: A novel permeation enhancer: N-succinyl chitosan on the intranasal absorption of isosorbide dinitrate in rats.

N-succinyl

isosorbide dinitrate


Input: The purpose of this paper is to study the potential of N-succinyl chitosan as a novel permeation enhancer for the intranasal absorption of isosorbide dinitrate (ISDN).

N-succinyl

isosorbide dinitrate

ISDN


Input: A series of N-succinyl chitosan (NSCS) with different degree of succinylation (DS) and molecular weight were synthesized.

N-succinyl


Input: An in situ nasal perfusion technique in rats was utilized to investigate the effect of NSCS substitution degree, NSCS molecular weight and concentration on the intranasal absorption of ISDN.

ISDN


Input: The absorption enhancing effect of NSCS was compared with that of chitosan.


Input: It was found that all the NSCS investigated improved the intranasal absorption of ISDN remarkably.

ISDN


Input: Better promoting effect was observed for 0. 1% NSCS 50 (63) compared with 0. 5% chitosan 50.


Input: In nasal ciliotoxicity test, both NSCS and chitosan investigated showed good safety profiles.


Input: Thereafter, in vivo studies of the selected formulations were carried out in rats and the pharmacokinetic parameters were calculated and compared with that of intravenous injection.


Input: Both in situ and in vivo studies demonstrated that NSCS is more effective than chitosan in promoting intranasal absorption of ISDN.

ISDN


Input: Taking both absorption enhancing and safety reason into account, we suggest NSCS is a promising intranasal absorption enhancer.


Input: Implementation and evaluation of an optical fiber system as novel process monitoring tool during lyophilization.


Input: Lyophilization is an important and well-established pharmaceutical drying process.


Input: Product temperature is the most critical process parameter during lyophilization as it impacts both product quality and process efficiency.


Input: Traditionally, thermocouples (TCs) or resistance temperature detectors (RTDs) and recently, manometric temperatures measurements (MTMs) have been used to monitor the product temperature.


Input: But, all of these techniques have several drawbacks.


Input: The objective of this study was the implementation and evaluation of an optical fiber system as novel process monitoring tool during lyophilization.


Input: Therefore, temperature profiles of mannitol, sucrose, or trehalose were recorded with various prototypes of the optical fiber sensors (OFSs) and compared to data obtained with conventional TCs or Pirani/capacitance manometry with respect to the endpoint of primary drying.

mannitol

sucrose

trehalose


Input: The OFS allowed easy handling and easy center bottom positioning.


Input: Data obtained with the OFS in contact with product were in good agreement with data obtained via TCs or Pirani/capacitance manometry.


Input: The OFSs showed significantly higher sensitivity, faster response, and better resolution compared to TCs.


Input: This allowed for the detection of additional excipient crystallization events.


Input: It was found that force effects on unshielded sensors enabled to detect glass transitions.


Input: Three-dimensional temperature profiles were obtained with an OFS helix configuration.


Input: The possible integration of a glass fiber with several OFSs in series into the shelf surface enables non-invasive, automatic loading compatible monitoring of the drying process.


Input: In conclusion, these advantages turn the novel optical fiber systems into a highly attractive process monitoring tool during lyophilization.


Input: Establishment of a triple co-culture in vitro cell models to study intestinal absorption of peptide drugs.


Input: In vitro cell culture models for studying oral drug absorption during early stages of drug development have become a useful tool in drug discovery and development, with respect to substance throughput and reproducibility.


Input: The aim of this study was to establish an in vitro cellular model based on human colon carcinoma Caco-2, mucus-producing HT29, and Raji B cells in order to design a model that more accurately mimics the small intestinal epithelial layer.


Input: Normal oriented model was set up by seeding co-cultures of Caco-2 and HT29 cells into Transwell filters and maintained under identical conditions following addition of Raji B to the basolateral chamber.


Input: Inverted model was set up seeding Caco-2 and HT29 cells on the basolateral chamber and then transferred in the Transwell device with the epithelial cells facing the basolateral chamber following Raji B addition to the apical compartment.


Input: Morphological differences on size and thickness of cell membranes were detected between the models studied by using fluorescence microscopy.


Input: On the triple co-culture models, cell membranes were increasing in size and thickness from the Caco-2 to Caco-2/HT29 and Caco-2/Raji B. Also, the nuclei seem to be larger than in the other studied models.


Input: Insulin permeation was higher on the triple co-culture model when compared to the Caco-2/HT29 co-culture model.


Input: Also, insulin permeation as mediated by nanoparticles and insulin solution permeation was higher on the normal oriented Caco-2/HT29/Raji B model as compared to the inverted model.


Input: Overall, our results suggest that Caco-2/HT29/Raji B triple co-culture normal oriented cellular model may be reliable to obtain a more physiological, functional, and reproducible in vitro model of the intestinal barrier to study protein absorption, both in solution and when delivered by nanocarriers.


Input: Triclosan exposure alters postembryonic development in a Pacific tree frog (Pseudacris regilla) Amphibian Metamorphosis Assay (TREEMA).

Triclosan


Input: The Amphibian Metamorphosis Assay (AMA), developed for Xenopus laevis, is designed to identify chemicals that disrupt thyroid hormone (TH)-mediated biological processes.

thyroid hormone


Input: We adapted the AMA for use on an ecologically-relevant North American species, the Pacific tree frog (Pseudacris regilla), and applied molecular endpoints to evaluate the effects of the antibacterial agent, triclosan (TCS).

triclosan

TCS


Input: Premetamorphic (Gosner stage 26-28) tadpoles were immersed for 21 days in solvent control, 1. 5 mu g/L thyroxine (T (4)), 0. 3, 3 and 30 mu g/L (nominal) TCS, or combined T (4)/TCS treatments.

thyroxine

TCS

TCS


Input: Exposure effects were scored by morphometric (developmental stage, wet weight, and body, snout-vent and hindlimb lengths) and molecular (mRNA abundance using quantitative real time polymerase chain reaction) criteria.


Input: T (4) treatment alone accelerated development concomitant with altered levels of TH receptors alpha and beta, proliferating cell nuclear antigen, and gelatinase B mRNAs in the brain and tail.


Input: We observed TCS-induced perturbations in all of the molecular and morphological endpoints indicating that TCS exposure disrupts coordination of postembryonic tadpole development.

TCS

TCS


Input: Clear alterations in molecular endpoints were evident at day 2 whereas the earliest morphological effects appeared at day 4 and were most evident at day 21.


Input: Although TCS alone (3 and 30 mu g/L) was protective against tadpole mortality, this protection was lost in the presence of T (4).

TCS


Input: The Pacific tree frog is the most sensitive species examined to date displaying disruption of TH-mediated development by a common antimicrobial agent.


Input: Human paraoxonase double mutants hydrolyze V and G class organophosphorus nerve agents.

organophosphorus


Input: Variants of human paraoxonase 1 (PON1) are being developed as catalytic bioscavengers for the organophosphorus chemical warfare agents (OP).

organophosphorus


Input: It is preferable that the new PON1 variants have broad spectrum hydrolase activities to hydrolyze both G-and V-class OPs.


Input: H115W PON1 has shown improvements over wild type PON1 in its capacity to hydrolyze some OP compounds.


Input: We improved upon these activities either by substituting a tryptophan (F347W) near the putative active site residues for enhanced substrate binding or by reducing a bulky group (Y71A) at the periphery of the putative enzyme active site.

tryptophan


Input: When compared to H115W alone, we found that H115W/Y71A and H115W/F347W maintained VX catalytic efficiency but showed mixed results for the capacity to hydrolyze paraoxon.

paraoxon


Input: Testing our double mutants against racemic sarin, we observed reduced values of KM for H115W/F347W that modestly improved catalytic efficiency over wild type and H115W.

racemic sarin


Input: Contrary to previous reports, we show that H115W can hydrolyze soman, and the double mutant H115W/Y71A is nearly 4-fold more efficient than H115W for paraoxon hydrolysis.

soman

paraoxon


Input: We also observed modest stereoselectivity for hydrolysis of the P (-) stereoisomer of tabun by H115W/F347W.

tabun


Input: These data demonstrate enhancements made in PON1 for the purpose of developing an improved catalytic bioscavenger to protect cholinesterase against chemical warfare agents.


Input: Expression of cAMP-responsive element binding proteins (CREBs) in fast-and slow-twitch muscles: A signaling pathway to account for the synaptic expression of collagen-tailed subunit (ColQ) of acetylcholinesterase at the rat neuromuscular junction.

cAMP


Input: The gene encoding the collagen-tailed subunit (ColQ) of acetylcholinesterase (AChE) contains two distinct promoters that drive the production of two ColQ mRNAs, ColQ-1 and ColQ-1a, in slow-and fast-twitch muscles, respectively.


Input: ColQ-1a is expressed at the neuromuscular junction (NMJ) in fast-twitch muscle, and this expression depends on trophic factors supplied by motor neurons signaling via a cAMP-dependent pathway in muscle.

cAMP


Input: To further elucidate the molecular basis of ColQ-1a' s synaptic expression, here we investigated the expression and localization of cAMP-responsive element binding protein (CREB) at the synaptic and extra-synaptic regions of fast-and slow-twitch muscles from adult rats.

cAMP


Input: The total amount of active, phosphorylated CREB (P-CREB) present in slow-twitch soleus muscle was higher than that in fast-twitch tibialis muscle, but P-CREB was predominantly expressed in the fast-twitch muscle at NMJs.


Input: In contrast, P-CREB was detected in both synaptic and extra-synaptic regions of slow-twitch muscle.


Input: These results reveal, for the first time, the differential distribution of P-CREB in fast-and slow-twitch muscles, which might support the crucial role of cAMP-dependent signaling in controlling the synapse-specific expression of ColQ-1a in fast-twitch muscles.

cAMP


Input: The determination of exogenous formaldehyde in blood of rats during and after inhalation exposure.

formaldehyde


Input: Formaldehyde (FA) is suspected of being associated with the development of leukemia.

Formaldehyde


Input: An inhalation experiment with FA was performed in rats to study whether FA can enter the blood and could thus cause systemic toxicity in remote tissues such as the bone marrow.


Input: Therefore, a sophisticated analytical method was developed to detect blood concentrations of FA during and after single 6-h exposure by inhalation.


Input: In order to differentiate between exogenous and endogenous FA the rats were exposed to stable isotope ((13) C) labeled FA by inhalation.

(13) C


Input: During and after exposure of the rats to (13) C-FA their blood was analyzed to determine the ratio between labeled and natural FA in blood and the total blood concentration of FA.

(13) C-FA


Input: With respect to sensitivity, with the applied method exogenous (13) C-FA could have been detected in blood at a concentration approximately 1. 5% of the endogenous FA blood concentration.

(13) C-FA


Input: Exogenous (13) C-FA was not detectable in the blood of rats either during or up to 30 min after the exposure.

(13) C-FA


Input: It was concluded that the inhalation of (13) C-FA at 10 ppm for 6h did not result in an increase of the total FA concentration in blood.

(13) C-FA


Input: Analysis of microRNA and gene expression profiling in triazole fungicide-treated HepG2 cell line.

triazole


Input: MicroRNA (miRNA) plays an important role in various diseases and in cellular and molecular responses to toxicants.


Input: In the present study, we investigated differential expression of miRNAs in response to three triazole fungicides (myclobutanil, propiconazole, and triadimefon).

triazole

myclobutanil

propiconazole

triadimefon


Input: The human hepatoma cell line (HepG2) was treated with the above triazoles for 3 h or 48 h.

triazoles


Input: miRNA-based microarray experiments were carried out using the Agilent human miRNA v13 array.


Input: At early exposure (3h), six miRNAs were differentially expressed and at late exposure (48 h), three miRNAs were significantly expressed.


Input: Overall, this study provides an array of potential biomarkers for the above triazole fungicides.

triazole


Input: Furthermore, these miRNAs induced by triazoles could be the foundation for the development of a miRNA-based toxic biomarker library that can predict environmental toxicity.

triazoles


Input: Hydroxysafflor yellow a inhibits lipopolysaccharide-induced inflammatory signal transduction in human alveolar epithelial A549 cells.

Hydroxysafflor yellow a


Input: Hydroxysafflor yellow A (HSYA) is an active ingredient obtained from the flower of Carthamus tinctorius L.

Hydroxysafflor yellow A

HSYA


Input: The present study investigated the effects of HSYA on lipopolysaccharide (LPS)-induced inflammatory signal transduction in human alveolar epithelial A549 cells.

HSYA


Input: A549 cells stimulated with LPS were incubated with three doses of HSYA (1, 4 and 16 mu mol/L).

HSYA


Input: HSYA suppressed the expression of TLR-4, Myd88, ICAM-1, TNF alpha, IL-1 beta and IL-6 at the mRNA and protein level, and inhibited the adhesion of leukocytes to A549 cells.

HSYA


Input: HSYA treatment also decreased NF-kappa B p65 nuclear translocation and inhibited the phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK).

HSYA


Input: These findings suggest that HSYA effectively inhibits LPS-induced inflammatory signal transduction in A549 cells.

HSYA


Input: CD36 homolog divergence is responsible for the selectivity of carotenoid species migration to the silk gland of the silkworm Bombyx mori.


Input: Dietary carotenoids are absorbed in the intestine and delivered to various tissues by circulating lipoproteins; however, the mechanism underlying selective delivery of different carotenoid species to individual tissues remains elusive.


Input: The products of the Yellow cocoon (C) gene and the Flesh (F) gene of the silkworm Bombyx mori determine the selectivity for transport of lutein and beta-carotene, respectively, to the silk gland.

lutein

beta-carotene


Input: We previously showed that the C gene encodes Cameo2, a CD36 family member, which is thought to function as a transmembrane lipoprotein receptor.


Input: Here, we elucidated the molecular identity of the F gene product by positional cloning, as SCRB15, a paralog of Cameo2 with 26% amino acid identity.

amino acid


Input: In the F mutant, SCRB15 mRNA structure was severely disrupted, due to a 1. 4 kb genomic insertion in a coding exon.


Input: Transgenic expression of SCRB15 in the middle silk gland using the binary GAL4-UAS expression system enhanced selective beta-carotene uptake by the middle silk gland, while transgenic expression of Cameo2 enhanced selective lutein uptake under the same GAL4 driver.

beta-carotene

lutein


Input: Our findings indicate that divergence of genes in the CD36 family determines the selectivity of carotenoid species uptake by silk gland tissue and that CD36-homologous proteins can discriminate among carotenoid species.


Input: Emergence of superconductivity from the dynamically heterogeneous insulating state in La (2-x) Sr (x) CuO4.

La (2-x) Sr (x) CuO4


Input: A central issue for copper oxides is the nature of the insulating ground state at low carrier densities and the emergence of high-temperature superconductivity from that state with doping.

copper oxides


Input: Even though this superconductor-insulator transition (SIT) is a zero-temperature transition, measurements are not usually carried out at low temperatures.


Input: Here we use magnetoresistance to probe both the insulating state at very low temperatures and the presence of superconducting fluctuations in La (2-x) Sr (x) CuO (4) films, for doping levels that range from the insulator to the superconductor (x = 0. 03-0. 08).

La (2-x) Sr (x) CuO (4)


Input: We observe that the charge glass behaviour, characteristic of the insulating state, is suppressed with doping, but it coexists with superconducting fluctuations that emerge already on the insulating side of the SIT.


Input: The unexpected quenching of the superconducting fluctuations by the competing charge order at low temperatures provides a new perspective on the mechanism for the SIT.


Input: M1. 3--a small scaffold for DNA origami.


Input: The DNA origami method produces programmable nanoscale objects that form when one long scaffold strand hybridizes to numerous oligonucleotide staple strands.


Input: One scaffold strand is dominating the field: M13mp18, a bacteriophage-derived vector 7249 nucleotides in length.

nucleotides


Input: The full-length M13 is typically folded by using over 200 staple oligonucleotides.


Input: Here we report the convenient preparation of a 704 nt fragment dubbed " M1. 3 " as a linear or cyclic scaffold and the assembly of small origami structures with just 15-24 staple strands.


Input: A typical M1. 3 origami is large enough to be visualized by TEM, but small enough to show a cooperativity in its assembly and thermal denaturation that is reminiscent of oligonucleotide duplexes.


Input: Due to its medium size, M1. 3 origami with globally modified staples is affordable.


Input: As a proof of principle, two origami structures with globally 5'-capped staples were prepared and were shown to give higher UV-melting points than the corresponding assembly with unmodified DNA.


Input: M1. 3 has the size of a gene, not a genome, and may function as a model for gene-based nanostructures.


Input: Small origami with M1. 3 as a scaffold may serve as a workbench for chemical, physical, and biological experiments.


Input: RBCK1, an E3 ubiquitin ligase, interacts with and ubiquinates the human pregnane X receptor.

pregnane


Input: The pregnane X receptor (PXR, NR1I2) plays a pivotal role in the disposition and detoxification of numerous foreign and endogenous chemicals by increasing transcription of numerous target genes, including phase I and II drug-metabolizing enzymes and transporters.

pregnane


Input: In the present study, yeast two-hybrid screening identified an E3 ubiquitin ligase, RBCK1 (Ring-B-box-coiled-coil protein interacting with protein kinase C-1), as a human pregnane X receptor (hPXR)-interacting protein.

pregnane


Input: Coimmunoprecipitation studies confirmed the interaction between RBCK1 and hPXR when both were ectopically expressed in AD-293 cells.


Input: Domain mapping studies showed that the interaction between RBCK1 and hPXR involves all RBCK1 domains.


Input: We further demonstrate that RBCK1 ubiquitinates hPXR, and this may target hPXR for degradation by the ubiquitin-proteasome pathway.


Input: Simultaneous ectopic overexpression of RBCK1 and PXR decreased PXR levels in AD-293 cells, and this decrease was inhibited by the proteasomal inhibitor MG-132 (carbobenzoxy-Leu-Leu-leucinal).

carbobenzoxy-Leu-Leu-leucinal


Input: Furthermore, overexpression of RBCK1 decreased endogenous levels of PXR in HepG2 cells.


Input: Of importance, ectopic overexpression and silencing of endogenous RBCK1 in primary human hepatocytes resulted in a decrease and increase, respectively, in endogenous PXR protein levels and in the induction of PXR target genes by rifampicin.

rifampicin


Input: These results suggest that RBCK1 is important for the ubiquitination of PXR and may play a role in its proteasomal degradation.


Input: The effect of C-vacancy on hydrogen storage and characterization of H2 modes on Ti functionalized C60 fullerene a first principles study.

C

hydrogen

Ti

C60 fullerene


Input: Density functional theory calculations were performed to examine the effect of a C vacancy on the physisorption of H (2) onto Ti-functionalized C (60) fullerene when H (2) is oriented along the x-, y-, and z-axes of the fullerene.

C

H (2)

Ti

C (60) fullerene

H (2)

fullerene


Input: The effect of the C vacancy on the physisorption modes of H (2) was investigated as a function of H (2) binding energy within the energy window (-0. 2 to-0. 6 eV) targeted by the Department of Energy (DOE), and as functions of a variety of other physicochemical properties.

C

H (2)

H (2)


Input: The results indicate that the preferential orientations of H (2) in the defect-free (i. e., no C vacancy) C (60) TiH (2) complex are along the x-and y-axes of C (60) (with adsorption energies of-0. 23 and-0. 21 eV, respectively), making these orientations the most suitable ones for hydrogen storage, in contrast to the results obtained for defect-containing fullerenes.

H (2)

C

C (60) TiH (2)

C (60)

hydrogen


Input: The defect-containing (i. e., containing a C vacancy) C (59) TiH (2) complex do not exhibit adsorption energies within the targeted energy range.

C

C (59) TiH (2)


Input: Charge transfer occurs from Ti 3d to C 2p of the fullerene.

Ti

C

fullerene


Input: The binding of H (2) is dominated by the pairwise support-metal interaction energy E (i) (Cn... Ti), and the role of the fullerene is not restricted to supporting the metal.

H (2)

Ti

fullerene


Input: The C vacancy enhances the adsorption energy of Ti, in contrast to that of H (2).

C

Ti

H (2)


Input: A significant reduction in the energy gap of the pristine C (60) fullerene is observed when TiH (2) is adsorbed by it.

C (60) fullerene

TiH (2)


Input: While the C (n) fullerene readily participates in nucleophilic processes, the adjacent TiH (2) fragment is available for electrophilic processes.

C (n) fullerene

TiH (2)


Input: Functional characterization of three mouse formyl peptide receptors.

formyl


Input: The evolutionary relationship and functional correlation between human formyl peptide receptors (FPRs) and their mouse counterparts remain incompletely understood.

formyl


Input: We examined three members of the mouse formyl peptide receptor subfamily (mFprs) and found that they differ in agonist preference and cellular distributions.

formyl


Input: When stably expressed in transfected rat basophilic leukemia (RBL-2H3) cells, mFpr1 was readily activated by N-formylated peptides derived from Listeria monocytogenes (fMIVTLF), Staphylococcus aureus (fMIFL), and mitochondria (fMMYALF).

N


Input: In contrast, the Escherichia coli-derived fMLF was 1000-fold less potent.


Input: The aforementioned peptides were much less efficacious at mFpr2, which responded better to the synthetic hexapeptide WKYMVm, the synthetic agonists Quin-C1 (a substituted quinazolinone), and compound 43 (a nitrosylated pyrazolone derivative).

hexapeptide

quinazolinone

nitrosylated pyrazolone


Input: Saturation binding assays showed that mFpr1 and mFpr2 were expressed at similar levels on the cell surface, although their affinity for N-formyl-Met-Leu-Phe-Ile-Ile-Lys-fluorescein isothiocyanate varied by more than 1000-fold [dissociation constant (K (d)) values of 2. 8 nM for mFpr1 and 4. 8 mu M for mFpr2]).

N-formyl-Met-Leu-Phe-Ile-Ile-Lys-fluorescein isothiocyanate


Input: Contrary to these receptors, mFpr-rs1 responded poorly to all the previously mentioned peptides that were tested.


Input: Fluorescent microscopy revealed an intracellular distribution pattern of mFpr-rs1.


Input: On the basis of these results, we conclude that mFpr1 is an ortholog of human FPR1 with certain pharmacologic properties of human FPR2/ALX, whereas mFpr2 has much lower affinity for formyl peptides.

formyl


Input: The intracellular distribution of mFpr-rs1 suggests an evolutionary correlation with human FPR3.


Input: The role of voltage-gated potassium channels Kv2. 1 and Kv2. 2 in the regulation of insulin and somatostatin release from pancreatic islets.

potassium


Input: The voltage-gated potassium channels Kv2. 1 and Kv2. 2 are highly expressed in pancreatic islets, yet their contribution to islet hormone secretion is not fully understood.

potassium


Input: Here we investigate the role of Kv2 channels in pancreatic islets using a combination of genetic and pharmacologic approaches.


Input: Pancreatic beta-cells from Kv2. 1 (-/-) mice possess reduced Kv current and display greater glucose-stimulated insulin secretion (GSIS) relative to WT beta-cells.

glucose


Input: Inhibition of Kv2. x channels with selective peptidyl [guangxitoxin-1E (GxTX-1E)] or small molecule (RY796) inhibitors enhances GSIS in isolated wild-type (WT) mouse and human islets, but not in islets from Kv2. 1 (-/-) mice.


Input: However, in WT mice neither inhibitor improved glucose tolerance in vivo.

glucose


Input: GxTX-1E and RY796 enhanced somatostatin release in isolated human and mouse islets and in situ perfused pancreata from WT and Kv2. 1 (-/-) mice.

somatostatin


Input: Kv2. 2 silencing in mouse islets by adenovirus-small hairpin RNA (shRNA) specifically enhanced islet somatostatin, but not insulin, secretion.

somatostatin


Input: In mice lacking somatostatin receptor 5, GxTX-1E stimulated insulin secretion and improved glucose tolerance.

somatostatin

glucose


Input: Collectively, these data show that Kv2. 1 regulates insulin secretion in beta-cells and Kv2. 2 modulates somatostatin release in delta-cells.

somatostatin


Input: Development of selective Kv2. 1 inhibitors without cross inhibition of Kv2. 2 may provide new avenues to promote GSIS for the treatment of type 2 diabetes.


Input: Effects of a bioassay-derived ivermectin lowest observed effect concentration on life-cycle traits of the nematode Caenorhabditis elegans.

ivermectin


Input: The pharmaceutical ivermectin is used to treat parasitic infections, such as those caused by nematodes.

ivermectin


Input: While several studies have demonstrated the severe effects of ivermectin on non-target organisms, little is known about the drug' s impact on free-living nematodes.

ivermectin


Input: In the present work, a full life-cycle experiment was conducted to estimate how an ivermectin lowest observed effect concentration derived from a Caenorhabditis elegans bioassay (endpoint reproduction) might translate into effects at the population level of this free-living nematode.

ivermectin


Input: The results showed that fecundity decreased to levels similar to those determined in the bioassay after a time of corresponding duration (18. 6% inhibition compared to the control), but the impact then rather weakened until the end of the experiment, at which point the net reproductive rate (R (0)) was still, but not significantly, reduced by 12. 4%.


Input: Moreover, the average lifespan, length of the reproductive period, maximum daily reproduction rate, and intrinsic rate of increase (r (m)) were significantly reduced by 30. 0, 25. 9, 11. 2, and 3. 5%, respectively.


Input: The experiment revealed that a 4-day bioassay is protective enough for C. elegans with respect to ivermectin' s effects on fecundity.

ivermectin


Input: However, the pronounced effects of a low drug concentration on survival, a highly elastic trait, may better account for the observed population-level response, i. e., a decrease of r (m), than the effects on fecundity.


Input: These results emphasize that full life-cycle experiments are valuable for assessment of pollutants, because the effects on several life-cycle traits can be simultaneously measured and integrated into an ecologically relevant parameter, the population growth rate, that reflects a population' s response to a specific pollutant.


Input: Interspecific effects of 4A-DNT (4-amino-2, 6-dinitrotoluene) and RDX (1, 3, 5-trinitro-1, 3, 5-triazine) in Japanese quail, Northern bobwhite, and Zebra finch.

4-amino-2, 6-dinitrotoluene

RDX

1, 3, 5-trinitro-1, 3, 5-triazine


Input: The purpose of this study was to assess the toxicological effects of two munition compounds, 4-amino-2, 6-dinitrotoluene (4A-DNT) and 1, 3, 5-trinitro-1, 3, 5-triazine (RDX), on three different bird species: two common toxicological model species-the Northern Bobwhite (Colinus virginianus) and the Japanese Quail (Coturnix japonica), and a representative passerine-the Zebra Finch (Taeniopygia guttata).

4-amino-2, 6-dinitrotoluene

1, 3, 5-trinitro-1, 3, 5-triazine

RDX


Input: Bobwhite were exposed to 4A-DNT at 0, 8, 15, 30, 60, or 150 mg/kg body weight (bw) d by oral gavage for seven days; because the high dose of 4A-DNT was lethal to bobwhite, the maximum dose was changed to 100 mg/kg bw d for Japanese quail and finches to ensure tissue could be used for future toxicogenomic work.


Input: RDX was similarly administered at 0, 0. 5, 1. 5, 3, 6, or 12 mg/kg bw d.

RDX


Input: Blood was drawn prior to euthanasia for blood cellularity and chemistry analyses.


Input: Finches were clearly least affected by 4A-DNT as evidenced by a lack of observable effects.


Input: Bobwhite appeared to be the most sensitive species to 4A-DNT as observed through changes in blood cellularity and plasma chemistry effects.


Input: Bobwhite appeared to be more sensitive to RDX than Japanese Quail due to increased effects on measures of plasma chemistries.

RDX


Input: Finches exhibited the greatest sensitivity to RDX through increased mortality and seizure activity.

RDX


Input: This study suggests that sensitivity among species is chemical-specific and provides data that could be used to refine current avian sensitivity models used in ecological risk assessments.


Input: Ilexpublesnins C-M, eleven new triterpene saponins from the roots of Ilex pubescens.

Ilexpublesnins C-M

triterpene saponins


Input: Eleven new triterpene saponins, ilexpublesnins C-M (1-11), along with ten known analogues were isolated from the roots of Ilex pubescens.

triterpene saponins

ilexpublesnins C-M


Input: Their structures were elucidated on the basis of extensive spectroscopic analysis, including 1D and 2D NMR experiments.


Input: Compounds 1, 2, 10, and 11 contain a 24-aldehyde, which is rare for triterpene saponins from Ilex.

aldehyde

triterpene saponins


Input: These compounds were evaluated in vitro for their cytotoxic effects on human cancer cell lines HepG2, HLE, BEL7402, BEL7403, BEL7405, MCF-7, and HeLa.


Input: Among them, only compounds 6 and 19 showed cytotoxicity against the MCF-7 cell line [inhibition (%): 33. 14 and 34. 03, respectively].


Input: Two-stage metal-catalyst-free growth of high-quality polycrystalline graphene films on silicon nitride substrates.

graphene

silicon nitride


Input: By using two-stage, metal-catalyst-free chemical vapor deposition (CVD), it is demonstrated that high-quality polycrystalline graphene films can directly grow on silicon nitride substrates.

graphene

silicon nitride


Input: The carrier mobility can reach about 1500 cm (2) V (-1) s (-1), which is about three times the value of those grown on SiO (2)/Si substrates, and also is better than some examples of metal-catalyzed graphene, reflecting the good quality of the graphene lattice.

SiO (2)

Si

graphene

graphene


Input: Relationship of land use and elevated ionic strength in Appalachian watersheds.


Input: Coal mining activities have been implicated as sources that increase stream specific conductance in Central Appalachia.

Coal


Input: The present study characterized potential sources of elevated ionic strength for small subwatersheds within the Coal, Upper Kanawha, Gauley, and New Rivers in West Virginia.

Coal


Input: From a large monitoring data set developed by the West Virginia Department of Environmental Protection, 162 < 20-km (2)-watersheds were identified that had detailed land cover information in southwestern West Virginia with at least one water chemistry sample.


Input: Scatter plots of specific conductance were generated for nine land cover classifications: open water, agriculture, forest, residential, barren, total mining, valley fill, abandoned mine lands, and mining excluding valley fill and abandoned mine lands.


Input: Conductivity was negatively correlated with the percentage of forest area and positively associated with other land uses.


Input: In a multiple regression, the percentage of area in valley fill was the strongest contributor to increased ionic strength, followed by percentage of area in urban (residential/buildings) land use and other mining land use.


Input: Based on the 10th quantile regression, 300 micro S/cm was exceeded at 3. 3% of area in valley fill.


Input: In most catchments, HCO 3 (-) and SO 4 (2-) concentrations were greater than Cl (-) concentration.

HCO 3 (-)

SO 4 (2-)

Cl (-)


Input: These findings confirm coal mining activities as the primary source of high conductivity waters.


Input: Such activities might be redressed with the goal of protecting sources of dilute freshwater in the region.


Input: Next generation sequencing in predicting gene function in podophyllotoxin biosynthesis.

podophyllotoxin


Input: Podophyllum species are sources of (-)-podophyllotoxin, an aryltetralin lignan used for semi-synthesis of various powerful and extensively employed cancer-treating drugs.

(-)-podophyllotoxin

aryltetralin lignan


Input: Its biosynthetic pathway, however, remains largely unknown, with the last unequivocally demonstrated intermediate being (-)-matairesinol.

(-)-matairesinol


Input: Herein, massively parallel sequencing of Podophyllum hexandrum and Podophyllum peltatum transcriptomes and subsequent bioinformatics analyses of the corresponding assemblies were carried out.


Input: Validation of the assembly process was first achieved through confirmation of assembled sequences with those of various genes previously established as involved in podophyllotoxin biosynthesis as well as other candidate biosynthetic pathway genes.

podophyllotoxin


Input: This contribution describes characterization of two of the latter, namely the cytochrome P450s, CYP719A23 from P. hexandrum and CYP719A24 from P. peltatum.


Input: Both enzymes were capable of converting (-)-matairesinol into (-)-pluviatolide by catalyzing methylenedioxy bridge formation and did not act on other possible substrates tested.

(-)-matairesinol

(-)-pluviatolide

methylenedioxy


Input: Interestingly, the enzymes described herein were highly similar to methylenedioxy bridge-forming enzymes from alkaloid biosynthesis, whereas candidates more similar to lignan biosynthetic enzymes were catalytically inactive with the substrates employed.

methylenedioxy

lignan


Input: This overall strategy has thus enabled facile further identification of enzymes putatively involved in (-)-podophyllotoxin biosynthesis and underscores the deductive power of next generation sequencing and bioinformatics to probe and deduce medicinal plant biosynthetic pathways.

(-)-podophyllotoxin


Input: Phosphorylation of dopamine transporter serine 7 modulates cocaine analog binding.

dopamine

serine

cocaine


Input: As an approach to elucidating dopamine transporter (DAT) phosphorylation characteristics, we examined in vitro phosphorylation of a recombinant rat DAT N-terminal peptide (NDAT) using purified protein kinases.

dopamine

N


Input: We found that NDAT becomes phosphorylated at single distinct sites by protein kinase A (Ser-7) and calcium-calmodulin-dependent protein kinase II (Ser-13) and at multiple sites (Ser-4, Ser-7, and Ser-13) by protein kinase C (PKC), implicating these residues as potential sites of DAT phosphorylation by these kinases.

Ser

calcium

Ser

Ser

Ser

Ser


Input: Mapping of rat striatal DAT phosphopeptides by two-dimensional thin layer chromatography revealed basal and PKC-stimulated phosphorylation of the same peptide fragments and comigration of PKC-stimulated phosphopeptide fragments with NDAT Ser-7 phosphopeptide markers.

Ser


Input: We further confirmed by site-directed mutagenesis and mass spectrometry that Ser-7 is a site for PKC-stimulated phosphorylation in heterologously expressed rat and human DATs.

Ser


Input: Mutation of Ser-7 and nearby residues strongly reduced the affinity of rat DAT for the cocaine analog (-)-2 beta-carbomethoxy-3 beta-(4-fluorophenyl) tropane (CFT), whereas in rat striatal tissue, conditions that promote DAT phosphorylation caused increased CFT affinity.

Ser

cocaine

(-)-2 beta-carbomethoxy-3 beta-(4-fluorophenyl) tropane

CFT

CFT


Input: Ser-7 mutation also affected zinc modulation of CFT binding, with Ala and Asp substitutions inducing opposing effects.

Ser

zinc

CFT

Ala

Asp


Input: These results identify Ser-7 as a major site for basal and PKC-stimulated phosphorylation of native and expressed DAT and suggest that Ser-7 phosphorylation modulates transporter conformational equilibria, shifting the transporter between high and low affinity cocaine binding states.

Ser

Ser

cocaine


Input: A method for assessing causation of field exposure-response relationships.


Input: Because associations between agents and environmental effects are not necessarily causal, it is necessary to assess causation before using such relationships in environmental management.


Input: The authors adapted epidemiological methods to assess general causal hypotheses.


Input: General causation establishes that an agent is capable of causing an effect.


Input: The method uses all relevant and good-quality evidence in a weight-of-evidence system.


Input: The system is credible due to its explicit a priori criteria.


Input: The evidence is organized in terms of six characteristics of causation: co-occurrence, preceding causation, interaction, alteration, sufficiency, and time order.


Input: The causal assessment proceeds through six steps that generate, organize, and score evidence to determine whether causation is adequately supported by the body of evidence.


Input: Application of multiple geochemical markers to investigate organic pollution in a dynamic coastal zone.


Input: Multiple geochemical markers, including aliphatic hydrocarbons (n-alkanes), linear alkylbenzenes (LABs), and polycyclic aromatic hydrocarbons (PAHs), were employed to relate sediment organic chemical pollution in the coastal zone off South China to socioeconomic development there.

aliphatic hydrocarbons

n-alkanes

linear alkylbenzenes

LABs

polycyclic aromatic hydrocarbons

PAHs


Input: Concentrations of Sigma n-C (15-35) (n-alkanes with 15-35 carbon atoms), Sigma LAB (sum of C (10) to C (13) LABs), and Sigma (26) PAH (sum of 26 PAH compounds) ranged from 110 to 3, 160, 11 to 160, and 26 to 600 ng/g, with medians of 730, 40, and 230 ng/g, respectively.

n-C (15-35)

n-alkanes

carbon

LAB

C (10) to C (13) LABs

PAH

PAH


Input: Natural hydrocarbons were mainly derived from terrestrial higher plant waxes, and in minor amounts from aquatic plankton and bacteria.

hydrocarbons


Input: Compositions of LABs indicated that considerable amounts of poorly treated wastewater had been directly discharged or transported to the eastern and western coastal areas of Guangdong Province.

LABs


Input: In addition, anthropogenic hydrocarbons were derived largely from vehicular emissions and combustion of domestic coal and biomass and to a lesser extent from oil spills.

hydrocarbons


Input: Eastern and western coastal sediments contained higher levels of LABs but lower levels of PAHs than those of the Pearl River Estuary, a coastal area of the Pearl River Delta.

LABs

PAHs


Input: This spatial pattern of organic pollution was consistent with chemical use patterns.


Input: The eastern and western regions of Guangdong Province are economically less developed than the Pearl River Delta region, where more domestic wastewater treatment plants have been built.


Input: However, greater amounts of energy are consumed in the latter region to produce more combustion-derived PAH contamination.

PAH


Input: Comparison of gel-based phosphoproteomic approaches to analyse scarce oviductal epithelial cell samples.


Input: The reversible change of the phosphorylation state of proteins regulates key cellular processes.


Input: In the present study, three different gel-based approaches were compared with regard to their applicability to quantitatively analyse the phosphoproteome of scarce biological material obtained ex vivo.


Input: Our results show that the phosphoproteome characterisation of oviductal epithelial cells isolated from the female reproductive tract requires affinity enrichment and pre-electrophoretic labelling using fluorescence dyes.


Input: Using this approach, 30 mu g of enriched phosphoproteins proved to be sufficient for the phosphoproteome characterisation.


Input: In contrast, sequential fluorescence staining of 2D-separated total cell lysates as well as sequential staining in conjunction with a pre-enrichment step led to detection discrepancies and excluded further analysis steps.


Input: Information gained from this study provides a successful approach for the phosphoproteome analysis of scarce samples.


Input: In addition, the cellular processes taking place in the female reproductive tract can be monitored ex vivo.


Input: Large area resist-free soft lithographic patterning of graphene.

graphene


Input: Large area low-cost patterning is a challenging problem in graphene research.

graphene


Input: A resist-free, single-step, large area and cost effective soft lithographic patterning strategy is presented for graphene.

graphene


Input: The technique is applicable on any arbitrary substrate that needs to be covered with a graphene film and provides a viable route to large-area patterning of graphene for device applications.

graphene

graphene


Input: Do Subtoxic levels of chlorate influence the desiccation tolerance of Egeria densa?

chlorate


Input: Among the different factors hypothesized to be responsible for the virtual disappearance of Egeria densa, once a dominant aquatic macrophyte in a southern Chile wetland ecosystem, are the negative effects of certain chemical compounds (mainly chlorate) and harsh environmental conditions (desiccation caused by prolonged atmospheric exposure).

chlorate


Input: The authors performed an integrated experiment in which E. densa plants were first exposed for four weeks inside a mesocosm system to levels of chlorate that existed in the wetland at the time of the plant' s demise and then exposed to desiccation conditions that also resembled those that the system had experienced.

chlorate


Input: Hence, the authors tested the hypothesis that E. densa plants exposed to sublethal levels of chlorate are more susceptible to the deleterious effect of desiccation compared with plants that had not been exposed to chlorate.

chlorate

chlorate


Input: This hypothesis was tested by means of quantifying physiologically related parameters in plants right after the four weeks under water and then after the desiccation period of 6 h.


Input: Their results rejected this hypothesis, because all plants, regardless of their history, are equally affected by desiccation.


Input: Solid-state NMR structure determination of whole anchoring threads from the blue mussel Mytilus edulis.


Input: The molecular structure of the blue mussel Mytilus edulis whole anchoring threads was studied by two-dimensional (13) C solid-state NMR on fully labeled fibers.

(13) C


Input: This unique material proves to be well ordered at a molecular level despite its heterogeneous composition as evidenced by the narrow measured linewidths below 1. 5 ppm.


Input: The spectra are dominated by residues in collagen environments, as determined from chemical shift analysis, and a complete two-dimensional assignment (including minor amino acids) was possible.

amino acids


Input: The best agreement between predicted and experimental backbone chemical shifts was obtained for collagen helices with torsion angles (-75 degrees, + 150 degrees).


Input: The abundant glycine and alanine residues can be resolved in up to five different structural environments.

glycine

alanine


Input: Alanine peaks could be assigned to collagen triple-helices, beta-sheets (parallel and antiparallel), beta-turns, and unordered structures.

Alanine


Input: The use of ATR-FTIR microscopy confirmed the presence of these structural environments and enabled their location in the core of the thread (collagen helices and antiparallel beta-sheets) or its cuticle (unordered structures).


Input: The approach should enable characterization at the molecular level of a wide range of byssus macroscopic properties.


Input: A question of time: the land snail Murella muralis (Gastropoda: Pulmonata) reveals constraints on past ecological speciation.


Input: The lively debate about speciation currently focuses on the relative importance of factors driving population differentiation.


Input: While many studies are increasingly producing results on the importance of selection, little is known about the interaction between drift and selection.


Input: Moreover, there is still little knowledge on the spatial-temporal scales at which speciation occurs, that is, arrangement of habitat patches, abruptness of habitat transitions, climate and habitat changes interacting with selective forces.


Input: To investigate these questions, we quantified variation on a fine geographical scale analysing morphological (shell) and genetic data sets coupled with environmental data in the land snail Murella muralis, endemic to the Mediterranean island of Sicily.


Input: Analysis of a fragment of the mitochondrial DNA cytochrome oxidase I gene (COI) and eight nuclear microsatellite loci showed that genetic variation is highly structured at a very fine spatial scale by local palaeogeographical events and historical population dynamics.


Input: Molecular clock estimates, calibrated here specifically for Tyrrhenian land snails, provided a framework of palaeogeographical events responsible for the observed geographical variations and migration routes.


Input: Finally, we showed for the first time well-documented lines of evidence of selection in the past, which explains divergence of land snail shell shapes.


Input: We suggest that time and palaeogeographical history acted as constraints in the progress along the ecological speciation continuum.


Input: Our study shows that testing for correlation among palaeogeography, morphology and genetic data on a fine geographical scale provides information fundamental for a detailed understanding of ecological speciation processes.


Input: The structure and properties of septin 3: a possible missing link in septin filament formation.


Input: The human genome codes for 13 members of a family of filament-forming GTP-binding proteins known as septins.

GTP


Input: These have been divided into four different subgroups on the basis of sequence similarity.


Input: The differences between the subgroups are believed to control their correct assembly into heterofilaments which have specific roles in membrane remodelling events.


Input: Many different combinations of the 13 proteins are theoretically possible and it is therefore important to understand the structural basis of specific filament assembly.


Input: However, three-dimensional structures are currently available for only three of the four subgroups.


Input: In the present study we describe the crystal structure of a construct of human SEPT3 which belongs to the outstanding subgroup.


Input: This construct (SEPT3-GC), which includes the GTP-binding and C-terminal domains, purifies as a nucleotide-free monomer, allowing for its characterization in terms of GTP-binding and hydrolysis.

GTP

C

nucleotide

GTP


Input: In the crystal structure, SEPT3-GC forms foreshortened filaments which employ the same NC and G interfaces observed in the heterotrimeric complex of human septins 2, 6 and 7, reinforcing the notion of' promiscuous' interactions described previously.


Input: In the present study we describe these two interfaces and relate the structure to its tendency to form monomers and its efficiency in the hydrolysis of GTP.

GTP


Input: The relevance of these results is emphasized by the fact that septins from the SEPT3 subgroup may be important determinants of polymerization by occupying the terminal position in octameric units which themselves form the building blocks of at least some heterofilaments.


Input: Receptors, endocytosis, and trafficking: the biological basis of targeted delivery of antisense and siRNA oligonucleotides.


Input: The problem of targeted delivery of antisense and siRNA oligonucleotides can be resolved into two distinct aspects.


Input: The first concerns devising ligand-oligonucleotide or ligand-carrier moieties that bind with high selectivity to receptors on the cell type of interest and that are efficiently internalized by endocytosis.


Input: The second concerns releasing oligonucleotides from pharmacologically inert endomembrane compartments so that they can access RNA in the cytosol or nucleus.


Input: In this review, we will address both of these aspects.


Input: Thus, we present information on three important receptor families, the integrins, the receptor tyrosine kinases, and the G protein-coupled receptors in terms of their suitability for targeted delivery of oligonucleotides.

tyrosine


Input: This includes discussion of receptor abundance, internalization and trafficking pathways, and the availability of suitable high affinity ligands.


Input: We also consider the process of oligonucleotide uptake and intracellular trafficking and discuss approaches to modulating these processes in a pharmacologically productive manner.


Input: Hopefully, the basic information presented in this review will be of value to investigators involved in designing delivery approaches for oligonucleotides.


Input: A new ganoderic acid from Ganoderma lucidum mycelia and its stability.

ganoderic acid


Input: A new ganoderic acid (GA), 3 alpha, 22 beta-diacetoxy-7 alpha-hydroxyl-5 alpha-lanost-8, 24E-dien-26-oic acid (1), together with four known compounds GA-Mk (2),-Mc (3),-S (4) and-Mf (5), was isolated and characterized from Ganoderma lucidum mycelia.

ganoderic acid

3 alpha, 22 beta-diacetoxy-7 alpha-hydroxyl-5 alpha-lanost-8, 24E-dien-26-oic acid

GA-Mk


Input: The structure of compound 1 was elucidated on the basis of interpretation of extensive spectroscopic data (HRMS, IR, UV, 1D and 2D NMR).


Input: Due to its apparent degradation during preparation procedures, the stability of compound 1 was assessed in several solvents in a short-term study that demonstrated the optimal stability in aproptic environment.


Input: A possible mechanism of acid-catalyzed degradation of compound 1 in methanol was proposed, consisting of a fast protonation, followed by a committed step of hydroxyl group removal.

methanol

hydroxyl


Input: In addition, all isolated compounds were tested in vitro for their cytotoxic activities against 95D and HeLa tumor cell lines, with IC (50) values ranging from14. 7 to 38. 5 mu M.


Input: The results may improve the understanding of chemical stability of GAs and provide valuable information on their separation, analysis and application.


Input: Ipsilateral feeding-specific circuits between the nucleus accumbens shell and the lateral hypothalamus: regulation by glutamate and GABA receptor subtypes.

glutamate

GABA


Input: The nucleus accumbens shell (AcbSh) and the lateral hypothalamus (LH) are both involved in the control of food intake.


Input: Activation of GABA (A) receptors or blockade of AMPA and kainate receptors within the AcbSh induces feeding, as does blockade of GABA (A) receptors or activation of NMDA receptors in the LH.

GABA

AMPA

kainate

GABA

NMDA


Input: Further, evidence suggests that feeding induced via the AcbSh can be suppressed by LH inhibition.


Input: However, it is unclear if this suppression is specific to feeding.


Input: Adult male Sprague-Dawley rats with 3 intracranial guide cannulas, one unilaterally into the AcbSh and two bilaterally into the LH, were used to explore this issue.


Input: DNQX (1. 25 mu g) or muscimol (100 ng) infused into the AcbSh unilaterally elicited feeding, and this elicited intake was suppressed by bilateral LH injection of d-AP5 (2 mu g) or muscimol (25 ng).

DNQX

muscimol

muscimol


Input: The effectiveness of d-AP5 or muscimol infusion into either the LH site ipsilateral or contralateral to the AcbSh injection was compared.

muscimol


Input: Ipsilateral LH injection of d-AP5 or muscimol was significantly more effective than contralateral injection in suppressing food intake initiated by AcbSh injection of DNQX or muscimol.

muscimol

DNQX

muscimol


Input: These results add to the prior evidence that inhibition of the LH through pharmacological modulation of NMDA or GABA (A) receptors specifically suppresses feeding initiated by AcbSh inhibition, and that these two regions communicate via an ipsilateral circuit to specifically regulate feeding.

NMDA

GABA


Input: The glycogen synthase kinase-3 beta/nuclear factor-kappa B pathway is involved in cinobufagin-induced apoptosis in cultured osteosarcoma cells.

cinobufagin


Input: Cinobufagin, a major component of cinobufacini (huachansu), is an important cardenolidal steroid.

Cinobufagin

cardenolidal steroid


Input: Several studies have suggested that cinobufagin has potent anti-cancer effects.

cinobufagin