Input: After HK-SLEs were physically characterized, their pharmacokinetics, tissue distribution and antitumor activity after intravenous (i. v.) administration to tumor-burdened mice were examined, using honokiol solution (HK-SOL) as the control.

honokiol


Input: The results showed that the mean particle size, zeta potential, pH value, osmolality, drug loading (DL)% and entrapment efficiency (EE)% of HK-SLEs were 186. 6 +/-1. 7 nm,-35. 65 +/-0. 67 mV, 7. 22 +/-0. 26, 298 +/-2. 3 mOsm/L, 7. 1 +/-0. 2% and 95. 5 +/-0. 2%, respectively.


Input: HK-SLEs were stable for at least 12 months when stored at 4 +/-2 degrees C.


Input: The pharmacokinetic results showed that the drug concentration-time curves of HK-SLEs and HK-SOL could both be described by an open two-compartment model.


Input: The half-life of HK-SLEs (t1/2 (alpha) = 8. 014 min, t1/2 (beta) = 35. 784 min) was remarkably prolonged compared to that of HK-SOL (t1/2 (alpha) = 4. 318 min, t1/2 (beta) = 15. 522 min).


Input: HK-SLEs exhibited a greater AUC and reduced plasma clearance.


Input: The tissue distribution results indicated that HK-SLEs have better targeting properties to lung and tumor tissues compared with those of HK-SOL.


Input: Both HK-SLEs and HK-SOL tended to accumulate in brain tissue.


Input: In vivo study showed that HK-SLEs treatment caused significant inhibition of mouse sarcoma S180 tumor growth compared to HK-SOL.


Input: These results suggest that HK-SLEs might be an effective parenteral carrier for honokiol delivery in cancer treatment.

honokiol


Input: Membrane Topology of Yeast Alkaline Ceramidase YPC1.


Input: Ypc1p and Ydc1p are alkaline ceramide hydrolases, which reside in the ER.


Input: Ypc1p can catalyze the reverse reaction, i. e. the condensation of free fatty acids with phytosphingosine or dihydrosphingosine and overexpression of YPC1 or YDC1 can provide enough ceramide synthesis as to rescue the viability of cells lacking the normal acyl-CoA-dependent ceramide synthases.

fatty acids

phytosphingosine

dihydrosphingosine

ceramide

acyl-CoA


Input: To better understand the coexistence of acyl-CoA dependent ceramide synthases and ceramidases in the ER we investigated the membrane topology of Ypc1p by probing cysteine accessibility of natural and substituted cysteines with membrane non-permeating mass-tagged probes.

acyl-CoA

ceramide

ceramidases

cysteine

cysteines


Input: The N-and C-terminal ends of Ypc1p are oriented towards the lumen and cytosol, respectively.

N

C


Input: Two of the 5 natural cysteines, Cys27 and Cys219, are essential for enzymatic activity and form a disulfide bridge.

cysteines

disulfide


Input: The data allow inferring that all amino acids of Ypc1p that are conserved in the pfam PF05875 ceramidase motif and the CREST superfamily are located in or near the ER lumen.

amino acids


Input: Microsomal assays using a lysine-specific reagent show that the reverse ceramidase activity can only be blocked when the reagent has access to Ypc1p from the lumenal side.

lysine


Input: Overall the data suggest that the active site of Ypc1p resides at the lumenal side of the ER membrane.


Input: Optoelectronic Functional Materials Based on Alkylated-pi Molecules: Self-Assembled Architectures and Nonassembled Liquids.


Input: The engineering of single molecules into higher-order hierarchical assemblies is a current research focus in molecular materials chemistry.


Input: Molecules containing pi-conjugated units are an important class of building blocks because their self-assembly is not only of fundamental interest, but also the key to fabricating functional systems for organic electronic and photovoltaic applications.


Input: Functionalizing the pi-cores with " alkyl chains " is a common strategy in the molecular design that can give the system desirable properties, such as good solubility in organic solvents for solution processing.

alkyl


Input: Moreover, the alkylated-pi system can regulate the self-assembly behavior by fine-tuning the intermolecular forces.


Input: The optimally assembled structures can then exhibit advanced functions.


Input: However, while some general rules have been revealed, a comprehensive understanding of the function played by the attached alkyl chains is still lacking, and current methodology is system-specific in many cases.

alkyl


Input: Better clarification of this issue requires contributions from carefully designed libraries of alkylated-pi molecular systems in both self-assembly and nonassembly materialization strategies.


Input: Here, based on recent efforts toward this goal, we show the power of the alkyl chains in controlling the self-assembly of soft molecular materials and their resulting optoelectronic properties.

alkyl


Input: The design of alkylated-C60 is selected from our recent research achievements, as the most attractive example of such alkylated-pi systems.


Input: Some other closely related systems composed of alkyl chains and pi-units are also reviewed to indicate the universality of the methodology.

alkyl


Input: Finally, as a contrast to the self-assembled molecular materials, nonassembled, solvent-free, novel functional liquid materials are discussed.


Input: In doing so, a new journey toward the ultimate organic " soft " materials is introduced, based on alkylated-pi molecular design.


Input: Rapid method for the separation and recovery of endocrine-disrupting compound bisphenol AP from wastewater.

bisphenol AP


Input: The removal of bisphenol AP (BPAP) by a multiwalled carbon nanotube (MWCNT) was investigated.

bisphenol AP

BPAP

carbon


Input: BPAP, representing typical scenarios for the BPAP-MWCNT interactions, was employed as a probe molecule.

BPAP

BPAP


Input: It was found that BPAP exhibited great adsorptive affinity to MWCNT, and the adsorption kinetics equilibrium was arrived within 4. 0 min following the pseudo-second-order model.

BPAP


Input: The overall rate process was mainly controlled by the external mass transfer.


Input: The hydrogen bond, hydrophobic, and pi-pi stacking interactions were dominant factors for the strong adsorption of BPAP, instead of the pH ionic strength and other ionic species in contaminated water.

hydrogen

BPAP


Input: The MWCNT has higher stability within 8 removal-regeneration recycles, and up to 95% of recovery could be obtained by eluting the adsorbed BPAP on MWCNT adsorbent using ethanol/sodium hydrate solution.

BPAP

ethanol

sodium hydrate


Input: The results of the experiment on real samples verified the effectiveness for the recovery and removal of BPAP from wastewater samples.

BPAP


Input: Signaling between Transforming Growth Factor beta (TGF-beta) and Transcription Factor SNAI2 Represses Expression of MicroRNA miR-203 to Promote Epithelial-Mesenchymal Transition and Tumor Metastasis.


Input: TGF-beta promotes tumor invasion and metastasis by inducing an epithelial-mesenchymal transition (EMT).


Input: Understanding the molecular and epigenetic mechanisms by which TGF-beta induces EMT may facilitate the development of new therapeutic strategies for metastasis.


Input: Here, we report that TGF-beta induced SNAI2 to promote EMT by repressing miR-203.


Input: Although miR-203 targeted SNAI2, SNAI2 induced by TGF-beta could directly bind to the miR-203 promoter to inhibit its transcription.


Input: SNAI2 and miR-203 formed a double negative feedback loop to inhibit each other' s expression, thereby controlling EMT.


Input: Moreover, we found that miR-203 was significantly down-regulated in highly metastatic breast cancer cells.


Input: The restoration of miR-203 in highly metastatic breast cancer cells inhibited tumor cell invasion in vitro and lung metastatic colonization in vivo by repressing SNAI2.


Input: Taken together, our results suggest that the SNAI2 and miR-203 regulatory loop plays important roles in EMT and tumor metastasis.


Input: Newer insulin analogs: advances in basal insulin replacement.


Input: Basal insulin analog therapy is the most common method of introducing insulin replacement therapy for the majority of patients with type 2 diabetes mellitus.


Input: Long-acting insulin analogs provide relatively peakless and more physiologic insulin replacement therapy than neutral protaminated Hagedorn insulin.


Input: Recently 2 new basal insulin analogs have been developed with superior pharmacokinetic and pharmacodynamics properties; insulin degludec and a pegylated insulin lispro.


Input: These agents are generally well tolerated and have been evaluated in both type 1 and type 2 diabetes.


Input: In this article we review the results of clinical trials assessing the efficacy, safety and tolerability of these newer longer-acting insulin analogs.


Input: In general rates of hypoglycaemia in these trials were low, glucose control was comparable to currently available basal insulin analogs, and rates of nocturnal hypoglycaemia were significantly and substantially lower.

glucose


Input: While further study will be required, advances in basal insulin replacement may offer important advantages over existing options for starting insulin strategies.


Input: Direct observation of a bent carbonyl ligand in a 19-electron transition metal complex.

carbonyl

transition metal


Input: The photochemistry of [CpRu (CO) 2] 2 in P (OMe) 3/CH2Cl2 solution has been studied using picosecond time-resolved infrared (TRIR) spectroscopy.

[CpRu (CO) 2] 2

P (OMe) 3


Input: Photolysis at 400 nm leads to the formation of 17-electron CpRu (CO) 2 (*) radicals, which react on the picosecond time scale to form 19-electron CpRu (CO) 2P (OMe) 3 (*) adducts.

CpRu (CO) 2 (*)

CpRu (CO) 2P (OMe) 3 (*)


Input: The TRIR spectra of this adduct display an unusually low CO stretching frequency for the antisymmetric CO stretching mode, suggesting that one carbonyl ligand adopts a bent configuration to avoid a 19-electron count at the metal center.

CO

CO

carbonyl


Input: This spectral assignment is supported by analogous experiments on [CpFe (CO) 2] 2 in the same solvent, combined with DFT studies on the structures of the 19-electron adducts.

[CpFe (CO) 2] 2


Input: The DFT results predict a bent CO ligand in CpRu (CO) 2P (OMe) 3 (*), whereas approximately linear Fe-C-O bond angles are predicted for CpFe (CO) 2P (OMe) 3 (*).

CO

CpRu (CO) 2P (OMe) 3 (*)

Fe-C-O

CpFe (CO) 2P (OMe) 3 (*)


Input: The observation of a bent CO ligand in the 19-electron ruthenium adduct is a surprising result, and it provides new insight into the solution-phase behavior of 19-electron complexes.

CO

ruthenium


Input: TRIR spectra were also collected for [CpRu (CO) 2] 2 in neat CH2Cl2, and it is interesting to note that no singly bridged [CpRu (CO)] 2 (mu-CO) photoproduct was observed to form following 400-or 267-nm excitation, despite previous observations of this species on longer time scales.

[CpRu (CO) 2] 2

[CpRu (CO)] 2 (mu-CO)


Input: Enzyme responsive hyaluronic Acid nanocapsules containing polyhexanide and their exposure to bacteria to prevent infection.

polyhexanide


Input: Antibacterial nanodevices could bring coatings of plastic materials and wound dressings a big step forward if the release of the antibacterial agents could be triggered by the presence of the bacteria themselves.


Input: Here, we show that novel hyaluronic acid (HA)-based nanocapsules containing the antimicrobial agent polyhexanide are specifically cleaved in the presence of hyaluronidase, a factor of pathogenicity and invasion for bacteria like Staphylococcus aureus and Escherichia coli.

polyhexanide


Input: This resulted in an efficient killing of the pathogenic bacteria by the antimicrobial agent.


Input: The formation of different polymeric nanocapsules was achieved through a polyaddition reaction in inverse miniemulsion.


Input: After the synthesis, the nanocapsules were transferred to an aqueous medium and investigated in terms of size, size distribution, functionality, and morphology using dynamic light scattering, zeta potential measurements and scanning electron microscopy.


Input: The enzyme triggered release of a model dye and the antimicrobial polyhexanide was monitored using fluorescence and UV spectroscopy.

polyhexanide


Input: The stability of the nanocapsules in several biological media was tested and the interaction of nanocapsules with human serum protein was studied using isothermal titration calorimetry.


Input: The antibacterial effectiveness is demonstrated by determination of the antibacterial activity and determination of the minimal bactericidal concentration (MBC).


Input: Formulation, optimization, in vivo pharmacokinetic, behavioral and biochemical estimations of minocycline loaded chitosan nanoparticles for enhanced brain uptake.

minocycline


Input: The minocycline hydrochloride (MH), at higher doses, is useful in the treatment of neurodegenerative disorders and owing to its antioxidant potential, it may have nootropic effects.

minocycline hydrochloride


Input: MH loaded nanoparticles (MHNP) were coated with tween 80 (cMHNP) to improve its brain uptake followed by their optimization employing two factor-three level (3 (2)) central composite design (CCD) in order to minimize particle size and maximize drug entrapment efficiency (DEE) and validated.

tween 80


Input: The optimized formulations were further subjected to in vitro drug release study; in vivo biodistribution studies in male wistar rats.


Input: The pharmacodynamic study was carried out using elevated plus maze (EPM) and Morris water maze (MWM) behavioral models for nootropic activity in swiss albino mice; and biochemical estimations (acetylcholine esterase, reduced glutathione, malondialdehyde and brain nitrite level).

acetylcholine

reduced glutathione

malondialdehyde

nitrite


Input: After intravenous (i. v.) administration, the concentration of MH in brain of cMHNP (6. 21 +/- 0. 64 micro g/mL) treated rats was significantly higher with MH solution treated (0. 70 +/- 0. 06 micro g/mL) as well as MHNP (1. 03 +/- 0. 12 micro g/mL) treated animals.


Input: Pharmacodynamic studies revealed a significant improvement in memory of MH, MHNP and cMHNP treated swiss albino mice than saline treated control group.


Input: However, cMHNP revealed maximum decrease in transfer latency (TL) in EPM and maximum increase in time spent in target quadrant (TSTQ) in MWM.


Input: Although cMHNP did not produce significant change in brain acetylcholinesterase, but, significantly increased reduced glutathione, malondialdehyde and reduced brain nitrite level as compared to saline, MH solution and MHNP treated groups.

reduced glutathione

malondialdehyde

nitrite


Input: The results suggest that cMHNP is a promising candidate for improved brain uptake of MH with better nootropic effect.


Input: Discovery of 7-methoxy-6-[4-(4-methyl-1, 3-thiazol-2-yl)-1H-imidazol-5-yl]-1, 3-benzothiazole (TASP0382088): a potent and selective transforming growth factor-beta type I receptor inhibitor as a topical drug for alopecia.

7-methoxy-6-[4-(4-methyl-1, 3-thiazol-2-yl)-1H-imidazol-5-yl]-1, 3-benzothiazole


Input: 7-Methoxy-6-[4-(4-methyl-1, 3-thiazol-2-yl)-1H-imidazol-5-yl]-1, 3-benzothiazole 11 (TASP0382088) was synthesized and evaluated as transforming growth factor-beta (TGF-beta) type I receptor (also known as activin receptor-like kinase 5 or ALK5) inhibitor.

7-Methoxy-6-[4-(4-methyl-1, 3-thiazol-2-yl)-1H-imidazol-5-yl]-1, 3-benzothiazole


Input: Compound 11, a potent and selective ALK5 inhibitor, exhibited good enzyme inhibitory activity (IC50 = 4. 8 nM) as well as inhibitory activity against TGF-beta-induced Smad2/3 phosphorylation at a cellular level (IC50 = 17 nM).


Input: The introduction of a methoxy group to the benzothiazole ring in 1 and the break up of the planarity between the imidazole ring and the thiazole ring improved the solubility in the lotion base of 11.

methoxy

benzothiazole

imidazole

thiazole


Input: Furthermore, the topical application of 3% 11 lotion significantly inhibited Smad2 phosphorylation in mouse skin at 8 h after application (71% inhibition, compared with vehicle-treated animals).


Input: Self-organizing map analysis using multivariate data from theophylline tablets predicted by a thin-plate spline interpolation.

theophylline


Input: The " quality by design " concept in pharmaceutical formulation development requires the establishment of a science-based rationale and a design space.


Input: We integrated thin-plate spline (TPS) interpolation and Kohonen' s self-organizing map (SOM) to visualize the latent structure underlying causal factors and pharmaceutical responses.


Input: As a model pharmaceutical product, theophylline tablets were prepared based on a standard formulation.

theophylline


Input: The tensile strength, disintegration time, and stability of these variables were measured as response variables.


Input: These responses were predicted quantitatively based on nonlinear TPS.


Input: A large amount of data on these tablets was generated and classified into several clusters using an SOM.


Input: The experimental values of the responses were predicted with high accuracy, and the data generated for the tablets were classified into several distinct clusters.


Input: The SOM feature map allowed us to analyze the global and local correlations between causal factors and tablet characteristics.


Input: The results of this study suggest that increasing the proportion of microcrystalline cellulose (MCC) improved the tensile strength and the stability of tensile strength of these theophylline tablets.

theophylline


Input: In addition, the proportion of MCC has an optimum value for disintegration time and stability of disintegration.


Input: Increasing the proportion of magnesium stearate extended disintegration time.

magnesium stearate


Input: Increasing the compression force improved tensile strength, but degraded the stability of disintegration.


Input: This technique provides a better understanding of the relationships between causal factors and pharmaceutical responses in theophylline tablet formulations.

theophylline


Input: Discovery of aromatic components with excellent fragrance properties and biological activities: beta-ionols with antimelanogenetic effects and their asymmetric syntheses.

beta-ionols


Input: Both enantiomers of dihydro-beta-ionol and beta-ionol, contained in the aromatic components of Osmanthus flower and of Hakuto peach, were obtained with high optical purity by lipase-catalyzed kinetic resolution of the racemates.

dihydro-beta-ionol

beta-ionol


Input: It was found that all these enantiomers had different characteristic favorable scents and high antimelanogenetic effects.


Input: The absolute configuration and the enantiomer ratios of dihydro-beta-ionol in the aromatic components of Osmanthus flower and of Hakuto peach were determined.

dihydro-beta-ionol


Input: The asymmetric synthesis of (R)-dihydro-beta-ionol, one of the most valuable raw materials for fragrance and flavor, was performed from inexpensive beta-ionone via lipase-catalyzed dynamic kinetic resolution followed by reduction.

(R)-dihydro-beta-ionol

beta-ionone


Input: Three new orcinol-conjugated hydrolysable tannins from the leaves of Cleyera japonica.

orcinol

tannins


Input: Three new orcinol (3-hydroxy-5-methylphenol)-conjugated hydrolysable tannins, together with two known compounds were isolated from the leaves of Cleyera japonica (CJ), and have been tentatively named cleyeratannin A (1), cleyeratannin B (2) and cleyeratannin C (3).

orcinol

tannins

cleyeratannin A

cleyeratannin B

cleyeratannin C


Input: The chemical structures of these compounds were elucidated using 1 dimensional (1D)/2D NMR and high resolution FAB-MS, and the absolute configuration was confirmed by circular dichroism (CD).


Input: To evaluate their anti-oxidative activities, 1, 1-diphenyl-2-picrylhydrazyl (DPPH)/free radical scavenging activity and nitroblue tetrazolium (NBT)/superoxide anion scavenging activity were determined.

1, 1-diphenyl-2-picrylhydrazyl

DPPH

nitroblue tetrazolium

NBT

superoxide


Input: ARF represses androgen receptor transactivation in prostate cancer.

androgen


Input: Androgen receptor (AR) signaling is essential for prostate cancer (PCa) development in humans.

Androgen


Input: The initiation of prostate malignancy and progression to a castration-resistant stage are largely contributed by the modulation of AR activity through its coregulatory proteins.


Input: We and others previously reported that p14 alternative reading frame (ARF) expression is positively correlated with the disease progression and severity of PCa.


Input: Here, we provide evidence that p14ARF physically interacts with AR and functions as an AR corespressor in both an androgen-dependent and androgen-independent manner.

androgen

androgen


Input: Endogenous ARF (p14ARF in human and p19ARF in mouse) and AR colocalize in both human PCa cells in vitro and PCa tissues of mouse and human in vivo.


Input: Overexpression of p14ARF in PCa cells significantly attenuates the activities of androgen response region (ARR2)-probasin and prostate-specific antigen (PSA) promoters.

androgen


Input: The forced expression of p14ARF in cells resulted in a suppression of PSA and NK transcription factor locus 1 (NKX3. 1) expression.


Input: Conversely, knockdown of endogenous p14ARF in human PCa cells with short hairpin RNA enhanced AR transactivation activities in a dose-dependent and p53-independent manner.


Input: Furthermore, we demonstrated that p14ARF binds to both the N-terminal domain and the ligand-binding domain of AR, and the human double minute 2 (HDM2)-binding motif of p14ARF is required for the interaction of p14ARF and AR proteins.

N


Input: p14ARF perturbs the androgen-induced interaction between the N terminus and C terminus of AR.

androgen

N

C


Input: Most importantly, we observed that the expression of PSA is reversely correlated with p14ARF in human prostate tissues.


Input: Taken together, our results reveal a novel function of ARF in modulation of AR transactivation in PCa.


Input: Ceramide phosphoethanolamine biosynthesis in Drosophila is mediated by a unique ethanolamine phosphotransferase in the Golgi lumen.

Ceramide phosphoethanolamine

ethanolamine


Input: Sphingomyelin (SM) is a vital component of mammalian membranes, providing mechanical stability and a structural framework for plasma membrane organization.

Sphingomyelin


Input: Its production involves the transfer of phosphocholine from phosphatidylcholine onto ceramide, a reaction catalyzed by SM synthase in the Golgi lumen.

phosphocholine

phosphatidylcholine

ceramide


Input: Drosophila lacks SM and instead synthesizes the SM analogue ceramide phosphoethanolamine (CPE) as the principal membrane sphingolipid.

ceramide phosphoethanolamine

CPE

sphingolipid


Input: The corresponding CPE synthase shares mechanistic features with enzymes mediating phospholipid biosynthesis via the Kennedy pathway.

CPE


Input: Using a functional cloning strategy, we here identified a CDP-ethanolamine: ceramide ethanolamine phosphotransferase as the enzyme responsible for CPE production in Drosophila.

CDP

ethanolamine

ceramide ethanolamine

CPE


Input: CPE synthase constitutes a new branch within the CDP-alcohol phosphotransferase superfamily with homologues in Arthropoda (insects, spiders, mites, scorpions), Cnidaria (Hydra, sea anemones), and Mollusca (oysters) but not in most other animal phyla.

CPE

CDP

alcohol


Input: The enzyme resides in the Golgi complex with its active site facing the lumen, contrary to the membrane topology of other CDP-alcohol phosphotransferases.

CDP

alcohol


Input: Our findings open up an important new avenue to address the biological role of CPE, an enigmatic membrane constituent of a wide variety of invertebrate and marine organisms.

CPE


Input: The gas-phase reaction of methane sulfonic acid with the hydroxyl radical without and with water vapor.

methane sulfonic acid

hydroxyl


Input: The gas phase reaction between methane sulfonic acid (CH3SO3H; MSA) and the hydroxyl radical (HO), without and with a water molecule, was investigated with DFT-B3LYP and CCSD (T)-F12 methods.

methane sulfonic acid

MSA

hydroxyl

HO


Input: For the bare reaction we have found two reaction mechanisms, involving proton coupled electron transfer and hydrogen atom transfer processes that produce CH3SO3 and H2O.

hydrogen


Input: We also found a third reaction mechanism involving the double proton transfer process, where the products and reactants are identical.


Input: The computed rate constant for the oxidation process is 8. 3 x 10 (-15) cm (3) s (-1) molecule (-1).


Input: CH3SO3H forms two very stable complexes with water with computed binding energies of about 10 kcal mol (-1).


Input: The presence of a single water molecule makes the reaction between CH3SO3H and HO much more complex, introducing a new reaction that consists in the interchange of H2O between HO and CH3SO3H.

HO

HO


Input: Our kinetic calculations show that 99. 5% of the reaction involves this interchange of the water molecule and, consequently, water vapor does not play any role in the oxidation reaction of methane sulfonic acid by the hydroxyl radical.

methane sulfonic acid

hydroxyl


Input: Principles of electron capture and transfer dissociation mass spectrometry applied to peptide and protein structure analysis.


Input: This tutorial review describes the principles and practices of electron capture and transfer dissociation (ECD/ETD or ExD) mass spectrometry (MS) employed for peptide and protein structure analysis.


Input: ExD MS relies on interactions between gas phase peptide or protein ions carrying multiple positive charges with either free low-energy (~ 1 eV) electrons (ECD), or with reagent radical anions possessing an electron available for transfer (ETD).


Input: As a result of recent implementation on sensitive, high resolution, high mass accuracy, and liquid chromatography timescale-compatible mass spectrometers, ExD, more specifically, ETD MS has received particular interest in life science research.


Input: In addition to describing the fundamental aspects of ExD radical ion chemistry, this tutorial provides practical guidelines for peptide de novo sequencing with ExD MS, as well as reviews some of the current capabilities and limitations of these techniques.


Input: The merits of ExD MS are discussed primarily within the context of life science research.


Input: New directions in thermoresponsive polymers.


Input: Interest in thermoresponsive polymers has steadily grown over many decades, and a great deal of work has been dedicated to developing temperature sensitive macromolecules that can be crafted into new smart materials.


Input: However, the overwhelming majority of previously reported temperature-responsive polymers are based on poly (N-isopropylacrylamide) (PNIPAM), despite the fact that a wide range of other thermoresponsive polymers have demonstrated similar promise for the preparation of adaptive materials.

poly (N-isopropylacrylamide)

PNIPAM


Input: Herein, we aim to highlight recent results that involve thermoresponsive systems that have not yet been as fully considered.


Input: Many of these (co) polymers represent clear opportunities for advancements in emerging biomedical and materials fields due to their increased biocompatibility and tuneable response.


Input: By highlighting recent examples of newly developed thermoresponsive polymer systems, we hope to promote the development of new generations of smart materials.


Input: Droplet-based lipid bilayer system integrated with microfluidic channels for solution exchange.


Input: This paper proposes a solution exchange of a droplet-based lipid bilayer system, in which the inner solution of a droplet is replaced for the purpose of efficient ion channel analyses.


Input: In our previous report, we successfully recorded the channel conductance of alpha-hemolysin in a bilayer lipid membrane using a droplet contact method that can create a spontaneous lipid bilayer at the interface of contacting droplets; this method is widely used as highly efficient method for preparing planar lipid membranes.


Input: When only pipetting droplets of the solution, this method is highly efficient for preparing lipid membranes.


Input: However, the drawback of droplet-based systems is their inability to exchange the solution within the droplets.


Input: To study the effect of inhibitors and promoters of ion channels in drug discovery, it would be beneficial to conduct a solution exchange of droplets to introduce membrane proteins and to apply or wash-out the chemicals.


Input: In this study, we propose a droplet contact method that allows for the solution exchange of droplets via microfluidic channels.


Input: We experimentally and numerically investigated the bilayer stability with respect to exchanging flow rates, and then demonstrated a binding assay of an alpha-hemolysin using one of its blockers.


Input: The solution exchange in this system was conducted in less than 20 s without rupturing the membrane.


Input: We believe that the proposed system will enhance the efficiency of ion channel analyses.


Input: Bacteriopheophytin a in the active branch of the reaction center of rhodobacter sphaeroides is not disturbed by the protein matrix as shown by 13C photo-CIDNP MAS NMR.

Bacteriopheophytin a


Input: The electronic structure of bacteriopheophytin a (BPhe a), the primary electron acceptor (Phi A) in photosynthetic reaction centers (RCs) of the purple bacterium Rhodobacter sphaeroides, is investigated by photochemically induced dynamic nuclear polarization (photo-CIDNP) magic-angle spinning (MAS) NMR spectroscopy at atomic resolution.

bacteriopheophytin a

BPhe a


Input: By using various isotope labeling systems, introduced by adding different (13) C selectively labeled delta-aminolevulinic acid precursors in the growing medium of R. sphaeroides wild type (WT), we were able to extract light-induced (13) C NMR signals originating from the primary electron acceptor.

(13) C

delta-aminolevulinic acid

(13) C


Input: The assignments are backed by theoretical calculations.


Input: By comparison of these chemical shifts to those obtained from monomeric BPhe a in solution, it is demonstrated that Phi A in the active branch appears to be electronically close to free bacteriopheophytin.

BPhe a

bacteriopheophytin


Input: Hence, there is little effect of the protein surrounding on the cofactor functionally which contributes with its standard redox potential to the electron transfer process that is asymmetric.


Input: Interplay between BDF1 and BDF2 and their roles in regulating the yeast salt stress response.


Input: The homologous genes BDF1 and BDF2 in Saccharomyces cerevisiae encode bromodomain-containing transcription factors.


Input: Although double deletion of BDF1 and BDF2 is lethal, single deletion does not affect cell viability.


Input: The bdf2 increment cells showed normal growth upon salt stress.


Input: However, the absence of Bdf1p resulted in a salt-sensitive phenotype, and the salt sensitivity was suppressed by overexpression of BDF2.


Input: In this study, we further demonstrated that BDF2 shows dosage compensation in suppressing the salt sensitivity of bdf1 increment.


Input: None of the tested domains replaced the function of intact Bdf1p.


Input: The 494-626 region in Bdf1p was more important than the other domains for salt resistance.


Input: In addition, Bdf1p negatively regulated the expression of BDF2 by binding its promoter at loci-387 to-48.


Input: However, Bdf2p did not affect the expression of BDF1.


Input: In addition, Bdf1p and its defective functional domain mutants could combine with Bdf2p.


Input: This physical interaction increased the salt tolerance of bdf1 increment.


Input: The mitochondrial dysfunctions caused by BDF1 deletion were restored by overexpression of BDF2 under salt stress conditions.


Input: STRUCTURED DIGITAL ABSTRACT: BDF2 physically interacts with BDF1 by anti tag coimmunoprecipitation (View interaction) BDF2 physically interacts with BDF1 by pull down (View interaction).


Input: Highly enantioselective rhodium-catalyzed [2 + 2 + 2] cycloaddition of diynes to sulfonimines.

rhodium

diynes

sulfonimines


Input: A new asymmetric [2 + 2 + 2] cycloaddition of diynes to sulfonimines under rhodium catalysis that provides the corresponding enantioenriched 1, 2-dihydropyridines in good yields is described.

diynes

sulfonimines

rhodium

1, 2-dihydropyridines


Input: 1, 3, 4-thiadiazole and its derivatives: a review on recent progress in biological activities.

1, 3, 4-thiadiazole


Input: The 1, 3, 4-thiadiazole nucleus is one of the most important and well-known heterocyclic nuclei, which is a common and integral feature of a variety of natural products and medicinal agents.

1, 3, 4-thiadiazole


Input: Thiadiazole nucleus is present as a core structural component in an array of drug categories such as antimicrobial, anti-inflammatory, analgesic, antiepileptic, antiviral, antineoplastic, and antitubercular agents.

Thiadiazole


Input: The broad and potent activity of thiadiazole and their derivatives has established them as pharmacologically significant scaffolds.

thiadiazole


Input: In this study, an attempt has been made with recent research findings on this nucleus, to review the structural modifications on different thiadiazole derivatives for various pharmacological activities.

thiadiazole


Input: mGluR2 positive allosteric modulators: a patent review (2009-present).


Input: Introduction: The mGlu2 receptor, which belongs to the group II subfamily of metabotropic glutamate receptors (mGlu) along with the mGlu3 receptor, has proven to be of particular importance in neuropharmacology.

glutamate


Input: Preferentially expressed on presynaptic nerve terminals, the mGlu2 receptor negatively modulates glutamate and GABA release and is widely distributed in the brain.

glutamate

GABA


Input: High levels of mGlu2 receptors are seen in brain areas such as prefrontal cortex, hippocampus and amygdala where glutamate hyperfunction may be implicated in disorders and diseases such as anxiety and schizophrenia.

glutamate


Input: Given the promise offered by mGlu2/3 receptor activation, there is increased interest in identifying small molecules which activate the receptor.


Input: A preferred approach is via positive allosteric modulators (PAMs) which bind at an alternative site to agonists.


Input: Areas covered: This review covers the patent applications which were published between April 2009 and December 2012 on PAMs of the mGlu2, and it is a continuation of an earlier review published in this journal.


Input: Expert opinion: Advances in medicinal chemistry and pharmacology have set the stage in the field of mGlu2 receptor PAMs.


Input: Compounds currently advancing in clinical trials will soon establish the therapeutic potential of this allosteric approach.


Input: Extensive paternal mtDNA leakage in natural populations of Drosophila melanogaster.


Input: Strict maternal inheritance is considered a hallmark of animal mtDNA.


Input: Although recent reports suggest that paternal leakage occurs in a broad range of species, it is still considered an exceptionally rare event.


Input: To evaluate the impact of paternal leakage on the evolution of mtDNA, it is essential to reliably estimate the frequency of paternal leakage in natural populations.


Input: Using allele-specific real-time quantitative PCR (RT-qPCR), we show that heteroplasmy is common in natural populations with at least 14% of the individuals carrying multiple mitochondrial haplotypes.


Input: However, the average frequency of the minor mtDNA haplotype is low (0. 8%), which suggests that this pervasive heteroplasmy has not been noticed before due to a lack of power in sequencing surveys.


Input: Based on the distribution of mtDNA haplotypes in the offspring of heteroplasmic mothers, we found no evidence for strong selection against one of the haplotypes.


Input: We estimated that the rate of paternal leakage is 6% and that at least 100 generations are required for complete sorting of mtDNA haplotypes.


Input: Despite the high proportion of heteroplasmic individuals in natural populations, we found no evidence for recombination between mtDNA molecules, suggesting that either recombination is rare or recombinant haplotypes are counter-selected.


Input: Our results indicate that evolutionary studies using mtDNA as a marker might be biased by paternal leakage in this species.


Input: Characterization of a pre-export enzyme-chaperone complex on the twin-arginine transport pathway.

arginine


Input: The Tat (twin-arginine translocation) system is a protein targeting pathway utilized by prokaryotes and chloroplasts.

arginine


Input: Tat substrates are produced with distinctive N-terminal signal peptides and are translocated as fully folded proteins.

N


Input: In Escherichia coli, Tat-dependent proteins often contain redox cofactors that must be loaded before translocation.


Input: Trimethylamine N-oxide reductase (TorA) is a model bacterial Tat substrate and is a molybdenum cofactor-dependent enzyme.

Trimethylamine N-oxide

molybdenum


Input: Co-ordination of cofactor loading and translocation of TorA is directed by the TorD protein, which is a cytoplasmic chaperone known to interact physically with the TorA signal peptide.


Input: In the present study, a pre-export TorAD complex has been characterized using biochemical and biophysical techniques, including SAXS (small-angle X-ray scattering).


Input: A stable, cofactor-free TorAD complex was isolated, which revealed a 1: 1 binding stoichiometry.


Input: Surprisingly, a TorAD complex with similar architecture can be isolated in the complete absence of the 39-residue TorA signal peptide.


Input: The present study demonstrates that two high-affinity binding sites for TorD are present on TorA, and that a single TorD protein binds both of those simultaneously.


Input: Further characterization suggested that the C-terminal' Domain IV' of TorA remained solvent-exposed in the cofactor-free pre-export TorAD complex.

C


Input: It is possible that correct folding of Domain IV upon cofactor loading is the trigger for TorD release and subsequent export of TorA.


Input: beta-Sheet Nanocrystalline Domains Formed from Phosphorylated Serine-Rich Motifs in Caddisfly Larval Silk: A Solid State NMR and XRD Study.

Phosphorylated Serine


Input: Adhesive silks spun by aquatic caddisfly (order Trichoptera) larvae are used to build both intricate protective shelters and food harvesting nets underwater.


Input: In this study, we use (13) C and (31) P solid-state NMR and wide angle X-ray diffraction (WAXD) as tools to elucidate molecular protein structure of caddisfly larval silk from the species Hesperophylax consimilis.

(13) C

(31) P


Input: Caddisfly larval silk is a fibroin protein based biopolymer containing mostly repetitive amino acid motifs.

amino acid


Input: NMR and X-ray results provide strong supporting evidence for a structural model in which phosphorylated serine repeats (pSX) 4 complex with divalent cations Ca (2 +) and Mg (2 +) to form rigid nanocrystalline beta-sheet structures in caddisfly silk.

phosphorylated serine

Ca (2 +)

Mg (2 +)


Input: (13) C NMR data suggests that both phosphorylated serine and neighboring valine residues exist in a beta-sheet conformation while glycine and leucine residues common in GGX repeats likely reside in random coil conformations.

(13) C

phosphorylated serine

valine

glycine

leucine


Input: Additionally, (31) P chemical shift anisotropy (CSA) analysis indicates that the phosphates on phosphoserine residues are doubly ionized, and are charge-stabilized by divalent cations.

(31) P

phosphates

phosphoserine


Input: Positively charged arginine side chains also likely play a role in charge stabilization.

arginine


Input: Finally, WAXD results finds that the silk is at least 7-8% crystalline, with beta-sheet interplane spacings of 3. 7 and 4. 5 A.


Input: Hydrocarbons (jet fuel JP-8) induce epigenetic transgenerational inheritance of obesity, reproductive disease and sperm epimutations.

Hydrocarbons


Input: Environmental compounds have been shown to promote epigenetic transgenerational inheritance of disease.


Input: The current study was designed to determine if a hydrocarbon mixture involving jet fuel (JP-8) promotes epigenetic transgenerational inheritance of disease.

hydrocarbon


Input: Gestating F0 generation female rats were transiently exposed during the fetal gonadal development period.


Input: The direct exposure F1 generation had an increased incidence of kidney abnormalities in both females and males, prostate and pubertal abnormalities in males, and primordial follicle loss and polycystic ovarian disease in females.


Input: The first transgenerational generation is the F3 generation, and the jet fuel lineage had an increased incidence of primordial follicle loss and polycystic ovarian disease in females, and obesity in both females and males.


Input: Analysis of the jet fuel lineage F3 generation sperm epigenome identified 33 differential DNA methylation regions, termed epimutations.


Input: Observations demonstrate hydrocarbons can promote epigenetic transgenerational inheritance of disease and sperm epimutations, potential biomarkers for ancestral exposures.

hydrocarbons


Input: Synthesis and evaluation of nicotinamide derivative as anti-angiogenic agents.

nicotinamide


Input: Previously, we have found that BRN-103, a nicotinamide derivative, inhibits vascular endothelial growth factor (VEGF)-mediated angiogenesis signaling in human endothelial cells.

nicotinamide


Input: During our continuous efforts to identify more potent anti-angiogenic agents, we synthesized various nicotinamide derivatives and evaluated their anti-angiogenic effects.

nicotinamide


Input: We found that 2-{1-[1-(6-chloro-5-fluoropyrimidin-4-yl) ethyl] piperidin-4-ylamino}-N-(3-chlorophenyl) pyridine-3-carboxamide (BRN-250) significantly inhibited human umbilical vascular endothelial cells (HUVECs) proliferation, migration, tube formation, and microvessel growth in a concentration range of 10-100 nM.

2-{1-[1-(6-chloro-5-fluoropyrimidin-4-yl) ethyl] piperidin-4-ylamino}-N-(3-chlorophenyl) pyridine-3-carboxamide


Input: Furthermore, BRN-250 inhibited the VEGF-induced phosphorylation and intracellular tyrosine kinase activity of VEGF receptor 2 (VEGFR2) and the activation of its downstream AKT pathway.

tyrosine


Input: Taken together, these findings suggest that BRN-250 be considered a potential lead compound for cancer therapy.


Input: Small molecule modulators of Wnt/beta-catenin signaling.


Input: The Wnt signal transduction pathway is dysregulated in many highly prevalent diseases, including cancer.


Input: Unfortunately, drug discovery efforts have been hampered by the paucity of targets and drug-like lead molecules amenable to drug discovery.


Input: Recently, we reported the FDA-approved anthelmintic drug Niclosamide inhibits Wnt/beta-catenin signaling by a unique mechanism, though the target responsible remains unknown.

Niclosamide


Input: We interrogated the mechanism and structure-activity relationships to understand drivers of potency and to assist target identification efforts.


Input: We found inhibition of Wnt signaling by Niclosamide appears unique among the structurally-related anthelmintic agents tested and found the potency and functional response was dependent on small changes in the chemical structure of Niclosamide.

Niclosamide

Niclosamide


Input: Overall, these findings support efforts to identify the target of Niclosamide inhibition of Wnt/beta-catenin signaling and the discovery of potent and selective modulators to treat human disease.

Niclosamide


Input: Jacaric acid and its octadecatrienoic acid geoisomers induce apoptosis selectively in cancerous human prostate cells: a mechanistic and 3-D structure-activity study.

Jacaric acid

octadecatrienoic acid


Input: Plant-derived non-essential fatty acids are important dietary nutrients, and some are purported to have chemopreventive properties against various cancers, including that of the prostate.

fatty acids


Input: In this study, we determined the ability of seven dietary C-18 fatty acids to cause cytotoxicity and induce apoptosis in various types of human prostate cancer cells.

C-18 fatty acids


Input: These fatty acids included jacaric and punicic acid found in jacaranda and pomegranate seed oil, respectively, three octadecatrienoic geometric isomers (alpha-and beta-calendic and catalpic acid) and two mono-unsaturated C-18 fatty acids (trans-and cis-vaccenic acid).

fatty acids

jacaric and punicic acid

alpha-and beta-calendic and catalpic acid

mono-unsaturated C-18 fatty acids

trans-and cis-vaccenic acid


Input: Jacaric acid and four of its octadecatrienoic geoisomers selectively induced apoptosis in hormone-dependent (LNCaP) and-independent (PC-3) human prostate cancer cells, whilst not affecting the viability of normal human prostate epithelial cells (RWPE-1).

Jacaric acid


Input: Jacaric acid induced concentration-and time-depedent LNCaP cell death through activation of intrinsic and extrinsic apoptotic pathways resulting in cleavage of PARP-1, modulation of pro-and antiapoptotic Bcl-2 family of proteins and increased cleavage of caspase-3,-8 and-9.

Jacaric acid


Input: Moreover, activation of a cell death-inducing signalling cascade involving death receptor 5 was observed.


Input: Jacaric acid induced apoptosis in PC-3 cells by activation of the intrinsic pathway only.

Jacaric acid


Input: The spatial conformation cis, trans, cis of jacaric and punicic acid was shown to play a key role in the increased potency and efficacy of these two fatty acids in comparison to the five other C-18 fatty acids tested.

jacaric and punicic acid

fatty acids

C-18 fatty acids


Input: Three-dimensional conformational analysis using the PubChem Database (http://pubchem. ncbi. nlm. nih. gov) showed that the cytotoxic potency of the C-18 fatty acids was related to their degree of conformational similarity to our cytotoxic reference compound, punicic acid, based on optimized shape (ST) and feature (CT) similarity scores, with jacaric acid being most' biosimilar' (ST (ST-opt) = 0. 81; CT (CT-opt) = 0. 45).

C-18 fatty acids

punicic acid

jacaric acid


Input: This 3-D analysis of structural similarity enabled us to rank geoisomeric fatty acids according to cytotoxic potency, whereas a 2-D positional assessment of cis/trans structure did not.

fatty acids


Input: Our findings provide mechanistic evidence that nutrition-derived non-essential fatty acids have chemopreventive biological activities and Exhibit 3-D structure-activity relationships that could be exploited to develop new strategies for the prevention or treatment of prostate cancer regardless of hormone dependency.

fatty acids


Input: The n-SET domain of Set1 regulates H2B ubiquitylation-dependent H3K4 methylation.


Input: Past studies have documented a crosstalk between H2B ubiquitylation (H2Bub) and H3K4 methylation, but little (if any) direct evidence exists explaining the mechanism underlying H2Bub-dependent H3K4 methylation on chromatin templates.


Input: Here, we took advantage of an in vitro histone methyltransferase assay employing a reconstituted yeast Set1 complex (ySet1C) and a recombinant chromatin template containing fully ubiquitylated H2B to gain valuable insights.


Input: Combined with genetic analyses, we demonstrate that the n-SET domain within Set1, but not Swd2, is essential for H2Bub-dependent H3K4 methylation.


Input: Spp1, a homolog of human CFP1, is conditionally involved in this crosstalk.


Input: Our findings extend to the human Set1 complex, underscoring the conserved nature of this disease-relevant crosstalk pathway.


Input: As not all members of the H3K4 methyltransferase family contain n-SET domains, our studies draw attention to the n-SET domain as a predictor of an H2B ubiquitylation-sensing mechanism that leads to downstream H3K4 methylation.


Input: Synthesis and anti-acetylcholinesterase properties of novel beta-and gamma-substituted alkoxy organophosphonates.

beta-and gamma-substituted alkoxy organophosphonates


Input: Activated organophosphate (OP) insecticides and chemical agents inhibit acetylcholinesterase (AChE) to form OP-AChE adducts.

organophosphate


Input: Whereas the structure of the OP correlates with the rate of inhibition, the structure of the OP-AChE adduct influences the rate at which post-inhibitory reactivation or aging phenomena occurs.


Input: In this report, we prepared a panel of beta-substituted ethoxy and gamma-substituted propoxy phosphonoesters of the type p-NO (2) PhO-P (X) (R) [(O (CH (2)) (n) Z] (R = Me, Et; X = O, S; n = 2, 3; Z = halogen, OTs) and examined the inhibition of three AChEs by select structures in the panel.

beta-substituted ethoxy and gamma-substituted propoxy phosphonoesters

p-NO (2) PhO-P (X) (R) [(O (CH (2)) (n) Z]

R = Me, Et; X = O, S; n = 2, 3; Z = halogen, OTs


Input: The beta-fluoroethoxy methylphosphonate analog (R = Me, Z = F, n = 2) was the most potent anti-AChE compound comparable (ki ~ 6 x 10 (6) M (-1) min (-1)) to paraoxon against EEAChE.

beta-fluoroethoxy methylphosphonate

R = Me, Z = F, n = 2

paraoxon


Input: Analogs with Z = Br, I, or OTs were weak inhibitors of the AChEs, and methyl phosphonates (R = Me) were more potent than the corresponding ethyl phosphonates (R = Et).

Z = Br, I, or OTs

methyl phosphonates

R = Me

ethyl phosphonates

R = Et


Input: As expected, analogs with a thionate linkage (PS) were poor inhibitors of the AChEs.

thionate


Input: N-Alkyldeoxynojirimycin derivatives with novel terminal tertiary amide substitution for treatment of bovine viral diarrhea virus (BVDV), Dengue, and Tacaribe virus infections.

N-Alkyldeoxynojirimycin

tertiary amide


Input: Novel N-alkyldeoxynojirimycins (NADNJs) with two hydrophobic groups attached to a nitrogen linker on the alkyl chain were designed.

N-alkyldeoxynojirimycins

NADNJs

alkyl


Input: A novel NADNJ containing a terminal tertiary carboxamide moiety was discovered that was a potent inhibitor against BVDV.

NADNJ

tertiary carboxamide


Input: Further optimization resulted in a structurally more stable lead compound 24 with a submicromolar EC50 against BVDV, Dengue, and Tacaribe; and low cytotoxicity.


Input: 2-Substituted-2-amino-6-boronohexanoic acids as arginase inhibitors.

2-Substituted-2-amino-6-boronohexanoic acids


Input: Substitution at the alpha center of the known human arginase inhibitor 2-amino-6-boronohexanoic acid (ABH) is acceptable in the active site pockets of both human arginase I and arginase II.

2-amino-6-boronohexanoic acid

ABH


Input: In particular, substituents with a tertiary amine linked via a two carbon chain show improved inhibitory potency for both enzyme isoforms.

tertiary amine

carbon


Input: This potency improvement can be rationalized by X-ray crystallography, which shows a water-mediated contact between the basic nitrogen and the carboxylic acid side chain of Asp200, which is situated at the mouth of the active site pocket of arginase II (Asp181 in arginase I).

nitrogen

carboxylic acid


Input: We believe that this is the first literature report of compounds with improved arginase inhibitory activity, relative to ABH, and represents a promising starting point for further optimization of in vitro potency and the identification of better tool molecules for in vivo investigations of the potential pathophysiological roles of arginases.

ABH


Input: Memantine-sulfur containing antioxidant conjugates as potential prodrugs to improve the treatment of Alzheimer' s disease.

Memantine

sulfur


Input: The approved treatments for Alzheimer' s disease (AD) exploit mainly a symptomatic approach based on the use of cholinesterase inhibitors or N-methyl-d-aspartate (NMDA) receptor antagonists.

N-methyl-d-aspartate

NMDA


Input: Natural antioxidant compounds, able to pass through the blood-brain barrier (BBB), have been extensively studied as useful neuroprotective agents.


Input: A novel approach towards excitotoxicity protection and oxidative stress associated with excess beta amyloid (A beta) preservation in AD is represented by selective glutamatergic antagonists that possess as well antioxidant capabilities.


Input: In the present work, GSH (1) or (R)-alpha-lipoic acid (LA) (2) have been covalently linked with the NMDA receptor antagonists memantine (MEM).

GSH

(R)-alpha-lipoic acid

NMDA

memantine

MEM


Input: The new conjugates, proposed as potential antialzheimer drugs, should act both as glutamate receptor antagonists and radical scavenging agents.

glutamate


Input: The physico-chemical properties and " in vitro " membrane permeability, the enzymatic and chemical stability, the demonstrated " in vitro " antioxidant activity associated to the capacity to inhibit A beta (1-42) aggregation makes at least compound 2 a promising candidate for treatment of AD patients.


Input: Return flight to the Canary Islands-The key role of peripheral populations of Afrocanarian blue tits (Aves: Cyanistes teneriffae) in multi-gene reconstructions of colonization pathways.


Input: Afrocanarian blue tits (Cyanistes teneriffae) have a scattered distribution on the Canary Islands and on the North African continent.


Input: To date, the Canary Islands have been considered the species' main Pleistocene evolutionary center, but their colonization pathways remain uncertain.


Input: We set out to reconstruct a dated multi-gene phylogeny and ancestral ranges for Cyanistes tit species including the currently unstudied, peripheral Libyan population of C.


Input: t. cyrenaicae.


Input: In all reconstructions the most easterly and westerly peripheral populations (in Libya and on La Palma) represented basal offshoots of C. teneriffae.


Input: These two peripheral populations shared all four major indels and differed in this respect from all other members of the Afrocanarian core group.


Input: The basal split of Afrocanarian blue tits from their European relatives was dated to the early Pliocene.


Input: The two ancestral area reconstructions were contradictory and suggested either a Canarian or a North African origin of C. teneriffae-but unambiguously ruled out a continental European ancestral range.


Input: We conclude that the peripheral populations of C. teneriffae represent relic lineages of a first faunal interchange, presumably downstream colonization from North Africa to the Canary Islands.


Input: Subsequent eastward stepping-stone colonization within the Canarian Archipelago culminated in a very recent late (possibly even post-) Pleistocene back-colonization from the Canary Islands to North Africa.


Input: Tumor delivery of Photofrin (R) by PLL-g-PEG for photodynamic therapy.

Photofrin

PLL-g-PEG


Input: Photofrin (R) (porfimer sodium) is a photosensitive reagent used for photodynamic therapy (PDT) of tumors and dysplasias.

Photofrin

porfimer sodium


Input: Because only photo-irradiated sites are damaged, PDT is less invasive than systemic treatments.


Input: However, a photosensitive reaction is a major side effect of systemically delivered Photofrin.

Photofrin


Input: To enhance localization of Photofrin to tumors, we have formulated Photofrin with the tumor-localizing graft copolymer poly (ethylene glycol)-grafted poly (l-lysine), PLL-g-PEG.

Photofrin

Photofrin

poly (ethylene glycol)-grafted poly (l-lysine)

PLL-g-PEG


Input: We demonstrate that Photofrin preferentially interacts with PLL-g-PEG through both ionic and hydrophobic interactions.

Photofrin

PLL-g-PEG


Input: The serum competitive study showed that the highly PEG-grafted PLL is better for preventing serum binding to the Photofrin/PLL-g-PEG complex.

PEG-grafted PLL

Photofrin

PLL-g-PEG


Input: In tumor-bearing mice, formulation of Photofrin with PLL-g-PEG enhanced tumor localization of Photofrin as twice as Photofrin alone and concomitantly suppressed the photosensitivity reaction drastically.

Photofrin

PLL-g-PEG

Photofrin

Photofrin


Input: Examination of the effect of increasing the number of intra-disulfide amino functional groups on the performance of small molecule cyclic polyamine disulfide vectors.

disulfide amino

polyamine disulfide


Input: Establishing structure-activity relationships is vital if the efficacy of non-viral vectors is to match that of their viral counter-parts.


Input: Recently, we reported on the ability of a series of small molecule, cyclic polyamine disulfides to condense and cage plasmid DNA (pDNA) by a process of thermodynamically controlled template polymerization, leading to a series of corresponding pDNA-polyplex nanoparticles able to mediate high levels of transfection with no associated cytotoxicities.

cyclic polyamine disulfides


Input: The leading cyclic polyamine disulfide was shown to be the spermine tetra-amine disulfide (TetraN-3, 4, 3).

cyclic polyamine disulfide

spermine tetra-amine disulfide

TetraN-3, 4, 3


Input: Herein we report on the significantly more challenging syntheses of cyclic disulfides with longer polyamine motifs.

cyclic disulfides


Input: Two new cyclic polyamine disulfides, based on hexa-and octa-amine inserts, were prepared and their transfection efficacies and cytotoxicities compared with our previously reported cyclic tri-and tetra-amine disulfides.

cyclic polyamine disulfides

hexa-and octa-amine

cyclic tri-and tetra-amine disulfides


Input: The new cyclic hexa-and octa-amine disulfides prove more effective at transfection in vitro, especially of lung epithelial A549 cell line.

cyclic hexa-and octa-amine disulfides


Input: By contrast, our original cyclic tetra-amine disulfide remains the most efficient agent for the transfection of lung epithelial cells in vivo following intra-nasal administration.

cyclic tetra-amine disulfide


Input: Hypothetical mechanistic reasons are presented to explain this outcome.


Input: Our data in toto support the concept of shorter cyclic polyamine disulfides as preferred agents for polycation-mediated controlled condensation and functional delivery of pDNA to lung epithelial cells in vivo.

cyclic polyamine disulfides


Input: DNA delivery via cationic solid lipid nanoparticles (SLNs).


Input: In recent years the use of solid lipid nanoparticles (SLNs) as transport systems for the delivery of drugs and biomolecules has become particularly important.


Input: The use of cationic SLNs developed by the technique of microemulsion, which are complexed with DNA in order to study their application as non-viral vectors in gene therapy, is reported.


Input: The nanoparticles are characterized by scanning electron microscopy and transmission electron microscopy (SEM and TEM), atomic force microscopy (AFM) and differential scanning calorimetry (DSC).


Input: Furthermore, the process of lyophilization of the samples and their stability was studied.


Input: The nanoparticles obtained presented a particle size of 340nm with a positive surface charge of 44mV and the capability of forming lipoplexes with DNA plasmids was stated.


Input: Nitrosylation: An adverse factor in Uremic Hemolytic Syndrome.


Input: Antitoxin effect of Ziziphus mistol Griseb.


Input: Toxins of Escherichia coli (STEC) causing Uremic Hemolytic Syndrome (UHS) generate oxidative stress in human blood with more production of nitric oxide (NO) than reactive oxygen species (ROS).

nitric oxide

NO

oxygen


Input: Shiga toxin (Stx) together with the hemolysin (Hly) increased lipid oxidation, as evaluated by malondialdehyde MDA and oxidation of proteins.

malondialdehyde MDA


Input: The addition of Ziziphus mistol Griseb extracts decreased NO, ROS, MDA and simultaneously caused an increase in the degradation of oxidized proteins to advanced oxidation protein products (AOPPs) in controls and samples with toxins.

NO

MDA


Input: Furthermore, the nitrosylated proteins/AOPP ratio was reduced, due to the increase of AOPP.


Input: Z. mistol Griseb extracts exhibited a high proportion of polyphenols and flavonoids, with evident correlation with ferrous reduction antioxidant potential (FRAP).

polyphenols

flavonoids

ferrous


Input: The plasma of eight children with UHS showed oxidative stress and NO stimulus, comparable to the effect of toxins during the assays in vitro.

NO


Input: UHS children presented high levels of nitrosylated proteins respect to control children of similar age.


Input: Although the degradation of oxidized proteins to AOPP rose in UHS children, the nitrosylated proteins/AOPP rate increased as a consequence of the elevated nitrosative stress observed in these patients.


Input: PK/PD assessment in CNS drug discovery: Prediction of CSF concentration in rodents for P-glycoprotein substrates and application to in vivo potency estimation.


Input: The unbound drug concentration in brain parenchyma is considered to be the relevant driver for interaction with central nervous system (CNS) biological targets.


Input: Drug levels in cerebrospinal fluid (C _ CSF) are frequently used surrogates for the unbound concentrations in brain.


Input: For drugs actively transported across the blood-brain barrier (BBB), C _ CSF differs from unbound plasma concentration (Cu _ p) to an extent that is commonly unknown.


Input: In this study, the relationship between CSF-to-unbound plasma drug partitioning in rats and the mouse Pgp (Mdr1a) efflux ratio (ER) obtained from in vitro transcellular studies has been investigated for a set of 61 CNS compounds exhibiting substantial diversity in chemical structure and physico-chemical properties.


Input: In order to understand the in vitro-in vivo extrapolation of Pgp efflux, a mechanistic model was derived relating in vivo CNS distribution kinetics to in vitro active transport.


Input: The model was applied to predict C _ CSF from Cu _ p and ER data for 19 proprietary Roche CNS drug candidates.


Input: The calculated CSF concentrations were correlated with CNS pharmacodynamic responses observed in rodent models.


Input: The correlation between in vitro and in vivo potency for different pharmacological endpoints indicated that the predicted C _ CSF is a valuable surrogate of the concentration at the target site.


Input: Overall, C _ CSF proved superior description of PK/PD data than unbound plasma or total brain concentration for Mdr1a substrates.


Input: Predicted C _ CSF can be used as a default approach to understand the PK/PD relationships in CNS efficacy models and can support the extrapolation of efficacious brain exposure for new drug candidates from rodent to man.


Input: Three-month subchronic intramuscular toxicity study of rotigotine-loaded microspheres in SD rats.

rotigotine


Input: Continuous dopaminergic stimulation (CDS) has been an important strategy of drug development for the treatment of Parkinson' s disease (PD).


Input: Rotigotine is a non-ergoline D3/D2/D1 dopamine agonist for treating PD.

Rotigotine

ergoline

dopamine


Input: As a new treatment option for CDS, rotigotine-loaded microspheres (RoMS), a long-acting sustained-release microspheres for injection with poly (lactide-co-glycolide) as drug carrier, are now being evaluated in clinical trial.

rotigotine

poly (lactide-co-glycolide)


Input: In this study, subchronic toxicity of RoMS in SD rats has been characterized via intramuscular administration with RoMS (0-240mg/kg/week) on a consecutive weekly dosing schedule for 3months followed by 1-month recovery period.


Input: The No Observed Adverse Effect Level (NOAEL) was 45mg/kg/week.


Input: One male at 240mg/kg died from an extensive pulmonary embolism.


Input: The major toxicological effects were associated with the dopamine agonist-related pharmacodynamic properties of rotigotine (e. g. hyperactivity and stereotype, enlarged ovary, sporadic gastric mucous membrane lesions, decreased body weight, food consumption and prolactin, and increased mononuclear cell, neutrophil granulocyte, aspartate aminotransferase and alanine aminotransferase) and foreign body removal reaction induced by poly (lactide-co-glycolide) and carboxymethycellulose sodium.

dopamine

rotigotine

aspartate

alanine

poly (lactide-co-glycolide)

sodium


Input: At the end of recovery period, all findings had recovered to a normal level or to a certain degree except foreign body reaction at injection sites.


Input: RoMS has exhibited high safety on SD rats.


Input: A cell-penetrating peptide suppresses the hypoxia inducible factor-1 function by binding to the helix-loop-helix domain of the aryl hydrocarbon receptor nuclear translocator.

aryl hydrocarbon


Input: The heterodimeric hypoxia inducible factor-1 (HIF-1) complex is composed of the hypoxia inducible factor-1 alpha (HIF-1 alpha) and the aryl hydrocarbon receptor nuclear translocator (ARNT).

aryl hydrocarbon


Input: Activation of the HIF-1 function is essential for tumor growth and metastasis.


Input: We previously showed that transfection of a plasmid containing an ARNT-interacting peptide (Ainp1) cDNA suppresses the HIF-1 signaling in Hep3B cells.


Input: Here we generated TAT fusion of the Ainp1 peptide (6His-TAT-Ainp1) to determine whether and how the Ainp1 peptide suppresses the HIF-1 function.


Input: The bacterially expressed 6His-TAT-Ainp1 was purified under denatured condition and then refolded by limited dialysis.


Input: The refolded 6His-TAT-Ainp1 interacts with the helix-loop-helix (HLH) domain of ARNT in a similar fashion as the native 6His-Ainp1.


Input: 6His-TAT-Ainp1 colocalizes with ARNT in the nucleus of HeLa and Hep3B cells after protein transduction.


Input: The transduced protein reaches the maximum intracellular levels within 2h while remains detectable up to 96h in HeLa cells.


Input: At 2 mu M concentration, 6His-TAT-Ainp1 is not cytotoxic in HeLa cells but suppresses the cobalt chloride-activated, hypoxia responsive enhancer-driven luciferase expression in a dose-dependent manner.

cobalt chloride


Input: In addition, it decreases the cobalt chloride-dependent induction of the HIF-1 target genes at both the message (vascular endothelial growth factor and aldolase C) and protein (carbonic anhydrase IX and glucose transporter 1) levels.

cobalt chloride

glucose


Input: The protein levels of HIF-1 alpha and ARNT are not altered in the presence of 6His-TAT-Ainp1.


Input: In summary, we provided evidence to support that the Ainp1 peptide directly suppresses the HIF-1 function by interacting with the ARNT HLH domain, and in turn interfering with the heterodimerization of HIF-1 alpha and ARNT.


Input: Genotoxicity assessment of vaccine adjuvant squalene.

squalene


Input: The genotoxic potential of the vaccine adjuvant Squalene was assessed by the chromosomal aberrations (CAs), sister chromatid exchanges (SCEs) and micronucleus (MNs) tests in human lymphocytes and comet assay in both human and rat lymphocytes.

Squalene


Input: Five different concentrations of squalene (1250-20, 000 mu g/ml for human lymphocytes and 0. 07-1. 12mg/kg for rat lymphocytes) were studied.

squalene


Input: Squalene did not affect the CAs and MN frequency, in all treatments in vitro.

Squalene


Input: A significant increase in SCEs was observed in almost all concentrations at 24h treatment.


Input: Squalene did not affect significantly the comet tail length (CTL) (except 2500 mu g/ml) and comet tail intensity (CTI) at all treatments in vitro.

Squalene


Input: In rats, squalene significantly increased and decreased CTL and CTI in some doses.

squalene


Input: Although there are increasing and reduction in the effect, squalene cannot be regarded as genotoxic in human lymphocytes.

squalene


Input: However, further in vivo studies are required to be sure on the effect.


Input: Phenotypic analysis of ovine antigen presenting cells loaded with nanoparticles migrating from the site of vaccination.


Input: Virus-sized particulate adjuvants such as ISCOMs, polystyrene nanoparticles and virus-like particles have been shown to target dendritic cells, resulting in the activation of T and B cells in vivo.

polystyrene


Input: Using an ovine pseudo-afferent lymph cannulation model to capture APC that traffic from the site of injection to the local lymph node, we show that 40-50nm nanoparticles are taken up at the site of injection by dendritic cells (DCs) migrating to the draining lymph node.


Input: These DCs can express CD11c, CD1b, CD5, MHC class II and CD8.


Input: Nanoparticles transported by DCs migrating from the site of injection to the local lymph node therefore needs to be considered as a new mechanism underlying the immunogenicity of virus-sized vaccine delivery systems.


Input: Toxic and genotoxic effects of Roundup on tadpoles of the Indian skittering frog (Euflictis cyanophlyctis) in the presence and absence of predator stress.

Roundup


Input: Glyphosate, a post emergent herbicide, has become the backbone of no-till agriculture and is considered safe for animals.

Glyphosate


Input: However, the impact of glyphosate on non-target organisms, especially on amphibians, is the subject of major concern and debate in recent times.

glyphosate


Input: We examined the toxic and genotoxic effects of Roundup, a commercial formulation of glyphosate, in the tadpoles of the Indian skittering frog (Euflictis cyanophlyctis).

Roundup

glyphosate


Input: Roundup at different concentrations (0, 1, 2, 3, 4 and 8mg acid equivalent (ae)/L), tested in a 2 x 6 factorial design in the presence and absence of predator stress, induced concentration-dependent lethality in tadpoles.

Roundup


Input: The 96-h LC50 for Roundup in the absence and presence of predator stress were 3. 76mgae/L and 3. 39mgae/L, respectively.

Roundup


Input: The 10-day LC50 value for Roundup was significantly lower, 2. 12mgae/L and 1. 91mgae/L in the absence and presence of predator stress, respectively.

Roundup


Input: Lower concentrations of Roundup (1, 2 and 3mgae/L) induced the formation of micronuclei (MN) in the erythrocytes of tadpoles at 24-h (F3, 56 = 10. 286, p < 0. 001), 48-h (F3, 56 = 48. 255, p < 0. 001), 72-h (F3, 56 = 118. 933, p < 0. 001) and 96-h (F3, 56 = 85. 414, p < 0. 001) in a concentration-dependent manner.

Roundup


Input: Presence of predator stress apparently increased the toxicity and genotoxicity of Roundup; but these effects were not statistically significant.

Roundup


Input: These findings suggest that Roundup at environmentally relevant concentrations has lethal and genotoxic impact on E. cyanophlyctis; which may have long-term fitness consequence to the species.

Roundup


Input: Synthesis and biochemical activities of antiproliferative amino acid and phosphate derivatives of microtubule-disrupting beta-lactam combretastatins.

amino acid

phosphate

beta-lactam combretastatins


Input: The synthesis and biochemical activities of novel water-soluble beta-lactam analogues of combretastatin A-4 are described.

beta-lactam

combretastatin A-4


Input: The first series of compounds investigated, beta-lactam phosphate esters 7a, 8a and 9a, exhibited potent antiproliferative activity and caused microtubule disruption in human breast carcinoma-derived MCF-7 cells.

beta-lactam phosphate esters


Input: They did not inhibit tubulin polymerisation in vitro, indicating that biotransformation was necessary for their antiproliferative and tubulin binding effects in MCF-7 cells.


Input: The second series of compounds, beta-lactam amino acid amides (including 10k and 11l) displayed potent antiproliferative activity in MCF-7 cells, disrupted microtubules in MCF-7 cells and also inhibited the polymerisation of tubulin in vitro.

beta-lactam amino acid amides


Input: This indicates that the beta-lactam amides did not require metabolic activation to have antiproliferative effects, in contrast to the phosphate series.

beta-lactam amides

phosphate


Input: Both series of compounds caused mitotic catastrophe and apoptosis in MCF-7 cells.


Input: Molecular modelling studies indicated potential binding conformations for the beta-lactam amino acid amides 10k and 11l in the colchicine-binding site of tubulin.

beta-lactam amino acid amides

colchicine


Input: Due to their aqueous solubility and potent biochemical effects, these compounds are promising candidates for further development as microtubule-disrupting agents.


Input: Synthesis, evaluation and absolute configuration assignment of novel dihydropyrimidin-2-ones as picomolar sodium iodide symporter inhibitors.

sodium iodide


Input: A small library of dihydropyrimidin-2-ones (DHPMs) was synthesized and evaluated for their potency to block iodide entrapment in rat thyroid cells.

DHPMs

iodide


Input: Synthesis was achieved using the multicomponent Biginelli reaction.


Input: Twelve compounds were tested for the inhibition of sodium iodide symporter (NIS) in a cell-based assay.

sodium iodide


Input: One newly synthesized derivative exhibited a remarkably strong activity, with a half-maximum inhibitory concentration value (IC50) of 65 pM.


Input: Three DHPMs were further resolved from racemates using chiral HPLC and absolute configurations were assigned using circular dichroism spectroscopy.

DHPMs


Input: Biological evaluation showed that most of the activity against NIS resides in one enantiomer.


Input: This study provides new insights for the development of anti-thyroid drugs, as well as for the synthesis of novel pharmacological tools designed to investigate iodide transport mechanisms at cellular and molecular levels.

iodide


Input: Effect of chronic heroin and cocaine administration on global DNA methylation in brain and liver.

heroin

cocaine


Input: Drug abuse is associated with epigenetic changes, such as histone modifications and DNA methylation.


Input: The purpose of the present study was to examine the effect of chronic cocaine and heroin administration on global DNA methylation in brain and liver.

cocaine

heroin


Input: Male, 8 week old, C57BL/6J mice received heroin in a chronic' intermittent' escalating dose paradigm, or cocaine in a chronic escalating dose' binge' paradigm, which mimic the human pattern of opioid or cocaine abuse respectively.

heroin

cocaine

cocaine


Input: Following sacrifice, livers and brains were removed and DNA was extracted from them.


Input: The extracted DNA was hydrolyzed and 2'-deoxycytidine and 5-methyl-2'-deoxycytidine were determined by HPLC-UV.


Input: The% 5-methyl-2'-deoxycytidine content of DNA was significantly higher in the brain compared to the liver.


Input: There were no differences between the control animals and the cocaine or heroin treated animals in neither of the tissues examined, which is surprising since cocaine administration induced gross morphological changes in the liver.

cocaine

heroin

cocaine


Input: Moreover, there was no difference in the% 5-methyl-2'-deoxycytidine content of DNA between the cocaine and the heroin treated animals.

cocaine

heroin


Input: The global DNA methylation status in the brain and liver of mice chronically treated with cocaine or heroin remains unaffected, but this finding cannot exclude the existence of anatomical region or gene-specific methylation differences.

cocaine

heroin


Input: This is the first time that global DNA methylation in the liver and whole brain has been studied following chronic cocaine or heroin treatment.

cocaine

heroin


Input: Rational design, synthesis and QSAR study of vasorelaxant active 3-pyridinecarbonitriles incorporating 1H-benzimidazol-2-yl function.


Input: A variety of 2-alkoxy-4-aryl-6-(1H-benzimidazol-2-yl)-3-pyridinecarbonitriles 4a-r were prepared via either regioselective reaction of 3-aryl-1-(1H-benzimidazol-2-yl)-2-propen-1-ones 3 with malononitrile or ylidenemalononitriles 6 with 2-acetyl-1H-benzimidazoles 1 in the presence of sodium alkoxide in the corresponding alcohol.

2-alkoxy-4-aryl-6-(1H-benzimidazol-2-yl)-3-pyridinecarbonitriles

3-aryl-1-(1H-benzimidazol-2-yl)-2-propen-1-ones

malononitrile

ylidenemalononitriles

sodium alkoxide

alcohol


Input: All the synthesized compounds showed significant vasodilation properties using isolated thoracic aortic rings of rats pre-contracted with norepinephrine hydrochloride standard technique.

norepinephrine hydrochloride


Input: Compounds 4d, 4p, 4l, and 4f exhibited remarkable activity compared with prazosin hydrochloride, which was used as a reference standard in the present study.

prazosin hydrochloride


Input: QSAR studies revealed a good predictive and statistically significant 3 descriptor model (r (2) = 0. 913, radjusted (2) = 0. 8808, rprediction (2) = 0. 7911).


Input: Nonclassical antifolates, part 3: Synthesis, biological evaluation and molecular modeling study of some new 2-heteroarylthio-quinazolin-4-ones.


Input: A new series of 2-heteroarylthio-6-substituted-quinazolin-4-one analogs was designed, synthesized, and evaluated for their in vitro DHFR inhibition, antimicrobial, and antitumor activities.

2-heteroarylthio-6-substituted-quinazolin-4-one


Input: Compounds 21, 25, and 39 proved to be active DHFR inhibitors with IC50 range of 0. 3-0. 8 mu M.


Input: Compounds 25, 28, 33, 35 and 36 showed broad spectrum antimicrobial activity comparable to the known antibiotic gentamicin.

gentamicin


Input: Compound 29 showed broad spectrum antitumor activity toward several tumor cell lines with GI values range of 25. 8-41. 2%.


Input: Molecular modeling studies concluded that recognition with key amino acid Arg38 and Lys31 are essential for binding and biological activities.

amino acid Arg38


Input: Flexible alignment; electrostatic and hydrophobic mappings revealed that the obtained model could be useful for the development of new DHFR inhibitors.


Input: Human exposure to mycotoxins and their masked forms through cereal-based foods in Belgium.


Input: In the present study, a quantitative dietary exposure assessment of mycotoxins and their masked forms was conducted on a national representative sample of the Belgian population using the contamination data of cereal-based foods.


Input: Cereal-based food products (n = 174) were analysed for the occurrence of deoxynivalenol, 3-acetyldeoxynivalenol, 15-acetyldeoxynivalenol, zearalenone, alpha-zearalenol, beta-zearalenol, T-2-toxin, HT-2-toxin, and their respective masked forms, including, deoxynivalenol-3-glucoside, zearalenone-4-glucoside, alpha-zearalenol-4-glucoside, beta-zearalenol-4-glucoside and zearalenone-4-sulfate.

deoxynivalenol

zearalenone

alpha-zearalenol

beta-zearalenol


Input: Fibre-enriched bread, bran-enriched bread, breakfast cereals, popcorn and oatmeal were collected in Belgian supermarkets according to a structured sampling plan and analysed during the period from April 2010 to October 2011.


Input: The habitual intake of these food groups was estimated from a national representative food intake survey.


Input: According to a probabilistic exposure analysis, the mean (and P95) mycotoxin intake for the sum of the deoxynivalenol-equivalents, zearalenone-equivalents, and the sum of HT-2-and T-2-toxin for all cereal-based foods was 0. 1162 (0. 4047, P95), 0. 0447 (0. 1568, P95) and 0. 0258 (0. 0924, P95) mu g kg (-1) body weight day (-1), respectively.

deoxynivalenol

zearalenone

HT-2-and T-2-toxin


Input: These values were below the tolerable daily intake (TDI) levels for deoxynivalenol, zearalenone and the sum of T-2 and HT-2 toxin (1. 0, 0. 25 and 0. 1 mu g kg (-1) body weight day (-1), respectively).

deoxynivalenol

zearalenone

T-2 and HT-2 toxin


Input: The absolute level exceeding the TDI for all cereal-based foods was calculated, and recorded 0. 85%, 2. 75% and 4. 11% of the Belgian population, respectively.


Input: Evaluation of microelectrode array data using Bayesian modeling as an approach to screening and prioritization for neurotoxicity testing.


Input: The need to assess large numbers of chemicals for their potential toxicities has resulted in increased emphasis on medium-and high-throughput in vitro screening approaches.


Input: For such approaches to be useful, efficient and reliable data analysis and hit detection methods are also required.


Input: Assessment of chemical effects on neuronal network activity using microelectrode arrays (MEAs) has been proposed as a screening tool for neurotoxicity.


Input: The current study examined a Bayesian data analysis approach for assessing effects of a 30 chemical training set on activity of primary cortical neurons grown in multi-well MEA plates.


Input: Each well of the MEA plate contained 64 microelectrodes and the data set contains the number of electrical spikes registered by each electrode over the course of each experiment.


Input: A Bayesian data analysis approach was developed and then applied to several different parsings of the data set to produce probability determinations for hit selection and ranking.


Input: This methodology results in an approach that is approximately 74% sensitive in detecting chemicals in the training set known to alter neuronal function (23 expected positives) while being 100% specific in detecting chemicals expected to have no effect (7 expected negatives).


Input: Additionally, this manuscript demonstrates that the Bayesian approach may be combined with a previously published weighted mean firing rate approach in order to produce a more robust hit detection method.


Input: In particular, when combined with the weighted mean firing rate approach, the joint analysis produces a sensitivity of approximately 96% and a specificity of 100%.


Input: These results demonstrate the utility of a novel approach to analysis of MEA data and support the use of neuronal networks grown on MEAs as a for neurotoxicity screening approach.


Input: Lipophilic components from Fructus Viticis Negundo and their anti-tumor activities.


Input: Two new triterpenoids, (24R/S)-24-hydroxy-3 alpha 10 alpha-epoxy-9-eip-cucurbita-25-ene (1a, b), as well as six known compounds (3-8), were isolated from the extraction of Fructus Viticis Negundo.

triterpenoids

(24R/S)-24-hydroxy-3 alpha 10 alpha-epoxy-9-eip-cucurbita-25-ene


Input: Their structures were established on the basis of spectral analysis.


Input: In addition, all the compounds were tested for inhibitory effect against K-562 and A-549 cell lines.


Input: Molecular determinants of drug-receptor binding kinetics.


Input: It is increasingly appreciated that the rates at which drugs associate with and dissociate from receptors-the binding kinetics-directly impact drug efficacy and safety.


Input: The molecular determinants of drug-receptor binding kinetics remain poorly understood, however, especially when compared with the well-known factors that affect binding affinity.


Input: The rational modulation of kinetics during lead optimization thus remains challenging.


Input: We review some of the key factors thought to control drug-receptor binding kinetics at the molecular level-molecular size, conformational fluctuations, electrostatic interactions and hydrophobic effects-and discuss several possible approaches for the rational design of drugs with desired binding kinetics.


Input: In vitro nanotoxicity of single-walled carbon nanotube-dendrimer nanocomplexes against murine myoblast cells.

carbon


Input: Single-wall carbon nanotubes (SWCNTs) and polyamidoamine dendrimers (PAMAM) have been proposed for a variety of biomedical applications.

carbon

polyamidoamine


Input: The combination of both molecules makes this new composite nanomaterial highly functionalizable and versatile to theranostic and drug-delivery systems.


Input: However, recent toxicological studies have shown that nanomaterials such as SWCNTs and PAMAM may have high toxicity in biological environments.


Input: Aiming to elucidate such behavior, in vitro studies with different cultured cells have been conducted in the past few years.


Input: This study focuses on the effects of SWCNT-PAMAM nanomaterials and their individual components on the C2C12 murine cell line, which is a mixed population of stem and progenitor cells.


Input: The interactions between the cells and the nanomaterials were studied with different techniques usually employed in toxicological analyses.


Input: The results showed that SWCNT-PAMAM and PAMAM inhibited the proliferation and caused DNA damage of C2C12 cells.


Input: Data from flow cytometry revealed a less toxicity in C2C12 cells exposed to SWCNT compared to the other nanomaterials.


Input: The results indicated that the toxicity of SWCNT, SWCNT-PAMAM and PAMAM in C2C12 cells can be strongly correlated with the charge of the nanomaterials.


Input: The suppression of hematopoiesis function in Balb/c mice induced by prolonged exposure of microcystin-LR.

microcystin-LR


Input: Microcystins (MCs) cause normocytic anemia in patients in a hemodialysis unit in Caruaru, Brazil in 1996, but the underlying mechanisms are still unclear.

Microcystins


Input: In the present study, Balb/c mice were intraperitoneally injected with microcystin-LR (MC-LR) at the doses of 0. 5, 2 and 8 mu g/kg body weight (bw) every 48h for 30d.

microcystin-LR

MC-LR


Input: After the prolonged exposure of MC-LR, significant decreases of red blood cell count (RBC), hemoglobin (Hb) and hematocrit (Ht) were observed in 2 and 8 mu g/kg bw groups, but erythrocyte mean corpuscular volume (MCV) showed no significant changes.

MC-LR


Input: Significantly elevated micronucleus frequency was observed in bone marrow cells (BMCs) in all MC-LR treatments.

MC-LR


Input: The proliferation of BMCs significantly declined in both 2 and 8 mu g/kg bw groups.


Input: Serum levels of some hematopoietic growth factors significantly changed in 8 mu g/kg bw group, mainly including granulocyte-macrophage (GM-CSF), erythropoietin (EPO), interleukin-3 (IL-3) and TNF-alpha.


Input: The transcriptional levels of these 4 genes in BMCs were also significantly changed in 8 mu g/kg bw group.


Input: MC-LR exposure significantly increased the apoptosis rates in all MC-LR treatments.

MC-LR

MC-LR


Input: The present study indicates prolonged exposure of MC-LR induces normocytic anemia, and the disturbed hematopoietic growth factors and BMCs apoptosis are responsible for this normocytic anemia.

MC-LR


Input: Evaluation of the adjuvant effect of silver nanoparticles both in vitro and in vivo.

silver


Input: The immunological adjuvant effect of silver nanoparticles (AgNPs) was investigated both in vitro and in vivo.

silver


Input: The in vivo adjuvant effect of AgNPs was evaluated with model antigen ovalbumin (OVA) and bovine serum albumin (BSA) in mice by intraperitoneal and subcutaneous immunization.


Input: Serum antigen-specific IgG level significantly increased in AgNPs-treated mice comparing to the control group.


Input: AgNPs induced the increase of IgG1/IgG2a ratio and antigen-specific IgE, indicating that AgNPs elicited Th2-biased immune responses.


Input: By in vitro assay, the mechanism of adjuvant effect was explored.


Input: After 48h treatment with AgNPs, both the number of leukocytes and levels of cytokines TNF-alpha and IFN-gamma in abdominal lavage fluid of mice increased.


Input: The expression of the major histocompatibility complex class II molecule on the surface of peritoneal macrophages significantly increased.


Input: AgNPs can be easily phagocytosed by peritoneal macrophages, while do not affect antigen uptake by the cell.


Input: We therefore conclude that AgNPs have significant adjuvant effect and the mechanism of this effect is mainly ascribed to the recruitment and activation of local leukocytes and especially macrophages.


Input: For the first time we found the remarkable adjuvant effect of AgNPs, and the result is beneficial for the future applications, especially in biomedicine.


Input: Platinum (II) complexes with mono-aminophosphonate ester targeting group that induce apoptosis through G1 cell-cycle arrest: Synthesis, crystal structure and antitumour activity.

Platinum (II)

mono-aminophosphonate ester


Input: Six new platinum (II) complexes with mono-aminophosphonate ester were synthesized and characterized by elemental analysis, (1) H NMR, ESI-MS as well as single crystal X-ray diffraction analysis.

platinum (II)

mono-aminophosphonate ester

(1) H


Input: They are mononuclear structures.


Input: In all the crystal structures of complexes 1-6, the platinum centre adopts an approximately square-planar geometry, which were found to possess excellent solubility in both organic solvents and water and exhibit considerable cytotoxicity against MG-63, SK-OV-3 and HepG2 cell lines, but low cytotoxicity towards normal human liver cell HL-7702.

platinum


Input: In contrast to cisplatin, their antitumour activities are achieved through the induction of cell apoptosis by G1 cell-cycle arrest.

cisplatin


Input: Activation of Both Protein Kinase A (PKA) Type I and PKA Type II Isozymes Is Required for Retinoid-Induced Maturation of Acute Promyelocytic Leukemia Cells.

Retinoid


Input: Acute promyelocytic leukemia (APL) is characterized by granulopoietic differentiation arrest at the promyelocytic stage.


Input: In most cases, this defect can be overcome by treatment with all-trans-retinoic acid (ATRA), leading to complete clinical remission.

all-trans-retinoic acid

ATRA


Input: Cyclic AMP signaling has a key role in retinoid treatment efficacy: it enhances ATRA-induced maturation in ATRA-sensitive APL cells (including NB4 cells) and restores it in some ATRA-resistant cells (including NB4-LR1 cells).

Cyclic AMP

retinoid

ATRA

ATRA

ATRA


Input: We show that the two cell types express identical levels of the C alpha catalytic subunit and comparable global cAMP-dependent protein kinase A (PKA) enzyme activity.

cAMP


Input: However, the maturation-resistant NB4-LR1 cells have a PKA isozyme switch: compared with the NB4 cells, they have decreased content of the juxtanuclearly located PKA regulatory subunit II alpha and PKA regulatory subunit II beta, and a compensatory increase of the generally cytoplasmically distributed PKA-RI alpha.


Input: Furthermore, the PKA regulatory subunit II exists mainly in the less cAMP-responsive nonautophosphorylated state in the NB4-LR1 cells.

cAMP


Input: By the use of isozyme-specific cAMP analog pairs, we show that both PKA-I and PKA-II must be activated to achieve maturation in NB4-LR1 as well as NB4 cells.

cAMP


Input: Therefore, special attention should be paid to activating not only PKA-I but also PKA-II in attempts to enhance ATRA-induced APL maturation in a clinical setting.

ATRA


Input: Insula' s functional connectivity with ventromedial prefrontal cortex mediates the impact of trait alexithymia on state tobacco craving.


Input: RATIONALE: Alexithymia is a personality trait characterized by difficulty indentifying and describing subjective emotional experiences.


Input: Decreased aptitude in the perception, evaluation, and communication of affectively laden mental states has been associated with reduced emotion regulation, more severe drug craving in addicts, and structural/functional alterations in insula and anterior cingulate cortex (ACC).


Input: The insula and ACC represent sites of convergence between the putative neural substrates of alexithymia and those perpetuating cigarette smoking.


Input: OBJECTIVES: We examined the interrelations between alexithymia, tobacco craving, and insula/ACC neurocircuitry using resting-state functional connectivity (rsFC).


Input: METHODS: Overnight-deprived smokers (n = 24) and nonsmokers (n = 20) completed six neuroimaging assessments on different days both in the absence of, and following, varenicline and/or nicotine administration.

varenicline

nicotine


Input: In this secondary analysis of data from a larger study, we assessed trait alexithymia and state tobacco craving using self-reports and examined the rsFC of bilateral insular subregions (anterior, middle, posterior) and dorsal ACC.


Input: RESULTS: Higher alexithymia in smokers predicted reduced rsFC strength between the right anterior insula (aI) and ventromedial prefrontal cortex (vmPFC).


Input: Higher alexithymia also predicted more severe tobacco craving during nicotine withdrawal.

nicotine


Input: Critically, the identified aI-vmPFC circuit fully mediated this alexithymia-craving relation.


Input: That is, elevated alexithymia predicted decreased aI-vmPFC rsFC and, in turn, decreased aI-vmPFC rsFC predicted increased craving during withdrawal.


Input: A moderated mediation analysis indicated that this aI-vmPFC mediational effect was not observed following drug administration.


Input: CONCLUSIONS: These results suggest that a weakened right aI-vmPFC functional circuit confers increased liability for tobacco craving during smoking abstinence.


Input: Individual differences in alexithymia and/or aI-vmPFC functional coupling may be relevant factors for smoking cessation success.


Input: Acute behavioural effects of bupropion and naltrexone, alone and in combination, in non-deprived male rats presented with palatable mash.

bupropion

naltrexone


Input: RATIONALE: In appetite research, drugs frequently progress to clinical trials on the basis of outcome (reduced food intake/body weight gain) with insufficient attention to process (behavioural analysis).


Input: Although bupropion and naltrexone (alone and in combination) reduce food consumption in rodents and humans, their effects on behaviour during feeding tests have not been thoroughly investigated.

bupropion

naltrexone


Input: OBJECTIVES: This study aimed to assess the behavioural specificity of anorectic responses to bupropion, naltrexone and their combination.

bupropion

naltrexone


Input: METHODS: Video analysis was employed to characterise the behavioural effects of acute systemic treatment with bupropion (10. 0-40. 0 mg/kg), naltrexone (0. 1-3. 0 mg/kg) and combined bupropion (20 mg/kg) plus naltrexone (0. 1-1. 0 mg/kg) in non-deprived male rats exposed for 1 h to palatable mash.

bupropion

naltrexone

bupropion

naltrexone


Input: Particular attention was paid to the behavioural satiety sequence (BSS).


Input: RESULTS: In experiment 1, the anorectic response to 40 mg/kg bupropion was associated with significant psychomotor stimulation and a complete disruption of the BSS.

bupropion


Input: In experiment 2, the anorectic response to 3 mg/kg naltrexone was associated with an accelerated but otherwise normal BSS.

naltrexone


Input: In experiment 3, the co-administration of 20 mg/kg bupropion and naltrexone (0. 1 and 1. 0 mg/kg) not only produced an additive anorectic profile (including a reduced rate of eating), but the addition of the opioid receptor antagonist also concurrently attenuated the psychomotor stimulant response to the atypical antidepressant.

bupropion

naltrexone


Input: CONCLUSIONS: Low-dose co-treatment with naltrexone and bupropion produces a stronger suppression of appetite than that seen with either agent alone and has the additional advantage of reducing some of the unwanted effects of bupropion.

naltrexone

bupropion

bupropion


Input: Effects of vegetative-periodic-induced rhizosphere variation on the uptake and translocation of metals in Phragmites australis (Cav.) Trin ex.


Input: Steudel growing in the Sun Island Wetland.


Input: To evaluate the vegetative periodic effect of rhizosphere on the patterns of metal bioaccumulation, the concentrations of Mg, K, Ca, Mn, Zn, Fe, Cu, Cr, Ni, Cd and Pb in the corresponding rhizosphere soil and tissues of Phragmites australis growing in the Sun Island wetland (Harbin, China) were compared.

Mg

K

Ca

Mn

Zn

Fe

Cu

Cr

Ni

Cd

Pb


Input: The concentrations of Zn, Fe, Cu, Cr, Ni, Cd and Pb in roots were higher than in shoots, suggesting that roots are the primary accumulation organs for these metals and there exists an exclusion strategy for metal tolerance.

Zn

Fe

Cu

Cr

Ni

Cd

Pb


Input: In contrast, the rest of the metals showed an opposite trend, suggesting that they were not restricted in roots.


Input: Harvesting would particularly be an effective method to remove Mn from the environment.

Mn


Input: The concentrations of metals in shoots were generally higher in autumn than in summer, suggesting that Ph. australis possesses an efficient root-to-shoot translocation system, which is activated at the end of the growing season and allows more metals into the senescent tissues.


Input: Furthermore, metal bioaccumulation of Ph. australis was affected by vegetative periodic variation through the changing of physicochemical and microbial conditions.


Input: The rhizospheric microbial characteristics were significantly related to the concentrations of Mg, K, Zn, Fe and Cu, suggesting that microbial influence on metal accumulation is specific and selective, not eurytopic.

Mg

K

Zn

Fe

Cu


Input: Hypoxia-inducible factor and vascular endothelial growth factor are targets of dietary soy during acute stroke in female rats.


Input: Dietary soy and soy isoflavones are neuroprotective in experimental cerebral ischemia.

isoflavones


Input: Because these isoflavones have estrogenic properties, we hypothesized that, like estrogens, they would inhibit acute vascular injury and the detrimental acute increase in hypoxia-induced vascular endothelial growth factor (VEGF) that leads to cerebral edema after stroke.

isoflavones

estrogens


Input: Mature ovariectomized female Sprague Dawley rats were fed soy-free or soy-containing diets for 4 weeks followed by 90 minutes of transient middle cerebral artery occlusion.


Input: Similar to estrogens, dietary soy significantly reduced cerebral edema and vascular apoptosis 24 hours after stroke.

estrogens


Input: Soy also inhibited the ischemia-induced increase in cortical VEGF and VEGF receptor (VEGFR)-2 protein expression observed 4 and 24 hours after stroke, although mRNA levels increased.


Input: The reduction in VEGF/VEGFR-2 was associated both with decreases in receptor phosphorylation and signaling to AKT and endothelial nitric oxide synthase.


Input: Furthermore degradation of the VEGFR-2 was increased with dietary soy.


Input: The primary ischemic stimulus for VEGF, hypoxia-inducible factor 1 alpha (HIF1 alpha), was similarly reduced by dietary soy 4 hours after transient middle cerebral artery occlusion in both the cortex and striatum.


Input: The inhibition of HIF1 alpha activity was further confirmed by a significant decrease in the HIF1 alpha-activated apoptotic mediator BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (Nip3-like protein X).


Input: These data suggest that soy isoflavones target events early in the ischemic cascade as part of their neuroprotective actions and counterbalance some of the detrimental effects of the endogenous response to cerebral injury.

isoflavones


Input: Genotoxic, antigenotoxic and antioxidant properties of methanol extracts obtained from Peltigera horizontalis and Peltigera praetextata.

methanol